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Roche from A to Z Serving health

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									Roche from A to Z
Serving health
Roche from A to Z
Serving health
© 2007
F. Hoffmann-La Roche Ltd
Corporate Communications
4070 Basel, Switzerland

http://www.roche.com

All trademarks mentioned in this publication are protected by law.

Eighth, revised edition

7 000 782
                                                                       Editorial




For over 110 years now, Roche has been a pioneer in the discovery, development,
production and marketing of novel healthcare solutions. Roche is one of the
world’s leading research-focused healthcare groups in the fields of pharmaceu-
ticals and diagnostics. As the world’s biggest biotech company and an innovator
of products and services for the early detection, prevention, diagnosis and treat-
ment of diseases, the Group contributes on a broad range of fronts to improving
people’s health and quality of life. Roche is the world leader in in-vitro diagnos-
tics and drugs for cancer and transplantation, a market leader in virology and
active in other major therapeutic areas such as autoimmune diseases, inflamma-
tion, metabolic disorders and diseases of the central nervous system.
    Every day tens of thousands of innovative, dedicated and highly professional
people team their efforts for the continued success of our Group. It is only right,
then, that this reference guide should be concerned primarily with people,
methods, products and services. Since it was first published over thirty years ago,
the Corporate Publication Roche from A to Z serving health has become some-
thing of an institution. It provides readers with wide-ranging, yet in-depth
information on different aspects of our Group. Written in simple language,
it guides readers through the Roche world, providing insights into our many and
varied activities.
    The success of the book speaks for itself. Now in its eighth, revised edition,
the book has gone through printings totalling over 800,000 copies in German,
English, French and Spanish. Like its predecessors, this new edition can offer no
more than a snapshot of our Group at a particular moment in time. For Roche is
constantly evolving as we rise to the challenges posed by new technologies and
discoveries and by a changing business environment.
    Roche’s history is one of change and progress – in short, of innovation. And
these are the very things that are the bedrock of our success. This reference guide
is thus offered as a source of facts and background information about a Group
striving to better serve health.




                                                        Franz B. Humer

                                                        Chairman and
                                                        Chief Executive Officer

Roche from A to Z                                                                  3
    ACE inhibitors


                                       A
ACE inhibitors. Angiotensin-convert-
ing enzyme inhibitors. Blood pres-
sure-lowering agents that inhibit
the conversion of angiotensin, a tissue
hormone produced by the body, from
its inactive to its active form. In its ac-
tive form angiotensin increases blood         Model of an AIDS virus (HIV).
pressure by causing blood vessels to
constrict and reducing salt excretion         immune defences break down, leaving
via the kidneys (¡cardiovascular).            patients susceptible to life-threatening
                                              infections with pathogens that are
Agonist. A drug producing a pharma-           normally relatively harmless. These
cological effect, analogous to that of a      opportunistic infections, as they are
naturally occurring ligand, by occupy-        called, can affect the lungs, brain, liver,
ing a specific biologically active bind-      esophagus, bowel and other organs.
ing site (receptor) on the surface of a       The incidence of various cancers, such
cell (¡antagonist).                           as Kaposi’s sarcoma and lymphomas,
                                              is also increased in HIV patients.
AIDS. Abbreviation for acquired im-           This clinical picture of full-blown
munodeficiency syndrome. AIDS is an           immunodeficiency disease is known as
extremely serious infectious disease          AIDS.
caused by the human immunodefi-                  Because of the high replication and
ciency virus (HIV). HIV is transmitted        mutation rate of HIV, drug resistance
via the blood (transfusions, blood            emerges relatively quickly. For this
products, transplants, injections, in-        reason patients are now treated with
juries) and by unprotected sexual             a combination of agents belonging
activity. The ¡virus primarily attacks        to different pharmacological classes.
the ¡immune system and parts of the           By combining agents with different
central nervous system.                       mechanisms of action, multidrug reg-
   Current evidence indicates that HIV        imens can greatly retard the develop-
replication begins immediately after          ment of resistant viruses. Numerous
infection with the virus. Up to 100 bil-      studies are underway to establish
lion new viruses are produced daily in        which combination of currently avail-
helper T cells, a vitally important pop-      able antiviral medications is best.
ulation of ¡blood cells which serve as           One focus of AIDS research at
hosts for the virus. As the virus repli-      Roche is to develop novel additions to
cates, these helper cells are damaged         existing classes of anti-HIV medica-
and destroyed. Eventually, the body’s         tion that will be effective against

4
                                                       Air pollution, control of


strains of the virus which have become         In addition, Roche also supplies
resistant to currently available drugs.     medicines for the clinical compli-
The Group also continues its search         cations of HIV infection such as
for innovative medicines that will          Cymevene/Cytovene for CMV infec-
block viral replication via completely      tions (¡antimicrobials).
new mechanisms of action. One ap-
proach is to inhibit the chemokine          AIDS Walk. A sponsored walk by
coreceptors (¡receptors) present on         Roche employees worldwide held on
the surface of helper T cells, thus pre-    World AIDS Day, 1 December, in order
venting HIV from entering these cells.      to raise money for children in Malawi
Fuzeon is the first in a new class of       who have been impacted by HIV and
drugs (known as fusion inhibitors)          AIDS. Funds collected by employees
which act in this way. It received          are matched by Roche. Partner organ-
¡FDA approval in the United States,         isations use the money from Roche to
its first market, in March 2003.
   Intensive work is being done on
developing new diagnostic tests for
HIV and hepatitis. The ¡Diagnostics
Division offers increasingly automated
tests based on real-time PCR technol-
ogy to detect active infections. These
tests enable direct qualitative or quan-
titative detection of the viruses for
diagnosis as well as viral load monitor-    support centres in which these chil-
ing, an indication of patient response      dren are given food, clothing and basic
to drug therapy. Conventional tests,        healthcare. Malawi is one of the poor-
by contrast, provide only indirect evi-     est countries in the world. Twenty per-
dence of infection, without distinction     cent of its 11 million inhabitants are
between past or active infection, by        HIV positive; half a million children
detecting ¡antibodies produced by           have lost one or both parents to AIDS
the immune system to fight the virus.       (¡social responsibility).
Coinfection (simultaneous infection)
with HIV and hepatitis is a significant     Air pollution, control of. Air pollu-
problem that requires special care. In      tion has become a problem of global
the case of mother-to-child transmis-       proportions, as reflected by broad
sion of HIV during birth, DNA tests         public concern about the greenhouse
are the only reliable indicator of infec-   effect, ozone holes, summer smog and
tion in infants, since mothers pass         acid rain. Roche endeavours to protect
their antibodies to the infants during      the environment from harmful and
gestation and breast feeding.               unpleasant air pollution.

Roche from A to Z                                                                  5
    Airol


    At Roche it is mainly production        for products made outside Germany.
and laboratory facilities that generate     This restriction led to the establish-
air emissions. The principal air pollu-     ment of Hoffmann-La Roche Aktien-
tants in exhaust air from production        gesellschaft, Roche’s first production
facilities are volatile organic com-        site outside Switzerland. In 1897 Fritz
pounds (VOCs) from the organic sol-         ¡Hoffmann-La Roche purchased
vents often used in chemical reactions      property in ¡Grenzach for a German
and purification steps. In the last few     factory in order to qualify Airol for a
years Roche has significantly reduced       patent extension by manufacturing it
VOC emissions groupwide by in-              domestically (¡patents).
stalling engineering controls such as          The Airol ¡trademark was reintro-
gas scrubbers, vapour recovery lines,       duced in some countries in 1973 as the
filters, low-temperature condensers         name of a retinoid product used for
and thermal oxidation systems for           the topical treatment of acne.
waste gases.
    The burning of natural gas, fuel oil    Alarm centre. A Group-wide tele-
and waste solvents to produce power         phone centre operated by Safety and
and steam results in emissions con-         Environmental Protection in Basel for
taining carbon dioxide, oxides of           international calls in the event of inci-
nitrogen and sulphur, hydrochloric          dents or accidents and for information
acid or soot. Over the last few years       regarding product safety (toxicity, en-
progressive conversion of facilities        vironmental toxicity, etc.). It provides
from heavy fuel oil to natural gas and      around-the-clock assistance, receives
“extralight” heating oil has signifi-       site-specific alarms from automatic
cantly reduced carbon dioxide and           surveillance and process monitoring
sulphur dioxide emissions per unit of       systems and passes on reports of mal-
energy produced. Installation of gas        functions to the responsible units.
scrubbers and electrostatic precipita-
tors has largely eliminated gaseous         Alternatives to animal testing. Tech-
pollutants such as hydrogen chloride        niques designed to supplement or
and soot particles from flue gases.         replace testing in animals, through
                                            the use of cell, tissue or organ cultures
Airol. A wound-healing powder con-          (¡in vitro), isolated organs, lower or-
taining bismuth and iodine. Devel-          ganisms (bacteria or worms) or com-
oped in 1894, it was the first product to   puter simulations. Alternative meth-
come out of the laboratories of Hoff-       ods need to supply results equally as
mann, Traub & Co., the forerunner of        good as those from animal tests. There
F. Hoffmann-La Roche & Co. Ltd. At          is no lack of interest in such methods,
the time German patent law allowed a        particularly in industry. For a number
maximum of three years’ protection          of years now Roche has been spending

6
                                                                     Amino acids


several million CHF annually on proj-        which is still unknown. Alzheimer’s
ects in this area.                           disease usually strikes after the age of
   Alternative testing methods provide       65 and is characterised by the gradual
in-depth insights into events at the cel-    death and disappearance of nerve cells
lular and subcellular levels – the very      in the cerebral cortex. Early clinical
events which often give rise to disease,     signs include marked forgetfulness
and which effective remedies need to         and episodes of mental confusion. In
target. Whether such findings are clin-      advanced stages, memory is almost
ically useful, however, can often only       completely obliterated, and the dis-
be established by studying the complex       abling effects of the disease are so se-
interplay of biological processes in an      vere that patients require institutional
intact living animal, for animals and        care. There is a good deal of evidence
people are more than the sum of their        to suggest that genetic factors play a
parts.                                       role in Alzheimer’s disease. For ex-
   In vitro tests are particularly helpful   ample, carriers of what is termed the
for screening drugs that might be            ApoE-e4 allele are more likely to suffer
effective. They reduce the number of         from Alzheimer’s, and ¡mutations in
tests that have to be done in animals        certain genes can lead to an earlier
since only promising compounds are           onset of the disease. Roche researchers
investigated further.                        in Basel are using transgenic mice to
   The case is different in toxicity test-   investigate potential causes of the dis-
ing (¡toxicology) and the evaluation         ease and explore ways of developing
of side effects. The toxicity tests that     drugs to treat it. The brains of these
have to be done before a drug can be         mice display some of the characteristic
tried in man or before it can be mar-        features of Alzheimer’s disease (¡re-
keted are prescribed by the regulatory       search, ¡research expenditure).
authorities. Alternatives to toxicity
testing in animals are not yet advanced      Amino acids. The basic structural
enough to be fully acceptable to health      units of ¡proteins; organic molecules
regulators.                                  capable of undergoing a wide range of
   In short, alternative methods are a       biochemical reactions, most notably
valuable adjunct to animal testing.          reactions in which they bind to each
They cannot replace it entirely but do       other to form long chains. Despite
help reduce the number of animals            their tremendous diversity, proteins
needed.                                      (also called polypeptides) are all com-
                                             posed of roughly 20 amino acids
Alzheimer’s disease. A degenerative          found in nature. The sequence in
brain disease named after the Munich         which amino acids are arranged in a
neurologist and psychiatrist Alois           protein molecule is determined by
Alzheimer (1864–1915), the cause of          ¡genes. Ten of the naturally occurring

Roche from A to Z                                                                  7
    AmpliCare programme


amino acids, known as essential amino
acids, cannot be made by the human
body in adequate amounts or at all,
and therefore have to be obtained from
dietary protein.

AmpliCare programme. This pro-
gramme is a contribution by Roche
Diagnostics to the improved manage-
ment of HIV/AIDS patients where the
need is greatest – in sub-Saharan
countries in Africa and in other coun-
tries defined by the United Nations as
belonging to the least developed na-      ses the genotype of the cytochrome
tions. In this programme, which was       P450 2D6 and 2C19 genes in the
initiated in 2002, Roche supplies tests   genomic DNA of patients’ blood sam-
for measuring HI viral load at greatly    ples. The test results enable doctors
reduced prices. Roche also assists with   to take account of patients’ specific
the patient monitoring programme          genetic information when selecting
and is involved in the basic and ad-      drugs and establishing the best dosage
vanced training of doctors and nurses.    for the treatment of various common
Roche always endeavours to adapt its      illnesses such as heart disease, pain
involvement to local needs. For ex-       syndromes and cancer. This new test
ample, the company works with labora-     will give doctors access to information
tories and hospitals to identify, where   that could prove useful both in avoid-
feasible, those services or technical     ing harmful drug interactions and in
support operations that are best suited   the using drugs to maximum effect.
to the local environment and then to      Side effects of drugs are responsible
develop a customised solution. Roche      for a very large number of hospital
Diagnostics intends to extend the pro-    referrals. Thanks to this new test it
gramme to other countries, primarily      will also be possible, in certain cases,
those defined by the UN as having         to avoid the selection of a less suitable,
a low income. In this context, Roche      or even harmful, drug treatment. It is
has already initiated talks in Eastern    very important for patients to know
Europe, Latin America and other Asian     whether painkillers or narcotics will
countries (¡sustainability, ¡social       work differently, or even at all, in their
responsibility).                          own case. The effect of drugs can last
                                          for much longer in patients who
AmpliChip CYP450 Test. Based on           metabolise them poorly or slowly.
DNA chip technology, this test analy-     Patients who are aware of such things

8
                                                              Analytical systems


can then ask for other, better tolerated,   bolites formed in the body and how,
drugs (¡DNA chips, ¡tests, diagnos-         and to what extent, they are excreted.
tic, ¡gene chip).                           Until just a few years ago, measuring
                                            blood levels of an agent like acetylsali-
Analysis. In chemistry, the determina-      cylic acid posed almost insurmount-
tion of the identity and amounts of         able difficulties, even though it is taken
the constituents of a chemical com-         in doses of up to 500 mg. Today agents
pound or mixture. The chemical ana-         administered in amounts as small as
lyst’s job is to answer questions about     a millionth of a milligram can be
the structure and composition of sam-       tracked in the blood despite the signif-
ples sent to the laboratory for analysis.   icant dilution that occurs once a drug
Which methods he or she employs will        enters the circulation. To measure
depend on the properties of a given         quantities of an agent too small to be
sample. Generally, chemical, physico-       detected by chemical procedures, mi-
chemical, biochemical and biological        crobiologists also use microorganisms.
methods are used. Modern technolo-             Analysis plays a pivotal role in many
gies have made it possible to penetrate     operational areas at Roche (¡quality
the infinitesimal realm of atomic bonds.    control, ¡product safety). ¡Occupa-
   In research and chemical manufac-        tional hygiene and ¡environmental
turing, chemists use analytical meth-       protection are no exceptions; activities
ods to elucidate the sequence of events     in these areas are likewise based ulti-
in a chemical reaction, to identify the     mately on analytical findings.
molecular structure of a compound
or to determine its purity. Control of      Analytical systems. Instruments sup-
large-scale chemical and pharmaceuti-       plying reliable, precise and cost-effec-
cal manufacturing processes involves        tive diagnostic information; they help
automatic monitoring and evaluation         increase laboratory efficiency and
of analytical data.                         often contribute to major treatment
   Biological systems are employed to       decisions. The ¡Diagnostics Division’s
test the efficacy or toxicity of sub-       ¡Professional Diagnostics business
stances. Such systems make it possible      area supplies fully automated, com-
to assess the activity or harmfulness       puter-aided analytical systems under
(¡toxicology) of an active drug ingre-      the ¡Cobas trademark and the ¡Elec-
dient and to establish its “fate” in the    sys and Modular Analytics lines of
body. For example, it is possible to        laboratory diagnostic systems. Roche
determine how much of a dose reaches        can provide customers with a coordi-
the bloodstream (bioavailability) and       nated system of analysers and reagents
how much is excreted by the body in         tailored to their specific needs. Clinical
unchanged form. Equally important           chemistry test methods are based on
questions concern the drug meta-            proven analytical measuring techno-

Roche from A to Z                                                                   9
 Anemia


                                           gen-carrying red pigment hemoglobin
                                           in the blood. Anemia can have any of
                                           a wide variety of causes. When kidney
                                           function is impaired (after a severe
                                           kidney infection, for example, or as a
                                           complication of ¡diabetes), the body
                                           produces too little or no ¡erythropoi-
                                           etin (EPO); this ¡cytokine stimulates
                                           the production of erythrocytes from
                                           precursor cells derived from ¡stem
logies, including absorbance photo-        cells in the bone marrow. Today re-
metry, turbidimetry, fluorescence po-      combinant human EPO (¡NeoRecor-
larisation and ion selective electrode     mon) (epoetin beta) is available to
potentiometry. The wide range of           treat this form of acquired anemia.
immunoassays are measured by elec-         Anemia can also result from malnutri-
trochemiluminescence technology.           tion, particularly if a person’s dietary
   Thanks to our comprehensive serv-       intake of iron or vitamin B12 is too low.
ice portfolio, customers are able to use   In some African and Mediterranean
our innovative diagnostic products in      countries there is an increased inci-
a simple, safe and efficient manner.       dence of congenital, hereditary abnor-
Software solutions and comprehensive       malities in hemoglobin structure, such
data management tools provided by          as sickle cell anemia and various forms
Roche link centralised and decen-          of thalassemia. Anemia is also com-
tralised diagnostic systems, allowing      mon in cancer patients undergoing
the customer to view laboratory data,      chemotherapy who, while already
measurements and comprehensive             compromised by their primary dis-
patient information at a glance. The       ease, have also to cope with low hemo-
broad range of analytical systems for      globin levels. This leads to fatigue and
¡clinical chemistry and immunology         lack of concentration, rated as one of
can also be combined on one platform       the most debilitating of all cancer side
(modular concept). These systems           effects (¡C.E.R.A.).
relieve laboratory staff of much of the
workload of routine analysis, freeing      Angiogenesis. The physiological pro-
them up to concentrate on specific         cess involving the growth of new blood
operations.                                vessels from pre-existing vessels, facil-
                                           itating enhanced oxygen and nutrient
Anemia. A condition characterised by       delivery to the tissues. Under normal
a decrease in the number of red blood      cellular conditions angiogenesis is
cells (erythrocytes) or by an abnor-       essential for human growth, wound
mally low concentration of the oxy-        repair and embryonic development.

10
                                                            Animal experiments


It continues from birth to death and         correspond exactly to those of hu-
plays a fundamental role in the body’s       mans. This fact has given rise to the
healthy development. Angiogenesis            fallacy prevalent in animal rights cir-
also forms an essential component of         cles, and even among some doctors,
tumour maturation. In cancer patients        that animal experiments are pointless
a protein called VEGF (Vascular En-          and that the results of such experi-
dothelial Growth Factor) is released by      ments can never be applied to man.
the tumour, initiating the growth of         This is only partly true. Experiments
new blood vessels. This in turns results     must often be conducted on several
in increased oxygen and nutrient de-         animal species and the findings sub-
livery to the tumour, allowing it to         jected to careful evaluation and inter-
grow and ultimately spread through           pretation.
the body (known as metastasis). Due             Some laboratory animals are used
to its importance to tumour develop-         for identifying the effects of sub-
ment, angiogenesis is a valid therapeu-      stances that might prove useful in a
tic target for many cancers. ¡Avastin        particular treatment. Research is in-
is the first anticancer agent that acts by   creasingly directed towards identifying
binding to circulating VEGF, thereby         and correcting defective biochemical
preventing the formation of immature         processes that cause illness in humans.
blood vessels proximal to the tumour.        Such individual reactions are more
                                             easily observed outside the living or-
Animal experiments. Preliminary ex-          ganism (¡in vitro) than in the intact
periments on animals are absolutely          body, where they occur alongside nu-
essential if we are to determine the         merous other reactions. Such in vitro
possible effects and side effects of         investigations (¡alternatives to ani-
chemical compounds or biological             mal testing,) are gaining in impor-
therapeutic agents in humans. They           tance, and only those compounds that
provide invaluable information on the        appear promising are now tested in
desired action, distribution and bio-        animals. This largely explains why ani-
transformation of substances in indi-        mal experiments cannot be dispensed
vidual organs and, in particular, on         with altogether.
their possible harmful effects. It would        Nowadays, laboratory animals also
be irresponsible to test a substance in      have to be used for identifying and
human beings without first testing it        eliminating the adverse effects of
in carefully designed animal experi-         drugs or new compounds. These ani-
ments.                                       mal experiments are essential for an
   The scientists who carry out these        evaluation of risks and benefits prior
experiments are aware of the limita-         to human trials, because the reaction
tions of animals as models, as their         of a complete organism to the sub-
bodies and metabolic processes do not        stance must be determined. Not only

Roche from A to Z                                                                11
 Antagonist


are these investigations a prerequisite   Behring (Nobel Prize, 1901) and his
for subsequent tests on healthy volun-    Japanese assistant Shibasaburo Ki-
teers and patients, they are also re-     tasato recognised the presence of anti-
quired by law for drug registration       bodies in blood serum and became the
purposes (¡toxicology).                   first to successfully use such polyclonal
   Roche also works with organisa-        antibodies (antibodies produced by
tions dedicated to reducing the use of    many different B cells) from the blood
animals. In Switzerland Roche actively    of immunised animals as antitoxins
supports the 3R Research Foundation.      for diphtheria and tetanus. The first
This body provides funding to develop     theory of antibody structure and
new or improved methods based             activity was proposed a decade later
on what is known as the 3R strategy:      by Paul Ehrlich (Nobel Prize, 1908),
Reduce – Improve existing methods         but it was not until more recently that
so that fewer laboratory animals are      immunologists began to gain a clearer
required. Refine – Refine existing        understanding of the complexities
methods so that animals are exposed       involved. For example, the number of
to as little discomfort and distress as   lymphocytes (white blood cells) circu-
possible. Replace – Use alternatives to   lating in the human body is now
animal testing wherever possible.         known to be immense (over 1010 to
                                          1012), and to include millions of cells
Antagonist. An agent that nullifies       capable of producing antibodies.
or counteracts the pharmacological        Another major figure in research on
action of another agent (called the       the antibody system was Niels Kaj
¡agonist). An example is Anexate, a       Jerne (¡Nobel Prize, 1984). Working
benzodiazepine antagonist developed       with Albert Nordin in the United
by Roche and used in anesthesia and       States in the early 1960s, Jerne devised
emergency medicine.                       a simple, visual test for measuring the
                                          number of cells producing antibodies
Antibodies. Vast spectrum of special      to a given antigen. Known as the Jerne
¡proteins formed by the ¡immune           plaque assay, this test has played an
systems of higher animals in response     important role in the development of
to invading ¡antigens; antibodies are     modern immunology, and particularly
also called immunoglobulins. In Paris     of cellular immunology. In 1969, while
Louis Pasteur did the first systematic    the former Basel Institute for Im-
¡animal experiments exploiting anti-      munology was still in its infancy, Jerne,
gen-antibody reactions to induce im-      the institute’s first director, proposed
munity – work which resulted in           a theory based on molecular genetics
a rabies vaccine that saved the life of   to explain the tremendous diversity of
a young boy in 1885. A few years          specific antibodies in each individual.
later the German physician Emil von       Jerne’s work culminated in his theory,

12
                                                                       Antigen


also developed in Basel, of the immune    Antibodies, monoclonal. Identical
system as a self-regulating network of    antibodies formed by a single cell line;
cells and antibodies which is kept in     they can be produced artificially in
balance by highly specific mecha-         large quantities and in highly pure
nisms. Jerne not only made pioneering     form for use in research, diagnostic
discoveries of his own, but provided      testing and therapy. Monoclonal anti-
the impetus for new experimental          bodies are produced using hybrido-
work by younger researchers with his      mas, cultures of hybrid cells obtained
stimulating ideas. Among the scien-       by fusing cells from two different
tists whose work he influenced were       mammalian cell lines. Georges Köhler
Georges Köhler and César Milstein,        and César Milstein were awarded a
who shared the 1984 Nobel Prize with      ¡Nobel Prize in 1984 for developing
Jerne for their discovery of a method     the hybridoma technique (¡oncol-
of producing monoclonal ¡antibod-         ogy) (see diagramme on page 14).
ies. Working at the former Basel Insti-
tute for Immunology in the late 1970s,    Antibodies, polyclonal. Antibodies
Susumu Tonegawa (Nobel Prize, 1987)       produced by a multitude of different
elucidated the genetic basis of anti-     ¡B-lymphocyte clones (in contrast
body diversity. He showed that the        to monoclonal ¡antibodies), and
enormous structural variety of anti-      which therefore differ in molecular
bodies results from genetic rearrange-    structure in the binding site for the
ments and numerous chance ¡muta-          ¡antigen.
tions in specific gene sequences during
the earliest stage of an organism’s       Antigen. Term denoting any substance
development; at the same time his         recognised as foreign by the ¡immune
discoveries confirmed Jerne’s theory      system and which provokes a defensive
of antibody diversity.                    reaction by the body (immune re-
                                          sponse). Immune responses may be
Antibodies, humanised. Antibodies         directed against ¡bacteria, ¡viruses
produced with the help of genetic en-     or parasites, but also include allergic
gineering techniques by grafting the      reactions and rejection reactions to
respective DNA regions of ¡antigen-       tissues transplanted from other per-
binding sites from animal (usually        sons (¡organ transplantation). Pro-
mouse) immunoglobulin onto the            teins, such as the surface proteins on
framework of a human immunoglob-          microbial pathogens or natural toxins
ulin. Humanised antibodies are recog-     (snake and bee venom), comprise the
nised as foreign and neutralised by the   main group of antigens. In principle,
human immune system (reduced im-          though, any relatively large molecule
munogenicity) less frequently than        can act as an antigen. Ordinarily the
antibodies of mouse or rat origin.        body’s own components are not at-

Roche from A to Z                                                              13
 Antimicrobials



     Monoclonal antibodies from hybridoma cells
      Antigen
                                                                         Blood
                                                            Spleen


      Tumour cells                                                            Conventional
                                                                              serum containing
                                         Spleen cells                         polyclonal
                                                                              antibodies

                                Fusion

                                         Hybridoma cells




         Selection of hybridomas with antibody reactivity,
      expansion of cell lines (clones) from positive cell cultures




                                                                     Monoclonal antibodies




Genetically identical cell lines (clones) of hybridomas are obtained by fusing
short-lived antibody-producing spleen cells from the mouse with continuously
dividing, “immortal” tumour cells. These hybrid cells can be grown indefinitely
in culture, with each cell line producing a single uniform type of antibody.
Because of their extremely high specificity, such monoclonal antibodies (MAbs)
are indispensable tools in research and diagnostics; humanised MAbs serve as
novel, highly effective medicines.



tacked by the immune system, unless                     are used to treat infectious diseases
an individual has an ¡autoimmune                        caused by ¡bacteria, fungi, parasites
disease. The term “antigen” has noth-                   or ¡viruses. Highly effective drugs
ing to do with ¡genes.                                  against these pathogens have been
                                                        available since the advent of the sul-
Antimicrobials.   Chemotherapeutic                      fonamides in the 1930s and the peni-
agents produced chemically or by a                      cillins and other antibiotics somewhat
biotechnological process and which                      later.

14
                                                                Antimicrobials


                                           at Roche has resulted in ground-
                                           breaking therapeutic approaches with
                                           innovative drugs and diagnostic tests.
                                           Completely new avenues have been
                                           opened up to patients and doctors by
                                           Roche drugs for HIV, such as Invirase
                                           and Fuzeon, and increasingly by auto-
                                           mated diagnostic tests such as qualita-
                                           tive PCR for the detection of HIV and
                                           quantitative real-time PCR for the
                                           monitoring of viral load.
                                              Roferon A, based on the natural
Pegasys, the drug developed by Roche for   protein called interferon, was one of
the treatment of chronic hepatitis C.      the first treatments for hepatitis C.
The blue-violet chains are branched           Pegasys, the world’s best-selling
polyethylene glycol (PEG) molecules        treatment for ¡hepatitis C, contains
that surround the active ingredient in-    pegylated interferon alfa 2a (40KD).
terferon alfa-2a (a protein). This is      Pegasys is specifically designed to stay
known as pegylation. The PEG mole-         in the body longer fighting the virus.
cules protect the interferon against ex-   Patients are given Pegasys as an injec-
cessively rapid breakdown in the body.     tion just once a week and many have
They thus increase the stability of the    an excellent chance of being cured of
protein and improve the therapeutic        their disease. Pegasys is approved for
effect significantly compared to non-      a broad range of patients with hepati-
pegylated interferon alfa-2a.              tis C, including those patients who
                                           have cirrhosis, are coinfected with HIV
   Roche has developed numerous            or who have “normal” ALT levels. In
drugs for the treatment of viral ill-      addition, Pegasys is the only pegylated
nesses, for instance Fuzeon ¡Invirase,     interferon approved for the treatment
and Viracept for the treatment of          of patients with chronic hepatitis B.
¡AIDS, and Cymevene/Cytovene and              Copegus (ribavirin) is given in
Valcyte for cytomegalovirus infec-         combination with Pegasys and sub-
tions. If left untreated, cytomegalo-      stantially increases a patient’s chances
virus infection can lead to blindness      of being cured. Copegus tablets are
and death. The development of the          taken once a day for the duration of
first antiviral drugs represented an       treatment with Pegasys. This combina-
important milestone. The assumption        tion is now considered to be the gold
that vaccination was the only suitable     standard. Since the introduction of
weapon against viruses had to be re-       new diagnostic tests based on ¡PCR
vised. Research and development work       and real-time PCR technology, it is

Roche from A to Z                                                               15
 Antiparkinsonian agents


now possible to obtain better and          search at the time, led to the develop-
more detailed results in the diagnosis     ment of levodopa (Markus ¡Guggen-
of this viral disease and the monitor-     heim) as the first effective treatment
ing of the response to treatment.          for Parkinson’s disease. Levodopa
   Approval of the antiflu drug            (dihydroxyphenylalanine, l-dopa, also
¡Tamiflu has made it possible to treat     known by its trade name Larodopa) is
¡influenza by targeting the virus that     the precursor of the depleted neuro-
causes it. Introduced by Roche in 1999,    transmitter dopamine; the body is able
Tamiflu and a test for detecting           to convert it to dopamine. Unfortu-
influenza infection are an extremely       nately, a satisfactory response can only
effective pair of tools for diagnosing     be achieved with high doses and corre-
and treating the illness. The flu out-     spondingly marked adverse events.
breaks that occur regularly can place a    The discovery that adverse events
considerable burden on public health       could be suppressed by concomitantly
systems and claim many lives as a re-      administering benserazide, an enzyme
sult of complications.                     inhibitor, led to the development of
   Another Roche antimicrobial that        Madopar, a medicine combining
deserves to be mentioned is the anti-      levodopa and benserazide. Madopar is
biotic ¡Rocephin.                          significantly more effective and has a
                                           significantly better tolerability profile
Antiparkinsonian agents. Medicines         than Larodopa; the benefits it provides
for the treatment of Parkinson’s dis-      to patients with Parkinson’s disease
ease (also called paralysis agitans and    have yet to be surpassed by any other
shaking palsy), which is characterised     medicine.
by trembling (tremor), rigidity (rigor),
slowness and poverty of movements          Apothecary jars, historical. Albarelli,
(akinesia) and other physical and men-     syrup jugs and flasks from Italy, Spain
tal symptoms. The first detailed de-       and other European countries. Roche
scription of the disease was published     owns a valuable collection of approxi-
by James Parkinson in 1817. The inci-      mately 400 apothecary jars, on display
dence of Parkinson’s disease increases     in exhibit cases in various buildings
dramatically from age 55 on.               in Basel and Grenzach. The collection
    In the 1960s Prof. Walther Birk-       comprises pieces from the early 16th to
mayer of Vienna and others discovered      the 19th century. A scientific catalogue
that certain regions of the brain in       makes the collection accessible to re-
parkinsonian patients produced too         searchers.
little of a chemical messenger (¡neu-
rotransmitter) called dopamine. Close      Applied Science. Business area of the
collaboration between Birkmayer and        ¡Diagnostics Division. With over half
Alfred Pletscher, Roche’s head of re-      a century of experience in its field,

16
                                                               Apprenticeships




An especially beautiful piece from
Roche’s collection of apothecary ceram-
ics. An ornamental majolica vase from
Talavera, Spain, circa 1710 (48 cm high).
                                            LightCycler 2.0 Instrument – a system
Applied Science is one of the world’s       for fully automated PCR that not only
leading producers of reagents and           reduces PCR cycles to a fraction of the
systems for life science research. Ap-      usual time (32 PCR cycles in less than
plied Science develops and markets          20 minutes), but also simultaneously
components for medical and biotech-         monitors PCR reaction kinetics online
nological research, focusing especially     and in real time. A system for high-
on ¡genomics and ¡proteomics. This          throughput PCR is also now available
business area also supplies reagents        in the form of the LightCycler 480
                                            Instrument.

                                            and consumables for the pharmaceuti-
                                            cal and diagnostics industry.

                                            Apprenticeships. Roche has trained
                                            apprentices since the 1950s. Every year
                                            in Basel, for example, some 300 young
                                            people are prepared for a technical or
MagNA Pure LC Instrument – a highly         commercial career or receive training
flexible instrument for isolating DNA       in a trade. Similar programmes that
and RNA from a wide range of sample         operate in line with local training
materials; it is an ideal complement to     practices are in place at Roche compa-
the LightCycler system.                     nies in other countries.

Roche from A to Z                                                               17
 Architecture


   Besides offering apprenticeships for
chemical and laboratory technicians
– occupations typically in demand in
the pharmaceuticals industry – Roche
also trains apprentices for technical
careers in mechanical engineering,
electronics, automation, mechanical
design and fitting, draughting, IT and
logistics, and the company even has
training programmes for animal
keepers, medical practice assistants
and clerical employees.
   In Basel apprentices are trained for
three or four years by instructors in
the workplace, while also attending
the Roche works school and sector-
specific industrial training colleges or
the city’s commercial college, where
they take both vocational and general
education courses. The knowledge
acquired on the job and in the college     Top: Executive office building in Basel,
classroom is consolidated and ex-          built in 1935–36. Bottom: The build-
panded at the works school, with its       ing’s sweeping spiral staircase, one of
apprentice labs and workshops, a           the hallmarks of architect Otto R.
modern training factory for chemical       Salvisberg’s designs. A similar staircase
technicians opened in 1996 and a com-      can be found in the original Roche
puter training centre, under the expert    building in Welwyn Garden City.
guidance of Roche’s own training staff.
This ensures that apprentices receive
highly practical, hands-on training.       which they fit in with the surrounding
The results achieved year after year in    townscape.
the final trades examinations in Basel        The company’s building policies
are just one example of the success        were shaped in part by the association
of the Roche apprentice training sys-      of architect Otto R. Salvisberg (a pro-
tem.                                       fessor at Zurich’s Federal Institute of
                                           Technology) and the then head of
Architecture. In 1971 the Basel con-       Roche, Dr Emil C. ¡Barell. And they
servation society awarded Roche a          are also a reflection of the interest of
prize for its well-designed industrial     the founder families represented on
buildings and the harmonious way in        the ¡Board of Directors in the visual

18
                                                                              Art


¡arts and architecture. Salvisberg’s         administration buildings along its
first building for Barell was a private      western edge. What little chemical
residence. Following this successful         production is still done in Basel is
“trial run”, Barell commissioned him         located at the centre of the complex.
to design a new executive office build-      Most chemical manufacturing activi-
ing in Basel. To this day it stands out      ties have been relocated to other sites
as an exceptional piece of industrial        for lack of space and for economic rea-
architecture. Salvisberg subsequently        sons.
drew up a master development plan               The style of industrial architecture
for the entire Roche site in Basel.          promoted in Basel, with its emphasis
Despite numerous modifications, it           on quality and functionality, has been
was retained essentially intact and          retained in more recent projects, such
largely determined the present appear-       as the pharmaceutical research lab-
ance of the site. After Salvisberg’s         oratory building designed by the ar-
death Dr Roland Rohn took over his           chitectural firm Herzog & de Meuron
teacher’s studio and commissions, in-        completed in 2000 and the newest
cluding the Basel site development           building, the ¡Avastin production
project. It was under Rohn’s direction       centre. This style has also been
that the most visible and striking parts     adopted by the other companies in the
of the complex were built: the office        Roche Group, though each of them has
highrise, the staff amenities building       adapted the basic stylistic elements to
and the buildings along the Rhine and        suit local needs. Copies, in the strict
those abutting the Wettsteinallee.           sense, of Salvisberg buildings can be
Rohn’s plans for an office building on       found at the ¡Nutley site in New
the last vacant plot fell victim to objec-   Jersey (United States). Salvisberg
tions by the city’s conservation society,    personally designed the original com-
and Rohn died while the project was          plex in Welwyn Garden City (Great
still under study.                           Britain), which unfortunately has
   The guiding idea in developing the        undergone substantial changes in the
Basel campus was to create a “buffer         meantime. The notable buildings in
zone” around the production facilities       Istanbul and Kamakura (Japan), on
so as to protect neighbouring residen-       the other hand, were designed by
tial areas as much as possible from          members of the planning and building
industrial emissions. The strips along       department at Roche Basel.
the Rhine and Wettsteinallee were ac-
cordingly used for research buildings;       Art. Also has its place in the world of
the staff amenities building, a ware-        work and science. Countless works
house and production facilities solely       of art, usually by contemporary local
for pharmaceuticals were sited along         artists, decorate the walls of work and
the eastern edge of the campus; and          recreation areas and corridors in

Roche from A to Z                                                                19
 Arthritis, rheumatoid


                                           – Interlocking Two Pieces Sculpture,
                                             stone sculpture in the garden be-
                                             tween the old administration build-
                                             ing and the office highrise, by Henry
                                             Moore (1898–1986).
                                           – Pépin-Géant, in the garden in front
                                             of the foyer of Building 71, by Hans
                                             Arp (1887–1966).

                                           Arthritis, rheumatoid. ¡Autoim-
                                           mune disease whose cause remains
                                           unknown. Typical symptoms of this
                                           disorder include symmetrical joint in-
                                           flammation on both sides of the body,
                                           with destruction of the joint lining
Sculpture by Hans Arp on the Roche         and, in the rapidly progressive form,
site in Basel.                             destruction of the adjacent bone and
                                           cartilage. The condition is generally
                                           chronic and progressive with acute
Roche buildings all over the world. As     disease flares leading to painful joint
an experiment, seven painted panels        swelling. Rheumatoid arthritis is a
and sculptures were put up in the main     generalised inflammatory disease that
Basel workshops in 1969. These works       is not limited to the joints, but one that
of art were created especially for these   can also lead to systemic effects such as
surroundings by young artists.             ¡anemia, chronic fatigue, ¡osteo-
   Other works of art are also acces-      porosis, and ultimately to a shortened
sible to visitors or the general public,   life span. Even if treated with classical
among them the following sculptures        anti-inflammatory drugs, rheumatoid
on display at corporate headquarters       arthritis (RA) can still lead to gradual
in Basel:                                  destruction of the joints and loss of
– Concrete sculpture on the east front     function. Over 21 million people
   of the staff amenities building, by     worldwide suffer from the disease.
   Ödön Koch (1906–1979).                  MabThera/Rituxan (rituximab) is cur-
– Eyecatching red iron sculpture out-      rently approved for the treatment of
   side the staff amenities building,      active rheumatoid arthritis in patients
   visible from afar, by Bernhard Lu-      who have an inadequate response or
   ginbühl (*1929).                        who are intolerant to one or more tu-
– Oyarek II, iron sculpture in the         mour necrosis factor inhibitor thera-
   foyer of the large auditorium, by       pies and is in development for further
   Eduardo Chillida (1924–2002).           use in rheumatoid arthritis.

20
                                                       Autoimmune diseases


                                          or excessive response by components
                                          of the ¡immune system. The cause is a
                                          breakdown in the mechanisms con-
                                          trolling immunological tolerance to
                                          the body’s own tissues; as a result,
                                          ¡antibodies or certain ¡T lympho-
                                          cytes (white ¡blood cells) attack the
                                          body’s own ¡proteins or healthy cells.
                                          T lymphocyte precursors learn self-
                                          tolerance – which also means learning
Rheumatoid arthritis particularly         to discriminate between “self ” and
affects the small joints and the hands    “nonself ” – in a kind of training school
and feet.                                 in the thymus gland (hence the name
                                          “T lymphocytes”) through exposure to
                                          cell surface proteins that are unique
   At the beginning of 2003 Roche and     to each individual. The mature T lym-
¡  Chugai announced their intention       phocytes that emerge from the selec-
to jointly develop and market the         tion process in the thymus normally
Chugai molecule tocilizumab. Tocili-      do not bind to these self-proteins. As
zumab is a humanised monoclonal           killer T cells, mature T lymphocytes
¡antibody which selectively targets       are directly involved in cellular immu-
interleukin-6 (IL-6), one of several      nity, mounting attacks against any
cytokines involved in the activation of   cells expressing foreign antigens –
autoantibodies, and other mediators       foreign cells in tissue or organ trans-
of inflammatory mechanisms. With          plants (¡organ transplantation), for
its novel mechanism of action, tocili-    example, or virus-infected or cancer
zumab could represent a new, effective    cells. Other T lymphocytes mature
approach to the treatment of rheuma-      into helper T cells, which control the
toid arthritis. A Phase III clinical      activity of antibody-producing B lym-
development programme is underway         phocytes through various complex
globally with more than 4,000 patients    reactions. When errors occur in the
enrolled in 41 countries including        “training” of T lymphocytes, the result
countries in Europe and the USA.          may be an appropriate immune re-
Tocilizumab has one of the largest        sponse (say, to a microbial pathogen)
clinical development programmes           which is too weak, or the immune
within Roche.                             system may recognise self as nonself
                                          and run amok against the body’s own
Autoimmune diseases. Any of nu-           constituents.
merous disorders, most of them seri-         A long list of clinical entities are
ous, resulting from an inappropriate      now recognised as autoimmune dis-

Roche from A to Z                                                               21
 Avastin


eases. These include multiple sclerosis,
certain types of ¡diabetes and
rheumatoid ¡arthritis. The discovery
of the mechanisms involved in the de-
velopment of “naive” T cell precursors
into mature, fully immunocompetent
T cell families was largely the work of
an international team of researchers
at the former Basel Institute for
Immunology in the late 1980s. For
Roche’s immunologists, findings from
¡basic research are the cornerstone of
the quest for novel, highly specific
medicines aimed as closely as possible
at the root causes of autoimmune dis-      a naturally occurring protein called
eases and rejection reactions following    VEGF (vascular endothelial growth
¡organ transplantation.                    factor), a key mediator of angio-
                                           genesis, thereby choking off the blood
Avastin. The first anticancer drug that    supply that is essential for the growth
inhibits ¡angiogenesis, i. e. the growth   of the tumour and its spread through-
of a network of blood vessels that sup-    out the body. Due to its mode of action
ply nutrients and oxygen to cancerous      Avastin has the potential to become
tissues. Avastin (active ingredient be-    the backbone of cancer treatment. As
vacizumab) is a monoclonal ¡anti-          such, Roche and Genentech are pur-
body currently being codeveloped by        suing a comprehensive clinical pro-
Roche and ¡Genentech for use in a          gramme, the largest ever undertaken
number of cancer types. Avastin was        for an anticancer agent, which is ex-
launched in 2004 for the first-line        pected to include over 40,000 patients,
treatment of patients with advanced        investigating Avastin’s use in many
colorectal cancer. It was also approved    tumour types including colorectal,
in 2006 for the treatment of non-small     breast, lung, pancreatic, ovarian, renal
cell lung cancer. Avastin is the only      and many other kinds of cancer (¡on-
antiangiogenic agent that has consis-      cology).
tently demonstrated an overall and/or
progression-free survival benefit in the
three most common tumour types:
colorectal cancer, ¡breast cancer and
non-small cell lung cancer. Avastin
possesses a novel mode of action and
works by targeting and binding to

22
                                                     Barell, Emil Christoph


                                        indispensable to plant and animal life.
                                  B     Bacteria and other single-cell organ-
Bacteria. Ubiquitous single-cell mi-    isms are responsible for a vast range of
croorganisms. Some bacteria are pa-     natural processes such as humus for-
thogens, causing diseases that can be   mation and the breakdown of organic
treated with antibiotics and other      wastes in sewage. The human body
¡antimicrobials. Far from being         also harbours bacteria as permanent
harmful, most bacteria are actually     residents, notably the coli bacteria
                                        (Escherichia coli) which are part of the
                                        normal intestinal flora.
                                           In ¡biotechnology, naturally oc-
                                        curring bacterial strains are used for
                                        fermentation, a centuries-old tech-
                                        nique. High-performance strains pro-
                                        duced by continuous selection are
                                        used in today’s biotechnological pro-
                                        duction processes. Bacteria with spe-
Salmonella typhimurium.                 cial properties can also be produced
                                        by genetic recombination for use in
                                        biotechnology and ¡genetic engineer-
                                        ing. Escherichia coli K12 is frequently
                                        employed for such applications. This
                                        non-pathogenic strain of E. coli re-
                                        sulted from spontaneous mutation in
                                        the laboratory and is scarcely viable in
                                        nature.

                                        Barell, Emil Christoph (1874–1953).
Streptococcus pyogenes.                 Chemist, member of the ¡Board of
                                        Directors, chairman and delegate of
                                        the Board and an instrumental figure
                                        in Roche’s expansion into an interna-
                                        tional company. Barell was born and
                                        raised in the canton of Schaffhausen,
                                        of which he later became a citizen. His
                                        father was from Gressoney-Saint-Jean
                                        in Piedmont, Italy; his mother was
                                        Swiss.
                                           He earned his PhD in chemistry in
Klebsiella pneumoniae.                  Bern. In 1896 he joined Roche, becom-

Roche from A to Z                                                            23
 Barell, Emil Christoph


                                             unequalled in his mastery of product
                                             promotion and medical communica-
                                             tions – activities vital to the branded
                                             pharmaceuticals business – and as a
                                             born financier he was the company’s
                                             undisputed head. The anecdotes about
                                             Barell’s frugalness are legion. Realising
                                             that people, not rules, are the main
                                             thing, he was his own personnel man-
                                             ager. Roche’s international expansion
                                             after the First World War was due
                                             mainly to Barell. He also saw to it that
                                             buildings and production facilities
                                             were built in a unified style. ¡Archi-
                                             tecture fascinated him as an expression
Emil Christoph Barell, 1874 –1953.           of the human creative impulse.
                                                 Barell was elected to the Board of
ing Fritz ¡Hoffmann’s right-hand             Directors in 1933, and in 1939 became
man. World War I and the upheavals in        chairman and delegate of the Board. At
revolutionary and post-revolutionary         the outbreak of World War II, when it
Russia dealt a serious blow to the com-      looked as if headquarters was about to
pany’s fortunes, and as Hoffmann’s           be cut off from its affiliates and offices
health failed, Barell assumed responsi-      abroad, Barell decided to move to
bility for managing Roche. In the early      ¡Nutley with a small staff and manage
1920s he reorganised the company             the Group from there. At the end of the
with almost draconian harshness,             war he immediately returned to Basel,
stamping his own highly personal style       assuming control of the ¡parent com-
on its organisational structure and way      pany and the entire Group. He was
of doing business.                           now over 70 years old; and when he fell
   Barell had actually joined Roche as       ill in 1952, it was clear that the Barell
a plant chemist, but quickly expanded        era, which had shaped Roche so pro-
his duties while the fledgling company       foundly, was drawing to a close. “It is a
was still relatively small. As the chemist   fortunate man”, he remarked in one of
responsible for supervising produc-          his last interviews, “who can spend his
tion he insisted on scrupulous cost          whole working life with the same em-
accounting for every stage of manufac-       ployer. Some never find the right job,
ture. It was Barell who enlisted the first   others have to change jobs. I’m thank-
chemical and medical researchers,            ful for the privilege of having been able
many of whom collaborated with               to work for the same company for
Roche as external consultants. He was        nearly 57 years.”

24
                                                               Benzodiazepines


Basel. ¡Parent company.                     coat of arms. For this reason it formed
                                            part of the first Roche brand mark
Basic research. Research whose goal         (¡trademarks), representing phar-
is an understanding of the causes and       macy’s deep roots in Basel.
effects of fundamental natural phe-
nomena. The boundaries between              Benzodiazepines.          ¡Psychotropic
basic and applied research are fluid.       drugs characterised by anxiety-reliev-
Often a very simple distinction is          ing, sedative/sleep-inducing, anticon-
drawn: the scientific work done by ac-      vulsant and muscle-relaxant effects.
ademia is basic research; what industry     They are accordingly indicated for
does is applied research. But matters       the treatment of anxiety disorders,
are not quite that simple.                  sleep disturbances (¡hypnotics) and
   Time and again industrial re-            epileptic seizures. Benzodiazepines are
searchers encounter the limitations of      indispensable in anesthesiology and
current scientific knowledge and find       intensive care medicine, where they
that they must therefore tackle funda-      are used as premedication before gen-
mental problems. Such work is then          eral anesthesia and as sedatives in the
usually undertaken in collaboration         intensive care unit and before proce-
with research groups at universities,       dures performed under local or re-
independent institutes or biotech com-      gional anesthesia.
panies (¡Nobel Prize, ¡research).              Development of the benzodiaze-
                                            pines was pioneered in the 1950s by
Basilisk. Greek for little king. Origi-     chemist Leo H. ¡Sternbach and phar-
nally a legendary serpent reputed to be     macologist Lowell Randall, working at
able to kill by its mere look; ancient      Roche in Nutley. The world’s first
                                            commercially available drug of this
                                            class, Librium, was launched by Roche
                                            in 1960, followed in 1963 by Valium
                                            Roche. These two products marked a
                                            watershed in Roche’s history and
                                            sparked intense efforts (both at Roche
                                            and in other companies) to explain
                                            how the benzodiazepines work. One of
references to it include a passage in the   the high points of this research was the
Bible (Isaiah 59:5). The name is also       discovery of the benzodiazepine re-
applied to a tropical American lizard.      ceptor in certain regions of the brain.
Probably because of its similar sound-         Two further benzodiazepine prepa-
ing name, the basilisk was adopted as       rations, Lexotan for anxiety and Rivo-
the symbol of Basel. It is usually de-      tril for epilepsy, were launched on the
picted as the shield bearer of the Basel    market in 1973. Rivotril subsequently

Roche from A to Z                                                                25
 Biologics


came to be used to treat anxiety as          inition includes all diagnostic ¡tests,
well. Of the many benzodiazepines            imaging technologies and any other
that have since been developed and           objective measure of a person’s health
marketed, the benzodiazepine recep-          status. Thus, biomarkers are not new,
tor ¡antagonist Anexate deserves spe-        but because we have a large number of
cial mention. This compound binds            new tools such as ¡proteomics and
to benzodiazepine receptors without          ¡genomics, we are discovering more
stimulating them. As a result, the effects   novel markers that may have greater
of benzodiazepine ¡agonists are atten-       applicability to improving drug devel-
uated or completely reversed. Anexate        opment and healthcare. The goals of
is used in anesthesiology to terminate       biomarker researchers are many, in-
general anesthesia and in intensive          cluding identifying biomarkers that
care medicine for the management of          can provide a more precise definition
benzodiazepine overdose.                     of disease, risk and clearer prognoses,
                                             and also serve as useful indicators of
Biologics. Biologics, or biopharma-          a drug’s activity, efficacy, and safety.
ceuticals are much more complex than         Efforts are also underway to find
the chemically clearly defined small         markers that can aid drug develop-
¡molecules that still make up the            ment. Playing a key role in many areas
majority of medicines. Biologics can         of human healthcare, biomarkers have
be ¡proteins (especially antibodies),        been around since scientists began to
¡DNA or ¡RNA and are derived                 evolve an understanding of human
from living material using biotechno-        biology, diseases and therapeutic in-
logical processes.                           terventions.

Biology. Science of the structure and        BioS. Biotech services facility at Roche
function of living organisms. The main       Basel. In this fermentation plant, pro-
traditional subdisciplines are zoology,      teins for preclinical research and de-
botany and anthropology. Today, inter-       velopment are manufactured using
est centres on ¡molecular biology,           genetically modified microorganisms
with the allied fields of ¡genetic engi-     and animal and human cell cultures.
neering and genomics, and on im-             The BioS is also used to develop and
munology, neurology (the study of the        optimise fermentation processes for
nervous system) and biochemistry.            the manufacture of therapeutic pro-
                                             teins (e. g. antibodies). The scientists
Biomarkers. Biomarkers are measur-           at the BioS work closely with their
able biological indicators that can be       colleagues from other Roche depart-
used to evaluate normal biologic             ments (particularly in ¡Penzberg) and
and/or disease processes or responses        maintain contacts with universities
to a drug or treatment. This broad def-      and industrial partners worldwide.

26
                                                                      Biosafety


   The BioS is equipped with a total of   particular purpose. In many cases,
27 fermenters, with capacities ranging    staff health can also be improved by
from 2 to 1,400 litres. These fer-        protective vaccinations. Apart from
menters contain microorganisms or         the customised design and construc-
cell cultures that produce the proteins   tion of buildings, laboratories or pro-
in either the cells or culture medium.    duction areas, technical measures in-
The proteins are then purified in bio-    clude the use of laboratory facilities,
chemical laboratories and used in the     equipment and resources designed to
search for new drugs or even as poten-    prevent the contamination of humans
tial new drugs themselves.                with leaked biological material. Mi-
                                          crobiological safety cabinets and ster-
Biosafety. Term used to refer to the      ilising autoclaves are particularly im-
safe handling of biological agents such   portant in this respect. Good personal
as microorganisms (particularly ge-       hygiene, correct working practices and
netically modified microorganisms)        a meticulously observed disinfection
and of animals, blood, blood compo-       programme also contribute to em-
nents and other human and animal          ployee safety.
body fluids. The goals of biosafety are       Biosafety is governed by a number
to ensure occupational safety by pro-     of regulations and standards, includ-
tecting staff from accidents and dis-     ing national legislation and interna-
ease, and environmental safety, by        tional guidelines and internal Roche
preventing the release of potentially     directives and operating procedures.
hazardous biological materials into       A biological safety officer at each site
the environment. These goals are          coordinates and monitors compliance
achieved through a combination of         with all relevant regulations and
physical and biological containment       guidelines and represents Roche in its
measures and protective measures for      dealings with advisory committees
staff. Biological containment measures    and regulatory authorities.
include the use of non-pathogenic mi-         On the basis of guidelines issued by
croorganisms or those with the lowest     the US National Institutes of Health
risk potential and the culturing of       and the recommendations promul-
microorganisms with hazard-reducing       gated by the Organization for Eco-
properties such as a dependency on        nomic Cooperation and Develop-
certain culture media or specific con-    ment, a biosafety system with four
ditions of temperature and humidity.      safety levels has been established
Molecular biological safety measures      worldwide. In order to take appropri-
include the deliberate restriction of     ate account of the biological risks, four
undesirable gene transfers and the        biosafety levels have been assigned to
avoidance of superfluous genetic in-      the four risk groups (Biosafety Level
formation that is not required for a      BL 1 “no risk” to BL4 “high risk”).

Roche from A to Z                                                               27
 Biosimilars or follow-on biologics (FOBs)


Each consists of a set of technical,       etc.), can be handled at this biosafety
organisational, staff-related, medical     level without jeopardising the public
and biotechnological safety measures.      or the environment. Such operations
Thus, the laboratory and production        are required only when serious dis-
strains of ¡Escherichia coli, Bacillus     eases such as AIDS, caused by the
subtilis and Saccharomyces cerevisiae      HI virus (risk group 3), need to be
(bakers’ yeast) can be classified as       researched.
“risk-free” under all known criteria,
provided they are processed in appro-      Biosimilars or follow-on biologics
priate areas (BL1) and in accordance       (FOBs). A biosimilar is a new biologi-
with the rules of good microbiological     cal medicinal product claimed to be
practice. The same applies to hamster      “similar” to a reference medicinal
cells, which play a key role in the pro-   product which is submitted for mar-
duction of monoclonal ¡antibodies.         keting approval by an independent
Such cells do not pose any health risk     applicant after the patent for the origi-
to staff member or the environment.        nator product has expired.
The regulations for working at bio-           While it is relatively easy to copy
safety level BL2 are more comprehen-       small chemical molecules, it is more of
sive, requiring the use of safety cabi-    a challenge to copy biological products
nets on the technical side and the         because the manufacturing processes,
systematic inactivation of liquid and      which involve living cells, are ex-
solid waste products. At the staffing      tremely complex and difficult to
and organisational level, BL2 requires     reproduce. For this reason these sec-
safety training courses, access restric-   ond-wave products or “second-entry
tions and certain safe working proce-      biologics” cannot be classified as
dures. These measures substantially        generics, and the term “biogeneric” is
reduce the release of microorganisms       inappropriate because the testing
and enable laboratory staff to work        required to develop these products is
safely even with pathogens that can        more demanding than that for a tradi-
trigger treatable human diseases, e. g.    tional generic for which the regulatory
salmonella infections. The very strict     authorities in Europe and the United
BL3 and BL4 safety levels require com-     States will accept a limited set of
plex technical facilities. Air filters,    data. For this reason, these authorities
air-locks, and negative-pressure work      are naming them “similar biological
areas used in combination with regu-       medicinal products” or “biosimilars”
lated working procedures, ensure that      (Europe), and “follow-on biologics/
dangerous materials are hermetically       proteins” (USA). Roche’s position is
sealed off from the outside world. All     that second-entry biologics should
pathogenic or otherwise dangerous          adhere to and meet the same rigorous
organisms (¡viruses, ¡bacteria, fungi,     preclinical, clinical, and quality stan-

28
                                                                     Blood cells


dards as innovative originator prod-        matically by ¡genetic engineering.
ucts, and be submitted to the same          Genetic engineering is a branch of
strict post-marketing surveillance          modern biotechnology which makes it
(pharmacovigilance). In addition,           possible to “programme” microorgan-
biosimilars/FOBs should not be inter-       isms to perform specific tasks by
changeable with originator products         inserting the appropriate genetic in-
and should have distinct naming and         formation into their ¡DNA. Thus vir-
labelling requirements (INN) to make        tually any ¡protein, regardless of its
them individually identifiable.             origin, can be produced by micro-
   Since the first innovative biological    organisms or cell cultures, provided
products (e.g. proteins, antibodies) are    its genetic blueprint (the gene coding
already going off patent, a second wave     for the protein) is known.
of products claimed by the manufac-            Roche uses genetically modified mi-
turers to be similar to an innovative       croorganisms or cell cultures to pro-
product could appear on the market in       duce various proteins for research pur-
the near future.                            poses, for diagnostic tools (antibodies)
                                            and to manufacture drugs including
Biotechnology. The use of micro-            Pegasys, Herceptin, MabThera/Rituxan
organisms, cell cultures, tissue cultures   and ¡NeoRecormon (¡production,
or parts thereof for manufacturing          biotechnological). Furthermore, Roche
purposes. In its most common form           sources biotechnologically manufac-
it involves using the metabolism of         tured intermediates for the antibiotic
microorganisms to obtain products           ¡Rocephin and the immunosuppres-
that it would be extremely difficult        sant ¡CellCept from toll manufac-
or impossible to synthesise chemically.     turers.
Biotechnological processes (or bio-
processes) were used long before any-       Biotransformation. Chemical conver-
one was aware that microorganisms           sion of a substance by microorganisms
existed. Beer, cheese and yoghurt,          or ¡enzymes.
for example, are just as much biotech-
nology products as a genetically engi-      Blood cells. Collective term for the
neered ¡interferon. Biological waste-       cells circulating in the blood: leuko-
water treatment is another example of       cytes, erythrocytes and platelets. The
a large-scale bioprocess.                   erythrocytes, or red blood cells, are
   Traditional biotechnology is based       responsible for oxygen transport, the
on the use of common non-pathogenic         platelets for blood clotting. Blood
microorganisms, primarily to promote        clotting disorders may take the form of
fermentation (e. g. the conversion of       persistent bleeding in newborn infants
sugar to alcohol). The range of poten-      or following surgery or difficult births
tial applications was expanded dra-         when certain coagulation factors are

Roche from A to Z                                                                29
 Blood-screening


temporarily inactive or are produced       their ¡immune systems are generally
in inadequate amounts (e. g. in the        weaker and more susceptible to new
inherited disease hemophilia). A dif-      infections.
ferent type of clotting disorder occurs       Published articles in the scientific
when platelets form an obstruction in      literature suggest that ¡PCR-based
the arteries (a thrombus), causing         NAT (nucleic acid amplification test-
thrombosis, embolism or heart attack.      ing) can reduce the current window
   The leukocytes, or white blood cells,   for any possible transmission of hepa-
are subdivided into ¡granulocytes,         titis C down to 11 days from the cur-
¡B and ¡T lymphocytes, macro-              rent 70 days for antibody screening.
phages, monocytes, natural killer cells
and dendritic ¡cells. These are all        Board of Directors. Unlike the boards
important constituents of the body’s       of other major companies, the Roche
¡immune system. B lymphocytes pro-         Board of Directors (originally the
duce the host of ¡antibodies present       Board of the operating ¡parent com-
in the body, though not without vital      pany, and since 1989 the Board of
support from a group of T lympho-          Roche Holding Ltd [¡holding com-
cytes known as helper T cells (¡AIDS).     pany]) has always had relatively few
Abnormalities in the development of        members. It has always included mem-
mature white blood cells cause the var-    bers of the founding family and
ious forms of leukemia, some of which      prominent scientists from the biomed-
can be treated with ¡Roferon-A.            ical fields, and thus has been charac-
                                           terised by a high degree of continuity.
Blood-screening. In blood banks,           When Roche was incorporated as a
screening for infectious disease agents    limited company in 1919, the then
is a vital measure for ensuring blood      president of the Basler Handelsbank,
and plasma safety. This type of screen-    Albert Koechlin-Hoffmann (a brother-
ing focuses on the detection of infec-     in-law of the founder), was appointed
tious agents that may have eluded          chairman of the Board, retaining this
detection through routine donor            position until his death in 1927.
screening processes. The goal is to keep   He was succeeded by the lawyer Dr
infected units of blood out of the         A. Wieland-Zahn, followed, in 1940,
supply, and therefore prevent the acci-    by the then managing director, Dr
dental introduction of chronic or          Emil Christoph ¡Barell. Barell was
potentially life-threatening diseases      named honorary chairman in 1952.
such as HIV, hepatitis, or West Nile       Following Barell’s death in 1953, Dr
Virus to someone who is already being      Albert Caflisch became chairman, a
treated for a serious medical condi-       post he held until his untimely death
tion. Because patients receiving trans-    in 1965. The chairmanship passed to
fusions are often already very sick,       Dr Adolf Walter Jann, who was suc-

30
                                                                  Breast cancer


ceeded by Fritz Gerber in 1978 as             There are also several types of breast
Chairman and Chief Executive Officer.      cancer that grow at different rates and
Gerber stepped down as CEO in              respond in very different ways to treat-
December 1997, and in April 2001           ment. For this reason, malignant tissue
resigned as Chairman of the Board. He      should always undergo a number of
was appointed Honorary Chairman            tests to determine the type of tumour
and remained a member of the Board         e.g. its estrogen-receptor (ER), or HER2
until 2004. CEO Dr Franz B. Humer          (Human Epidermal growth factor
succeeded Gerber as Chairman of the        Receptor 2) status.
Board.                                        Depending on the type, spread and
                                           size of the tumour at the time of initial
Breast cancer. As many as eight to         diagnosis, it may be appropriate to
nine percent of women will develop         choose a primary systemic therapy
breast cancer during their lifetime,       (neoadjuvant therapy) to reduce the
making it the second most common           size of the tumour before it is surgi-
cancer in the world. The exact causes      cally removed. This approach im-
of breast cancer are not known, but age    proves the chances of breast-conserv-
and a family history of breast cancer      ing surgical treatment and also
are probably the most important risk       provides valuable information regard-
factors. Breast cancer is not just one     ing the tumour’s sensitivity to the
single disease, so if it is diagnosed, a   medication used, which can guide fur-
number of tests are performed to de-       ther treatment after surgery.
termine the stage and type of disease.        Approximately two-thirds of breast
   Breast cancer is generally classified   tumours overexpress a high number
as “early” or “advanced” (metastatic),     of estrogen receptors (ER) on the cell
in four stages, depending on tumour        surface. In these tumours, the female
size and whether the cancer has spread     hormone estrogen regulates cell
beyond the initial site in the breast to   growth. Breast cancers that are de-
other parts of the body. Most women        pendent on estrogen are called ER-
with breast cancer are diagnosed at an     positive. Hormonal therapies such as
early stage, and more than 80 percent      tamoxifen or aromatase inhibitors
survive more than five years after diag-   block the growth-promoting effects of
nosis. Advanced (metastatic) breast        estrogen and can be used as both an
cancer develops when cancer cells          adjuvant therapy after primary sur-
break away from the breast and settle in   gery or during the advanced (metasta-
other parts of the body. Approximately     tic) stages of the disease.
50 percent of patients will develop ad-       The human epidermal growth fac-
vanced (metastatic) breast cancer after    tor receptor 2 (HER2) is a protein
they have received primary treatment       produced by a specific gene with can-
for early-stage breast cancer.             cer-causing potential. HER2 acts as a

Roche from A to Z                                                                31
 Burgdorf


receptor for growth factors circulating    ment of insulin pumps for the treat-
in the blood and influences the rate of    ment of ¡diabetes since 1984. Roche
cell growth and differentiation. When      acquired the Insulin Pumps division of
the gene that provides the code for the    Disetronic in 2003 (¡insulin pump
HER2 protein is amplified, it triggers     therapy).
an overproduction, or “overexpres-            Disetronic’s amalgamation with
sion”, of HER2. Excess amounts of          Roche has facilitated a more integrated
HER2 lead to uncontrolled or malig-        approach to diagnosing, treating and
nant cell growth, i. e. to the develop-    monitoring diabetes. For Roche, the
ment of cancer. In HER2-positive           acquisition of Disetronic has further
breast cancer, increased quantities of     strengthened its position in diabetes
the HER2 protein are present on the        management (¡Diabetes Care).
surface of the tumour cells. This is
known as “HER2-positivity”. HER2-          B lymphocytes. White blood cells that
positive breast cancer affects 20 to 30    carry membrane-bound ¡antibody
percent of women with breast cancer,       molecules on the cell surface. The
and is a particularly aggressive form of   specificity of the membrane-bound
the disease that requires special and      antibody enables the ¡immune sys-
immediate attention because the tu-        tem to recognise defined ¡antigens.
mour is fast-growing, responds poorly      Depletion of B lymphocytes has
to chemotherapy and there is a higher      proved to be a successful treatment
likelihood of relapse.                     strategy for non-Hodgkin’s lymphoma
    Biologically engineered ¡mono-         and autoimmune rheumatoid arthri-
clonal antibodies offer specific treat-    tis, as ¡Genentech’s biotherapeutic
ment options for some breast cancers.      Rituxan (MabThera) has shown.
For the 20 to 30 percent of breast
tumours that are HER2-positive, for
example, ¡Herceptin (trastuzumab),
is the only approved monoclonal anti-
body therapy that specifically targets
HER2, inhibiting tumour growth and
leading to tumour cell death. Every
woman with breast cancer should be
tested for HER2 status to determine
whether she might benefit from Her-
ceptin therapy.

Burgdorf. Location of a Swiss medical
device supplier that has been a global
leader in the research and develop-

32
                                                                        CellCept


                                            test helps doctors decide on the treat-
                                     C      ment and evaluate the prognosis of
Cardiology. Study of the heart and          heart failure patients.
heart disease, including the diagnosis         Therapeutic monitoring with Elec-
and treatment of cardiovascular dis-        sys proBNP can help reduce the num-
ease. Cardiology is one of the key          ber of hospital referrals and fatalities
research areas in modern medicine           of cardiac origin.
(¡cardiovascular).
                                            CellCept (mycophenolate mofetil,
Cardiovascular.       Pertaining to the     MMF, ¡biotechnology). Immuno-
heart and blood vessels (cardiovas-         suppressant acquired by Roche in the
cular system). Since over 40 percent of     Syntex acquisition of 1994. It was
the population in the industrialised        developed in Palo Alto and was being
world die of cardiovascular disease,        reviewed by the health authorities (to
usually as a consequence of high blood      decide whether to grant a marketing
pressure (hypertension), it constitutes     licence) at the time of the takeover.
one of the key areas of pharmaceutical      Global approval of the product from
research. The ¡ACE inhibitor In-            1995 on marked Roche’s entry into
hibace, the beta-blocker Dilatrend and      the field of ¡organ transplantation, a
the diuretic Torem are important            new segment for the company. Cell-
contributions by Roche to the medical       Cept is used to prevent acute kidney
treatment of hypertension. Activase,        transplant rejection. In the United
the first genetically engineered            States and Europe it is also approved
(¡biotechnology, ¡production, bio-          for use after heart and liver transplan-
technological) tissue plasminogen           tation.
activator – a drug that dissolves blood        CellCept possesses a novel mecha-
clots after a heart attack – was launched   nism of action. The results of large-
in the United States by ¡Genentech.         scale international clinical ¡trials had
¡Chugai markets the antianginal             previously shown that, compared with
agent Sigmart. In diagnostics, Roche is     placebo or azathioprine, a drug fre-
pushing ahead with projects linking         quently used in transplant patients,
treatment and diagnosis for the ulti-       MMF reduces the incidence of kidney
mate benefit of patients. Thus, for         rejection by around 50 percent. Cell-
example, the innovative heart test          Cept has the additional advantage of
Elecsys proBNP is used in the diagno-       low chronic toxicity. Furthermore,
sis of early forms of heart failure by      when CellCept is used, dosages of
measuring the concentration of the          other immunosuppressants, whose
protein NT-proBNP in the blood.             side effects include kidney damage,
Since the NT-proBNP level rises in line     hypertension and hepato- and neuro-
with the severity of the condition, the     toxicity, can be reduced.

Roche from A to Z                                                                33
 Cell, human


   In October 2003 Aspreva Pharma-          initiate cellular immune responses by
ceuticals and Roche announced a             triggering activation of ¡T lympho-
unique collaboration that represents a      cytes.
new partnership model for the phar-
maceutical industry. Under the terms        Cephalosporins. A group of anti-
of the deal Aspreva Pharmaceuticals         biotics that are chemically related
acquired exclusive worldwide rights         to the penicillins. One example is
to develop and market CellCept in           ¡Rocephin.
all autoimmune disease applications,
such as psoriasis and lupus nephritis.      C.E.R.A. Stands for Continuous
                                            Erythropoietin Receptor Activator.
Cell, human. Every individual is made       C.E.R.A. is the first of a new class of
up of the almost inconceivable num-         agents that could represent significant
ber of 100 trillion cells. Excluding the    progress in ¡anemia management.
red ¡blood cells, the ¡cell nucleus of      The preparation has a unique mode of
each of these cells contains a complete     action. Traditional short-acting ery-
human ¡genome (a person’s genetic           thropoietin-stimulating agents (ESAs)
blueprint). This information is en-         are quickly internalised and degraded
coded in some 3 billion nucleobases,        after binding to the receptors involved
the building blocks of the genetic          in stimulating red blood cell produc-
material ¡DNA.                              tion. Unlike traditional ESAs, C.E.R.A.
                                            has a greatly reduced affinity for the
Cell nucleus. A person’s genetic mate-      receptors, allowing it to stimulate red
rial, or ¡DNA, is packed into 23 pairs      cell production without immediate
of ¡chromosomes contained in the            internalisation and degradation. This
nucleus of each cell. One chromosome        distinct molecular interaction is be-
in each pair is derived from the per-       lieved to play a role in providing tar-
son’s mother, the other from the father.    geted, stable and sustained control of
                                            anemia.
Cells, dendritic. White blood cells            Its brand name Mircera has been
that play a key sentinel role in the        approved by European health authori-
¡immune system: dendritic cells             ties (¡EMEA). In April 2006, on the
migrate to all mucosal tissues and the      basis of this approval and additional
skin in order to recognise and take up      data, Roche submitted licensing appli-
¡antigens of foreign invaders through       cations to the regulatory authorities in
macro-pinocytosis and phagocytosis          the United States and the European
for presentation as antigenic peptide       Union for the treatment of anemia in
fragments on the cell surface. In con-      chronic ¡kidney disease, including
trast to ¡macrophages, dendritic cells      dialysis patients.
function as antigen-presenting cells that

34
                                                                   Chromosomes


Chemotherapeutic       agents.    Active    creasingly plays a leading role in the
pharmaceutical ingredients produced         approval (¡registration) of new drugs
by chemical synthesis for the treatment     and drug monitoring in the EU coun-
of disease, as opposed to active ingre-     tries (¡EMEA).
dients of natural origin obtained en-
tirely by physical methods (extraction)     Cholesterol. A natural steroid belong-
or by fermentation or using biotechnol-     ing to the group of sterins (sterols)
ogy or recombinant DNA techniques.          classed as lipids (“fats”). Mention the
                                            word “cholesterol” and most people
Child-proof drug containers. Medi-          immediately think of something harm-
cines should always be kept out of          ful – something that is bad for the
reach of children. However, despite         heart and circulation. Less well known
printed warnings and educational            is the fact that cholesterol is a very
campaigns this rule is often ignored.       important and essential component of
Because of this, the packaging of med-      our diet, a vital constituent of all ani-
icines, particularly of those that pose     mal cell membranes, and that without
special risks, is designed to be child-     cholesterol the body would not be able
proof, as far as possible. Blister packs    to produce any bile acid or vitamin D,
have proved effective for tablets of var-   for example. Nevertheless, an elevated
ious types and give quite good protec-      cholesterol level is certainly harmful,
tion for babies and toddlers. Special       representing one of the principal risk
safety caps that can be opened only by      factors for atherosclerosis (a disease
a combination of movements (simul-          affecting large and medium-sized
taneous pushing and twisting, for ex-       arteries) and coronary heart disease.
ample) are used on plastic bottles.         These conditions occur when excess
However, this is just the sort of thing     cholesterol is deposited and calcifies
that playful, inquisitive children can      in the vessel walls. For this reason, an
find particularly attractive. Packaging     accurate measurement of cholesterol
technology is constantly faced with         levels is an essential part of a patient’s
two conflicting requirements: ¡medi-        risk assessment.
cines should be inaccessible to chil-
dren but easily accessible to disabled      Chromosomes. Rod- or hook-shaped
or elderly patients. This means that        structures comprised of ¡proteins
compromises are inevitable. Keeping         and ¡DNA that carry a cell’s genetic
medicines out of children’s reach is        information (¡cell, human). In the
still the best solution.                    cells of higher plants and animals and
                                            in man, chromosomes are always
CHMP. Abbreviation for the (Euro-           arranged in pairs. Humans have 23
pean) Committee for Human Medici-           chromosome pairs. The genetic infor-
nal Products in London, which in-           mation is determined by the arrange-

Roche from A to Z                                                                  35
 Chromosomes


        Chromosome 01     Chromosome 02   Chromosome 03

        Prostate cancer   Bowel cancer    Lung cancer

        Alzheimer’s       Essential       Bowel cancer
                          tremor
                                          Essential
                                          tremor




        Chromosome 04     Chromosome 05   Chromosome 06

        Huntington’s      Asthma          Juvenile
        chorea                            diabetes
                          Cockayne
                          syndrome        Epilepsy

                          Hair loss




        Chromosome 07     Chromosome 08   Chromosome 09

        Obesity           Werner’s        Chronic
                          syndrome        myeloid
        Cystic fibrosis                   leukemia
                          Burkitt’s
        Juvenile          lymphoma        Malignant
        diabetes                          melanoma




        Chromosome 10     Chromosome 11   Chromosome 12

        Refsum disease    Juvenile        Phenyl-
                          diabetes        ketonuria
        Gyrate atrophy
                          Various types
                          of cancer

                          Long qt
                          syndrome




36
                                                     Chromosomes


           Chromosome 13      Chromosome 14             Chromosome 15

           Breast cancer      Alzheimer’s               Marfan
                                                        syndrome
           Retinoblastoma
                                                        Prader-Willi
                                                        syndrome




           Chromosome 16      Chromosome 17             Chromosome 18

           Crohn’s disease    Breast cancer             Pancreatic
                                                        cancer
                              Various types
                              of cancer                 Bowel cancer




           Chromosome 19      Chromosome 20             Chromosome 21

           Arteriosclerosis   Severe                    Trisomy 21
                              combined
           Myotonic           immuno-                   Amyotrophic
           dystrophy          deficiency                lateral
                                                        sclerosis

                                                        Alzheimer’s




           Chromosome 22      Chromosome XY

           Di-George-         Duchenne
           Syndrome           muscular
                              dystrophy
           Chronic myeloid
                              Fragile x
           leukemia
                              syndrome
           Neuro-             Severe          The diagramme shows a
           fibromatosis       immuno-
           type 2             deficiency
                                              small selection of here-
                              Testis          ditary disorders which
                              determining     have been linked to spe-
                              factor
                                              cific chromosomes.

Roche from A to Z                                                      37
 Chugai


ment of the base pairs (¡gene “build-     quantitative analytical methods to
ing blocks”) on the DNA double helix.     determine the constituents of body
In humans the full chromosome set is      fluids. Among other things, this in-
made up of roughly 6 billion base         cludes tests for ¡enzymes, substrates,
pairs. (See diagramme on pages 36 and     electrolytes or specific ¡proteins,
37.)                                      which may be performed before treat-
                                          ment is started or to monitor its
Chugai.      Leading research-based       effects. The techniques used include
pharmaceutical firm in which Roche        enzymatic assays, measurements with
acquired a majority stake at the end      ion-selective electrodes, photometric,
of 2002, creating the fourth-largest      turbidimetric or potentiometric tech-
pharmaceutical company in Japan.          niques. The ¡Diagnostics Division of-
Chugai focuses its activities primarily   fers a comprehensive range of clinical
on bioengineered products and the         chemistry reagents and ¡analytical
therapeutic areas of oncology, renal      systems that enable automated sample
disorders, bone and joint disorders,      processing in the clinical laboratory.
cardiovascular disease, transplanta-
tion, infectious diseases and immune      Clinical Research Ethics Advisory
disorders. The company has develop-       Group (CREAG). As well as providing
ment sites in the United States and       input in specific instances, the CREAG
Europe and sales and marketing or-        keeps Roche updated on ethical issues
ganisations in France, Germany and        from the wider health arena and acts
Great Britain. Worldwide, Chugai          as a sounding board by regularly parti-
employed approximately 5500 people        cipating in periodic ethics discussions
at the end of 2005. Its key products      with Roche. In addition, the CREAG
include Epogin (drug for treating         will also monitor Roche’s posting of
anemia in chronic renal insufficiency),   trials on www.Roche-Trials.com to
Alfarol (for osteoporosis), Neutrogin     ensure that information on the website
(for the treatment of chemotherapy-       always accurately reflects the Roche
induced neutropenia) and Sigmart          Policy on Transparency in Clinical
(antianginal agent).                      Trials.
   At the start of 2003 Roche and
Chugai announced their intention to       Clone. A group of genetically identical
jointly develop and market MRA,           cells derived by repeated division from
Chugai’s innovative biopharmaceuti-       a single parent. Cells are called poly-
cal drug for the treatment of rheuma-     clonal if they are derived from more
toid ¡arthritis.                          than one clone and are therefore ge-
                                          netically different. Monoclonal cells or
Clinical chemistry. In diagnostics,       microorganisms are identical copies of
the application of qualitative and/or     a single parent cell or organism.

38
                                                                         Cobas


Coagulation self-monitoring. Long-         destined for the professional diagnos-
term anticoagulant treatment is a          tics user. The cobas brand embodies
strain for many patients, and the fre-     outstanding product quality and relia-
quent venepunctures needed to moni-        bility.
tor variations in clotting time add to        The division has accumulated sev-
this burden. Since 1993 there has been     eral years’ experience with modular
                                           systems. In 2002 the division intro-
                                           duced the first integrated modular lab-
                                           oratory system for ¡clinical chemistry
                                           and immunochemistry, the Modular
                                           Analytics SWA (serum work area) for
                                           laboratories with a high workload.
                                           The cobas 6000 product range intro-
                                           duced in June 2006 represented the
                                           first in a new generation of systems
                                           (cobas modular platform) for labora-
CoaguChek S – a simple, convenient         tories with a medium-sized workload.
and reliable system for coagulation        Additional systems for laboratories
self-monitoring.                           with low and high workloads are to
                                           follow.
                                              With five modules that can be com-
an easier way for patients to check        bined to create customised solutions,
their clotting time – CoaguChek,           two reagent carriers and appropriate
which was replaced by the CoaguChek        software, the cobas modular platform
XS system in 2005. Based on a dry          can handle over 150 analytes. These in-
chemical method with only a few            clude more than 90 assays for clinical
steps, this system enabled patients to     chemistry, for example electrolytes or
check their prothrombin time (clot-        serum proteins, homogeneous ¡im-
ting time) in an even simpler, safer and   munoassays for drug doping tests and
more precise procedure taking just one     therapeutic monitoring, and over 40
minute. The CoaguChek systems are          heterogeneous immunoassays for thy-
the most frequently used patient self-     roid, hormone, tumour and cardiac
monitoring systems, offering rapid,        diagnostics and other applications.
accurate and almost painless, mini-        The cobas e pack and cobas c pack
mally invasive measurement of pro-         reagent carriers are used for these
thrombin time.                             assays. Users of Cobas Integra will
                                           be familiar with these easy-to-handle
Cobas. All the products and services       packs, which require no reagent prepa-
of the ¡Diagnostics Division’s ¡Pro-       ration and remain stable for a long
fessional Diagnostics business area        time once on board the system.

Roche from A to Z                                                              39
 Communication, employee


   The concept inherent in the cobas       inates information about the company
modular platform ensures flexibility,      in his or her family and social circles
speed and cost-effective working.          and in that way influences the com-
Additional components such as pre-         pany’s standing.
analysis systems, IT tools and inno-          Basic responsibility for providing
vative new markers can also be used        information to employees rests with
to assemble a complete laboratory          the managements of the individual
solution.                                  ¡divisions and affiliates. They obtain
   The cobas 6000 product range is a       the relevant details directly from the
compact, efficient ¡analytical system      divisions and functional units con-
that has been optimised specifically for   cerned.
medium-sized laboratories and their           Vehicles for information include
need to cover a wide variety of param-     briefing sessions, seminars, newslet-
eters. This new equipment generation       ters, notices, circulars and the com-
builds on the strengths of the existing    pany intranet. In addition, most affili-
serum work area concepts and gives         ates also publish in-house periodicals
Roche customers versatility in meeting     for their employees. At Group level the
the growing needs of the laboratory.       most important activities going on
From a single analytical module to a       around the Roche world are reported
complete unit for clinical chemistry       in Hexagon, a newspaper that is pub-
and immunology, the cobas 6000             lished quarterly and distributed to all
product range covers over 95% of the       employees.
daily routine, producing significant
gains in laboratory diagnosis – in-        Communication, financial. A com-
creased flexibility, increased safety,     pany like Roche, whose shares are
increased efficiency and increased         quoted on the stock exchange, has to
convenience. The proven modular            keep the financial world regularly
equipment concept offers an excep-         informed of its general business situa-
tionally broad diagnostic spectrum         tion. The main vehicle for financial
with the maximum of consolidation.         information is the company’s annual
                                           report, which is supplemented by half-
Communication, employee. Of those          yearly and quarterly sales reports dis-
groups interested in information from      tributed via internal channels and to
the company, the employees occupy          the public media. In addition, rep-
a special position. They must be in-       resentatives of the shareholders or of
formed at first hand about important       groups interested in acquiring shares
developments in their work environ-        (financial analysts, representatives of
ment. Only well informed employees         banks and institutional investors such
can identify fully with their company.     as pension funds and trusts) are in-
Moreover, each employee also dissem-       vited to regular briefings.

40
                                                                      Competition


Communication, general. Commu-              nificant proportion of a company’s
nication, particularly of data, facts and   overall costs, but it is an essential serv-
intentions. The Group’s information         ice, particularly in the launch phase of
policy is defined in the Roche ¡Cor-        innovative products.
porate Principles. Apart from the com-         In the case of drugs this means the
pany’s own employees and the general        pack and the package insert on the one
public, information is also dissemi-        hand and the information and promo-
nated to specific groups, such as the       tional activities directed at customers
media, government authorities, share-       on the other. For decades the health-
holders, financial analysts, political      care professions held the view that
groups and local residents living near      product information should be aimed
company facilities, along with con-         exclusively at doctors and pharma-
sumer organisations, schools, trade         cists, not at patients. However, it is
unions and churches.                        now generally recognised that con-
   At Roche headquarters the “raw           sumers – in other words, patients –
information” is collected by contact        must be given information that will
persons in the individual ¡divisions        allow them to use a medicine correctly.
and operational units, prepared by the         The information and promotional
Corporate Communications depart-            material sent to doctors and other
ment in line with the needs of the          healthcare professionals independ-
various recipients and then released.       ently of the product are, of course, of
Group companies have their own              a scientific nature. In many countries,
information departments that are            including Switzerland, pharmaceutical
adapted to their own particular needs.      manufacturers adhere to self-imposed
All available information channels are      rules concerning the provision of such
employed: media releases, audiovisual       information. The information must be
materials, Internet, Intranet, books        accurate, objective, scientifically sound
(Editiones Roche) and other publica-        and supported by scientific publica-
tions, personal contacts, media confer-     tions.
ences and seminars. This reference
guide is also intended as a source of       Competition. Efficient mechanism for
general information.                        coordinating economic activity. Com-
                                            petition results in a complex process of
Communication, product-related. A           learning, exploration and discovery; it
sophisticated industrial product and        presupposes a large number of com-
the information that goes with it form      petitors vying for customers’ business.
an indivisible whole. The product              Experience teaches that countries
cannot be used properly without the         with competitive market economies
corresponding information. Product-         are better able to attain standard-of-
related information accounts for a sig-     living targets than economies in which

Roche from A to Z                                                                   41
 Copyright


central planning or regulation pre-        thereby impeding the innovative com-
dominates. Roche is therefore a firm       petition which is vital to medical
believer in competitive markets and        progress.
regards them as essential for the tech-
nological advances needed to drive         Copyright. There are two basic ideas
long-term prosperity.                      behind copyright laws. First, because
   Competition is the rule in all          an author’s work is an expression of
Roche’s businesses. Whether this is        his personality, he should have a right
really the case in the pharmaceuticals     to determine the forms in which it is
sector is often (and unjustly) ques-       made available to the public and
tioned because drug prices are subject     whether it must appear with his
to official controls in most countries.    name. And secondly, an author should
Nevertheless, competition does pre-        be remunerated for his creative work.
dominate, manifesting itself in three      Only the specific expression of an idea
distinct forms. In straightforward         is copyrightable, and only a tangible
commodity competition (often the           embodiment constitutes the work.
only type considered), price is the sole   Copyrights need not be registered and
deciding factor involved in a purchase.    are usually valid for up to 70 years after
In imitative competition, buyers and       the author’s death (50 years in the case
sellers also operate with established      of computer programmes). The degree
methods and products, but in this          of protection varies from one country
case the usefulness and quality of the     to another, and cross-border protec-
products and the standard of service       tion is governed by international
– not only the price – play a part in      agreements.
decisions to buy. These two forms             Technological advances have opened
of competition predominate in the          up new ways of utilising copyright
market for non-patented medications        materials (particularly in films, radio
and ¡generics. Finally, innovative         and television), as well as previously
competition operates through the           undreamed-of means of reproducing
development of new products and by         and distributing them (radio and tele-
solving hitherto unresolved problems,      vision broadcasts via satellite, publica-
thus displacing older products from        tion on the Internet). As a result, copy-
the market. In the research-based          rights are widely and routinely abused,
pharmaceutical industry, this third        sometimes consciously but more often
form of competition is extremely in-       not.
tensive.                                      Industry has a powerful interest in
   The market basically accepts all        seeing copyright laws enforced, since
three forms of competition. Govern-        the works covered include scientific
ment authorities, however, tend to         publications, computer programmes,
consider only competition on price,        audio-visual productions and teaching

42
                                                          Corporate Principles


and learning systems. Owing to the            Roche is committed to all its stake-
uninhibited use of modern techniques       holders and strives to serve the diverse
of recording and reproduction, this        interests of customers, employees,
whole field is now in a state of flux.     shareholders and holders of Roche
  A copyrighted work from 2006, for        non-voting equity securities in a bal-
example, should be declared as follows:    anced fashion. This commitment is
©2006 F. Hoffmann-La Roche Ltd.            reflected in our operating businesses’
                                           focus on value creation, in a manage-
Corporate functions. Name given to         ment culture that conforms to modern
units based at Group headquarters,         standards of corporate governance
whose duties are not connected directly    and in our Group’s policy of commu-
with Roche products, but involve the       nicating transparently.
provision of services for the entire          Detailed information is accessible
Group. Such functions include legal        to all stakeholders – shareholders,
affairs, finance and accounting, hu-       employees, customers, suppliers and
man resources, communications and          the general public – on the Internet
safety, health and environmental pro-      (www.roche.com).
tection. Roche’s corporate functions
are analogous to a ¡division.              Corporate Principles. A compilation
                                           of guidelines, objectives and principles
Corporate Governance. A system for         defining the way in which the Group
ensuring open, transparent and respon-     conducts its business. In a very broad
sible management and control of a          sense, these principles can be com-
company. The Roche Group meets all of      pared to the constitution of a country
the requirements with respect to Cor-      or state, though they are not meant
porate Governance, complying with the      to be interpreted (and it would be
existing legal regulations, the SWX        impracticable to interpret them) as
(Swiss stock exchange) directives (in-     having legal force. They enable the
cluding their Commentaries) and the        Group’s employees to situate their own
Swiss Code of Best Practice for Corpo-     activities within a broader context.
rate Governance as promulgated by the         Published in eight languages, the
Swiss business federation “economie-       Roche Corporate Principles, which were
suisse”. The existing internal company     slightly revised in 2003, set out guide-
regulations, in particular the company’s   lines on the key issues of service to
Articles of Incorporation and Bylaws,      patients and customers, respect for the
consider all the principles that govern    individual, commitment to responsi-
the management and supervision of          bility, commitment to performance,
our company including the necessary        commitment to society, commitment
checks and balances in order to ensure     to the environment, commitment to
good corporate governance.                 innovation and continuous impro-

Roche from A to Z                                                               43
 Counterfeit drugs


vement. Training courses are held to       Cultural sponsoring (cultural com-
instruct the Group’s employees             mitment). Roche has been an active
around the world on what the prin-         patron of contemporary art and cul-
ciples mean and how to apply them          tural projects since it was founded in
in their daily work.                       1896 – a heritage reflecting the influ-
                                           ence of the founder’s family. This side
Counterfeit drugs. Drug products in        of corporate giving has tended to focus
which the active ingredient has been re-   most strongly on music, but also in-
placed by an agent with similar actions.   cludes support for the visual arts and
The use of such products to treat severe   architecture. Roche sees close affinities
illnesses can thus have life-threatening   between innovation in the arts and
consequences. Counterfeit drugs also       in a research-based company. Roche
damage people’s trust in the healthcare    is convinced that the intellectual
systems. Fraudulent drugs crop up reg-     stimulation of contemporary culture
ularly in a good many countries, and       enriches employees’ daily lives and
there have even been instances of coun-    contributes to making Roche an inno-
terfeit Roche products being sold.         vative company.
   The magnitude of the drug counter-         Most Roche employees work in an
feiting problem is difficult to gauge,     environment where original works of
since fraudulent drug products are of-     contemporary ¡art are “part of the
ten sold on the black market; in some      atmosphere”. Distinctive modern
countries they are commonplace. The        ¡architecture in the Bauhaus tradi-
contributing factors are diverse and       tion has been one of the hallmarks of
are often related to a country’s eco-      Roche sites since Otto Salvisberg cre-
nomic, legislative and political situa-    ated the first masterplan for Roche
tion. Foreign exchange shortages,          Basel and defined the architectural
inadequate ¡patent and ¡trademark          idiom that still shapes the way Roche
protection, lax import controls, hap-      builds today. The Roche buildings are
hazard distribution networks and,          also designed for transparency and
not least, corruption all facilitate the   flexibility, so that they can be adapted
traffic in counterfeit drugs.              to changing circumstances without
   These illegal activities can only be    compromising their architectural in-
combated in cooperation with the au-       tegrity. Roche Basel’s new research and
thorities. As the health policy aspects    biotech production buildings, both
of the problem generally transcend         designed by Herzog & de Meuron,
national boundaries, observed cases        are recent examples of a responsible
of drug counterfeiting are reported        approach to site development.
to the appropriate departments of the         Launched in 2003, Roche Commis-
¡WHO, as well as to the national           sions regularly awards commissions
authorities.                               for new musical works by outstanding

44
                                Cultural sponsoring (cultural commitment)




Premiere of the Roche Commissions work by Hanspeter Kyburz.



contemporary composers. Roche se-         Paul Sacher, who represented Roche’s
lects the composer on the basis of        founding family on the Roche Board
recommendations made by the artistic      for many years. It sums up the essence
directors of the Lucerne Festival,        of the Roche innovation model: the
Carnegie Hall and the Cleveland           pursuit of excellence, a willingness to
Orchestra. The commissioned work is       engage with the new and the courage
premiered by the Cleveland Orchestra      to take risks.
at the Lucerne Festival SOMMER. The          These fundamental values are now
following season, the same orchestra      being opened up to more and more
performs it for the first time in the     Roche employees through projects
United States at Carnegie Hall. Infor-    such as Roche ’n’ Jazz – a series of
mal contacts and discussions between      concerts run in partnership with local
the composers and Roche scientists        jazz clubs. In Basel Roche ’n’ Jazz was
form an essential part of the project,    launched in partnership with the
highlighting the parallels between in-    Basel-based bird’s eye jazz club and
novation in art and in science and the    the Museum Tinguely, each of which is
challenge of doing creative work in any   an equal stakeholder. As part of this
area. Roche Commissions continues a       project the Museum Tinguely will be
tradition shaped largely by the influ-    hosting laid-back, but musically high-
ence of the conductor and arts patron     class, jazz concerts featuring first-rate

Roche from A to Z                                                               45
 Cystic fibrosis (CF)


performers from Switzerland and            good breeding ground for bacteria.
abroad.                                    This leads to the destruction of tissue
   To mark its centenary in 1996,          and progressive impairment of respi-
Roche donated to its home city of          ratory functions. Consequently, most
Basel the Museum Tinguely, a museum        CF sufferers have a life expectancy of
featuring the work of the Swiss sculp-     no more than 30–40 years.
tor Jean ¡Tinguely (1925–1991). The           The ¡DNA of dead bacteria and
museum, designed by the famous             phagocytes makes the mucus in the
Swiss architect Mario Botta, is located    lungs viscous. The genetically engi-
close to Roche headquarters in Basel’s     neered drug Pulmozyme, which con-
historic Solitude Park, overlooking the    tains the enzyme DNase as its active
Rhine river. The museum’s permanent        ingredient, reduces mucus viscosity
collection includes mechanical sculp-      and improves airway clearance. In-
tures, reliefs and drawings from all       haled as an aerosol spray, Pulmozyme
periods of Tinguely’s career. The mu-      was discovered by ¡Genentech and
seum also offers a varied and lively       codeveloped in Europe by Roche.
programme of special exhibitions ex-       Roche also markets the product in
ploring Tinguely’s relationship with       Europe.
artists of his own and earlier genera-
tions (from Marcel Duchamp and Kurt        Cytokines. Hormone-like ¡proteins
Schwitters to Niki de Saint Phalle and     which, even in minute concentrations,
Yves Klein) and themes of particular       mediate and regulate interactions be-
relevance to Tinguely’s work (e. g. con-   tween different cells, creating an inter-
temporary kinetic art).                    cellular communications network. As
                                           a rule, cytokines are synthesised only
Cystic fibrosis (CF). The commonest        in activated cells as a reaction to an ex-
inherited disease in many European         ternal signal (often another cytokine)
countries and the United States,           and are released into the extracellular
caused by a mutated gene on ¡chro-         environment. They then bind to cy-
mosome 7. This gene often displays         tokine-specific receptors on the sur-
several ¡mutations. The result is an       face of target cells, where they trigger
abnormal ¡protein in the pancreas,         biochemical signals. Many cytokines,
the glands lining the airways and lungs    such as ¡interferons, interleukins and
and in the sweat glands, causing thick-    colony-stimulating factors, influence
ening of pancreatic secretions and the     the cells of the hematopoietic and
mucus secreted in the lungs because of     ¡immune systems. Four cytokine
lack of fluid. CF patients suffer from     families exist: hematopoietins, ¡inter-
respiratory tract infections because       ferons, chemokines, and tumour
the sticky mucus which they are un-        necrosis factors.
able to clear from their airways is a

46
                                         Cytostatic agent


Cytostatic agent. Natural or syn-
thetic substance that inhibits the
growth of cells. Cytostatic agents are
used mainly for cancer chemotherapy
(¡oncology).




Roche from A to Z                                       47
 Derivative


                                            late complications. ¡Glucose self-
                                     D      monitoring is important here. The
Derivative. A compound with modi-           ¡Diagnostics Division’s ¡Diabetes
fied properties derived from a basic        Care business area supplies a wide
chemical structure.                         range of products and services for
                                            treating and monitoring diabetes.
Diabetes. Disease in which the body
is unable to produce insulin or cannot      Diabetes Care. Business area in the
properly utilise the insulin it produces.   ¡Diagnostics Division. Its aims are
It is characterised by high blood glu-      not only to improve the quality of life
cose levels and affects approximately       of people with ¡diabetes by offering
1–5 percent of the world population.        them innovative products (e. g. Accu-
Diabetes can be dangerous not only          Chek Aviva and Compact Plus glucose
because of the short-term problems it       meters, Accu-Chek Multiclix lancing
causes, but also, and more particularly,    device, Accu-Chek Pocket Compass
because of the long-term damage that        and Accu-Chek SmartPix data man-
can occur in the course of the disease.     agement systems, Accu-Chek Spirit
Patients with this chronic, lifelong        insulin pump and the Accu-Chek
disease have above all to learn how best    FlexLink infusion set), services and in-
to live with it and how to prevent its      formation, but also to make the disease
                                            manageable in the long term and
                                            thereby reduce the overall economic
                                            cost of ¡diabetes and its complica-
                                            tions.
                                               In early 2003 Roche submitted a
                                            tender offer to Disetronic (¡Burg-
                                            dorf) for its Insulin Pumps division.
                                            Bringing these two businesses together
                                            will make Roche a pioneering leader
                                            in systems combining blood glucose
                                            monitoring and insulin delivery. This
                                            is the ideal way to link diagnosis and
                                            therapy for people with diabetes.

                                            Diagnostics Division. Global leader
                                            in the diagnostics market. Formed in
Accu-Chek Compact Plus: Blood glu-          1969, the division offers a unique
cose measuring system with integrated       range of innovative tests and services
lancing device and test strip drum. An      for researchers, doctors, patients,
ideal device for use away from home.        hospitals and laboratories worldwide.

48
                                                          Diagnostics research


The division now consists of the            diseases can already now be treated
following business areas: ¡Applied          more selectively through a targeted
Science, ¡Molecular Diagnostics,            combination of diagnosis and treat-
¡Professional Diagnostics and ¡Dia-         ment. Using the latest technologies
betes Care.                                 (e. g. the ¡AmpliChip), Roche is devel-
   The Applied Science business area        oping innovative molecular diagnostic
develops and markets components             tests. This technological advance will
and reagents for life science research,     also benefit patients, since accurate
focusing on genome research and             diagnosis is crucial to the successful
proteomics, for the pharmaceutical          outcome of treatment.
and diagnostics industry and for food
monitoring. Molecular Diagnostics has       Diagnostics research. Research field
made the ¡polymerase chain reac-            concerned with developing reagents,
tion (PCR) into a world-leading tech-       methods and analysers used to study
nique for DNA tests. This business          the causes of disease, or which provide
area specialises in the development         rapid, reliable information on the
and marketing of six unique PCR             presence of a disease or its course so
applications: women’s health, virol-        that appropriate treatment can be ini-
ogy, blood banks, microbiology, on-         tiated as early as possible. Methods of
cology and genomics. Professional           monitoring treatment are also devel-
Diagnostics is a leading developer and      oped for the important job of checking
supplier of new technologies and inte-      how effective a given therapy is once it
grated solutions that help to maximise      has been started. Regardless of which
the efficiency and cost-effectiveness of    of these categories a project falls into,
clinical laboratories. The business area    the aim is to help patients by improv-
also supplies products and systems for      ing the diagnosis and treatment of
near-patient diagnosis in hospitals and     disease, while at the same time helping
outpatient facilities. As a market leader   to reduce health care costs (¡analyti-
in the field of diabetes management,        cal systems).
Diabetes Care focuses on the develop-          The Diagnostics Division invests
ment of novel technologies and serv-        substantial amounts in research and
ices that make life easier for people       development, focusing on the areas
with diabetes and which it markets          of diabetes, immunodiagnostics and
under the Accu-Chek brand name.             molecular diagnostics. Research and
Efforts to develop innovative products      development activities associated with
are supported by research centres in        ¡diabetes are designed to make life
Switzerland, Germany, Austria and the       easier and safer for people with dia-
United States. The division responds        betes, for example by means of inte-
directly to customer needs by provid-       grated, even more user-friendly equip-
ing special programmes. Many chronic        ment components and insulin pumps

Roche from A to Z                                                                 49
 Distribution centres


and by providing blood glucose meas-        and functions to bring the products
urement methods that only require           distributed by the divisions to the cus-
minimal amounts of blood or even no         tomer with maximum efficiency.
blood at all. Software programmes for          Top priority is given to compliance
those who need to perform several           with product-specific requirements.
tests a day and therefore have to man-      Thus, for example, it must be possible
age a large amount of data represent        to prove that refrigerated products
another key area.                           remain within the stipulated tempera-
   Researchers working in laboratory        ture range during transport.
diagnostics are developing automated           As part of the Supply Chain Strategy
integrated solutions designed to in-        for the ¡Diagnostics Division, two
crease productivity and reduce costs,       global distribution centres are respon-
and reliable diagnostic techniques that     sible for distributing goods and prod-
can help to maximise the efficacy of        ucts both to regional warehouses
medical treatments.                         managed by the national companies
   New, high-quality ¡biomarkers are        and to end customers: The German
being produced with the aim of ob-          site in Mannheim is responsible for
taining information about the course        supplying the EMEA regions (Europe,
of diseases or the efficacy of treatment.   Middle East and Africa), Asia–Pacific,
With the next generation of system          Iberia/Latin America and Japan, while
platforms it should be possible to          Indianapolis supplies North America
measure combinations of markers             and many other countries with test
using protein chips. The correspon-         strips manufactured in the United
ding IMPACT system is currently             States. Wherever possible, the two
undergoing feasibility testing and          global distribution centres supply
should initially help to speed up clini-    end customers directly. Customers in
cal trials with new markers.                Europe order products from their local
   Diagnostic tests and systems based       distributor, which forwards their
on DNA chip and ¡PCR technologies           orders electronically to the centre in
represent another focus of intensive        Mannheim within minutes. Mann-
research activity.                          heim delivers direct to customers in
   Roche is also working on the devel-      Germany, the Netherlands, Belgium,
opment of high-quality systems and          Austria, Italy, Switzerland, Scandi-
reagents for life science research,         navia, Great Britain and other coun-
specifically in the highly promising        tries within 24 hours. Spare parts,
areas of ¡sequencing, ¡proteomics           which are dispatched to all European
and gene analysis.                          countries from the DCS (Distribution
                                            Centre Spareparts) in Mannheim, can
Distribution centres. Centres which         even be delivered to any location in
employ optimised logistics processes        Europe within a few hours.

50
                                                                       Divisions


   Where direct delivery is either not     greatly expanded from 1950 on. After
cost-effective or not possible or appro-   1980 the Group started to reconcen-
priate for service-related reasons, the    trate its activities on its core areas of
national organisations restock their       competence and divested its cosmet-
warehouses from the distribution cen-      ics, instrumentation and crop pro-
tre so that they can supply customers      tection businesses. In mid-2000, the
in their country. Seventy percent of       fragrances and flavours business
all diagnostic products supplied to        (Givaudan) was spun off. In 2003 the
subsidiaries and customers worldwide       Vitamins and Fine Chemicals Division
start their journey in Mannheim. Most      was sold to the Dutch company DSM.
distribution centres are operated by       Although the relative importance of
Roche Diagnostics itself, but physical     each division to the Group’s overall
distribution is outsourced to specialist   business has varied considerably, the
service providers wherever economi-        Pharmaceuticals Division still retains
cally advantageous.                        its pre-eminent position.
   In contrast to the Diagnostics Divi-       Roche is pursuing a ground-break-
sion, the Pharmaceuticals Division has     ing strategy designed to position the
no global or regional distribution cen-    company as a clear global leader in
tres. Every Roche subsidiary has one       the healthcare market. This strategy is
or more national distribution centres,     systematically geared to medical inno-
which deliver direct to customers. In      vation. We aim to develop customised
countries with no Roche-owned sub-         solutions to medical problems for
sidiary, products are supplied direct      which no satisfactory option currently
to one or more agents. These agents        exists and thereby create added value
ensure that products are distributed       for all relevant stakeholders – patients,
to doctors, pharmacies and hospitals       doctors and healthcare systems as a
through a local distribution network.      whole.
                                              Roche is committed to giving doc-
Divisions. Independent operating           tors the tools they need for better diag-
units covering all important activities    nosis and more specific treatment by
from research and development,             providing them with a clearer under-
through production, to marketing and       standing of the molecular principles
sales. Each division is responsible for    of disease. This is the only approach
the success of its business activities.    capable of achieving a consistent
Roche has a ¡Pharmaceuticals Divi-         improvement in patients’ treatment
sion and a ¡Diagnostics Division.          options. With the aid of innovative
   Originally Roche was strictly a         diagnostic methods doctors are able to
pharmaceuticals company. Subsequent        identify patient groups with compa-
divisions started as offshoots of          rable clinical conditions with increasing
pharmaceutical operations and were         accuracy and offer these patients the

Roche from A to Z                                                                51
 DNA


benefits of specific therapeutic strate-   DNA (Deoxyribonucleic acid). The
gies.                                      double helix molecule containing the
   We concentrate our resources to-        ¡genetic information of almost all
tally on two research-intensive busi-      living cells. DNA is able to replicate
ness areas: pharmaceuticals and diag-      itself when cells divide. Its main build-
nostics. We focus particularly on those    ing blocks, and the actual carriers of
areas where needs are great and our        genetic information, are the bases ade-
expertise can be applied to beneficial     nine, guanine, cytosine and thymine,
effect: oncology, virology, diabetes,      usually referred to by their initial
inflammatory disorders, the central        letters. The sequence in which the A,
nervous system and metabolic dis-          G, C and T bases are arranged in genes
eases. We strive to be a leader in these   forms the genetic code, the set of
areas. Today Roche is the market           instructions that determines an indi-
leader in growth areas such as oncol-      vidual’s hereditary makeup by direct-
ogy, transplantation and hepatitis and     ing the production of ¡proteins. In
a global leader in molecular diagnos-      protein synthesis the instructions in a
tics, clinical laboratories and diabetes   strand of DNA are first transcribed by
monitoring.                                special polymerase ¡enzymes into a
   Research at the highest interna-        mirror-image copy known as messen-
tional level lies at the heart of our      ger ribonucleic acid (mRNA). This
strategy. In creating innovative solu-     copy is then translated by ribosomes,
tions, Roche can rely on its own           the protein factories in a cell. DNA is
state-of-the-art pharmaceutical and        not restricted to human cells (¡cell,
diagnostic research and on a globally      human); it is found in viruses and bac-
cooperating research and develop-          teria as well as in the cells of all plants
ment network. ¡Genentech in the            and animals.
USA and ¡Chugai in Japan – compa-
nies in which Roche has a majority         DNA chips. DNA microchips mak-
shareholding – work largely au-            ing it possible to perform genetic
tonomously because we believe that         and functional analyses of complete
this significantly enhances diversity      ¡genomes or to carry out other
and thus the ultimate result.              complex gene-based inquiries. These
   We expand our own research capac-       minute chips contain arrays of up to
ities through a series of scientific and   hundreds of thousands of DNA probes
commercial cooperative ventures with       (¡genetic engineering techniques).
external biotech companies, universi-      At present DNA chip technology is
ties and research institutions at home     primarily being used in biomedical
and abroad.                                research, for example in cancer re-
                                           search, and in identifying factors that
                                           cause certain patient groups to re-

52
                                                          Drug Safety Monitoring



             Information storage in the DNA of genes
          Body        Cell      Chromosome          DNA           Nucleotides



                    Nucleus




          Server         PC         Hard disk      Programme         Bits




                                                                 101101001

The aim of human genome research is to decipher the information encoded in
man’s genes (in the form of roughly three billion pairs of the nucleotide bases A,
T, C and G) and establish how defects in the storage and processing of this infor-
mation and changes in a cell’s genetic material (e. g. mutations) cause disease.



spond to particular drugs. In 1995           test for analysis of inherited genetic
Roche became the first major pharma-         variations that influence metabolism
ceutical company to enter into a first       of many widely prescribed drugs.
collaborative venture with Affymetrix,       Roche continues to explore develop-
one of the world’s largest DNA chip          ment of this technology for use in the
manufacturers, and thus was one of           differential diagnosis of cancers such
the pioneers in applying chip technol-       as leukemia and lymphoma.
ogy in therapeutics and diagnostics. In
2003 Roche ¡Molecular Diagnostics,           Drug resistance. Ability of some mi-
a business area of the ¡Diagnostics          crobial pathogens to withstand attack
Division, became the first company to        from specific ¡antimicrobials.
sign a landmark non-exclusive agree-
ment to develop Affymetrix micro-            Drug Safety Monitoring. Central unit
array technology for diagnostic use.         at Roche which systematically collects
In 2005 the company received FDA             all information on adverse drug reac-
clearance for the ¡AmpliChip CYP450          tions (also known as side effects), eval-
test, the first and only FDA-approved        uates this information on the basis of

Roche from A to Z                                                                  53
 Drug Safety Monitoring


the available data or literature reports
and submits the findings to regulatory
authorities throughout the world. This
unit provides management with infor-
mation on which to base decisions on
whether to include a particular warn-
ing in a product’s package insert or
even completely withdraw the product
from the market.
   It draws up proposals on the best
ways of informing doctors, pharma-
cists and patients so as to avoid any
possible harm.
   The tools used to monitor drug
safety include voluntary spontaneous
reporting systems (SRSs), literature
reviews, intensive hospital monitoring
and clinical ¡trials. Each has its
advantages and disadvantages, and an
accurate picture of potential and
proven side effects can be obtained
only by combining information from
all of these sources. Information ex-
change with other companies and
organisations which collect informa-
tion on drug side effects is also impor-
tant.




54
                                                                         Ecology


                                           Ecology. First coined by Ernst Haeckel
                                     E     in 1866, the term “ecology” comes
Early detection. Targeted medical in-      from the Greek and means the study of
vestigation designed to detect diseases    a system or organism in relation to its
or developmental disorders as early as     environment, with particular empha-
possible and thus prevent their occur-     sis on the interdependence of all the
rence.                                     forces and phenomena involved. In
                                           a more general sense, ecology is the
E-business (electronic business).          study of the conservation of the life-
Business activities carried out via the    supporting elements in our environ-
Internet. The term is another addition     ment, in particular the soil, water and
to the growing list of e-words, which      air, and of plant and animal habitats.
includes “e-mail” and “e-commerce”.        From this viewpoint, ecological
E-business is a product of the revolu-     knowledge and approaches are rela-
tion which the Internet and associated     tively new.
technologies (in short, the “Web”)            The world we live in is a world of
have brought about in key sectors of       substances. The air we breathe, every-
trade and commerce. By no means is it      thing we touch, eat and drink consists
confined to buying and selling. Among      of real, chemically definable sub-
other things, the Internet is also a       stances. In addition, however, man
channel for providing services to cus-     has produced numerous substances
tomers and for collaboration between       which do not occur in nature – we have
businesses. Today major companies          only to think of plastics, dyes, fibres,
are increasingly taking advantage of       lubricating and cleaning materials
the Internet – and the new culture and     and, of course, drugs. Synthetic start-
opportunities it has created – in their    ing materials are often required for the
business operations. Because of its ver-   manufacture of these products. With-
satility, availability and global reach,   out these synthetic substances today’s
companies are using the Web for pur-       civilisation would be unthinkable. In
chasing, joint promotional campaigns       this area, therefore, a return to nature
and collaboration in research, to give     has become an evolutionary impossi-
just a few examples.                       bility. But we know that man-made
   The pharmaceutical industry is not      substances can upset natural systems
allowed to sell medicines direct to con-   and it is the task of ecology to identify
sumers – not even over the Internet.       such sources of disruption and then
Roche uses the World Wide Web for          either prevent, modify or, if necessary,
purchasing, sales and marketing activ-     eliminate them.
ities and to support business-to-busi-        In technical parlance this field is
ness cooperation in all areas.             called ecotoxicology. There are two
                                           main aspects: ¡occupational hygiene,

Roche from A to Z                                                                55
 Elecsys


that is, the protection of the individual   business area of the ¡Diagnostics
at his place of work, and ¡environ-         Division. Elecsys 2010 and Modular
mental protection, that is, protection      Analytics E170 are modern, innovative
of the air, water and soil. A third         laboratory ¡immunoassay analysers
aspect, industrial safety, should also      capable of testing for a wide range
be mentioned in this context, since         of parameters including thyroid and
accidents and incidents can cause           fertility hormones, ¡tumour and
injury and harm the environment.            cardiac markers or markers of infec-
Roche adopts an integrated approach,        tious diseases and ¡osteoporosis. The
grouping ¡safety, health, environ-          underlying technology is based on
mental protection and occupational          electrochemiluminescence (ECL), i. e.
hygiene together as a single organisa-      chemiluminescence initiated by an
tion. It is a basic tenet of company        electrical voltage.
policy not to carry out any industrial
activity which has been proved to be        EMEA (European Agency for the
harmful (¡sustainability).                  Evaluation of Medicinal Products).
                                            London-based European Union agency
Elecsys. Tradename and family name          which works in cooperation with the
given to ¡analytical systems supplied       regulatory authorities of each Member
by the ¡Professional Diagnostics            State in the EU-wide drugs ¡registra-
                                            tion system established in 1995. The
                                            EMEA coordinates the scientific re-
                                            sources made available by national
                                            authorities. New drugs are registered
                                            either via a centralised procedure
                                            (biotech preparations, drugs for HIV,
                                            diabetes, cancer and neurodegenera-
                                            tive disease and optionally for other
                                            indications) that involves applying
                                            directly to the EMEA, or by a decen-
                                            tralised procedure in which an appli-
                                            cation is submitted in the Member
                                            States. If, in centralised procedures,
                                            the ¡CHMP delivers a positive opin-
                                            ion, the Commission will then issue a
                                            marketing authorisation that is valid
                                            in all member states. Once products
                                            have been authorised, the EMEA con-
Modular for clinical and immunologi-        tinues to supervise them by measures
cal tests.                                  such as inspections of manufacturing

56
                                                      Employee representation


sites and monitoring of side effects.       or group-specific counselling sessions
The EMEA also contributes to the de-        (e. g. for night-shift workers), and
velopment of European and interna-          campaigns or forums on health-
tional harmonisation, in particular         related topics (e. g. vision in the work-
within the framework of the EU-             place, travel-related health, melanoma
Japan-US tripartite International Con-      and other cancer prevention cam-
ference on Harmonisation.                   paigns). Input from experts in occupa-
                                            tional health and ergonomics can
Employee     health     service    (also    make a valuable contribution to pre-
known as the medical service).              ventive health even at the planning
Confidential contact point for all em-      phase of new construction or renova-
ployees who have questions about            tion projects. The company physio-
health problems or about protecting         therapist at Basel can improve the
themselves against health hazards in        behaviour of employees by offering
the workplace. Its services fall into       ergonomic training courses (behav-
four main categories:                       ioural prevention with training in
   Occupational healthcare services         screen ergonomics, lifting and carry-
include treatment for work-related ill-     ing, back exercises, etc.). The goal here
nesses, occupational injuries or expo-      is not only to prevent damage to health
sures to noxious agents, and preplace-      but to help promote increased well-
ment examinations to assess suitability     being at work.
for certain work assignments. If an            During the day employees have
employee is found to be unsuitable for      access to an on-site first-aid clinic. The
a particular job, the options for reha-     emergency room is used for prelimi-
bilitation, reintegration or retraining     nary treatment and triage during med-
in a different job are investigated.        ical emergencies and also for fine
Since the emphasis here is on prevent-      decontamination and treatment for
ing harm to employees’ health, work-        the effects of noxious substances. The
places undergo systematic risk analy-       company has its own ambulance (with
ses and structured health and safety        emergency doctor) and an on-call
plant inspections (audits). The aim of      medical service to deal with incidents
curative occupational medicine is to        that have injured several people. The
ensure the prompt specialist assess-        aim is to ensure that employees receive
ment and treatment of work-related          competent preclinical aid at the scene
injuries, health problems or injuries.      and to provide access to an expanded
   The preventive services available in     range of treatment facilities in the
Basel, for example, include individual      clinic.
health assessments and counselling
sessions (cardiovascular risk factors,      Employee representation. Employee
nutrition, stress, substance abuse, etc.)   representative bodies are provided for

Roche from A to Z                                                                  57
 Energy supplies


in the labour laws of a large number of     thus possible to cut consumption of
countries. In addition to informing         expensive electricity from external
and consulting with local staff associa-    grids.
tions and works councils, Roche con-           Since energy is joining raw materials,
cluded a voluntary agreement in 1996        labour and plant maintenance as an
to set up the Roche Europe Forum            increasingly important production cost
(REF), made up of representatives           factor, energy conservation measures
elected by employees at Roche compa-        have been an important topic at Roche
nies in countries of the European           for several years. Correspondingly
Union and Switzerland. The REF              ambitious energy saving targets have
includes representatives from Switzer-      been set. Efforts are being concentrated
land and Great Britain, even though         on improving utilisation of process
these countries are not covered by the      heat, for example from waste streams
relevant European Union directive.          such as condensate or cooling water.
Company representatives brief and              Secondary energy sources such as
consult the Roche Europe Forum on           steam, boiler feed water for steam
economic issues at annual meetings.         production, sanitary hot water, cool-
                                            ing water and brine for chemical
Energy supplies. All Roche plants           processes and compressed air are
require large amounts of energy for         mostly produced or reprocessed in
production, heating, ventilation, air       company plants.
conditioning and transport.
   In 2005, the Roche Group met             Environmental protection. The pre-
around 70% of its total primary en-         vention or reduction of environmen-
ergy requirement with fossil fuels and      tally harmful emissions and waste and
refuse, 28% with bought-in electricity      the conservation of raw materials and
and 2% with district steam. In the          energy (¡energy supplies). This not
fossil fuels category, natural gas ac-      only has ecological advantages but – by
counted for over 57% of fuel con-           reducing manufacturing costs – yields
sumption. The remainder was covered         economic benefits as well. At Roche
by heating oil (41%) and refuse (2%).       the overriding importance of environ-
   Electricity is needed not only for       mental protection is set down in the
production processes, but also for air      Group’s policy on safety, health and
conditioning, ventilation and lighting      environmental protection and in cor-
and to power equipment and comput-          responding directives. The consider-
ers in laboratories and offices. For this   able sums spent on environmental
reason an increasing number of sites        protection have come to be regarded
are using cogeneration plants to gener-     as normal expenditures on a par with
ate steam for heating and low-cost          labour, raw materials and utility costs.
electricity for their own needs. It is      Every new process and every new

58
                                                     Environmental protection


production facility is now optimised       to valorise by-products – in other
at the development stage with regard       words, to process potential waste ma-
to environmental protection. At Roche      terials in such a way that they can be
cost-conscious environmental protec-       used by third parties as secondary raw
tion is recognised as a success factor     materials. As it is impossible to pro-
for the future.                            duce anything without creating some
   ¡Wastewater treatment is one of         waste, methods of disposal must be
the oldest, and also one of the most       sought which do not jeopardise or un-
important and costliest, of the forms      duly impact on the environment.
of environmental protection under-         Waste products are therefore analysed,
taken by the chemical industry. By no      categorised by chemical composition
means is it the only area where the        and then treated and disposed of
industry takes its environmental           accordingly.
stewardship seriously.                        In terms of volume, the biggest
   Gaseous emissions from production       problem is posed by contaminated
facilities and boiler rooms at Roche       organic solvents originating for the
sites are treated using advanced emis-     most part from the manufacture of
sion control technologies (¡air pollu-     active pharmaceutical ingredients.
tion, control of). Noise emissions are     Owing to high quality requirements
monitored periodically around site         for these end-products, it is often im-
perimeters and corrective action taken     possible to reprocess solvents, which
should noise levels ever become a nui-     then have to be incinerated in an envi-
sance to nearby residents.                 ronmentally compatible way in Group-
   Every biotechnological, chemical or     owned or external facilities. In dispos-
pharmaceutical production process          ing of waste, Roche opts wherever
generates unusable by-products, and        possible for thermal destruction
at times they can pose special prob-       rather than dumping in landfill sites.
lems. Roche’s waste control policy is      Thermal destruction not only makes it
based on the following sequence of         possible to utilise the calorific value of
priorities: “avoidance – reduction –       wastes for generating energy but
recycling – environmentally responsi-      produces mineral residues with no
ble disposal”. Waste is thus not a prob-   adverse environmental impact.
lem that gets set aside until production      Until a few years ago environmental
is done; on the contrary, processes are    protection was still a secondary activ-
designed to keep waste arisings and        ity of a few individuals. Today, by
hazardous by-products to a minimum.        contrast, production facilities can call
¡Recycling, that is, the reprocessing      upon the services of on-site specialist
and reuse of waste, and particularly of    departments to cope with the vast
waste solvents, is of great importance.    number of tasks and problems in this
Moreover, Roche also makes an effort       area. Nevertheless, it is important to

Roche from A to Z                                                                 59
 Environmental risk assessment


bear in mind that environmental pro-         biotechnological applications. One
tection begins at the individual work-       very important example is the heat-
place: everyone can, and must, help.         stable Taq polymerase enzyme from
   Precautionary environmental pro-          Thermus aquaticus, a bacterium found
tection is also promoted by the collec-      in hot springs in the Yellowstone
tion of experimental data on the fate        National Park. Thanks to its special
and effects of substances in the envi-       properties, this enzyme has played a
ronment. The results are made avail-         pivotal role in automating the ¡PCR
able to the users of intermediates and       method.
end products in the form of ¡safety             Enzymes are also implicated in dis-
data sheets or incorporated in ¡envi-        ease. Many pathogenic situations are
ronmental risk assessments. These            at least partly due to defects in the reg-
information tools form the basis for a       ulation of enzyme activity. In such
targeted approach based specifically         cases excess enzyme activity can be
on appropriate safety measures               inhibited by drug treatment. Some
(¡ecology, ¡safety).                         bacterial enzymes are the sites of
                                             action of antibiotics, and most anti-
Environmental      risk    assessment.       viral agents act on virus-specific en-
Since the possible environmental risks       zymes, for example reverse transcrip-
associated with drugs have to be             tase and a special protease in the case
assessed during the ¡registration pro-       of the ¡AIDS virus HIV. The in-
cedure, both the EU and the USA have         fluenza medicine ¡Tamiflu inhibits
introduced appropriate regulations.          the viral enzyme neuraminidase.
Accordingly the degradability and en-
vironmental fate of new products are         Epidemiology. The study of the distri-
estimated and the results compared           bution and determinants of disease
with any toxic effects on organisms          frequency in human populations (in
in the environment (primarily algae,         specific geographical areas, popula-
water fleas and fish). Roche has been        tion groups or periods).
producing environmental risk assess-
ments for over 10 years, not only for        Erythropoietin. Hormone secreted by
drugs but also for its production oper-      the kidney which controls the produc-
ations and intermediates.                    tion of red ¡blood cells (erythro-
                                             cytes). Abbreviated to EPO or ESA
Enzymes. Proteins which act as bio-          (erythropoietin-stimulating agent). If
catalysts in living ¡cells, initiating and   too little erythropoietin is produced,
accelerating a wide variety of reac-         severe ¡anemia results. The successful
tions, including metabolic processes.        deciphering of EPO’s genetic code
Enzymes, often bound to solid carrier        opened the way for biotechnological
materials, are used in numerous              production. Recombinant EPO, or

60
                                           Escherichia coli


epoetin beta (tradename ¡NeoRecor-
mon, Epogin), has been used since the
early 1990s to successfully treat ane-
mia in patients with chronic ¡kidney
disease, premature infants and pa-
tients with certain types of cancer. New
erythropoietin-stimulating agents are
in development for treating renal
and cancer-related anemia, including
Mircera, the first continuous erythro-
poietin receptor activator (¡C.E.R.A.).

Escherichia coli. Abbreviation: E.
coli. Non-pathogenic intestinal bacte-
ria in humans. Laboratory strains of
these bacteria are used to produce re-
combinant ¡proteins. The most com-
monly used strain is K12, which is
unable to survive in the human gut as
a result of various defects, and can
only grow under controlled laboratory
and production conditions.




Roche from A to Z                                         61
 FDA


                                      F
FDA. Abbreviated name of the Food
and Drug Administration, the US drug
regulatory authority responsible for
promoting and protecting public
health by helping safe and effective
products reach the market in a timely
way, monitoring products for contin-
ued safety after they are in use, and       Inside look at the coating process:
helping the public obtain the accurate,     an ultrathin coating is sprayed onto
science-based information needed to         tablets as they are kept continually
improve health.                             in motion in a coating pan.

Fluoro-uracil Roche. A pioneering           Formulation. Science of preparing
treatment for cancer launched by            drugs in appropriate dosage forms.
Roche in 1962 which has become a            Correct formulation is essential for
standard treatment in breast, bowel,        efficacy and the prevention of adverse
pancreatic and several other kinds of       reactions. It also affects the shelf-life
cancer. The active ingredient, 5-fluo-      of drugs. The term “bioavailability” is
rouracil, works by mimicking one of         used to designate the total effect of
the building blocks of ¡DNA and             dosage form, active ingredient and
thereby disrupting DNA duplication,         excipients on the absorption and fate
preventing cells from dividing. It can      of the drug in the body (¡generics,
therefore stop the growth of rapidly        ¡counterfeit drugs).
dividing cancers, though it also leads
to the death of normal cells that are       Foundations, scientific. As a research-
actively dividing, including cells of the   based company, Roche has always
gastrointestinal tract, hair follicles,     fostered close links with universities
mucous membranes and others. This           and institutes that conduct ¡basic
can lead to unpleasant side effects. A      research. The Roche Study Foundation
major advance came thirty years after       was established in 1924 to enable
the drug was launched with Roche’s          young scientists to participate in
development of ¡Xeloda, which is not        scientific research projects. On the
converted to 5-fluorouracil until it is     company’s 40th anniversary (1936)
inside tumours. This greatly reduces        the Emil Barell Foundation (¡Barell)
side effects elsewhere in the body          was set up to provide start-up support
(¡oncology).                                and interim funding for biomedical
                                            research. In 1947, following the com-
                                            pany’s golden jubilee, the Fritz Hoff-

62
                                                                          Fuzeon


mann-La Roche Foundation was inau-         of exploration in the area of anemia.
gurated to promote an interdiscipli-       It is legally independent of Roche and
nary approach to scientific and med-       managed by an international Board of
ical problems (¡Hoffmann-La Roche,         Trustees.
Fritz). The 75th anniversary (1971)
saw the establishment of the Roche         Fuzeon. Product which was developed
Foundation for Scientific Exchange         in collaboration with Trimeris Inc., is
and Biomedical Collaboration with          the first of a new class of highly inno-
Switzerland. This organisation pro-        vative anti-HIV drugs known as ‘‘fu-
vides support for Swiss universities by    sion inhibitors’’. It is unique because it
encouraging exchange of experience         is the only anti-HIV drug that actually
with outstanding foreign scientists.       works outside the cell, protecting it
In 1983 the four foundations were          from being infected, whereas all other
merged, while retaining their original     anti-HIV drugs work only after the
aims, to form the Roche Research           cells have been infected. Fuzeon is ad-
Foundation. In 1999 the Roche              ministered by subcutaneous injection
Research Foundation extended its           twice daily, and is indicated for use
support to the research in biology,        in patients who have already received
chemistry and medicine. The primary        other anti-HIV therapy. Fuzeon brings
area of chemistry had hitherto formed      new hope to patients with resistant
part of the “Stipendienfonds der Basler    HIV strains by increasing their
Chemischen Industrie”.                     chances of achieving undetectable viral
   The Roche Organ Transplantation         load – the optimal treatment goal for
Research Foundation (ROTRF) was set        all people living with HIV (¡AIDS,
up in 1998 as a legally independent,       ¡antimicrobials, ¡Prix Galien).
non-profit organisation. Its aim is to
promote research in ¡organ trans-
plantation and thereby further im-
prove treatment outcomes for people
receiving organ transplants. The foun-
dation particularly supports the ad-
vancement of research in those areas
of transplant medicine where there are
still unmet medical needs. The Roche
Foundation for Anemia Research
(ROFAR), a new type of research foun-
dation with an international scope and
a specific therapeutic focus, was set up
in 2004 to stimulate innovative re-
search that will open up new avenues

Roche from A to Z                                                                 63
 Gene


                                             presence of specific ¡genes within a
                                     G       cell sample. They act like “screening
Gene. Unit of ¡genetic information.          antennae”, each of which is designed to
A gene is a segment of ¡DNA that             detect a highly specific gene. An unam-
carries instructions for making a            biguous reaction occurs if one of the
strand of messenger ribonucleic acid,        screened genes is present in the ap-
and hence is the blueprint for a specific    plied sample. Gene chips have become
¡protein. An organism’s complete             an indispensable tool for the detection
gene complement, which contains all          of specific infections (¡AmpliChip
its genetic information, is called the       CYP450 test).
¡genome.
                                             Gene segment. Functional ¡DNA
Gene chip. Gene chips are fingernail-        segment of a ¡gene.
sized slices of glass arrayed with up to
a million ¡DNA sections. Gene chips          Genentech, Inc. Leading biotechnol-
are used to unambiguously verify the         ogy company engaged in the discovery,



      Genes are blueprints for protein synthesis
                         Messenger RNA is read by a ribosome
     Cell nucleus                                              Amino acids
                                                       (building blocks of proteins)
                   Messenger RNA
                 Working copy of a gene

                                                                   Ribosome
                                          Enzyme                   (protein factory)
          Chromosomal
              DNA
                                          RNA poly-
                                          merase               Amino acid chain


                                                                      Folded protein
                                                                           (active)




An activated gene on a chromosome in the cell nucleus serves as a template for a
strand of messenger RNA (mRNA). This “working copy” of the gene passes out of
the nucleus to a ribosome, which uses the mRNA as a blueprint for synthesising
the protein coded for by the gene. As the chain of amino acids grows, it folds into
a characteristic shape to form a biologically active protein.

64
                                                               Generic names


production and marketing of bio-          countries in Europe, the Far East and
therapeutic products. Headquartered       Latin America (¡oncology). In the
in South San Francisco, California        United States, Genentech markets
(United States), Genentech employs        seven other products for diseases such
around 10,000 people. In 1990 Roche       as ¡cystic fibrosis, growth hormone
acquired 60 percent of Genentech’s        deficiency, myocardial infarction and
shares and the right to purchase the      stroke.
remaining shares at a later date. Roche
exercised this option in 1999. After      Generic names. Designations as-
several subsequent public offerings of    signed to chemical compounds. In
Genentech stock, Roche now holds          science chemical compounds are rep-
roughly a 56 percent stake in the com-    resented schematically by their struc-
pany. The company operates inde-          tural formulas and in writing by their
pendently and is listed on the New        full chemical names. Both types of
York Stock Exchange under the ticker      description are unsuitable for daily
symbol DNA. The Roche Group is rep-       use because of the need to draw the
resented on the Genentech board by        formulas and because the length and
three directors.                          complexity of the chemical names
   Genentech was a pioneer of modern      make them unpronounceable and dif-
¡biotechnology. In 1977 the company       ficult to remember. For this reason
synthesised the first recombinant         shortened generic names have always
human protein in a microorganism          been given to chemical compounds.
and played a key role in the production      With this practice a need to system-
of recombinant human insulin, the         atise these names and give them an
world’s first genetically engineered      official status emerged. Various coun-
drug, which was launched in 1982.         tries have an official body which
Genentech’s most important products       assigns and publishes generic names.
include the top-selling cancer drugs      These are then known as International
¡Avastin, Rituxan and ¡Herceptin.         Nonproprietary Names (INNs). The
Rituxan – for the treatment of non-       international use of generic names is
Hodgkin’s lymphoma – was developed        governed by the World Health Organi-
by Idec Pharmaceuticals, Genentech        zation (¡WHO). The first step is to
and Roche and launched in late            publish the proposed generic names. If
1997. The product is marketed as          no objection is received within four
¡MabThera outside the United States       months, they are given the official sta-
and Japan. Herceptin, the first mono-     tus of recommended INNs. In Great
clonal ¡antibody for the treatment of     Britain generic names of active phar-
metastatic breast cancer, was approved    maceutical ingredients are termed
by the ¡FDA in 1998 and has since         British Approved Names (BANs), and
been launched by Roche in additional      in the United States US Adopted

Roche from A to Z                                                              65
 Generics


Names (USANs). The distinction be-           tested formulation of active ingredient
tween generic name and trademark is          and excipients, there is no cast-iron
an extremely important one. Generic          guarantee that a generic copy will be
names refer to the active ingredient         equally effective, even though it con-
of a branded pharmaceutical product          tains the same dosage of the same
only and not to the product itself. A        active ingredient as the original. The
branded pharmaceutical is a ready-to-        generic is then said to have a different
use, precisely measured and defined          bioavailability (¡analysis).
dosage form containing numerous                 It is therefore possible for original
other substances (such as carriers, sta-     and generic to display differences in
bilisers and coatings) in addition to        quality even though their chemical
the active ingredient. The product is        composition is identical. Such differ-
identified by its trademark. Trademark       ences may be significant for the pa-
and generic name must never be used          tient. Optimal crystal shape or size and
synonymously.                                fine details of product ¡formulation
                                             can give the original an earlier or more
Generics. Term applied to “copies” of        constant onset of action, better bio-
brandname ¡pharmaceuticals. After            availability or longer action. In addi-
the ¡patent on a brandname drug has          tion, the manufacturer of the original
expired, other pharmaceutical compa-         product conducts international drug
nies can start to copy it using the          surveillance, often over a period of
extensive documentation filed with           decades, for the purpose of document-
the authorities by the original discov-      ing side effects and interactions with
erer and manufacturer. If the chemical       other drugs and providing warnings or
and pharmaceutical quality of the            information to doctors, if necessary in
generic is identical to that of the origi-   conjunction with the health authori-
nal product, the authorities will grant      ties.
marketing authorisation without de-             In many countries the health au-
manding clinical ¡trials to ascertain        thorities encourage generics for eco-
its side effects profile and efficacy.       nomic reasons because they provide
   This means that generic manufac-          short-term relief for healthcare bud-
turers, which are mostly specialised         gets. Generics make no contribution
companies geared to the needs of their       to medical progress, however.
domestic markets, have virtually no
research and development costs and           Genetic engineering. A set of tech-
can sell their products at considerably      niques for the isolation, characterisa-
lower prices than the original manu-         tion, specific alteration and transfer
facturer.                                    of genetic material. Every living cell
   However, since a branded pharma-          contains coded instructions for the
ceutical is a balanced, thoroughly           synthesis of thousands of ¡proteins

66
                                                          Genetic engineering


that enable the cell, and the whole        able when a substance is produced
organism, to perform its biological        only in minute quantities in the origi-
functions. The chemical substance          nal cell and can thus be obtained only
deoxyribonucleic acid (¡DNA) is the        by a complicated process, in insuffi-
carrier of these instructions, the ge-     cient amounts and in a highly impure
netic code. The ¡chromosomes are           form. Another important feature of
the biological structures that contain     this production method is safety.
DNA. Each ¡gene, or unit of inheri-        While protein concentrates isolated
tance, corresponds to a section of DNA     from human tissue can harbour path-
and contains the instructions for syn-     ogenic contaminants (e. g. HIV or
thesising a particular protein.            hepatitis viruses), this is not the case
   1973 is regarded as the year in which   with genetically engineered products.
genetic engineering was born. It was          One example of a genetically engi-
then that two Americans, Herbert           neered product from Roche is human
Boyer and Stanley Cohen, first suc-        ¡interferon alfa (¡Roferon-A), a pro-
ceeded in transferring functional ge-      tein that inhibits the spread of viruses
netic information for synthesis of a       in the body as part of the natural
foreign protein to E. coli bacteria.       immune response to viral infection.
Since then molecular biology tech-         In 1980 recombinant techniques made
niques have been developed that allow      it possible to produce large quantities
the isolation, analysis or de novo syn-    of interferon in pure form. Before the
thesis of individual genes from a          advent of genetic engineering, years
¡virus or organism and their transfer      of work had failed to yield sufficient
to microorganisms such as ¡bacteria        material even to completely clarify its
or mammalian cells (¡genetic engi-         chemical structure.
neering techniques). The foreign gene,        Genetic engineering techniques
which contains the instructions for        are an important and integral part
synthesising a particular protein, can     of Roche’s biomedical research as a
be read and expressed (activated) in       whole, in which biochemical, chemi-
the host cell only if “control regions”    cal, physicochemical, cell-biological,
guide the reading process in the host      immunological, microbiological and
cell. Only if the foreign gene is stable   genetic engineering techniques all
and active can the “genetically engi-      complement each other.
neered”, or recombinant, host cell be         Roche’s interest in genetic engineer-
used.                                      ing is focused on the medical use of
   In this way biologically useful sub-    recombinant substances in diagnosis
stances of human or animal origin can      and treatment.
be produced in large quantities in            The diverse portfolio of genetically
biotechnological processes. This pro-      engineered pharmaceutical and diag-
duction technique is especially valu-      nostics products comprises more than

Roche from A to Z                                                               67
 Genetic engineering techniques


10 recombinant biopharmaceuticals          – Site-directed mutagenesis: intro-
(MabThera/Rituxan, NeoRecormon,               duction of point mutations (alter-
Herceptin, Pegasys, Avastin, Nutropin,        ation of individual nucleotide
Pulmozyme, Neutrogin, Activase,               building-blocks) at a particular site
Xolair, Zenapax, Raptiva and Rofe-            in a DNA molecule that has under-
ron-A) and numerous diagnostic tests          gone in vitro manipulation.
incorporating genetically engineered       – Gene disruption: targeted inacti-
substances or based on techniques             vation of a single ¡gene in a micro-
such as ¡PCR or chip technology.              organism.
                                           – Sequencing: determination of the
Genetic    engineering     techniques.        order in which the nucleotide bases
Genetic engineering currently em-             are arranged in a DNA molecule
ploys the following techniques:               and decoding of the genetic infor-
– Transformation: incorporation of            mation contained therein (amino
  a natural ¡DNA molecule, or one             acid sequence of the corresponding
  produced ¡in vitro using recom-             proteins or structure of control
  binant methods, into a host cell so         regions).
  that the DNA molecule is passed on       – PCR technique (¡polymerase chain
  to the host’s offspring. The follow-        reaction): biochemical replication
  ing cells and organisms can now             of any isolated DNA segment; an
  be transformed: numerous species            important technique in biomedical
  of bacteria, yeasts, cell cultures of       ¡basic research, pharmaceuticals
  plant, animal or human origin, fruit        research and ¡in vitro diagnosis.
  flies, mice and certain plant species.   – DNA probe: a technique by which
  Higher animals and plants that              complementary DNA strands or
  have undergone transformation are           ¡RNA molecules are “fished out” of
  said to be transgenic. The transfor-        a cell extract or made visible using
  mation of human embryos is ille-            short pieces of single-stranded
  gal.                                        DNA; also known as hybridisation.
– Expression: When a ¡gene is ex-             The extracorporeal fertilisation of
  pressed, the ¡DNA is used as a           human or animal ova (in vitro fertili-
  template for the transcription of a      sation), the transfer of embryos and
  complementary strand of ¡mRNA            the breeding of chimeras (crossing
  (messenger RNA) which is trans-          of different animal species) are not
  lated into a ¡protein. Control           genetic engineering techniques, as
  sequences direct the expression of       they do not alter the DNA.
  genes at specific times and in spe-
  cific cell types of our body or in a     Genetic information. Originally a
  recombinant cell used for produc-        vague term to explain the transmission
  tion of proteins.                        of inherited traits. Today genetic infor-

68
                                                     GlycArt Biotechnology AG


mation is known to be stored in the         is formed from the breakdown of food
¡DNA in an individual’s chromo-             in the digestive tract and transported
somes. The information stored di-           to cells via the circulation. The con-
rectly in DNA specifies the structure       centration of glucose in the blood
of all the ¡proteins an individual          – the blood sugar level – can be meas-
produces along with instructions on         ured with ¡test strips and blood
where and when protein synthesis will       glucose monitoring systems (¡glu-
take place. The interplay between this      cose self-monitoring).
information and a person’s cellular
machinery supplies a genetic pro-           Glucose self-monitoring. Measure-
gramme controlling embryonal devel-         ment of ¡glucose in the blood by dia-
opment, the processes of life and,          betic patients, with the aim of achiev-
possibly, death.                            ing optimal control of blood glucose
                                            levels. The glucose level is usually
Genetics. Study of the mechanisms           measured with the aid of handy, un-
of inheritance. Classical genetics inves-   obtrusive blood glucose meters and
tigates the laws governing the inheri-      corresponding ¡test strips. A tiny
tance of traits over generations, par-      drop of blood, e. g. taken from the fin-
ticularly in higher organisms. The          gertip, is applied to a test strip, and the
underlying mechanism is the inheri-         meter very soon displays the precise
tance of ¡genes from parent to off-         blood glucose level. In special training
spring. Originally discovered by the        courses, and with the aid of helpful
monk Gregor Mendel in the 19th cen-         data management systems, patients
tury, genes are now known to be ¡DNA        learn how to draw the correct conclu-
molecules. Molecular genetics studies       sions from the readings and thus
the basic laws of inheritance at the mo-    achieve the best possible control of
lecular level (¡protein, ¡genome).          their blood glucose levels. Poor control
                                            can, in the long term, lead to serious
Genome. The complete set of ¡genes          health problems, e.g. blindness, kidney
of an organism, such as a ¡virus.           damage, vascular disorders and ampu-
The human genome is contained in            tations.
23 pairs of ¡chromosomes (see dia-
gramme on page 70).                         GlycArt Biotechnology AG. Biotech-
                                            nology company engaged in the dis-
Genomics. Study of the structure and        covery of biotherapeutic products.
function of the ¡genome and all             Based in Schlieren (Zurich, Switzer-
¡genes.                                     land), GlycArt employs about 40
                                            people. The company was founded in
Glucose. A simple sugar that is the         2000 as a spin-off from the Swiss Fed-
body’s main source of energy. Glucose       eral Institute of Technology (ETH) in

Roche from A to Z                                                                   69
 GlycArt Biotechnology AG


                       Comparison of viral, bacterial
                          and human genomes
                                                      All hereditary information
                                                      (genome) stored on chromosomes
                                                      in cell nucleus

                               Genome
              Viral envelope                Plasmid

              Hereditary
              information



      Virus                    Bacterium               Human cell
      The genome of            The genome of            The genome of
      a virus consists         a bacterium              a human cell
      of approx.               consists of approx.      consists of approx.
      1,000 base pairs         1,000,000 base pairs     3,000,000,000 base pairs




      Equivalent to            Equivalent to                Equivalent to
      one page                 one 1,000-page book          3,000 books
      with 20 lines of text                                 of 1,000 pages each



Viral, bacterial and human cells contain different amounts of genetic informa-
tion, which is deciphered by genomic research.



Zurich and raised about USD 16 mil-             cellular cytotoxicity). In 2004 Roche
lion from an investment syndicate.              and GlycArt entered into a license
GlycoMAb is the company’s propri-               option agreement to develop next-
etary technology for improving the              generation antibodies for one of
specific biological activity of thera-          Roche’s product candidates. In July
peutic monoclonal ¡antibodies for               2005 Roche acquired 100% of the
target cell ablation. GlycoMAb is based         company. GlycArt remains an inde-
on an active modulation of antibody             pendent research site, but works
glycosylation during production, which          closely with Roche’s Therapeutic
results in antibody products with               Protein Initiative in ¡Penzberg
increased ADCC (antibody-dependent              (Germany), bringing its GlycoMAb

70
                                     Good clinical practice regulations (GCP)


technology as well as its capabilities       adverse drug events, recording of data
in antibody humanisation, expression         and archiving of documentation. The
and screening to the Roche Group.            GCP regulations also define the qual-
GlycArt’s most advanced products             ity standards the trial medication
(called GA101 and GA201) are mono-           must meet and what ¡quality control
clonal antibodies with enhanced              (monitoring) and ¡quality assurance
ADCC in preclinical development              measures (audits and inspections) the
for cancer. The company has a num-           sponsor must take in order to ensure
ber of other research programmes             that the trial data are accurate and that
(¡research; ¡Pharmaceuticals Divi-           the investigating physicians and com-
sion).                                       pany employees observe all statutory
                                             and ethical requirements.
Good clinical practice regulations              The principles of GCP are based
(GCP). The standards that govern the         on the Nuremberg Code (which es-
planning, conduct and reporting of           tablished strict ethical standards for
clinical ¡trials; designed to ensure         research on human subjects and was
that the rights (e. g. patient briefing,     drawn up following the Nuremberg
liability in the event of a claim, data      war crimes tribunal) and its successor,
protection) and safety of patients and       the Declaration of Helsinki. The Euro-
volunteers (healthy, willing test sub-       pean Union’s GCP directive came into
jects) are protected and reliable data       force in July 1991. The World Health
are collected.                               Organization (¡WHO) has published
   GCP regulations set out the rights of     similar guidelines, and many coun-
volunteers and patients, the rights and      tries, including Switzerland, have
duties of ethics committees and the          made GCP part of their national regu-
duties of investigating physicians and       lations on clinical ¡trials. The ICH-
of pharmaceutical companies spon-            GCP guidelines, agreed in 1996 by the
soring trials. In particular, they deter-    US, Japanese and EU health authori-
mine the information that must be            ties, represent the culmination of ef-
contained in patient informed consent        forts to harmonise differing national
documentation and specify how inves-         requirements (ICH stands for Interna-
tigating physicians must go about            tional Conference on Harmonisation
obtaining consent from patients or           of Technical Requirements for Regis-
healthy volunteers who are to take part      tration of Pharmaceuticals for Human
in a clinical trial. They also contain       Use). Compliance with these guide-
detailed provisions on the duties of         lines in clinical research has since been
investigators and sponsors concerning        declared mandatory by the health
the formulation of trial protocols and       authorities in other countries, such as
compliance with the regulations that         Australia and Canada.
apply to clinical trials, the reporting of

Roche from A to Z                                                                  71
 Good laboratory practice regulations (GLP)


Good laboratory practice regula-             (SOPs), the experimental sequence of
tions (GLP). Internationally recog-          the test, the test report and the archiv-
nised guidelines for a quality assur-        ing and storage of all resulting data
ance system concerned with the               and materials.
organisational process and general              The GLP guidelines are legally bind-
conditions governing the performance         ing in all countries of the European
of certain experiments in the labora-        Union (since 1990), Switzerland (since
tory. The GLP guidelines rule on the         1986), the United States (since 1979)
planning, performance, monitoring,           and Japan (since 1982). In other
recording, archiving and reporting of        words, the above-mentioned non-
these tests (¡trial, experimental), so       clinical safety tests must be performed
that such tests can be fully reproduced      in accordance with GLP, otherwise the
at any time.                                 tests are not recognised and therefore
    The GLP principles apply to the          rejected in the corresponding licensing/
non-clinical safety testing of “test sys-    ¡registration procedures.
tems” (chemicals, biological products,          The above-mentioned legislation
e. g. proteins, living organisms) that       also requires all institutes/laboratories
are contained in drugs, pesticides and       performing GLP tests to undergo
biocides, veterinary drugs, cosmetics,       inspection at regular intervals (every 2
food additives and industrial chemi-         years in Switzerland) by officials of the
cals. The purpose of these safety tests is   respective country in order to check
to obtain data on the properties, toxic-     compliance with the GLP guidelines.
ity (¡toxicology) and safety of the test     Such inspections may be completed
systems for human health and the en-         within a day, or can last as long as three
vironment. Thus, before a pharmaceu-         weeks. Bilateral international agree-
tical preparation intended for use in        ments regulate the mutual recognition
humans or animals can enter clinical         of the GLP guidelines between indi-
trials, it must undergo extensive test-      vidual countries. In practice this
ing in animal experiments (¡in vivo          means, for instance, that GLP tests
tests) or the test-tube (¡in vitro tests).   conducted in the GLP facility at Roche
    The GLP guidelines lay down stan-        Basel are accepted in licensing proce-
dards concerning the tasks and qualifi-      dures in the United States, Japan and
cations of all the personnel in an insti-    the European Union, since the relevant
tute/laboratory, the quality assurance       Swiss authority, Swissmedic, has rated
programme (¡quality assurance), the          this facility as “fully complying with
premises, the equipment, materials           the GLP guidelines”.
and reagents used, the experimental
animals, the handling, storage and           Good manufacturing practice regu-
characterisation of the test systems,        lations (GMP). Regulatory standards
the standard operating procedures            for pharmaceutical manufacturing.

72
                                                                             Graz


Comprehensive monitoring of manu-           pathogens. Basophils and eosinophils
facturing processes is vital in the phar-   combat parasites but are also involved
maceutical industry in order to ensure      in allergic reactions and inflamma-
that the consumer receives high-qual-       tion. A lack of neutrophils, as can
ity medicines. As a company is respon-      occur after chemotherapy for cancer,
sible for the products it manufactures,     can lead to life-threatening infection.
not a single step in the process can
be left to chance. The guidelines issued    Graz. The only development and pro-
by the World Health Organization            duction centre in the world for blood
(¡WHO) concerning the manufac-              gas and electrolyte analytical systems
ture and quality control of drugs are       distributed by the ¡Diagnostics Divi-
now recognised as the “state of the art”    sion. This Austrian location further
by over 40 countries. The European          enhances research, development and
Commission began the phased intro-          production capacity for near-patient
duction of GMP in 1989. Today it            diagnosis. These analytical systems are
provides a binding directive that es-       used for measuring vital parameters
tablishes a uniform standard in all         from whole blood, not in a central lab-
member states. These regulations have       oratory but rather in the immediate
also been fully incorporated in Swiss       vicinity of the patient – for example in
legislation since 2002. In addition to      the operating theatre, emergency out-
qualified personnel, suitable rooms         patient department, intensive care
and equipment, the GMP regulations          unit, or even at the site of an accident.
specify a quality management system         The systems produced in Graz are dis-
that covers everything from the in-         tributed worldwide. By investing in
spection and storage of raw materials       this site, Roche has played a trailblaz-
to the actual production process (phar-     ing role in establishing the healthcare
maceutical formulation and packag-          cluster (Human.technology Styria
ing), production hygiene, analysis and      GmbH) in the Graz region. The com-
release, distribution records and com-      pany works closely with the univer-
plaints procedures. Similar guidelines      sities and hospitals in Graz. Around
exist for the manufacture of active         300 people work at the Graz site.
pharmaceutical ingredients.                    The new building with its futuristic
                                            architecture was designed by the Graz-
Granulocytes. Cells of the innate,          based architect Ernst Giselbrecht.
non-specific immune system. Like the        With its V-shape, the building not only
¡lymphocytes, they are a type of            stands out for its design, it also makes
white ¡blood cell. By far the most im-      the best use of the 20,000 square metre
portant subgroup of granulocytes are        site. This building is also at the cut-
the neutrophils, or neutrophilic leuko-     ting-edge in terms of ecoefficiency
cytes, which mainly destroy bacterial       with its innovative, environmentally

Roche from A to Z                                                                 73
 Grenzach-Wyhlen


compatible infrastructure – in con-            Roche Pharma AG employs around
trast with traditional buildings, the       1,000 people in Grenzach-Wyhlen.
concrete ceilings and walls, for ex-        They are responsible for the marketing
ample, are used to heat and cool the        and distribution of prescription medi-
internal rooms – and the energy-sav-        cines for the whole German market.
ing sun protection system capable of        Clinical ¡trials required for market-
generating a cushion of heat around         ing authorisation are also coordinated
the outer shell of the building. With its   from Grenzach. Depending on the in-
impressively clean lines, the company       dication, these trials are conducted in
building sets design standards that         conjunction with renowned university
will probably serve as a benchmark for      hospitals and selected suitably quali-
the subsequent development of the           fied medical practices across Germany.
Graz West Technology Park (¡ecology,        In Europe, Roche Pharma AG is the
¡architecture).                             Roche Group leader in terms of phar-
                                            maceutical sales.
Grenzach-Wyhlen.        A municipality
in the state of Baden-Württemberg           Group. A combination of companies
(Germany). Situated on the ¡Rhine,          that are legally independent but have a
it borders on Switzerland, immediately      common commercial goal. The Roche
east of Basel. Fritz ¡Hoffmann-La           Group incorporates all those compa-
Roche opened a production facility          nies that are wholly owned by Roche
in Grenzach in 1897, not long after         Holding Ltd, Basel, or in which it has a
operations had commenced in Basel,          majority interest. Group management
because the German state granted only       is based in Basel (¡share capital).
a limited period of patent protection
for imported products. Since then the       Guggenheim, Markus (1885–1970).
plants in Grenzach and Basel have           Dr Markus Guggenheim joined Roche
developed in parallel, although pro-        in 1910 but initially continued work-
duction facilities in Basel have increas-   ing in the laboratories of the Basel City
ingly had to compete for space with         Hospital, too. He was an outstanding
research and administration. Today,         representative of the then young sci-
from its headquarters in Grenzach-          ence of biochemistry. His scientific
Wyhlen, Roche Deutschland Holding           work covered an exceptionally broad
GmbH coordinates the operations of          range and was still bearing fruit
Roche in Germany. Employing over            decades later. The substance levodopa
10,000 employees at its sites in            (¡antiparkinsonian agents), whose
Grenzach-Wyhlen, ¡Mannheim and              l-dopamine structure had been eluci-
¡Penzberg, the company is one of            dated by Guggenheim before World
Roche’s most important national             War I, was first used to treat patients in
organisations worldwide.                    the 1960s. His work also laid the foun-

74
                                         Guggenheim, Markus


dation for subsequent research into
vitamins. In 1916 Guggenheim was
blinded by an explosion in his labora-
tory in ¡Grenzach. In spite of this he
remained head of research at Roche
and in 1920 published a standard work
on biogenic amines. He also created
a classification system for scientific
information that many years later was
adopted almost unchanged for use
with electronic data processing sys-
tems.




Roche from A to Z                                         75
 Health


                                            Monitoring the course of the illness
                                     H      with diagnostic tests (¡Diagnostics
Health. According to the World              Division) will enable the treatment
Health Organization (¡WHO), the             be tailored to the individual needs
“state of complete physical, mental         of the patient in order to ensure an
and social well-being”. So simply           improved quality of life (¡Pharma-
defining health in terms of the absence     ceuticals Division).
of illness and ailments is incomplete.
The UN’s Universal Declaration of           Health protection. The totality of
Human Rights states that health is a        measures designed to prevent employ-
basic right. According to the WHO,          ees being harmed by chemical, physi-
health promotion refers to those            cal, ergonomic, biological, psychologi-
measures designed to modify and pro-        cal or other adverse influences at work.
mote individual behaviour and living        Together with ¡safety and ¡environ-
conditions in a positive sense. Health-     mental protection, health protection
care includes all those public and pri-     is accorded equal priority with issues
vate institutions involved in preventive    of quality, productivity and cost effi-
healthcare and disease management.          ciency.
   The prevention, diagnosis and               New installations and workplaces
treatment of disease are closely inter-     are planned so as to satisfy all the
linked, and the links will be made even     requirements of modern health pro-
closer through solutions that target the    tection. In other words, employees are
medical needs of individual patients.       protected as much as possible from
Roche creates innovative, individual        noise, pollutants, infectious pathogens,
solutions for hitherto unmet medical        overexertion resulting from the lifting
needs (¡Divisions, ¡medicine, per-          and carrying of loads, etc. through
sonalised).                                 technical measures, for example en-
   Intensive ¡research activities en-       closed and mechanised production
able Roche to identify the causes of ill-   systems. Existing workplaces are sub-
ness and establish individual ¡pre-         jected to regular risk analyses. Any
dispositions. Targeted ¡screening tests     identified deficiencies are prioritised
can then be used to discover in good        and rectified according to a clearly
time whether a particular predisposi-       defined timetable.
tion might lead to an illness. This            ¡Occupational hygiene and the
knowledge will then clear the way for       medical service (occupational medi-
preventive medical measures.                cine, ¡employee health service) play
   If the illness has already manifested    an important role in health-related
itself, however, quick and accurate         risk analyses in the workplace. Occu-
diagnosis will provide the ideal basis      pational toxicology assesses the haz-
for state-of-the-art medical treatment.     ards associated with chemicals in the

76
                                                                        Herceptin


workplace. The results of these assess-     that drugs are available to treat the dis-
ments form the basis for substance          ease. The first ¡interferon, introduced
handling procedures. ¡Biosafety is          by Roche in 1989, was ¡Roferon-A.
concerned with questions of biological          The availability of Pegasys, used in
safety.                                     combination with Copegus (ribavirin),
   Occupational medical examina-            has dramatically increased the number
tions ensure that those with preexist-      of patients achieving a sustained
ing illnesses are appointed to jobs for     virological response (SVR rate) and
which they are suitable as regards          who are thus effectively cured of hepa-
health. These examinations also serve       titis C. Nowadays, patients with cer-
to demonstrate that no work-related         tain genotypes (subtypes of the virus)
harm to health has occurred and that,       have an over 90% chance of beating
should the worst happen, any corre-         the disease and having undetectable
sponding damage is detected and             levels of hepatitis C virus. Even pa-
treated in good time.                       tients with the more intractable types
   Health protection in the broader         of disease can expect a greater than
sense also includes health promotion.       50% chance of responding to Pegasys
It is in the interests of all employees,    plus Copegus.
and also in the interests of Roche, that        Following the introduction at the
everyone remains fit and productive.        end of 2002 of new diagnostic tests for
A healthy diet, physical activity and       detecting and monitoring the disease,
an even balance between work and            it is now possible to detect hepatitis C
private life are important objectives of    viruses with even greater speed and
health promotion. The health service        accuracy using ¡PCR and real-time
provides an ideal access point for          PCR technologies. This will facilitate
personnel in this respect.                  targeted drug treatment and optimal
                                            monitoring of the patient’s response to
Hepatitis, chronic. Inflammation of         drug therapy.
the liver. Chronic forms of viral hepa-
titis occur throughout the world. The       Herceptin. A humanised monoclonal
main pathogens are hepatitis B and C        ¡antibody (active ingredient trastu-
viruses. The long term consequences         zumab) for the treatment of a particu-
of chronic hepatitis B or C can be          lar kind of aggressive ¡breast cancer.
extremely serious. They primarily in-       Herceptin has been shown to be very
clude cirrhosis (build up of scar tissue    effective in treating patients with
in the liver), which can lead to liver      breast cancer who express elevated
damage and, ultimately, to a hepato-        levels of the protein HER2, to which
cellular carcinoma (liver cancer). Both     it binds. Because normal cells do
can prove fatal. As there is no vaccine     not over-express HER2, Herceptin is
against hepatitis C, it is very important   highly targeted towards cancer cells,

Roche from A to Z                                                                  77
 Hexagon


                                            suitable. It has also been approved as
                                            the first-line therapy in combination
                                            with docetaxel and as a tertiary treat-
                                            ment in monotherapy. The drug has
                                            also been approved for use after stan-
                                            dard adjuvant chemotherapy for early-
                                            stage breast cancer. It is administered
                                            by intravenous infusion.
                                               The product is marketed by ¡Chugai
Refrigerated storage of Herceptin.          in Japan.

causing very few of the kind of side        Hexagon. Six-sided polygon. A hexa-
effects normally associated with            gon representing the benzene ring and
chemotherapy. Clinical ¡trials have         containing the word Roche is the com-
shown Herceptin to improve survival         pany logo (¡trademarks, ¡basilisk),
by 25 percent in advanced breast can-       which appears on all products originat-
cer patients when given in combina-         ing from factories bearing the name
tion with conventional chemotherapy,
and to reduce the risk of relapse by
50 percent in patients with early breast
cancer when given with chemotherapy
following surgery. First introduced in
1998, Herceptin, marketed in the United     Roche. This includes the products of
States by ¡Genentech, has revolu-           the traditional ¡Pharmaceuticals and
tionised the treatment of HER2-posi-        ¡Diagnostics Divisions. The company
tive breast cancer. A joint global devel-   logo was also the inspiration for the
opment programme is underway at             name of the worldwide employee news-
Roche and Genentech to investigate the      paper, Hexagon, first published in 1998.
clinical efficacy and safety of Herceptin
in other forms of cancer that exhibit       Hitachi. Major industrial group with
overexpression of HER2 (¡oncology).         headquarters in Mito (Japan). For
   In 2000 Herceptin was approved           many years Hitachi and the ¡Diag-
in the European Union for advanced          nostics Division’s ¡Professional Diag-
(metastatic) HER2-positive breast can-      nostics business area have cooperated
cer. This was followed in 2006 by ap-       in the field of clinical and immuno-
proval for early-stage HER2-positive        chemical ¡analytical systems. Hitachi’s
breast cancer. Herceptin in combina-        random-access systems, launched in
tion with paclitaxel is now the first-      the early 1980s, were a major technical
line treatment for advanced breast          breakthrough that substantially im-
cancer when anthracyclines are un-          proved and simplified processing in

78
                                                    Hoffmann-La Roche, Fritz


                                          Founder of what is now the Roche
                                          Group.
                                             Fritz Hoffmann received his com-
                                          mercial training in companies trading
                                          in plant extracts and industrial chemi-
                                          cals. In 1893 he became a partner in
                                          the pharmacy Bohny, Hollinger & Cie.
                                          In 1895 he married Adèle La Roche. In
                                          1894, together with pharmacist Max
                                          Carl Traub, Hoffmann took over the
                                          Bohny, Hollinger & Cie. production
                                          facilities in Basel’s Grenzacherstrasse
                                          and in the same year founded the
                                          limited partnership Hoffmann, Traub
                                          & Co. This was renamed F. Hoffmann-
                                          La Roche & Co. on 1 October 1896
                                          after his partner’s withdrawal from the
                                          firm. In the same year Hoffmann hired
                                          Dr Emil Christoph ¡Barell as a
cobas 6000 (501/601) Analyzer – first     chemist. As early as 1897 Hoffmann
fully-automated system for the analy-     established a production facility in
sis of clinical and immunochemical        ¡Grenzach and then subsidiaries in
tests in an integrated platform for       Paris (1903), New York (1905), Vienna
laboratories with a medium-sized          (1907), London (1908), St. Petersburg
workload (¡cobas).                        (1910) and Yokohama (1912). Thus,
                                          Roche’s international structure was
clinical chemistry laboratories. With     shaped from its earliest years.
the introduction of the first inte-          With the outbreak of the Russian
grated, automated Modular Analytics       Revolution the entire Russian market,
SWA platform for laboratories with a      which at times had accounted for one
high sample throughput, the Roche/        fifth of sales, was lost at a single stroke.
Hitachi partnership became a pioneer      Coming on top of the difficulties expe-
in the merging of clinical chemistry      rienced in Grenzach and the losses
and immunochemistry on a single           suffered in the countries involved in
platform.                                 World War I, these events brought the
                                          company close to ruin. In April 1919
Hoffmann-La Roche, Fritz. Born in         the limited partnership was trans-
Basel, 24 October 1868, the third child   formed into a limited company with
of Friedrich Hoffmann and Anna            a ¡share capital of CHF 4 million, and
Elisabeth Merian; died 18 April 1920.     its finances were restructured. Hoff-

Roche from A to Z                                                                 79
 Holding company




Fritz and Adèle Hoffmann-La Roche, photographed in 1896, the year Fritz Hoff-
mann founded his company.

mann’s health had suffered as a result      the architect of the great success of
of the severe strains caused by the war,    ¡Sirolin and the other branded prod-
and Barell took increasing responsibil-     ucts he put on the market. Promo-
ity for running the company. In the         tional activities were aimed not only
spring of 1919 Hoffmann fell ill with       at consumers and pharmacists but, in
a severe kidney disease, to which he        the form of product-related ¡com-
finally succumbed on 18 April 1920.         munications, particularly at doctors.
He did not live to see his firm climb out   Hoffmann placed great importance on
of its deep trough.                         having good articles by Roche scien-
   Hoffmann was one of the first to         tists published in medical journals.
grasp the nature of the proprietary         And he introduced a genuine innova-
medicinal product: a ready-to-use           tion in Europe at that time by publish-
formulation with a standardised com-        ing the company’s own scientific
position and uniform potency, bearing       periodicals.
a ¡trademark. He foresaw that the
future belonged to such products and        Holding company. A limited com-
became one of the pioneers of market-       pany that owns a majority or all of the
ing, using what were then completely        shares of several operating companies
new promotional techniques. He was          – the controlling company of a ¡group.

80
                                                                      Hypnotics


The controlling company of the Roche        or mental stress. Most sleep disorders
Group is Roche Holding Ltd, Basel           are transient, disappearing once their
(¡share capital).                           causes have been eliminated. For this
                                            reason every effort should be made to
Hormones. Potent, biologically active       identify any underlying factors. Treat-
substances that are produced in the         ment with a hypnotic can be a useful
body by glands. Hormones reach their        temporary supporting measure.
target organs via the circulation and          Roche makes two hypnotics of the
regulate various bodily functions, such     ¡benzodiazepine class: Rohypnol, for
as growth, reproduction or metabo-          severe insomnia, and Dormicum/
lism. Insulin, for example, which is        Versed, an established treatment for
produced in the pancreas, regulates         sleep onset disorder.
the glucose balance in the body, and           Dormicum (active ingredient mida-
the pituitary gland produces a range        zolam) is the shortest-acting ¡benzo-
of hormones, including growth hor-          diazepine. Its chemical characteristics
mone.                                       make it particularly suitable for intra-
   An extensive test menu of thyroid        venous and intramuscular administra-
parameters, e. g. thyroid-stimulating       tion, and it is therefore used widely in
hormone (TSH) plus T3, T4, FT3, FT4         anesthesia and intensive care.
and T-uptake, and fertility hormones
such as ACTH, testosterone, beta
HCG, SHBG or estradiol is available
on the immunochemical analysers of-
fered by the ¡Professional Diagnos-
tics business area of the ¡Diagnostics
Division.

Hybridomas. Hybrid cells used in the
production of monoclonal ¡anti-
bodies.

Hypnotics. Drugs for the treatment of
sleep disorders. The various types of
sleep disorder include difficulty falling
asleep (sleep onset disorder), inability
to sleep through the night (broken
sleep), premature awakening or com-
binations of these. Sleep disorders
may be caused by illness but are more
often due to external factors, aging

Roche from A to Z                                                                81
 Immune system


                                           Immunology. A subdiscipline of biol-
                                      I    ogy concerned with the study of the
Immune system. All the organs, cells,      biochemical and biological principles
intercellular mediators, such as ¡cyto-    of the body’s defence system against
kines and cell functions that together     pathogens, e.g. ¡bacteria and ¡viruses
defend the body against attack by patho-   and other foreign substances such as
gens and other foreign substances.         biological toxins and environmental
                                           poisons. The ¡immune system consti-
Immunoassay. Laboratory test based         tutes its subject of research. Since the
on the “antigen–antibody” reaction.        immune system plays an important
The presence of specific ¡antigens         role in many illnesses, immunology is
and ¡antibodies in the body provides       a key aspect of medicine in enhancing
clear evidence of certain illnesses or     our understanding of ¡prevention,
functional disorders. The test provides    diagnosis and treatment.
specific information about the quality
and quantity of these substances.          Indianapolis. North American head-
                                           quarters of the ¡Diagnostics Division
Immunoglobulin (Ig). Term covering         and responsible for all products
various classes of proteins that func-     launched, distributed and sold in the
tion as ¡antibodies: IgA protects the      United States. The site is home to re-
surfaces of mucous membranes against       search and development, laboratories,
pathogens. IgD influences the way          manufacturing, distribution, informa-
¡lymphocytes function. IgE protects        tion technology and corporate head-
against intestinal parasites but also      quarters operations in support of the
contributes to many allergy symp-          business areas ¡Diabetes Care, ¡Pro-
toms; ¡Genentech and partners have         fessional Diagnostics, ¡Molecular
developed a humanised ¡antibody for        Diagnostics and ¡Applied Science.
neutralising IgE. IgG gives protection     Research, development and produc-
against microorganisms and their           tion of ¡test strips for ¡glucose self-
toxins. IgM is the first line of defence   monitoring and chemical reagents for
against microorganisms in the circula-     diagnostic tests are likewise based in
tion. Susumu Tonegawa, working at          Indianapolis.
the former Basel Institute for Im-            The site currently employs around
munology, elucidated the structure         3,700 people, almost a third of whom
and interaction of the ¡gene segments      are scattered across the United States
responsible for the synthesis of the       working in field sales and customer
enormous variety of immunoglobu-           service.
lins (approximately 1012 in number),          The origins of the Indianapolis site
an achievement for which he received       date back to the year 1964, when the
the ¡Nobel Prize in 1987.                  then BioDynamics was started and

82
                                                                   Influenza (flu)


soon constructed its office building on      heart muscle). Complications occur in
the current Roche plot (i. e. in the         15 percent of adults and even more
northeastern part of the city). The site     frequently in children and in patients
has grown in size to 150 acres and in-
cludes 18 buildings with a fully occu-
pied floor area of 1.3 million square
feet in both Marion and Hamilton
counties.
   Indianapolis is also responsible for
the production facility in Ponce,
Puerto Rico. Following the takeover of
Disetronic (¡Burgdorf), the Diabetes
Care business area in Indianapolis
has assumed responsibility for Dise-
tronic’s North American headquarters
in Fishers, Indiana, and their field sales
force.                                       Structure of the influenza virus –
                                             hemagglutinin (green) and neuram-
Indication. The reason or circum-            inidase (blue) are located on the surface
stances that justify a particular med-       of the virus. The genetic material of the
ical measure after an assessment of          virus can be seen in the viral core.
the relative risks and benefits. (A con-
traindication is the opposite, i. e. a
reason or circumstance that rules out
a particular measure.) In the case of
¡pharmaceuticals, an indication is a
disease or condition for which a par-
ticular preparation is thought to be an
appropriate treatment.

Influenza (flu). Serious, acute illness
caused by infection with an influenza
virus. Typical symptoms include sud-
den fever, headache, joint and muscle
aches, fatigue and cough. The acute          Schematic view of the head of a neu-
phase lasts five to seven days. Common       raminidase molecule – the active site
complications include bronchitis,            of neuraminidase is virtually identical
pneumonia, middle-ear infections and         in all viruses. The neuraminidase in-
sinusitis, and some patients develop         hibitor Tamiflu acts by binding tightly
myocarditis (inflammation of the             to this site.

Roche from A to Z                                                                  83
 Insulin pump therapy


with a chronic underlying disease.        fortably in a trouser pocket or pouch.
Influenza epidemics occur every year      The pump delivers the exact amount
in winter. They tend to spread explo-     of insulin required to cover the body’s
sively but last only a few weeks.         basic physiological needs 24 hours a
Influenza activity is continuously        day. The insulin pump is connected to
monitored by the health authorities.      the body at all times by an infusion set
About 10 percent of the adult popula-     – a thin tube with a tiny needle at the
tion and 30 percent of children catch     end. Since the needle of the infusion
influenza each year. Hundreds of          set is usually inserted subcutaneously,
thousands of flu sufferers develop        i. e. just beneath the skin, this form
complications requiring hospitalisa-      of treatment is known as continuous
tion, and, according to the WHO, the      subcutaneous insulin infusion.
annual death toll worldwide ranges            While the insulin pump is a highly
from 250,000–500,000. Until the in-       practical solution, it cannot “think” for
troduction of neuraminidase inhibitors    itself. It therefore has to be pro-
(¡Tamiflu), there were no such tar-       grammed and users have to measure
geted and effective medicines against     their blood glucose level at regular
the viruses that cause flu. Analgesics    intervals. At the press of a button it
and cough remedies were adminis-          can deliver an extra portion of insulin
tered in the hope of relieving symp-      (bolus) to cover the body’s increased
toms. Antibiotics were often pre-         requirement after food, just like a
scribed, even though they have no         healthy pancreas. Since the insulin
antiviral effect. Influenza vaccination   contained in the pump is a fast-acting
is recommended as a precaution in the     form, the insulin dose can be reduced
elderly and in people with chronic        or increased in the short term, e. g.
underlying disease.                       during sport or meals.

Insulin pump therapy. Continuous          Interferons. Members of the ¡cyto-
replacement of the vital human hor-       kine protein family. It has been known
mone insulin by means of a portable       for decades that humans and animals
pump for the treatment of insulin-        never suffer from two viral infections
dependent diabetes mellitus. Since in-    (¡viruses) – chicken-pox and measles,
sulin pump therapy is very similar to     for example – at the same time. This
the release of insulin in non-diabetics   prompted the British virologist Alick
it is the most physiological form of      Isaacs and his Swiss colleague Jean
insulin treatment currently available.    Lindenmann to conduct a momentous
   The insulin pump is worn on the        experiment at the National Institute
body as a kind of electronic insulin      for Medical Research in London in
reservoir. It is so small and light –     1957. They infected fertilised chicken
weighing just 100 g – that it fits com-   eggs with a virus. The cells of these

84
                                                                      Investment


eggs then apparently formed trace              In 1969 Dr Sidney Pestka, working
amounts of a previously unknown,            at the former ¡Roche Institute of
transmissible ¡protein that protected       Molecular Biology, began isolating
the egg and chicken cells against other     human interferon alfa and purifying it
viral infections. Isaacs and Linden-        to homogeneity. In 1980 researchers
mann called this substance interferon.      in ¡Nutley, in collaboration with the
In Tokyo two Japanese scientists,           Californian company ¡Genentech,
Yasuichi Nagano and Yasuhiko Kojima,        produced the first complete interferon
arrived independently at similar re-        alfa using recombinant techniques. In
sults.                                      January, 1981 Roche in Nutley became
   Interferon from one animal species       the first company in the world to begin
protects only cells of the same species     clinical ¡trials with recombinant in-
against viral infections. The human         terferon alfa. Roferon-A, the recombi-
¡immune system produces three               nant interferon alfa-2a product from
types of interferon: alfa, beta and         Roche, was approved for the treatment
gamma (but there are more than a            of some cancers (hairy-cell leukemia)
dozen different, though structurally        in the United States and Switzerland in
very similar, alfa interferons). All have   June 1986, and subsequently in other
antiviral and immunomodulatory              countries.
properties. They can, for a certain
time, make uninfected but susceptible       Investment. The use of funds to pur-
cells resistant to a broad spectrum of      chase land, buildings, plant, machin-
viruses. Interferons also have antipro-     ery and other equipment to create
liferative properties (inhibition of cell   or maintain jobs – in other words, to
multiplication and tissue growth) that      enable industrial activity. In addition
are of particular interest in relation to   to these capital expenditures, it is also
cancer. Interferon inhibits the growth      possible to invest in intellectual prop-
of both normal and malignant cells          erty (¡trademarks, ¡patents). The
(¡in vitro). Interferons are also part      acquisition of companies or parts of
of a complex mechanism that regu-           companies with the aim of expanding
lates the activity and maturation of        one’s own corporate activities can also
important cells of the body’s immune        be regarded as investment.
system.                                        The manufacture of pharmaceutical
   Thanks to recombinant DNA tech-          products is a capital-intensive busi-
nology (¡production, biotechnologi-         ness, requiring an unusually high level
cal; ¡genetic engineering), interferon      of investment.
alfa is now available for the treat-           The investments a company makes
ment of serious diseases in the form        over a certain period – a financial year,
of ¡Roferon-A. Roche was one of the         say – can serve a wide range of pur-
pioneers in the field of interferons.       poses, including the manufacture of

Roche from A to Z                                                                 85
 Invirase


new products, the expansion of exist-
ing production capacity, the improve-
ment of existing processes, plant re-
newal, ¡research or ¡environmental
protection. The various purposes are
usually interconnected. The motives
for making such investments are
equally diverse. Apart from market
growth, the reasons for investment
(or its opposite, disinvestment) in-
clude technical advances, the need to
safeguard a market position, govern-
ment regulations (concerning envi-
ronmental protection, for example)          Computer-generated model of the
and political changes, such as the          active ingredient of Invirase.
creation of supranational economic
zones. Since investment usually leads       ¡virus replication is the production of
to the creation of jobs, many countries     over-long polyprotein chains. During
encourage – or even try to compel –         the maturation process these chains
companies to invest. In many cases,         are cut to the right length by HIV
therefore, instead of being the result      protease. If this process is blocked,
of completely free business decisions,      maturation cannot continue, and a
investment is a consequence of partic-      non-infective virus is formed.
ular constraints (¡production sites).          Large-scale trials of the drug, which
   Analysis of the profitability of         was the first protease inhibitor devel-
planned investments has become a            oped for the fight against ¡AIDS,
science in its own right and, of course,    showed it to be very effects. First
is also undertaken on a large scale at      launched in 1995, Invirase has a highly
Roche. However, no matter how much          specific action against HIV and does
systematic analysis has been carried        not interact with human enzymes,
out, at the moment an investment            making it very well tolerated. This has
decision is taken no one can say with       been confirmed in numerous trials
certainty if it will prove correct, since   and during extensive clinical use.
all the factors that have been con-         From the original idea through to the
sidered may change over time. This          marketable product, Invirase was
accounts for a major part of entrepre-      developed within the Roche Group as
neurial risk.                               an international project, and it has
                                            been awarded a number of prizes for
Invirase. Drug that inhibits the en-        innovation (¡Prix Galien).
zyme HIV protease. The first step in

86
                                              In vivo diagnosis


In vitro. (Latin: “in glass”). Refers to
an experiment conducted outside a
living organism (¡trial, experimen-
tal).

In vitro diagnosis. Whereas the term
diagnosis on its own refers to the
disease screening process, the prefix
“in vitro” indicates where this takes
place, i.e. outside the body using body
fluids and tissues.

In vivo. Refers to an experiment on
a living organism (¡trial, clinical).

In vivo diagnosis. This form of track-
ing down illnesses is also defined by
the site at which it takes place. Thus,
“in vivo” translates into English as “in
life", i. e. directly in the body. Examples
of in vivo diagnostic investigations
include x-rays or ultrasound scans.




Roche from A to Z                                             87
 Kidney disease, chronic


                                    K
Kidney disease, chronic. Chronic
kidney disease (CKD) exists when kid-
ney function is reduced or there is evi-
dence that the kidney has been dam-
aged. In the most severe form of the
disease, the kidneys are no longer able
to remove fluid and waste products
from the body and the patient needs
dialysis or a kidney transplant. In ear-
lier stages, patients may not be aware
they have CKD, but are at risk of the
condition progressing and of develop-
ing serious complications. There are
many causes of CKD, the most com-
mon being diabetes and high blood
pressure. The kidneys also produce
a substance called ¡erythropoietin,
which is needed for the continuous
production of red ¡blood cells. Dam-
aged kidneys fail to produce sufficient
erythropoietin.




88
                                                      Landscaping, ecological

                                            widespread at the time and based on
                                      L     the relevant legal requirements.
Landfills. In the past, a lack of know-
how and the appropriate technical re-       Landscaping, ecological. At Roche
sources meant that landfill dumping         ecological landscaping means
was the disposal method of choice.          – creating natural living spaces for
This approach was governed by legis-           people, animals and plants;
lation, as a result of which various        – using mainly indigenous species of
local authorities have made suitable           plants;
plots of land available for a charge,       – covering roofs with turf wherever
often for joint use by a number of             possible and practicable;
companies. Improved knowledge of            – allowing runoff from roofs to soak
geological characteristics and negative        away;
experience have lead to the discontin-      – and giving preference to paving
uation of landfills for the disposal of        stones, marl or gravel instead of
chemical waste. Contaminated sites             asphalt.
are subject to increased monitoring            When planning new facilities,
and thorough examination in order to        Roche pays particular attention to the
evaluate the associated risks and initi-    choice of location and the siting of
ate the steps required for containment      buildings. Landscaping work is incor-
or remediation of the site in question.     porated into the planning process at
    Since Roche has always been a phar-     an early stage so as to achieve unity
maceutical company with relatively          in the finished design. Interdependent
low volumes of chemical production,         elements such as traffic flows, “green
our total quantities of chemical waste      belts”, soakaway areas and turf roofs
and share of deposits in common             are planned in a coordinated fashion.
landfill sites are, as a rule, small. As    Open spaces are laid out in such a way
soon as a contaminated site is brought      that they not only have amenity value
to our attention, Roche authorises the      for people but also offer a suitable
studies required to evaluate the associ-    habitat for animals and plants. Given
ated risks. Depending on the outcome,       proper maintenance, these areas come
steps for containment or, if necessary,     close to providing a natural environ-
remediation of the site are subse-          ment. At the Kaiseraugst site, for ex-
quently taken. This process is con-         ample, habitats similar to those of the
ducted in close collaboration with the      surrounding region have been created:
competent authorities and in compli-        low-nutrient meadows in which the
ance with current legislation. Roche        wind-borne seeds of plants from neigh-
accepts responsibility for all waste        bouring areas are able to take root;
deposited by Roche at its sites or land-    gravelly areas of fallow land where the
fills, even if the method of disposal was   natural vegetation is allowed to estab-

Roche from A to Z                                                               89
  Languages


lish itself, thus offering a suitable habi-   procurement methods and the prepa-
tat to numerous animal species; and           ration of ordering and delivery plans.
hedges of indigenous shrubs and               In production, the prompt, efficient
dwarf trees serving as a sanctuary            and reliable supply of the required raw
for many small mammals, birds and             materials, auxiliaries, intermediates,
insects.                                      active ingredients and packaging ma-
                                              terials to the factories is a complex task
Languages. A group of companies               requiring intelligent, integrated plan-
that operates in roughly sixty coun-          ning. The scope of the task varies
tries must decide on a single language        greatly according to the type of mate-
for its communications. Even at Group         rials involved. Active pharmaceutical
headquarters in Basel about fifty dif-        ingredients are supplied throughout
ferent nationalities are represented,         the Roche Group on a worldwide
though in constantly changing combi-          basis, but other goods are procured
nations. Since a common language is           locally, for example just for the facto-
essential for mutual understanding,           ries in Basel and Kaiseraugst together.
English has been chosen as the official           In the Diagnostics Division, the best
language of the Roche Group. English          and most important suppliers are
has become the international working          identified at a global level, and the
language in science and technology, as        local sites then buy the goods from
well as in the business world. In medi-       these suppliers.
cine Latin has long since been replaced           Another task of logistics in the
by English. Important documents that          Pharmaceuticals Division is to store
are binding for the whole Group are           the purchased and manufactured
thus always drawn up in English, and,         goods, and here the requirements vary
since 1986, departments at Basel head-        widely, according to the type of goods
quarters that serve the entire Group          involved. The warehouses for raw ma-
have had English designations (¡cor-          terials and auxiliaries and active ingre-
porate functions).                            dients are equipped for transferring or
                                              filling these goods into the containers
Logistics. Also known as supply chain         specified in individual orders and for
management or materials manage-               the necessary labelling and ¡packag-
ment, logistics is the management of          ing.
the whole value-added chain from the              The remit of logistics also includes
raw materials to the finished product.        processing goods as efficiently, rapidly
It covers all areas concerned with plan-      and safely as possible, taking due
ning, purchasing, storage, transport          account of their nature and the client’s
and distribution.                             wishes. Highly detailed specifications,
   Important tasks in logistics include       for example regarding refrigerated
supplier selection, the specification of      storage, batch tracking or separate

90
                                             Lymphokines


batch storage, have to be complied
with for many products. These and
other storage requirements are moni-
tored by Quality Management and ex-
ternal authorities, thereby ensuring
that goods of the highest quality are
delivered to the customer intact. For
certain goods and destinations Roche
uses the services of specialist compa-
nies to organise and carry out ship-
ment.
   Finally, the logistics staff have the
task of selecting suitable logistics sys-
tems and providing support for the
users of these systems. Logistics spe-
cialists also advise Group companies
on suitable supply chain systems, eco-
nomical shipment methods, inventory
requirements and appropriate storage
facilities.
   All of these activities must be car-
ried out in accordance with various
standards and principles, including
¡good manufacturing practice, “first
in, first out”, shelf life, safety regula-
tions and legal requirements.

Lymphocytes. White blood cells that
mount a specific defence against in-
vading pathogens; they are part of
the body’s ¡immune system. They are
generated from hematopoietic (blood-
forming) stem cells in the bone mar-
row, differentiating into ¡B lympho-
cytes and ¡T lymphocytes.

Lymphokines. Mediators of the im-
mune response, such as interleukins
and ¡interferons.



Roche from A to Z                                      91
 MabThera


                                             the Roche Group’s portfolio, but the
                                     M       world’s top-selling anticancer prod-
MabThera. A bioengineered chimeric           uct. Almost a million patients have re-
monoclonal ¡antibody (active ingre-          ceived MabThera treatment in its first
dient rituximab) for the treatment of        ten years on the market. The product is
¡non-Hodgkin’s lymphoma (NHL).               comarketed in the United States by
MabThera binds to a particular pro-          ¡Genentech and Biogen Idec and in
tein – the CD20 antigen – found on the       Japan by ¡Chugai and Zenyaku Kogyo
surface of normal and malignant B            Co Ltd. (¡oncology).
cells. It then recruits the body’s natural
defences to attack and kill the marked       Macrophages. Cells that form part of
B-cells. Stem cells (B-cell progenitors)     the ¡immune system. Macrophages
in bone marrow lack the CD20 anti-           engulf and digest bacteria and other
gen, allowing healthy B cells to regen-      foreign cells and help ¡lymphocytes
erate after treatment and return to          in mounting specific reactions to
normal levels within several months.         ¡antigens by secreting various sets of
First introduced in 1997, MabThera           ¡cytokines and other effector mole-
(marketed as Rituxan in the United           cules.
States, Japan and Canada) is indicated
for the treatment of indolent and ag-        Mannheim. City of 320,000 inhabi-
gressive NHL. Due to its exceptional         tants, situated at the confluence of the
efficacy, proven in multiple large clini-    Neckar and ¡Rhine rivers, in the state
cal trials, MabThera has grown to            of Baden-Württemberg (Germany). In
become not just the largest brand in         1872 Christoph Boehringer relocated
                                             his part of the original family company
                                             to this industrial and transport centre,
                                             which later became the headquarters
                                             of the globally operating Boehringer
                                             Mannheim group.
                                                As a result of the integration of
                                             Boehringer Mannheim into the Roche
                                             Group (1998), Mannheim has become
                                             an important Roche site.
                                                Employing around 7,000 people,
                                             Mannheim is one of the largest and
                                             most multifaceted Roche sites in the
                                             world. It is the nerve centre of large
                                             parts of the diagnostics business and
                                             the production site for important
                                             pharmaceuticals. Substances produced

92
                                              Measurement units, analytical


by ¡biotechnology techniques are be-      ending with a buyer becoming con-
coming increasingly important. Since      vinced that the product is what he or
1998 the company has invested around      she needs. With this objective in mind,
EUR 1 billion in the Mannheim site,       Roche is confronted with all conceiv-
creating almost 800 new jobs in the       able market challenges and conse-
process.                                  quently makes use of a comprehensive
   Its favourable location in Europe      range of marketing techniques. This is
and exceptional infrastructure make       due to the broad range of products
the city of Mannheim, with its grid       involved, the diversity of the customer
layout, the ideal base for the interna-   groups served and the strict regulatory
tional logistics centre for diagnostics   environment under which the market-
(¡logistics). Roche subsidiaries and      ing of prescription medicines and
customers in 170 countries are sup-       diagnostics operates. Purchasers of
plied directly from Mannheim. The         diagnostic products include e. g. doc-
diagnostics distribution centre for       tors, healthcare organisations and the
Germany is based in Mannheim, the         technicians who actually carry out the
EMEA sales region (Europe, Middle         tests in the clinical laboratory.
East, South Africa) is managed from          Prescription drugs are a special
there and all marketing strategies for    case. The actual consumer – the pa-
Germany are planned there. The Roche      tient – does not choose the product,
site in Mannheim is also responsible      nor does he usually pay for it; he just
for global research, development, pro-    takes it. The doctor is not the con-
duction and strategic marketing of        sumer; he does not pay for the drug
diagnostics for the ¡Diabetes Care        but merely chooses it. Health funds or
business area.                            insurers are not consumers, either;
   For over 40 years, tests and moni-     they make general choices by includ-
toring systems have been researched,      ing, or refusing to include, products in
developed and produced in Mannheim.       their reimbursement lists, but they do
Roche Diagnostics’ most successful        not choose treatments in individual
brand is Accu-Chek. For over 30 years,    cases; however, they pay for the drug in
Accu-Chek has been tasked with deliv-     most cases and are thus referred to,
ering innovative products and solu-       appropriately, as third-party payers in
tions that meet the needs of people       the healthcare system. This complex
with diabetes and their carers.           situation necessitates the use of a wide
                                          variety of marketing techniques.
Marketing. The complex process of
getting a product from the producer to    Measurement units, analytical. Mea-
the consumer, beginning with the cre-     surement units used in chemical
ation of a product to meet a demand       ¡analysis to investigate the composi-
(or a largely unmet medical need) and     tion, structure and quantity of sub-

Roche from A to Z                                                              93
 Medicine, personalised


stances contained in compounds and         tions. Not only do we combine ¡Phar-
mixtures. Nowadays, inconceivably          maceuticals and ¡Diagnostics under
minute amounts can be detected. The        one roof, but both divisions have a
principal measurement units are ppm        leading position in ¡biotechnology
= parts per million, ppb = parts per       and ¡molecular medicine – a decisive
billion and ppt = parts per trillion.      advantage in better understanding
Most people, however, find it difficult    how medicine can be tailored to spe-
to appreciate the relationships in-        cific patient populations. Personalised
volved. For example, while one ppm         medicine is expected to impact the
can be expressed as 31 seconds in a        healthcare industry significantly over
year, one ppb is equivalent to just        the next ten years. Roche has the abil-
3/100 of a second in a year and one ppt    ity to lead the change from salvage
is equivalent to one second in 31,688      strategies for drugs that only demon-
years. Admittedly, the detection of a      strate efficacy in limited patient popu-
particular substance says nothing          lations to developing proactive strati-
about its effects, whether harmful or      fication strategies for all projects with
beneficial, as these depend on the         relevant potential.
properties of a substance detected as
well as its concentration. Thus, the       Metabolism. Conversion of sub-
significance of an analytical finding      stances in the body (¡trial, experi-
can only be assessed in relation to the    mental). Metabolic disorders are one
natural or acceptable levels. In other     of Roche’s core therapeutic areas
words, a qualitative assessment is         (¡obesity, ¡osteoporosis).
needed in addition to the quantitative
analysis.                                  Molecular    biology. A branch of
   Another important measurement           science concerned with processes at
unit in chemistry is the pH value,         the molecular level, in particular the
which provides information about the       isolation and characterisation of ge-
“strength” of an acid (pH <7) or a base    netic material (¡DNA).
(pH 7–14).
                                           Molecular     Diagnostics. Business
Medicine,    personalised.       Person-   area of the ¡Diagnostics Division
alised medicine is the strategic           and the market leader in the field
approach of systematic and evidence-       of molecular diagnostics. Molecular
based application of clinical differen-    Diagnostics develops and produces
tiators to achieve maximum pharma-         gene-based tests using automated
ceutical efficacy and safety and thereby   PCR, real-time PCR, and microarray-
produce sustainable clinical benefits.     based analytical platforms for appli-
Roche is uniquely positioned to drive      cations in ¡genomics, ¡oncology,
forward personalised medicine solu-        virology, blood screening and micro-

94
                                                         Molecular medicine


                                             A key technology used in many
                                          areas of genome research, PCR has
                                          enabled a whole new generation of
                                          highly sensitive diagnostic tests to
                                          be developed that allow disease
                                          pathogens to be detected directly
                                          (in contrast to the detection of an
                                          immune response to the pathogen).
                                          PCR-based tests are frequently used
The cobas TaqMan is loaded with sam-      to diagnose infections or monitor the
ples for an analytical run.               progress of an illness or the therapeu-
                                          tic outcome. They can also be used to
                                          detect variations and mutations of
biology. The product range includes       ¡genes, including inherited variations
AmpliChip, Cobas Amplicor, Cobas          in humans or variations arising in dis-
AmpliPrep, Cobas TaqMan and Cobas         eases such as cancer. These are used for
AmpliScreen.                              differential diagnoses to better predict
   Molecular Diagnostics also offers a    prognosis, treatment selection, and
wide range of ¡enzymes for industry.      response to therapy.
With its unusually comprehensive             More than 500 laboratories and
portfolio in the field of nucleic acid    over 50 companies around the globe
technology (NAT), Molecular Diag-         have acquired licences from Roche for
nostics supplies a wide array of inno-    the patented PCR technology and
vative test products and services to      PCR-based products and services. As
researchers, physicians, patients, hos-   a result, PCR and real-time PCR
pitals and laboratories worldwide.        have become routine components of
   Currently based in ¡Pleasanton,        diagnostic tools and established them-
California (USA), Molecular Diagnos-      selves as the world’s leading DNA-
tics was created as a new business area   probe technology.
of Roche Diagnostics in December             Since it was formed, Molecular
1991 with the acquisition of the revo-    Diagnostics has produced a compre-
lutionary amplification process known     hensive range of PCR-based equip-
as ¡polymerase chain reaction (PCR)       ment systems and diagnostic tests that
from Cetus Corporation. PCR, a No-        have set new standards in the treat-
bel-prize-winning technology, allows      ment of infectious diseases and helped
scientists to copy specific ¡DNA or       improve the safety of blood and blood
RNA segments billions of times and        products across the world.
amplify the genetic material in even
minute samples sufficiently to produce    Molecular medicine. The elucida-
detectable quantities.                    tion, diagnosis and therapy of diseases

Roche from A to Z                                                              95
 Molecule


at the molecular level, especially on the   Impulses can be transmitted from the
basis of genetic causes: the growing        patient to the measuring device by
body of knowledge from the mapping          means of a sensor or electrodes, for
of the human ¡genome is making it           example. These devices are usually
possible to explain the causes and          equipped with a screen for immediate
mechanisms of a large number of dis-        viewing of the functions being meas-
eases (with the exception of infections     ured. The results can be stored and
and other diseases due to external          subsequently used for diagnostic
factors) in terms of genetic defects or     assessments or for documentation
disorders. Molecular diagnostics, in        purposes.
particular the ¡polymerase chain               Alternatively, the success of long-
reaction (PCR), will in future enable       term treatments can be observed
physicians to identify these causes at      (monitored) with diagnostic tests in
an early stage. The treatment and cor-      order to provide definite proof that a
rection of such disorders increasingly      particular treatment is actually work-
rely on recombinant proteins, highly        ing. Modern drugs can help keep viral
specific chemical substances that tar-      replication low in chronic infections
get the causes of disease.                  (e. g. HIV infection), but the develop-
                                            ment of resistance may require a
Molecule. A structure consisting of         change in medication,
two or more atoms held together in a
neutral state by chemical bonding           Multinationality. Since it was found-
forces. Expressed in the simplest           ed, Roche has been a multinational
terms, a molecule is the smallest pos-      company. In 1896, the very year it was
sible unit of a chemical compound.          founded, Fritz ¡Hoffmann trans-
One example of a molecular structure        ferred most of production across the
is H2O or water. A water molecule con-      border to ¡Grenzach in Germany,
sists of two hydrogen atoms and one         because at that time the German state
oxygen atom.                                granted imported products only very
                                            short patent protection. In order to
Monitoring. On the one hand, moni-          establish Roche’s market presence,
toring involves the continuous elec-        Fritz Hoffmann had a distinctly inter-
tronic observation of specific processes    national approach in his dealings (the
in patients, particularly at-risk pa-       concept of “multinational” did not yet
tients. Cardiac activity and respiration    exist).
are the primary processes monitored,           The first foreign subsidiaries were
but other additional functions such         established by Fritz Hoffmann, and
as temperature regulation or cerebral       more followed between the world
pressure can be included depending          wars. Companies were opened in
on the clinical condition in each case.     Brussels, Bucharest, Warsaw, Prague,

96
                                                                       Mutation


Shanghai, Bombay, Madrid, Buenos            to be covered by sales on international
Aires, Montreal and Stockholm. After        markets.
World War II, Roche continued to set           Roche is also multinational in terms
up subsidiaries, but also acquired          of its people: in Basel, for instance,
companies such as Syntex, ¡Genen-           more than 50 nationalities work to-
tech, Boehringer Mannheim or                gether at all levels. However, the most
¡Chugai to expand its international         important reason for Roche’s multi-
reach.                                      nationality is ultimately that neither
   The reasons for Roche’s multina-         disease nor medical science knows any
tional involvement are manifold. On         frontiers.
the one hand, they can be explained
by company- and industry-specific           Mutation. Changes in the genetic
factors and, on the other, by factors       material of a ¡cell; they can occur
external to the company. For instance,      spontaneously or be deliberately in-
government restrictions on the free         duced in the laboratory (point muta-
movement of goods as well as other          tions). Mutations can occur during the
regulations can make it necessary to        process of replication of genetic infor-
set up companies in other countries.        mation before cell division or as a
The establishment of a local sales com-     result of damage to the ¡DNA. Such
pany is generally voluntary, since every    damage may be caused by chemicals,
business likes to be close to its markets   irradiation or by ageing of the genetic
and customers. Frequently, however,         material.
the importing countries demand that
the products be manufactured in the
country itself, though as a rule the im-
port of active ingredients is initially
permitted. The creation of large eco-
nomic zones such as the EU’s single
market of course adds a new dimen-
sion to the concept of multinational-
ity.
   For Roche, the United States is the
largest single market. Roche, however,
is a Swiss company and the Swiss mar-
ket is very small. This market falls
short by a wide margin of generating
the necessary revenues to offset the
research and development costs for
innovative products. The costs in-
curred in Switzerland, therefore, have

Roche from A to Z                                                                97
 NeoRecormon

                                          ommend NeoRecormon for practical
                                   N      and economic reasons.
NeoRecormon. Genetically engi-
neered recombinant human ¡ery-            Neurotransmitters. Relatively simple
thropoietin that stimulates the forma-    chemical messenger molecules re-
tion of red ¡blood cells. It is used to   leased by nerve cells (neurons); they
treat serious forms of ¡anemia in         include epinephrine, dopamine and
patients with chronic ¡kidney dis-        glutamate. Dopamine deficiency is
ease, premature babies and patients       the cause of Parkinson’s disease
with certain types of tumour.             (¡antiparkinsonian agents).
   NeoRecormon is a leading product
for the treatment of anemia in cancer     Nobel Prize. An annual international
patients and patients with renal dis-     prize awarded by the Nobel Founda-
ease.                                     tion for outstanding scientific achieve-
   Marketed by ¡Chugai under the          ment. Several laureates of this coveted
trade name Epogin, it is approved in      award have contributed to Roche’s sci-
Japan for the indications of renal dis-   entific accomplishments. The synthe-
ease and anemia in premature infants.     sis of vitamin C (ascorbic acid) from
An application for the authorisation      glucose (corn starch) – one of Tadeusz
of its use in cancer was submitted in     Reichstein’s most important achieve-
2005.                                     ments in the field of biochemistry –
   NeoRecormon is indicated for the       was successfully carried out for the
treatment of symptomatic anemia in        first time in an industrial process at
adult cancer patients who are receiving   Roche and is still used today for large-
chemotherapy for solid tumours and        scale production. Numerous Roche
for symptomatic anemia in adult           scientists worked closely with Nobel
patients undergoing antitumour            laureates during their university
therapy for hematological tumours         studies, among them the chemists
(such as multiple myeloma, low-grade      Otto Isler, who developed the first
non-Hodgkin’s lymphoma or chronic         industrial synthesis technique for
lymphocytic leukemia).                    vitamins A and E, and Leo ¡Stern-
   NeoRecormon significantly reduces      bach, the discoverer of the ¡benzo-
the need for blood transfusions, spar-    diazepines.
ing patients their potentially detri-        A very close connection between
mental effects. Subcutaneous Neo-         Roche and the Nobel Prize was estab-
Recormon has demonstrated its cost        lished in 1984 when the Swedish selec-
effectiveness in renal disease, with      tion committee awarded the prize for
dose reductions of up to 30% com-         physiology and medicine to Professor
pared to intravenous dosing, and Eu-      Niels Kaj Jerne and Dr Georges Köhler
ropean Best Practice Guidelines rec-      of Basel and Professor César Milstein

98
                                                                   Nobel Prize


                                          tute for Immunology, founded and fi-
                                          nanced by Roche.
                                             Professor Niels Kaj Jerne (1911 to
                                          1994), a Dane, wrote his doctoral
                                          thesis on antibody–antigen reactions
                                          and it has remained a standard work
                                          on the subject to this day (¡anti-
                                          bodies, ¡antigen). His later theories,
                                          based on ¡molecular biology and
                                          genetics, laid the foundations for the
                                          modern science of immunology. He
In 1984 Niels Kaj Jerne (left) and        also developed the Jerne plaque assay,
Georges Köhler shared the Nobel Prize     an important method for the quantita-
for medicine with César Milstein          tive assessment of immune responses.
(Cambridge).                                 In 1969, having worked at a number
                                          of scientific institutions in Europe and
                                          the United States and at the World
                                          Health Organization (¡WHO), Pro-
                                          fessor Jerne accepted the challenging
                                          task of setting up the Roche-backed
                                          Basel Institute for Immunology, which
                                          he directed until his retirement in
                                          1980.
                                             One of the many young scientists
                                          inspired and mentored by Jerne was
                                          the Munich-born biologist Georges
                                          Köhler (1946–1995), who joined the
Susumu Tonegawa received the Nobel        institute in 1971, shortly after it
Prize for medicine in 1987 for his work   opened, to conduct the experiments
done at the then Basel Institute for      for his doctoral thesis. After obtaining
Immunology.                               his doctorate at the University of
                                          Freiburg (Germany) in 1974, Dr
                                          Köhler was granted a two-year post-
of Cambridge (Great Britain). The pi-     doctoral fellowship, during which he
oneering work of the three researchers    worked with Professor César Milstein
in elucidating the structure and mech-    at the Medical Research Council
anisms of the body’s immune system        Laboratory of Molecular Biology in
thus received international recogni-      Cambridge. Early in 1975 the two
tion and acclaim. Jerne and Köhler        researchers succeeded in producing
both worked at the former Basel Insti-    monoclonal antibodies by fusing two

Roche from A to Z                                                              99
 Non-Hodgkin’s lymphoma


types of immune cell. In 1976, Dr           such as infections. There are no tests
Köhler returned to the Basel Institute,     for early detection of non-Hodgkin’s
where he had further success with pio-      lymphoma (NHL), so a medical con-
neering experiments on the cellular         sultation is essential if the symptoms
genetics of antibody formation. In the      persist. The exact cause of NHL re-
spring of 1985 he was appointed head        mains unknown. However, research
of the Max Planck Institute for Im-         has focused on certain factors that
munology in Freiburg.                       may contribute to the development
   In 1987 another former member            of lymphoma including genetic fac-
of the erstwhile institute, Professor       tors, impaired immune system and
Susumu Tonegawa, was awarded the            viruses such as HIV. The Roche drug
Nobel Prize, in recognition of the work     ¡MabThera/Rituxan has dramatically
he had done in Basel in 1975–1981.          improved the treatment of NHL over
During this period, he had succeeded        the past decade (¡oncology).
in elucidating the structure and re-
arrangement mechanism of antibody           Nutley. A town in New Jersey (United
genes. In doing so, he demonstrated         States), near New York City. Since
that just a few hundred genes in the        1929, when Roche moved there from
immune system’s B cells are respon-         New York and began its own large-
sible for the astounding variety of         scale manufacture of pharmaceutical
antibodies, of which some billions of       products, Nutley has been the US
different types exist. Professor Tone-      headquarters of the Roche Group.
gawa has taught at the Massachusetts        Today Nutley is an important centre
Institute of Technology in Cambridge        for the discovery, development and
(United States) since 1981.                 sale of pharmaceuticals. In the USA,
   In 1993 the discoverer of the ¡poly-     active pharmaceutical ingredients are
merase chain reaction (PCR) method,         produced in Boulder (Colorado) and
the American Kary B. Mullis, was            Florence (South Carolina).
awarded the Nobel Prize for chemistry.

Non-Hodgkin’s lymphoma. A group
of several closely related cancers that
affect the lymphatic system. Symp-
toms include swollen lymph nodes (in
the neck, armpits or groin), coughing,
shortness of breath, unexplained weight
loss, fever, profuse sweating (particu-
larly at night), and/or severe itchiness.
However, these symptoms may also be
signs of non-cancerous problems,

100
                                                          Occupational hygiene


                                            the population fall into this category.
                                     O      Apart from eating habits and lifestyle,
Obesity. Also called adiposity. Obes-       research conducted in recent years has
ity is still frequently regarded as more    shown that genetic factors play a major
of a cosmetic than a health problem.        role in predisposing certain individu-
Numerous studies conducted over re-         als to obesity.
cent years in the United States, Europe         Nowadays health experts recom-
and several developing countries show       mend drug treatment not only for
that the number of grossly overweight       obese patients, but also for overweight
people has increased appreciably and        patients with risk factors such as
is continuing to grow. These people are     elevated lipids or high blood pressure.
almost always at high risk of develop-      To treat these patients Roche has
ing – or have already developed – com-      developed Xenical (active ingredient
plications such as high blood pressure,     orlistat), a drug which blocks the
elevated blood lipids, non-insulin-         breakdown and absorption of dietary
dependent diabetes, biliary disease         fat in the gastrointestinal tract. When
and certain types of cancer. In light of    it is used in conjunction with a moder-
this, the World Health Organization         ately fat-reduced diet, a permanent
(¡WHO) has set up the International         reduction in body weight in the order
Obesity Task Force to raise public          of 10 percent can be achieved.
awareness of obesity as a serious health        Unlike appetite suppressants, which
problem, encourage prevention and           act on ¡neurotransmitters in the brain
treatment and facilitate international      and thus produce a number of side ef-
collaboration between experts, patient      fects, Xenical acts only in the digestive
groups and health policy makers.            tract. It has the additional advantages
    Body mass index (BMI) has estab-        that it does not enter the circulation
lished itself as the international          and markedly lowers elevated blood
measure of obesity. It is calculated by     lipid levels. The weight loss achieved
dividing body weight in kilograms by        with Xenical can also improve risk
body height in metres squared. If BMI       factors associated with obesity, such as
is 20 or over and less than 25, weight is   type II diabetes, hyperlipidemia and
normal. A BMI of between 25 and 30          high blood pressure.
is a sign that the patient is overweight,
while an index over 30 indicates obes-      Occupational hygiene. Scientific dis-
ity or (over 40) severe obesity. Over       cipline concerned with protecting em-
40 percent of the population of             ployees from potentially detrimental
the United States, Great Britain and        environmental influences at the work-
Germany already have a BMI over 25,         place by identifying, evaluating and
and the upward trend continues. In          controlling chemical, physical, biolog-
Japan, by contrast, only 20 percent of      ical and other physiological work-

Roche from A to Z                                                               101
 Oncogene


related risks. Harmful influences can        Oncology. The study of the diagnosis
adversely affect health and may even         and treatment of cancer. An important
result, in a worst-case scenario, in oc-     therapeutic area at Roche. Cancer
cupational disease. The task of occu-        is the second most frequent cause
pational hygiene in a company is to          of death in industrialised countries.
ensure that health hazards associated        Strictly speaking, it is not a single
with the workplace are identified            disease but rather a group of highly
and eliminated before they cause any         diverse clinical entities, all of which,
harm. Among other things, this               however, are the result of uncontrolled
involves periodically monitoring em-         (malignant) proliferation of human
ployees and assessing the risks associ-      cells.
ated with their working environments.           The increasing success of cancer
Risks at the workplace are identified,       therapy is the result of a multimodal
for example, by analysing air samples,       treatment approach involving surgery,
which may possibly be backed up by           radiotherapy, chemotherapy and im-
wipe tests of work surfaces and biolog-      munotherapy. Immunotherapy, which
ical measurements (biomonitoring).           specifically activates the body’s own
Workplace assessments are carried            defence mechanisms, has gained in
out by means of risk analyses. To take       importance in recent years.
chemicals handling as an example, the           Roche has been involved in cancer
health risk associated with a given          research for decades and today is the
chemical is made up of its toxicity (the     world’s leading supplier of cancer
injurious effects it can potentially         drugs. The first successful cancer treat-
have) and by the way it is handled (e. g.    ments were agents that killed dividing
the degree and duration of exposure).        cells. Roche was a pioneer in this field
Expressed mathematically, risk =             with the introduction of ¡Fluoro-
hazard × exposure. Recommending any          uracil Roche (5-fluorouracil, or 5-FU
necessary remedial action is an integral     for short) in 1962. ¡Cytostatic or cy-
part of the occupational hygiene as-         totoxic agents like 5-FU preferentially
sessment. The identification, evalua-        kill cancer cells, because they generally
tion and control of the risks are the task   divide more rapidly than normal cells.
of occupational hygienists, who work         However, such drugs also act against
closely with other analysts (¡analysis),     rapidly dividing normal cells, such as
safety experts (¡safety), occupational       those of the gastrointestinal tract,
physicians (¡employee health service)        mucous membranes and bone mar-
and toxicologists (¡toxicology).             row. Consequently, they have serious
                                             side effects that are acceptable only in
Oncogene. A gene that can cause              the treatment of severe disease. Roche
cancer. More than one oncogene is            has now developed a very well toler-
involved in most types of cancer.            ated cytostatic agent called ¡Xeloda,

102
                                                         Organ transplantation


which is a significant advance in such      treatment during surgery, chemother-
therapies, offering an effective and        apy or radiotherapy, protects patients
convenient oral treatment option in         from the frequent and unpleasant side
breast and bowel cancer.                    effects of nausea and vomiting. Both
   New technologies have now opened         these products make a significant
up highly promising perspectives for        contribution to improving cancer
the diagnosis and treatment of cancer.      patients’ quality of life.
Recombinant DNA (¡biotechnology)               In the diagnostic field, Roche is
and hybridoma techniques were pre-          pushing ahead with projects linking
requisites for the development of           treatment and diagnosis for the ulti-
¡Roferon-A, the first of a series of        mate benefit of patients. The develop-
immunotherapeutic agents. And cer-          ment of ¡tumour markers that enable
tain antioxidants, such as vitamins C       tumours to be detected and classified
and E, may have an important role in        at an early stage should, in future,
cancer prevention.                          facilitate the early, targeted selection
   Roche and the US company                 of the right drug for the individual
¡ Genentech have collaborated in de-        patient and accurate monitoring of
veloping innovative agents which are        the therapeutic outcome.
revolutionising the treatment of can-
cer. These include the monoclonal           Organ transplantation. Patients with
¡antibodies ¡MabThera (also known           organ failure find themselves in a des-
as Rituxan), ¡Herceptin, ¡Avastin           perate situation because of the short-
and Omnitarg; and the small molecule        age of available organs and the long
¡tyrosine kinase inhibitor ¡Tarceva.        waiting period for transplants. Al-
More than two million patients world-       though those with kidney failure can
wide have benefited from Roche’s anti-      always be treated by dialysis, the best
cancer drugs in the past ten years.         solution is for them to receive a “new”
   In addition to these products, Roche     kidney. In the case of liver, heart
has also developed several drugs that       and/or lung failure, transplantation is
can help relieve the significant side       the only alternative and operations of
effects cancer patients have to endure      this kind are performed in specialised
as a result of their treatment, including   clinics all over the world. Certain other
Bondronat, ¡NeoRecormon and Kytril.         organs, such as the pancreas or small
Bondronat is used to treat bone metas-      intestine or sometimes several organs
tases, relieving pain and reducing          simultaneously, can now also be trans-
the frequency of bone fractures. Neo-       planted, but the necessary surgical
Recormon, for ¡anemia, is given to          techniques are still in the developmen-
reduce the need for blood transfu-          tal stage.
sions. Kytril, which is used in Europe         Rejection of a transplanted organ,
and the United States as concomitant        whether natural or artificial, can occur

Roche from A to Z                                                               103
  Orphan drugs


at an early stage (acute rejection) or        clonal ¡antibody for preventing re-
after a long process which destroys the       jection of transplanted kidneys. The
organ over a period of years (chronic         highly specific result of this work,
rejection). Most patients who receive         Zenapax (daclizumab), was launched
an organ transplant have to take med-         worldwide by Roche in 1998.
ication for the rest of their lives to pro-      Roche and Isotechnika, a company
tect the organ from rejection by their        based in Edmonton, Canada, have
own body. This is achieved by means           signed an agreement stating their in-
of drugs, often very aggressive ones,         tention to jointly develop Isotechnika’s
which suppress the ¡immune system,            innovative transplant drug ISA247
making the patients more susceptible          worldwide. ISA247 is an immuno-
to other diseases and to a series of          suppressive agent that can be used in
severe side effects. For patients unfor-      organ transplantation and for the
tunate enough to lose a transplanted          treatment of ¡autoimmune diseases.
kidney, there is always the fallback of       Preliminary studies indicate that
dialysis; but if the transplanted organ       ISA247 is much more effective and
is a vital one such as the heart, lungs,      possesses a much better side effect
liver or pancreas, the only resort is a       profile than other immunosuppres-
second transplantation. Drugs which           sants of this type. The impressive
can protect such patients against trans-      properties of ISA247 hold out the
plant rejection are of incalculable value.    prospect of substantial therapeutic
   Roche is working to develop drugs          advantages for patients over tradi-
which can help save the lives of pa-          tional calcineurin inhibitors.
tients with transplanted organs and              In 2005 Roche and BioCryst Phar-
ensure their well-being and autonomy.         maceuticals, Inc. announced an exclu-
CellCept (mycophenolate mofetil) is           sive license to develop and market
an immunosuppressant that reduces             BioCryst’s phase 1 compound BCX-
the incidence of acute rejection. It is a     4208 which prevents transplant rejec-
less aggressive form of treatment, with       tion by a unique action on the body’s
a very favourable tolerance profile.          own reaction to determine when to
Roche has also developed Valcyte (val-        initiate immune responses and when
ganciclovir), a tablet form of antiviral      to accept or reject newly transplanted
medicine for the prevention and treat-        organs. It is hoped that BCX-4208 may
ment of cytomegalovirus infection –           offer autoimmune and transplant
cytomegalovirus is responsible for            patients a potentially more effective
the opportunistic infections most fre-        treatment option.
quently observed in transplantation
patients. Roche collaborated with             Orphan drugs. An expression current
Protein Design Laboratories, Inc., to         in the United States for ¡pharmaceu-
develop the first humanised mono-             ticals used to treat rare but life-threat-

104
                                                                  Osteoporosis


ening diseases. Such products can          bution to monitoring the progress of
never recoup their research and devel-     osteoporosis treatment by giving some
opment costs, not to mention the mar-      indication of its efficiency and also by
keting expenditure involved, and are       providing a means of monitoring
thus often consigned to an “orphan-        patient compliance. Bone markers also
like” existence. Roche has developed       help to assess the fracture risk and
a number of such preparations as a         potential bone mass loss. They provide
result of its basic research activities    information on whether a prescribed
and, in the United States, has received    course of treatment is proving success-
special awards for these on several        ful a lot earlier than bone density meas-
occasions. In the United States, orphan    urements. The ¡Diagnostics Division’s
drug status is defined by legislation      ¡Professional Diagnostics business
which affords special protection from      area offers the following immunologi-
competition over a period of several       cal serum marker tests: Bone absorp-
years if the medicinal product in-         tion markers for sensitive monitoring
volved benefits no more than 200,000       of the progress of antiabsorption
patients.                                  treatment and predicting the risk of
                                           fractures; bone formation markers for
Osteoporosis. A condition that is          sensitive monitoring of the progress
characterised by depletion of bone         of anabolic and antiabsorption treat-
mass, deterioration of bone structure      ment; bone markers for monitoring
and an increased risk of fractures. In     treatment progress and predicting the
most cases the diagnosis is only made      risk of fractures; and intact para-
after a fracture has occurred, most        thyroid hormones for the differential
typically a fracture of the hip, spine     diagnosis of hypercalcemia and hypo-
or lower arm. Numerous factors con-        calcemia. To avoid bone damage, early
tribute to the development of osteo-       diagnosis and initiation of treatment
porosis, but by far the most significant   are essential.
is accelerated loss of bone mass, which    There is also a number of Elecsys tests
becomes a concern in women during          for the Elecsys 2010, the E170 module
the menopause and in elderly men. To       for the Modular Analytics SWA and
guard against this condition, doctors      the e 601 module for the cobas 6000
recommend a balanced diet rich in          family of analysers.
calcium and vitamin D and physical            In addition to calcium and vita-
exercise.                                  min D substitution, bisphosphonates,
   Osteoporosis is generally diagnosed     selective estrogen receptor modulators
by measuring bone density with quan-       (SERMs) and calcitonin in particular
titative computed tomography (QCT)         are used to treat osteoporosis. Roche
or quantitative ultrasound (QUS). Bone     has developed the preparation Bon-
markers can make a valuable contri-        viva (Boniva in the USA), which slows

Roche from A to Z                                                              105
 Osteoporosis


the accelerated breakdown of bone
and increases bone mass, thereby sig-
nificantly reducing the incidence of
fractures, e. g. vertebral fractures. Bon-
viva/Boniva is the first oral bisphos-
phonate approved for the treatment
of postmenopausal osteoporosis that
only needs to be taken once a month.
Roche and its marketing partner
GlaxoSmithKline have introduced the
preparation in the United States and
Europe. Launched in January 2006,
Boniva Injection is the first approved
intravenous form for the treatment of
postmenopausal osteoporosis. Boniva
Injection only needs to be adminis-
tered once every three months and is
primarily intended for patients who
are unable to tolerate oral bisphospho-
nate treatment.
   ¡Chugai distributes the drug Evista
(SERM) in Japan.




106
                                                                           Palo Alto


                                               logical aspects or safety (¡child-proof
                                        P      drug containers). Roche relies prima-
Packaging. Packaging serves to pro-            rily on environmentally-compatible
tect goods which often have to travel a        materials for its packaging, e. g. card-
long way to the consumer and in some           board.
cases pass through different climate
zones. It also conveys information and         Palo Alto. Research centre and one of
aids identification and distribution.          the ¡Pharmaceuticals Division’s global
Suitable packaging is often required           research sites. Situated on a park-like
simply to be able to transport and sell        campus, the centre currently employs
a product.                                     around 1,000 people. Work at Palo
    Packaging for pharmaceuticals must         Alto (California) focuses on the dis-
satisfy a wide variety of requirements.        covery and early clinical development
Dosage forms – tablets, capsules, pre-         of innovative new medicines to treat
filled syringes, vials, etc. – are sensitive   serious diseases, including arthritis,
products in loose form and only be-            asthma and other respiratory diseases;
come usable medicines in combination           anxiety, depression, schizophrenia and
with a number of packaging elements            other psychiatric diseases; genitouri-
(e. g. bottles, tubes or blister packs).       nary diseases, HIV infection/¡AIDS
    Packaging consisting of several ele-       and ¡hepatitis C. The research centre
ments (typically a container, labelling,       in Palo Alto makes a significant contri-
a leaflet and a carton) are the rule, with     bution to Roche’s portfolio of new
each element fulfilling specific func-         drugs.
tions. The choice of packaging mate-              Located on the Roche campus in
rial must be adapted to the contents.          Palo Alto on San Francisco Bay, the
Plastic containers or foil must be             company is in the heart of Silicon
tested for compatibility with the prod-        Valley, close to a number of renowned
ucts they are to contain, and even glass       academic       institutions, including
must fulfil quite specific requirements        Stanford University, the University of
regarding neutrality and compatibil-           California, San Francisco, and the
ity. An expiry date for the preparation        University of California, Berkeley.
is printed clearly on the pack, and            The synergies between the university
other symbols allow the contents to            and the private sector have created an
be identified by manufacturing batch.          environment in which leading-edge
Packaging should be user-friendly, but         research can be conducted in numer-
must also guard against the risk of            ous disciplines.
¡counterfeit drugs.                               Research operations began in 1961,
    The different requirements that            when Syntex set up its headquarters on
packaging has to meet can often con-           the current Roche site in Palo Alto.
flict, particularly with regard to eco-        From the time of its formation until it

Roche from A to Z                                                                 107
 Parent company


was taken over by Roche in 1994,           Patents. Legal protection for inven-
Syntex was widely renowned for its         tions. ¡Research is about discovery,
innovative approach in the synthesis       gaining new insights. In the interests
of steroidal and nonsteroidal drugs.       of progress, this knowledge should be
   Two medicines that were developed       made available to the public. But this
at the Palo Alto site and are now on the   would mean revealing it also to com-
market are CellCept (¡organ trans-         petitors, who could use the fruits of
plantation) and Valcyte (¡AIDS,            someone else’s work to further their
¡antimicrobials).                          own commercial ends. By patenting
                                           their findings, inventors or their legal
Parent company. The origins of the         representatives are guaranteed a cer-
Roche Group go back to the firm of         tain head start, which enables them to
F. Hoffmann-La Roche & Co. Ltd in          recoup the cost of the research in-
Basel. The company was registered as a     volved and, possibly, earn additional
limited partnership on the initiative of   funds to finance other research pro-
Fritz ¡Hoffmann-La Roche on 1 Oc-          jects. The publication of patents pro-
tober 1896 and became a public lim-        motes the exchange of scientific and
ited company in 1919. In terms of          technical information and lays the
commercial law it was a combined           foundations for new developments
production, trading and holding com-       and progress. By means of patents, a
pany. As part of a capital restructuring   company can either prevent the use of
carried out in 1989, the parent com-       its discoveries by third parties, or put
pany became Roche Holding Ltd.             them at their disposal under licence
Since then the Swiss operating com-        for an appropriate fee.
pany, F. Hoffmann-La Roche Ltd,               However, inventions can only be
Basel, has assumed some key parent         patented if they are genuinely new and
company functions on behalf of the         original and are suitable for commer-
¡holding company (¡Group).                 cial exploitation. The protection con-
   Today, the parent company is one        ferred by a patent is generally limited
of Roche’s largest centres of research,    to one country and lasts for about
production and administration. Group       twenty years from the filing date.
management and ¡corporate func-            Accordingly, patent applications have
tions are based in Basel, as are the       to be filed in each country in which
headquarters of the ¡Pharmaceuticals       protection is desired, although re-
and ¡Diagnostics Divisions. Basel is       gional and international patent
also home to the global pharmaceuti-       treaties have considerably simplified
cal functions and certain worldwide        the application process. Due to the
pharmaceutical research and produc-        long development phase for pharma-
tion operations.                           ceuticals, it can be years before a drug
                                           product is approved (¡registration)

108
                                                    Pediatric pharmaceuticals


and launched. This means that the           comes to neonates and toddlers. Most
effective period of protection is often     countries issue pediatric dosage tables
about ten years or less. However, in all    for guidance purposes, but these are
important markets, including the            not based on systematic clinical trials
United States, Europe and Japan,            and therefore do not meet the stan-
patents for ¡pharmaceuticals can be         dards that currently apply to dose-
extended for up to five years.              finding in adults.
   Roche holds or has licences for over        On the one hand, the rules of the
25,000 patents and patent applications      market on their own do not create suf-
in around 60 countries. These patent        ficient demand for pediatric clinical
rights are not always strictly observed     drug development. On the other,
by third parties, and must then be          impressive therapeutic breakthroughs
enforced by legal action.                   have been made over recent decades
                                            in the treatment of children that offer
Patient self-monitoring kits. Diag-         a glimpse of the growing possibilities
nostic tests for patients to perform        of modern drug treatments. Forty
themselves as a check on treatment for      years ago a diagnosis of acute lym-
a specific disease, for example ¡glu-       phatic leukemia (ALL) amounted to
cose self-monitoring kits and ¡coagu-       a death sentence for the child con-
lation self-monitoring systems.             cerned. Systematic studies conducted
                                            since then have increased the survival
PCR. ¡Polymerase chain reaction.            rate by 10 to 20% per decade, so that
                                            nowadays some 90% of children sur-
Pediatric pharmaceuticals. Until            vive ALL. These and other factors have
now drugs have been systematically          prompted social intervention. The
tested in children only if the disease in   first step was made in 1997 by the US
question was common in children and         government with the introduction of
there was felt to be a great need for       two complementary pieces of legisla-
treatment, e. g. medicines for viral        tion: one offered pharmaceutical com-
and bacterial infections, epilepsy or       panies a patent extension for clinical
asthma. Since most other medicines          pediatric studies; the other compelled
were not systematically tested for          companies to conduct pediatric stud-
safety and efficacy in children, doctors    ies if a relevant need in children
had to prescribe them outside the           existed or was expected.
approved indications (“off-label”). A          An equivalent discussion was ini-
discrepancy thus exists between the         tiated in the EU in 2000 and a draft
very advanced standards of drug treat-      regulation was passed by the EU par-
ment for adults and the “trial-and-         liament. The final regulation was sub-
error” approach for children. This          sequently published in the Official
discrepancy is most marked when it          Journal of the European Union in

Roche from A to Z                                                             109
 Pediatric pharmaceuticals


December 2006 and entered into force        ation of pediatric studies in the case of
in all countries of the EU one month        life-threatening diseases, and studies
later. In a welcome development, Swiss-     at a later stage for all other diseases,
medic was involved in the preparation       when much more is known about the
of the regulation even though Switzer-      safety and efficacy of the drug in
land is not a member of the EU. The         adults. Many development projects are
regulation requires the submission of       terminated before approval is granted
a clinical pediatric investigation plan     either because of safety issues or be-
to the European Medicines Evaluation        cause the drug under investigation is
Agency (EMEA) on completion of              less effective than anticipated. Routine
phase 1 studies in adults. In return for    testing of all early-stage projects in
preparing this investigation plan,          children or the routine preparation of
companies receive a 6-month patent          subsequent pediatric studies would
extension. A pediatric investigation        be extremely time-consuming. Such a
plan is also required for drugs that are    process would not only be unethical,
already on the market and for which         but would also massively increase
a new indication or pharmaceutical          overall development costs and, espe-
form is requested. For drugs that have      cially if a project were subsequently
already undergone pediatric studies in      terminated, serve no purpose. Fast-
other countries (primarily at the re-       tracked clinical development of new
quest of the US authority FDA), the         drugs for children will probably re-
existing data must be submitted to the      main the exception, only used when
European licensing authority. Specific      breakthroughs in the treatment of life-
projects are envisaged for older drugs.     threatening illnesses are achieved. Pos-
   The EU discussion has provided           sible examples would be new drugs for
greater clarity concerning the point at     the treatment of currently incurable
which children should be included in        pediatric cancers or neuromuscular
the drug development process. A care-       diseases.
ful assessment of the situation is re-         Introducing a pediatric factor into
quired, taking account of potential         the general drug development process
uses, other currently available medica-     represents a substantial investment for
tion and the risk of exposing children      all pharmaceutical companies since
to a new substance, the safety of which     they will have to accumulate knowl-
is still uncertain. Key guidelines for      edge about the epidemiology of the
such an assessment are provided in          target illness in children, the age-re-
the ICH (International Conference on        lated course of the disease, its natural
Harmonisation) Guidance E11 on the          course in children without therapeutic
“Clinical Investigation of Medicinal        intervention, its mechanism in various
Products in the Pediatric Population”,      age groups and many other aspects. In
which specifies the need for early initi-   the USA, this already forms the basis

110
                                                     Pharmaceuticals Division


for negotiations with the FDA. Mod-         Roche Diagnostics GmbH. The Penz-
ern drug development is a complex           berg site has developed into one of
process that involves much more than        Europe’s leading ¡genetic engineering
just clinical trials. Increased demands     and biotechnology research and pro-
will be made on two areas in particu-       duction centres. With a payroll of over
lar: the development of suitable pedi-      4,000, Penzberg is the only Roche site
atric formulations, usually in liquid       that combines research, development
form since small children are unable to     and production operations of the
swallow tablets, and the inclusion of       ¡Pharmaceuticals und ¡Diagnostics
young laboratory animals in preclini-       Divisions. The facility concentrates on
cal safety studies designed to predict      system development for immunologi-
the effects and side effects on the still   cal, clinical chemistry and molecular
developing organ systems of children.       diagnostic (¡PCR technology) appli-
   Global companies with a significant      cations and on the research, develop-
presence in the United States are           ment and manufacture of therapeutic
already having to comply with US            ¡proteins and other active ingre-
pediatric legislation. Roche has al-        dients.
ready conducted systematic clinical
studies of a series of drugs in children,   Pharmaceuticals. Collective term for
including Tamiflu, Xenical and              products intended to restore health
Fuzeon. Investigation plans for other       or prevent disease. Originally made up
drugs such as Xeloda and Bonviva are        by pharmacists, most pharmaceuticals
being discussed with the FDA. This          are now manufactured industrially.
aspect will become even more impor-         One possible definition might be:
tant with the introduction of Euro-         “Products of chemical, biotechnologi-
pean legislation, and corresponding         cal or biological origin which are
pediatric investigation plans are           intended or purported to have a
already being drafted. Roche has set up     medicinal effect in man or animals,
a permanent interdisciplinary group         and which are used especially for the
involving all the important pharma-         detection, prevention or treatment of
ceutical functions to meet the chal-        diseases, injuries or disabilities.” The
lenges posed by the pediatric legisla-      manufacture and sale of pharmaceuti-
tion in the USA and the EU.                 cals are subject to strict statutory con-
                                            trols in virtually all countries (¡regis-
Penzberg. A town south of Munich,           tration).
on the edge of the Bavarian Alps in
Germany, where Boehringer Mann-             Pharmaceuticals Division. The Phar-
heim found a suitable location in 1972      maceuticals Division comprises a
for its biotechnology activities. In        number of functions in Basel itself,
1998, the company was integrated into       together with the Roche companies

Roche from A to Z                                                               111
 Pharmacoeconomics


abroad that are responsible for the        Pharmacoeconomics.          A science
pharmaceuticals business. Roche be-        which helps determine what benefits
gan as a purely pharmaceutical com-        a new drug offers to offset its costs. As
pany (¡Hoffmann-La Roche, Fritz)           a result of the growing cost pressure
and the Pharmaceuticals ¡Division is       on healthcare providers, pharmaco-
still the most important in the Group.     economic research has steadily gained
The division consists of ¡Rx (pre-         in significance.
scription drugs), ¡Genentech and              Pharmacoeconomic research iden-
¡Chugai.                                   tifies and quantifies all relevant costs
   The division is organised on the        and consequences of a course of treat-
principle of full vertical integration,    ment and compares these with the
which means it encompasses all ¡re-        existing standard. By “consequences”
search and development, production         we mean the effects of the treatment,
and ¡marketing activities – as well as     wanted and unwanted, as well as the
the necessary support functions.           usage of resources it entails. This
   Roche seeks to research, develop        makes it possible, for example, to as-
and market clinically differentiated       certain whether an ostensibly high-
drugs that produce significant bene-       cost medicine could save even greater
fits for patients, either by saving life   costs in the long run, because it would
or by substantially improving quality      reduce the length of hospital stays.
of life.                                      In most countries, pharmacoeco-
   Roche has made significant contri-      nomic data are not required to obtain
butions to the prevention and control      approval for a drug. However, this
of widespread and often life-threaten-     information is valuable and in some
ing diseases. Its most important pre-      cases a prerequisite for inclusion on
scription drugs are used in the follow-    the drug reimbursement lists main-
ing therapeutic areas: metabolic           tained by health authorities, health
disease, virology, oncology, blood dis-    insurers and managed-care organisa-
eases, disorders of the central nervous    tions.
system, cardiovascular disease, inflam-
matory disease and transplantation         Pharmacogenetics. Investigates and
medicine.                                  describes the variations in the genes of
   Research is focused on the areas of     individuals and their effect on the effi-
inflammatory disease/bone disease,         cacy and side effects of ¡pharmaceu-
disorders of the central nervous sys-      ticals. This information can be helpful
tem, vascular disease, oncology, meta-     in the research and development of
bolic disease, genitourinary disease       drugs, but it can also be used in select-
and virology.                              ing the right dosage of the right medi-
                                           cine for particular patients.



112
                                                                     Phelophepa


Pharmacogenomics. Considers the              cific dosage forms and modes of drug
interaction between active pharma-           delivery.
ceutical ingredients and the totality           Whether or not the effects of a
of all genes, i.e. the ¡genome of an         promising drug are discovered de-
individual.                                  pends largely on the types of pharma-
                                             cological tests available. Not all dis-
Pharmacokinetics. The study of the           eases have suitable pathological
dynamic behaviour of pharmaceutical          models, for example, rats with high
substances in biological systems; in         blood pressure.
particular it is used to describe the ab-       The ¡immune system can be both
sorption of a substance into the body,       the target of treatment and a means
its distribution throughout the body         of fighting a disease. For many, the
and its tissues, and its elimination         term immunopharmacology means
from the body through metabolic con-         the influencing of the immune sys-
version to other substances (which           tem, through stimulation, suppression
may or may not be biologically active)       or modulation, by endogenous and
or expulsion in excreta, i. e. urine and     exogenous substances; others regard it
bile ( ¡pharmacology).                       as the study of the effects on the body
                                             of substances which also occur in the
Pharmacology. The branch of science          immune system, for example ¡anti-
that deals with the study of drugs (and      bodies and ¡cytokines (¡Roferon-A).
poisons) and their actions on living
systems. The study of the interactions       Phelophepa. Made up of two words
between exogenous substances, drugs          from different South African lan-
or poisons and biological systems, that      guages which, when translated liter-
is, living organisms. The study of the       ally, mean “good, clean health”,
effects of foreign substances on the         Phelophepa is the name of a mobile
body is referred to as pharmaco-             clinic on rails. Roche has been sup-
dynamics; the fate of a foreign sub-         porting the “Train of Hope”, as local
stance in the body – how it is absorbed,     people call it, since 1994 and is one of
distributed, altered and ultimately          its leading sponsors. In May 2002
eliminated – is known as ¡pharmaco-          Roche was honoured with an award
kinetics. The special area of pharma-
cology concerned with the nature
and effect of poisons and thus also
with the toxic effects of drugs, is called
¡toxicology. The results of pharma-
cological investigations form the basis
for the field of pharmaceutical ¡for-
mulation, which is concerned with spe-

Roche from A to Z                                                               113
 Plasmid


for this project (¡social responsibil-     named the “Roche Health Clinic” in
ity).                                      recognition of Roche’s long-standing
   The 16-coach train provides basic       and continuing support. Roche has as-
medical care in rural districts of South   sumed full financial responsibility for
Africa and spends 36 weeks a year trav-    this clinic and provides all funding for
elling around the country. A perma-        maintenance, salaries, medical equip-
nent staff of 14 work with about           ment, consumables and training mate-
40 students preparing for careers in a     rials. Since 2002 Roche has also been
variety of medical fields and who each     contributing to initial and in-service
spend 14-days on the train gaining         training activities to help the clinic’s
valuable practical experience. Over        staff stay abreast of the latest advances
40,000 people are treated on the train     in primary care and provide the best
every year. To date the Health Train has   possible services. Since 2003 the train
reached over seven million people in       has been able to offer several new serv-
remote parts of South Africa. In addi-     ices (cancer screening tests and dia-
tion to the Health Clinic, which is        betes prevention) thanks to additional
wholly funded by Roche, the train can      funding provided by Roche.
provide help in the areas of dental,          At a ceremony in 2002, South
ophthalmic and psychiatric care. Phe-      Africa’s Ambassador to the USA, Sheila
lophepa even has its own pharmacy          Sisulu, presented Roche with an award
on board. The personnel of the Roche       for its involvement in the project.
Health Clinic also travel to various
schools in the area in order to examine    Plasmid. A small piece of bacterial
and treat local children with specific     ¡DNA which is capable of independ-
problems, for example ear infections.      ent replication within a host organism.
   At each of the 36 annual stops vis-     Most genetic manipulations are per-
ited by the so-called Edu Clinic,          formed on bacterial plasmids.
around 20 members of the local com-
munity come aboard for a five-day          Pleasanton. Following the acquisition
course that provides basic information     of Boehringer Mannheim by Roche in
on subjects such as first aid, hygiene,    1998, ¡Molecular Diagnostics, a busi-
infectious diseases, sound nutrition       ness area of the ¡Diagnostics Divi-
and family health. This method of          sion, established its global headquar-
helping people to help themselves has      ters in Pleasanton, California, USA
brought about a significant and lasting    (east of San Francisco Bay and Silicon
improvement in the health of people        Valley). Today Pleasanton is one of
living in the regions visited by the       Molecular Diagnostics’ 3 centres of ex-
train.                                     cellence, home to one of two research
   In 2001 the coach housing the           and development centres for the com-
train’s health clinic was officially re-   pany’s growing range of ¡PCR- and

114
                                          Polymerase chain reaction (PCR)


real-time PCR-based analytical sys-       material (¡DNA) millions of times
tems and tools for ¡in vitro diagnosis.   over, as an aid to subsequent analysis.
The other research and development        PCR technology was developed during
centre of excellence for Molecular Di-    the period of 1985–1989 by scientists
agnostics is in Rotkreuz, Switzerland,    at the California biotechnology firm
with the Molecular Diagnostics’ main      Cetus Corporation, under the direc-
manufacturing centre of excellence in     tion of Kary B. Mullis (who was
Branchburg, New Jersey, US. These         awarded the ¡Nobel Prize for chem-
tools and automation platforms, in-       istry in 1993). In 1989 Roche scien-
cluding the first microarray-based        tists, in collaboration with Cetus
diagnostic system, are used worldwide     Corporation, began developing the
in the areas of donor ¡blood screen-      first commercial applications for the
ing, ¡genomics, infectious diseases,      diagnosis of infectious diseases. In
microbiology and ¡oncology. Around        1991 Roche reached an agreement with
400 of the 1,100 employees of Molecu-     Cetus concerning the acquisition of the
lar Diagnostics work in Pleasanton,       rights to all technology and processes,
500 in New Jersey, and 200 in Switzer-    as well as the patent rights for existing
land.                                     and as yet unknown PCR applications.
                                          Other assets of Cetus Corporation,
Point of Care Testing. General term       including HIV and hepatitis C patent
for all tests carried out not just in     rights, were acquired by Chiron Cor-
laboratories but wherever patients are    poration (now Novartis).
treated, for example in intensive care,      In basic biomedical research, PCR
emergency admissions, medical prac-       is one of the key molecular biological
tices, outpatient services, at pharma-    tools for detecting and deciphering the
cies or at home. In these user-friendly   genetic material of living organisms
tests, the specimen – a drop of blood     and analysing its function. PCR tech-
or urine sample – is applied to the re-   nology can also be employed to iden-
action zone and the result is available   tify the genetic causes of many ill-
within seconds or no more than a few      nesses. In pharmaceutical research this
minutes. Point of Care tests permit       can be vital for the development of
rapid and reliable diagnosis, so treat-   new types of drugs that target the ac-
ment can be started without delay. This   tual causes of disease. The technology
results in improved quality of health-    is also used in forensic analysis and
care and lower overall costs (¡test       medicine, for example to determine
strips, ¡Professional Diagnostics).       paternity or to establish the biological
                                          origin of traces of blood, hair or semen
Polymerase chain reaction (PCR).          found at the scene of a crime.
A molecular biological technique for         One of the main applications of
copying selected portions of genetic      PCR technology is in the early diagno-

Roche from A to Z                                                             115
 Polymerase chain reaction (PCR)




Using PCR technology, a single fragment of genetic material (DNA) can be copied
millions of times in just hours, yielding enough material for the detection of
hereditary diseases, cancer cells or viruses.

sis of infections and genetic condi-      and blood products used in a variety of
tions, and potentially of cancer. This    medical therapies by providing highly
applies, for example, to infections       sensitive screening for possible infec-
caused by ¡AIDS or ¡hepatitis C           tion.
viruses, Chlamydia or tuberculosis           The comprehensive range of tests
bacteria, or sepsis-causing bacteria      produced by the ¡Diagnostics Divi-
and fungi. PCR methods can detect         sion’s ¡Molecular Diagnostics busi-
latent pathogens which other tests        ness area, which are based on highly
cannot identify, or which they can only   sensitive PCR and real-time PCR tech-
identify with difficulty or after a       nologies, has brought about a revolu-
lengthy period. PCR tests are the most    tion in routine clinical diagnosis. The
efficient method currently available      first tests in this series were introduced
for direct, rapid detection of HIV and    in 1992; today, there are test kits
hepatitis infection. Quantitative PCR,    for hepatitis C virus (quantitative and
moreover, is the method of choice for     qualitative assays), for HIV-1 (quan-
monitoring the treatment of patients      titative and qualitative assays), for
with HIV or hepatitis infections.         Mycobacterium tuberculosis, M. avium,
   PCR tests can also be used to im-      M. intracellulare, Chlamydia trachoma-
prove the safety of the donated blood     tis/Neisseria gonorrhoeae, hepatitis B

116
                                           Polymerase chain reaction (PCR)


                                           approved by the US health authorities
                                           in mid-1996, a mere seven months
                                           after application for registration, and
                                           has had an extremely positive recep-
                                           tion in the market. Amplicor HIV-1
                                           Monitor, which has been available on
                                           the European market since 1995, has
                                           become the most frequently used test
                                           of the PCR range.
Cobas Amplicor – an automated mo-             In 1995 ¡Cobas Amplicor, the first
lecular diagnostic system that performs    automated system, was launched. This
amplification and detection automati-      instrument performs the amplifica-
cally.                                     tion and detection steps automatically,
                                           giving clinical laboratories a simpler,
                                           more efficient method for molecular
                                           diagnosis. The automation process
                                           was continued and completed in 2001
                                           with the introduction of the Cobas
                                           AmpliPrep. This device automates
                                           sample work-up so that all three stages
                                           of a diagnostic PCR test, i. e. sample
                                           preparation, amplification and detec-
                                           tion, can now be processed by the
Amplicor HIV-1 Monitor – a quan-           appropriate automated systems.
titative molecular diagnostic test for        The latest development in the field
measuring viral load in the blood of       of diagnostic PCR at Roche are devices
HIV-positive patients.                     offering “real time” PCR based on
                                           Roche “TaqMan” technology. The first
virus (quantitatively), the cytomegalo-    Cobas TaqMan was launched in 2003.
virus (quantitatively), and other patho-   The TaqMan technology accelerates
gens.                                      and simplifies the process of diagnos-
   The Amplicor HIV-1 Monitor test         tic PCR. It is, in fact, a highly sensitive
sets new standards: It is the first com-   quantitative method with a very wide
mercially available test for determin-     linear measuring range. “Real time”
ing the viral load in the blood of HIV     PCR, combined with automation of
patients. This provides a very reliable    the Cobas AmpliPrep and Cobas
method for tracking the course of the      TaqMan instrument platform, repre-
infection and helps doctors employ         sents another quantum leap in the
medications such as protease in-           development of diagnostic PCR
hibitors more effectively. The test was    methods.

Roche from A to Z                                                                117
  Predisposition


   In June 2005 Roche opened the              trolled by national pricing authorities.
world’s largest PCR production facility       In Europe in particular, there is a com-
in Branchburg, New Jersey, USA. The           plex network of price controls for
site will focus on the manufacture and        drugs. The main reasons given for state
delivery of sector-leading products           control of pharmaceutical prices are
based on this technology. Roche has           alleged lack of competition, payment
invested over USD 150 million in the          for drugs by state health insurance
construction of this new plant and the        schemes and a general drive to contain
renovation of the existing factory. The       healthcare costs. Funding limitations
new centre has enabled Roche to con-          have forced most healthcare systems to
centrate all the production operations        implement a wide range of cost-con-
of factories scattered across New Jersey      tainment measures. These range from
on a single site in Branchburg. Up to         systems that control the prices of new
800 employees will work in the new            products as they enter the market (e. g.
complex, which has created around             Europe), to systems that support the
350 new jobs.                                 fast entry of large numbers of cheap
                                              generic products at the end of the
Predisposition. A situation that              patent life of a product (e. g. United
favours the development of an illness         States). The mechanisms applied to
on the basis of an existing susceptibil-      control market prices also vary consid-
ity. Such a susceptibility is either in-      erably, from price comparisons with
herited or the result of constitutional       other countries (seen within and
factors such as age, sex or any kind of       across all geographic regions) to
previous illnesses.                           “fixed-price” systems within the same
                                              health care system, where similar
Prevention. Involves measures taken           products are referenced and eventually
to prevent diseases, etc. Prevention can      also clustered into one price category),
be subdivided into three categories:          to imposed periodic price cuts across
primary prevention, which eliminates          all pharmaceutical products (e. g.
harmful factors before they can take          Japan). In some countries market prices
effect; secondary prevention, which           are indirectly controlled through im-
identifies and treats diseases at the         posed limits on the profitability of
earliest possible stage; and, finally, ter-   pharmaceutical companies. Some coun-
tiary prevention, which attempts to           tries actually operate a mixed regime
prevent any deterioration or compli-          incorporating elements from various
cations once a disease has occurred.          systems. In most cases, such interven-
                                              tions adversely affect research-based,
Prices. In virtually all countries with       innovative companies and tend to
the exception of the United States,           strengthen the position of imitators.
pharmaceutical prices are set and con-        Though possibly of (short-term) ben-

118
                                                                      Prix Galien


efit to the health budget, or at least to      In 1984 the prize was awarded to
the health insurers, in the long term it    Tigason, the first truly effective treat-
is an obstacle to progress. Value-based     ment for severe forms of psoriasis.
pricing (based on clinical and phar-        The active ingredient of Tigason is a
maco-economic evidence) and the ex-         retinoid. Despite the considerable risk
ploration of a personalised medicine        of side effects, the jury felt that the
approach (which looks into optimal          relief of the severe, unsightly symp-
allocation of scarce healthcare re-         toms of psoriasis was so significant an
sources through identification of spe-      achievement as to merit the award.
cific target patient groups) are increas-      In 1988 the Prix Galien went to the
ingly requested by local healthcare         benzodiazepine antagonist Anexate,
authorities before they accept the price    which offers dose-controlled reversal
of a new pharmaceutical product.            of the effects of benzodiazepines and
                                            thus adds a new dimension to anesthe-
Prix   Galien   (Prix   Galien   de   la    sia (¡antagonists, ¡benzodiazepines,
Recherche Pharmaceutique). High-            ¡psychotropic drugs).
est and most prestigious award for             Neupogen and ¡Invirase (1998
pharmaceutical research. The Prix           International Prix Galien) have also
Galien is named after the ancient           won national Galen awards in various
Greek philosopher and physician,            European countries.
Claudius Galenus (AD 130–200), who             Herceptin was awarded the Prix
is generally recognised as the “father      Galien in 2002. Herceptin was the first
of modern pharmacology”. The Prix           drug specifically developed to inhibit
Galien has been awarded annually in         the function of the protein HER2,
France since 1970 (and latterly in other    which is present on the cell surface in
countries and at an international level)    increased quantities in some forms of
to a product which represents a signif-     breast cancer. For women with HER2-
icant medical breakthrough and can be       positive breast cancer, including those
said to display special innovative ther-    in an advanced stage of the illness,
apeutic properties. Various drugs from      Herceptin promises a significantly
Roche’s pharmaceutical research labo-       improved life expectancy. The prepa-
ratories have received the Prix Galien.     ration is not burdened with the side
   Roche first won the prize in 1974        effects of traditional chemotherapy,
with the ¡antiparkinsonian agent            thus giving back patients a better qual-
Madopar (levodopa plus benserazide).        ity of life (¡oncology).
The award was recognition of Roche’s           In 2004 the International Prix
concentrated efforts to eliminate the       Galien was awarded to ¡Fuzeon, the
severe side effects associated with pre-    first of a new class of highly innovative
vious therapies based on levodopa           anti-HIV drugs known as “fusion in-
alone.                                      hibitors”. Unlike existing HIV drugs,

Roche from A to Z                                                               119
 Product distribution


which attack the virus once it has al-     must be constantly available in perfect
ready infected the human cell, Fuzeon      condition. Similarly, adequate supplies
prevents the virus from entering the       of commonly used preparations must
cells in the first place.                  be assured to cope with emergencies
                                           (such as epidemics). The various links
Product distribution. The distance a       in the distribution chain between the
Roche product has to travel to get         manufacturer and the consumer pro-
from factory to consumer is often          vide for blanket coverage and make
long and, depending on the type of         distances shorter for the consumer.
product, may include a number of           Even though an efficient and reliable
stops en route. Generally speaking,        system of distribution exists in indus-
Group companies are responsible for        trial countries – including Switzerland
distribution within their domestic         – provision must be made for emer-
markets (¡logistics). Many diagnostic      gencies. For this reason a firm such as
products, e. g. laboratory equipment,      Roche must always have staff on call
are not sold through specialist dealers    who can arrange for the supply of
since they are usually supplied direct     urgently needed products even at
to customers such as teaching and          night and at weekends.
non-teaching hospitals, institutes,           Many diagnostic products – labora-
laboratories or pharmacies.                tory equipment, for example – are not
   Roche products intended for sale to     distributed via specialist wholesalers
individual users are distributed through   but are generally supplied directly to
a chain of specialist wholesalers and      customers, which in this case include
outlets (pharmacies and health-aid         hospitals, laboratories, pharmacies
outlets). This method of distribution      and other healthcare institutions.
is reliable and economical, given that
the products eventually have to reach      Product safety. The pharmaceutical
innumerable points of sale. Together       industry has the responsibility of
with pharmaceutical manufacturers,         developing products – medicines – that
specialists further down the supply        are safe to use and of monitoring them
chain, and particularly pharmacists,       for the duration of their market life.
often play a crucial role in providing     The term “safety” is used here in its
information about products and             widest sense and includes identifying
maintaining inventories of them. Ide-      and taking action to minimise poten-
ally, a drug should be available every-    tial risks, including possible effects on
where and at all times. In view of the     the environment, as well as guarding
great variety of preparations and the      against incorrect use and regularly
considerable differences in the quanti-    monitoring stability.
ties consumed, this can prove difficult.      Before a preparation is adminis-
Even drugs which are rarely needed         tered to human subjects as part of a

120
                                                   Production, biotechnological


clinical ¡trial, it is tested in the labo-    Diagnostics markets diagnostic sys-
ratory and in animals in accordance           tems consisting of measuring instru-
with a precisely defined programme            ments (including spare parts), soft-
(¡toxicology and animal pharmacol-            ware, reagents, control and calibration
ogy). In clinical testing, the drug’s effi-   solutions and consumables (e. g. blood
cacy and side effects profile are estab-      sample vessels). Differing product
lished. During this period, the unit          safety requirements need to be taken
responsible for pharmaceutical devel-         into account and satisfied for each of
opment works out the most suitable            these product categories. This is en-
dosage form. In addition, drugs should        sured through comprehensive checks,
not look like candies (above all to           controls and release procedures in the
avoid children eating them by mistake)        various phases of a product’s lifecycle,
and should be difficult to get at (¡for-      starting from the initial concept,
mulation, ¡child-proof drug con-              through development and production,
tainers). Each batch passes through           to the monitoring of product sales on
¡quality control and is released by           the market.
¡quality assurance. All reports of side
effects after market launch are dealt         Production, biotechnological. Bio-
with by the ¡Drug Safety Monitoring           technological production processes,
unit.                                         especially alcoholic fermentation (beer
   Many risks can already be recog-           brewing, winemaking, etc.), are thou-
nised at the animal testing stage or          sands of years old and widely used.
during clinical trials on human sub-          Roche has been using them since
jects. But others, such as allergic reac-     about 1980 for the production of
tions or addiction potential, come to         complex molecules and is now one of
light only through post-marketing             the world’s leading biotech companies.
surveillance.                                 Active therapeutic and diagnostic
   The safety of diagnostic products          substances and their precursors are
focuses on two aspects: the reliability       produced in the company’s biotechno-
of the diagnostic product (correctness        logical production facilities.
of the test result) and the safety of            Industrial-scale biomanufacturing
the diagnostic test procedure. While          processes generally employ bacteria,
diagnostic tests are often conducted          yeasts, moulds or cell cultures. The
by trained staff members in doctors’          main products that can be obtained
offices and medical laboratories, some        by biotechnological methods are anti-
are also performed by laypeople (e. g.        biotics, therapeutic ¡proteins and
blood glucose measurement by people           other active pharmaceutical ingredi-
with diabetes). This aspect is taken          ents and foodstuffs. The processes take
into consideration during the develop-        place in bioreactors (fermenters) of-
ment of diagnostic products. Roche            fering organisms an ideal environment

Roche from A to Z                                                                121
 Production, chemical


in which to multiply rapidly and per-     as a laboratory activity, conjuring up
form exactly the biosyntheses that are    images of brightly coloured liquids
wanted. This is followed by generally     bubbling in test tubes or flasks. A
elaborate separation and purification     visitor to one of Roche’s chemical pro-
steps.                                    duction facilities, however, will be sur-
   Roche makes use of conventional        prised by the spotless premises hous-
fermentation and isolation processes      ing numerous cylindrical vessels with
for products manufactured by the          complex fittings or stirring devices.
¡Diagnostics and ¡Pharmaceuticals         These reaction vessels are connected
Divisions. The precursors of the active   to each other by pipes and some are
ingredients of ¡CellCept and ¡Roce-       equipped with stirrers. Specialist de-
phin, for example, are produced by        vices such as filtering equipment, cen-
biotechnological methods.                 trifuges, distillation columns, dryers
   Products manufactured at ¡Penz-        or product filling lines are also used.
berg, one of Europe’s leading biotech-    Nowadays, most of the production
nology facilities, include ¡erythropoi-   processes are computer-controlled,
etin ( ¡NeoRecormon), trastuzumab         and technicians can intervene in the
(¡Herceptin), ¡interferon and pegy-       process sequence from monitors.
lated interferon (¡Pegasys), a wide          The provision of chemical products
range of monoclonal ¡antibodies           has to combine economic efficiency
used in diagnostic products and more      with consistently high quality. In par-
than 20 products for the ¡Applied         ticular, active pharmaceutical ingredi-
Science business area.                    ent production has to satisfy extremely
   All Roche biotechnological produc-     demanding product purity require-
tion activities worldwide comply with     ments (¡good manufacturing prac-
the guidelines of the Organization for    tice regulations).
Economic Cooperation and Develop-            Consequently, the manufacturing
ment and the US National Institutes       process is described in meticulous
of Health, supplemented by national       detail in master batch records, and
regulations and internal process-         compliance with the specifications is
specific operating procedures. The        constantly verified and documented.
production processes carried out at       In addition, all of the raw materials
Roche are all on the lowest risk level    and intermediates used are analysed
(¡ biosafety).                            and released by ¡quality control.
                                             Just as important are the measures
Production, chemical. Manufacture         taken to prevent, minimise and dis-
of chemical products. At Roche, active    pose of waste products, and pollutants
ingredients for ¡pharmaceuticals are      in waste air and effluent. The primary
produced by chemical synthesis. The       goal is to avoid waste and by-products
layperson tends to think of chemistry     insofar as possible (¡environmental

122
                                                   Production, pharmaceutical


protection). The chemical production        a production facility can take from two
of active pharmaceutical ingredients        to six years depending on its size and
involves various intermediate stages        complexity.
(known as steps), which are often
manufactured at different production        Production, pharmaceutical. To make
sites. Each step consists of several unit   sure patients take exactly the right dose
operations, such as mixing starting         of medication in a safe and simple
materials, reaction and working up          manner, active drug ingredients are
the reaction mixture, separating and        supplied in user-friendly dosage forms.
purifying the products and processing       Sterile solutions, for example, are in-
and recycling by-products. The plants       jected from infusion bottles, while solid
are usually designed as multipurpose        dosage forms such as tablets or capsules
units, that is, different products can      are swallowed (¡formulation).
be produced on the same apparatus.             The task of pharmaceutical produc-
Product changeover takes place at the       tion is to formulate pure active ingre-
end of a “production campaign” and          dients as one or more of the presenta-
requires thorough cleaning of the           tions just mentioned, and, at the end
apparatus.                                  of the production process, to package
                                            them as finished medicines (¡packag-
Production construction projects.           ing).
As a dynamic company that is con-              Production of these presentations
stantly launching new drugs and diag-       is generally a complex procedure, in-
nostic products, Roche attaches great       volving numerous intermediate steps,
importance to the ongoing moderni-          starting with the painstakingly precise
sation and, where appropriate, expan-       weighing of active ingredients and
sion of its production sites and build-     excipients and ending with the final
ings (¡investments). Accordingly, the       packaged product.
company implements construction                The golden rules of pharmaceutical
projects of varying scale. The con-         production are to manufacture high-
struction of production facilities in       quality, safe and effective products
particular is a highly time-consuming       and protect members of staff against
process, involving not just detailed        contamination. The priority given to
planning and construction, but also         quality-awareness is reflected in the
the installation of the machinery and       elaborate production facilities, the
equipment and the commissioning             sophisticated production monitoring
and testing of the whole plant. Roche       methods and the meticulous training
collaborates with numerous external         given to employees.
partners, including architects, engi-          The critical steps involved in the
neers and construction companies,           production of prefilled syringes, for
on such projects. The construction of       example, take place under a stream of

Roche from A to Z                                                               123
 Production, pharmaceutical




  Excipients,                Active              Excipient                               Active
  e. g. starch               ingredient                                                  ingredient
     and talc
                                                                                         Water,
                             Wetting                                                     active ingre-
                                                                                         dient and
                                                                                         excipient

                             Wet                                                         Filtration
                             mixture
                                                                                         Purified,
                                                                                         sterile
                                                                                         solution

                             Granules                                                    Ampoule
                                                                                         filling

                             Drying




                                                  Empty                                  Ampoules
                                               ampoules                                  sealed
                             Tabletting     cleaned and
                             press              sterilised
                             Tablet core
    Tablet



                                                                                         Sterilisation
                                                                                         in autoclave
                                             Inspection                                  (at 121°C)
                             Sugar
                             coating




                                             Suspended       Perfect Active ingredient     Sterility
                                               matter         seal        content

Greatly simplified diagrams showing how finished dosage forms are produced.

highly purified air flowing in strictly       Roche drugs must be of perfect
parallel layers and totally free of        quality and satisfy a wide variety of
particulate contaminants and micro-        regulatory requirements (¡generics,
organisms. In tablet production, auto-     ¡counterfeit drugs). This applies not
matic weighing machines help to elim-      only to pharmaceutical production in
inate any significant deviation from       Switzerland, but to every production
the specified tablet weight. Although      plant throughout the world. Certain
thanks to modern information tech-         pharmaceutical ¡production sites
nology many processes and control          specialise in certain pharmaceutical
routines are now computer-controlled,      forms (centres of excellence) and
human beings are still the most impor-     possess the corresponding manufactur-
tant element in the quality assurance      ing technologies and comprehensive
process.                                   know-how (¡technology transfer).

124
                                                     Professional Diagnostics


   Following the introduction of the       tribution structures towards a more
strict GMP (good manufacturing             regionalised supply chain.
practice) guidelines, visitors no longer
have direct access to the rooms where      Professional Diagnostics. In 2006
pharmaceutical production takes            the new business area of Professional
place, but several stages of production    Diagnostics was formed in the ¡Diag-
can be observed through glass parti-       nostics Division with the aim of opti-
tions.                                     mising the management of the current
                                           product portfolio, which ranges from
Production sites. Roche has a small        large central laboratories running
number of large chemical and biotech-      several thousand diagnostic tests a day
nological production sites, the most       to the self-monitoring of coagulation
important of which are in Europe and       therapy by individual patients. The
North America. The active ingredients      objective of this new business area is
are delivered from the production cen-     to generate added medical value with
tres to 16 or so Group companies.          innovative markers and diagnostic
These centres mainly produce active        systems that improve patient care.
ingredients for medicines. The active      Additionally, enhanced screening,
ingredients are delivered from these       diagnosis, patient stratification and
centres to pharmaceutical production       treatment monitoring using clinically
facilities across the globe, where they    relevant parameters will support
are processed and packed to produce        decision making on the patient’s
finished pharmaceuticals (syringes,        further treatment. The incorporation
tablets, etc.).                            of customer insights in its range of
   Historically, trade restrictions led    tailor-made workflow solutions and
Roche to build pharmaceutical pro-         information management for both
duction facilities mainly for the manu-    decentralised and centralised settings
facture of finished pharmaceuticals,       further reinforces the superiority of
in a large number of countries. Today      the business area’s diagnostics prod-
the pharmaceutical production facili-      ucts and services.
ties are highly specialised and gener-        As healthcare provision changes
ally supply a whole region or deliver      rapidly, so the business environment
their products to distribution centres     in the laboratories is expected to
worldwide.                                 develop rapidly as well. For example,
   Nowadays, with progressive market       as IT continues to grow in importance,
liberalisation, there is lively cross-     IT and workflow solutions have
border trade in medicinal products.        become a crucial field of diagnostics.
The successive elimination of trade        The ongoing trend towards further
barriers is resulting in a shift away      customer consolidation demands novel
from the old local production and dis-     business approaches. By establishing

Roche from A to Z                                                            125
 Profit


this new business area Roche has              In a good year the greater part of
addressed these challenges effectively     what is left over after taxes have been
and successfully. The global headquar-     deducted is usually retained and trans-
ters of the Professional Diagnostics       ferred to statutory and voluntary re-
unit is in Rotkreuz, Switzerland, where    serves. Reserves allow a company to be
most of the diagnostic systems are         prepared for all eventualities and to
developed and integrated.                  make provision for the facilities that
                                           will help improve productivity and job
Profit. The difference between income      security. The smaller part is paid out as
and expenses, as shown in a company’s      a shareholders’ dividend, a return on
statements of income. The statements       the capital they have placed at the
of income show how successful, in          company’s disposal.
terms of profit (or loss), a company is.
   In free market economies the profit     Protease. ¡Enzyme which cuts certain
motive is the driving force behind         other ¡proteins into shorter pieces.
entrepreneurial activity. The future is    Such “protein scissors” can either break
always uncertain, however, and the         down proteins (e. g. pepsin in the
opportunity for profit is counterbal-      gastrointestinal tract), activate them
anced by the risk of loss. A company       (e. g. thrombin in blood clotting) or
will make a profit only if the produc-     cleave large polypeptides into smaller
tion decisions it makes are correct and    peptides (e. g. HIV protease, ¡AIDS).
its products can be sold.
   The profit motive is one of the main    Proteins. Naturally occurring mole-
factors behind efforts to improve          cules composed of 20 different
production methods and create new          ¡amino acids arranged in long chains
products. By contrast, profits derived     of varying sequence and length. Pro-
from monopolies inhibit innovation,        teins consisting of just a few amino
as there is no incentive to constantly     acids are called peptides. As a result
offer new goods and services in the        of weak side chain bonds, they have a
marketplace.                               folded, three-dimensional structure of
   Only profitable companies can sur-      considerable elasticity and flexibility.
vive in the long term. Profits are used    This complex, three-dimensional struc-
to finance ¡investment in such things      ture can be visualised by x-ray struc-
as ¡research and development, main-        tural analysis or computer modelling.
tenance and expansion of production        Proteins can act as hormones (such
facilities and environmental protec-       as insulin), as signalling substances
tion. A sizeable portion also goes into    (such as ¡interferons) or as ¡en-
the public coffers in the form of the      zymes, ¡antibodies or ¡receptors.
taxes that enable the state to carry out      Proteins are found in all living
its functions.                             organisms and viruses. Without them,

126
                                                                           Proteomics


there would be no life. Even ¡DNA             and under a particular set of environ-
itself would be a biologically inactive       mental conditions. These proteins can
molecule without proteins. The hu-            be separated and then related to their
man body contains an estimated                corresponding genes by mass spec-
50,000–100,000 different proteins.            trometry. Roche scientists have already
                                              constructed a number of proteome
Proteomics. Study of the ¡proteins            maps, and to date, thousands of the
resulting from the information con-           proteins they contain have been
tained in a set of ¡genes. Unlike the         matched to the genes coding for them.
¡genome, which is a finite, essentially       Such analyses could conceivably be
static entity, proteomes are dynamic,         used to investigate the effects of
responding to shifts in temperature           pharmaceuticals, toxins or biological
and nutrient environment, for exam-           agents on an organism or to observe
ple, or to the effects of stress and med-     how, or how effectively, a drug acts
ication. A proteome thus comprises            during a specific stage of a disease.
the total complement of proteins ex-             Roche approaches this issue in a
pressed by the genes of a cell or organ-      variety of ways by using proteomics to
ism during a particular growth phase          try to identify new drug targets and


                   Proteomics: Promising new approach
                            to drug discovery
   Healthy cells




                                                     apply 2D-gel by
                                extract              electrophoresis
                                proteins             and separate
   Cancer cells
                                                                       !   possible cause
                                                                           of cancer




                                                   new strategy for cancer treatment?




                              analyse the
                             cancer protein




Roche from A to Z                                                                       127
 Psychotropic drugs


new diagnostic markers, for example
for cancers or rheumatism.

Psychotropic drugs. Pharmaceutical
agents that act on mental functions by
modulating nerve cell activity in the
brain. They are used primarily in the
treatment of psychiatric or psycho-
somatic disorders. Three main types of
psychotropic drug are distinguished:
   Neuroleptics (also called antipsy-
chotics or major tranquillisers), which
have a strongly sedative effect, are used
to treat psychotic and highly agitated
patients.
   The first antidepressants appeared in
1957. Their development at Roche
began with the observation of a side
effect of Rimifon, a drug for the treat-
ment of tuberculosis, which was found
to have a marked mood-elevating
effect. Investigation of the mechanism
of action revealed that Rimifon inhib-
ited monoamine oxidase A and B, two
¡enzymes with a key role in the
metabolism of neurotransmitters in the
brain. This gave rise to a whole new
group of drugs for the treatment of
depression. In the 1980s Roche found a
new compound, moclobemide, which
specifically inhibits monoamine oxi-
dase A. It is the active ingredient of
Aurorix, a very well tolerated anti-
depressant that is used to treat all forms
of depression and social phobias.
   Minor tranquillisers or anxiolytics
are psychotropic drugs used primarily
in the treatment of anxiety and ten-
sion. The majority of drugs in this
group are ¡benzodiazepines.

128
                                                                  Quality control


                                             with the latest instruments. Chemical,
                                      Q      physical, biological and pharmacolog-
Quality assurance. Far-reaching con-         ical assays are carried out. Quality
cept defining the conditions required        control contributes a significant part
for quality-conscious working prac-          of the analytical documentation need-
tices, nowadays often referred to as         ed for applications to the drug regula-
a quality management system. This            tory authorities for approval of new
quality management system embraces           products. Marketed products are also
all measures designed to ensure that         subjected to stability testing. In addi-
pharmaceutical and diagnostic prod-          tion to actual testing, quality control
ucts meet the standards of quality           departments can also approve the
appropriate to their intended use.           release of products after review of
Quality assurance encompasses com-           all quality-relevant analytical and
pliance with ¡good manufacturing             production data and monitor quality
practice, ¡good laboratory practice,         assurance activities related to purchas-
¡good clinical practice and other reg-       ing, manufacture, packaging, storage
ulatory requirements. For a healthcare       and the transport of products. Some of
company the manufacture of high-             these administrative tasks can also be
quality products constitutes both an         carried out by ¡quality assurance
ethical commitment and an economic           departments.
necessity. To achieve this goal, it is not
enough to subject products to a final
inspection: all employees must make
quality a fundamental part of their
contribution to the development,
manufacture, ¡quality control, stor-
age and distribution of each product.

Quality control. This concerns sam-
pling, specification and testing proce-
dures, as well as organisation, docu-
mentation and release of products. It
is part of the ¡good manufacturing
practice regulations. Proper testing
ensures that the product always meets
the specifications registered with the
regulatory authorities.
   Quality control tests are carried out
on raw materials, intermediates and
end products in laboratories equipped

Roche from A to Z                                                               129
 Rapid diagnostic tests


                                           ¡Diagnostics Division develops and
                                    R      markets reagents for ¡clinical chem-
Rapid diagnostic tests. Refers to tests    istry, ¡toxicology, immunochemistry,
capable of providing an on-the-spot        molecular diagnostics, microbiology
result – e. g. in doctors’ offices or      and blood coagulation tests.
emergency departments – within a few          Clinical chemistry accounts for
seconds or minutes. Such tests allow       most of the assays carried out in rou-
doctors to decide immediately on the       tine laboratory diagnostics. Examples
appropriate treatment.                     are tests for ¡enzymes, substrates,
   Offering a range of systems and         electrolytes and specific ¡proteins.
rapid tests for immediate analysis of         In the field of toxicology, tests are
cardiac function markers, blood clot-      performed to monitor the effects of
ting, urine diagnostics, ¡clinical chem-   drug therapy and to detect drug abuse.
istry, blood gases and electrolytes, the   Such tests can be carried out in the
¡Professional Diagnostics business         clinical laboratory or at the point
area of the ¡Diagnostics Division          of care (in the doctor’s office, for ex-
responds to customers’ requirements        ample).
with integrated solutions for use on          Immunochemical / immunological
the spot.                                  tests are based on the principle of the
   The product range includes Coagu-       antigen–antibody reaction. Specific
Chek systems, the Cardiac Reader           antibodies (in particular monoclonal
system, the Reflotron Plus and Sprint      ¡antibodies), are used for the qualita-
Analyzer, the Urisys 1100 urine            tive and quantitative determination of
analyzer, the Combur and Chemstrip         ¡antigens.
urine test strips, the Accutrend GCT          Techniques based on the ¡poly-
meter, the DataCare POC and cobas IT       merase chain reaction are particularly
1000 data management solutions.            important in molecular diagnostics.
   To meet modern hospitals’ wide          Qualitative tests based on this method
variety of test needs, Roche also offers   are used for diagnosing infections,
a selection of extremely flexible and      cancer and genetic disorders, as well
powerful software tools and IT inter-      as in transplantation medicine, while
faces for the management of data.          quantitative tests allow determination
                                           of viral load (during therapy for
Reagents, diagnostic. Products and         ¡AIDS, for example).
ancillary supplies used in ¡in vitro          Microbiological tests are used to
diagnosis to detect – both qualitatively   isolate and identify pathogens that
and quantitatively – the most minute       may be present in both the blood-
pathological changes in the compo-         stream and the urine in infectious
sition of body fluids, and occasion-       disease. Testing the sensitivity to anti-
ally stool and tissue specimens. The       biotics of pathogens isolated from

130
                                                                     Recycling


body fluids is an especially important     protein that provoke a pathological
part of this branch of diagnostics. This   change.
shows which drugs are most effective
against the organisms involved. Serol-     Recombination (in vitro recombina-
ogy is concerned with the quantitative     tion). A ¡genetic engineering tech-
and qualitative determination of anti-     nique that involves uniting specific
bodies produced by the human body.         pieces of ¡DNA from different sources
   Coagulation tests (¡blood cells) are    in a test tube and then reintroducing
used for such purposes as monitoring       them into a biological system.
anticoagulant therapy, detecting liver
damage and ascertaining the causes of      Recycling. The recovery of reusable
hereditary or acquired blood clotting      materials from by-products and waste
disorders such as hemophilia. Patients     to help conserve resources, reduce
can check their own prothrombin            waste volumes and cut pollution.
time, and thus determine their clotting    Before being recycled, the recovered
status, with ¡coagulation self-moni-       materials generally need to be sepa-
toring tests.                              rated and cleaned, a requirement that
                                           places economic and ecological limits
Receptors. Protein molecules, usually      on recycling, since these very opera-
found on the surface or nucleus of         tions and the associated energy con-
¡cells, that respond specifically to       sumption may themselves add sub-
natural endogenous messengers such         stantially to environmental pollution.
as ¡hormones, ¡neurotransmitters           Thus, the recycling options have to be
and ¡cytokines, thus triggering other      examined in each individual case. In
biological events in or on cells. Phar-    certain situations, incinerating waste
maceutical research seeks to identify      to produce energy is the preferred
chemicals that bind to receptors with      solution. On the other hand, costly
high specificity, thus activating or       recycling methods may be justified
blocking them. These mechanisms are        in the case of materials that present
exploited for therapeutic purposes, an     serious environmental hazards.
example being the ¡benzodiazepines            One of the most important forms of
and benzodiazepine ¡antagonist de-         recycling at Roche involves the recov-
veloped by Roche. Roche research is        ery, by distillation, of waste solvents
also seeking to identify and synthesise    from production processes; they are
antagonists for specific receptors on      then reused, usually in the same
cells of the ¡immune system. This          processes. Other substances, including
approach assumes that developing a         heavy metals, are collected and sent to
drug to treat the underlying cause of a    specialist companies for reprocessing.
disease requires a detailed knowledge      In general, the following materials are
of the receptor and receptor-binding       recycled: scrap metal, glass, paper and

Roche from A to Z                                                            131
 Regio


cardboard, chemical catalysts and           countries supports the economic de-
plastics.                                   velopment of the region. All the large
                                            Basel-based chemical and pharmaceu-
Regio. The name given to the region         tical firms have taken advantage of this
in the Upper Rhine valley where             location and set up factories and
France, Germany and Switzerland             companies in the “Regio”. Thus, both
meet. It is one of Europe’s best-inte-      Roche’s headquarters in Basel and
grated border areas in terms of popu-       Roche Deutschland Holding GmbH,
lation, trade, and tourism. The             in ¡Grenzach-Wyhlen (headquarters
¡Rhine forms the boundary first be-         of the German affiliate) are based in
tween Switzerland and Germany, then         the area.
between Germany and France. The
region shares a common Alemannic-           Registration. Before a drug that has
Burgundian cultural heritage that           completed development and clinical
finds expression, for instance, in archi-   testing can be put on the market, it
tectural styles, eating habits and the      must first be evaluated by the authori-
closely related dialects. Large numbers     ties of the country concerned and then
of commuters cross the frontiers here       be officially licensed for sale through
every day to go to work: mainly from        the issue of an official approval. The
France into Switzerland and Germany         EU also has a centralised registration
and from Germany into Switzerland.          process that is intended, and in certain
The towns of St. Louis, Mulhouse, Lör-      cases is mandatory, for innovative
rach and Müllheim and the Wiesental,        products. The thalidomide tragedy in
Leimental, Birstal and Fricktal valleys     Europe led to the realisation that safety
are all usually considered to be part of    needed to be greatly improved. As a
the region.                                 result, in the late 1960s drug approval
   The “Regio” offers a number of           requirements were tightened, and the
advantages as a location for a chemical     rigorous assessment of drug efficacy,
and pharmaceutical firm with world-         safety and quality made mandatory.
wide operations. The university of          This in turn meant substantially
Basel, together with its counterparts in    lengthier approval procedures.
nearby Freiburg (Germany) and Stras-           The complete documentation re-
bourg (France), fosters a favourable        quired for registering a new drug
climate for scientific work. In terms of    (known in the United States as an
transportation, the Basel region offers     NDA, or new drug application) gener-
considerable benefits: it is an interme-    ally extends to over 100 bulky files. It
diate point on the main north-south         contains a detailed account of all find-
rail and road routes, and the Rhine is      ings and results that have been ob-
Europe’s most important waterway. A         tained with the drug in laboratory
highly educated workforce in all three      tests, ¡animal experiments and clini-

132
                                                                        Research


cal ¡trials. Additional, comprehensive      (in exceptional cases) to several years
data on the manufacturing and quality       for a drug to complete the registration
control of the product includes: a          process. Efforts are being made to har-
summary, data on the manufacturing          monise approval procedures generally
process, the analytical and other qual-     (ICH = International Conference on
ity control methods used and the            Harmonisation) or at least in certain
chemical and physical properties of         groups of countries, such as the EU
the active substance, as well as details    (¡CHMP, ¡EMEA).
on the finished product. The part deal-
ing with pharmacology and toxicology        Research. The Roche Group’s pro-
contains findings from animal trials. A     ductive and commercial performance
clinical part consolidates the experi-      depends to a great extent on the dis-
ence gained with the drug during trials     covery and development of new prod-
in healthy subjects and, especially, in     ucts and systems. Furthermore, there
patients with respect to efficacy, the      are compelling legal and moral reasons
incidence and nature of side effects        why products related in any way to
and the drug’s metabolic fate in the        ¡health must be supported by solid
body. An evaluation of the possible         scientific evidence. Research is there-
risks to the environment arising from       fore of fundamental importance to
the use of the drug is also a compul-       Roche (¡research expenditure). Roche
sory part of the registration process.      research is interdisciplinary and inter-
   The growing complexity of the reg-       national.
ulations that must be observed when            Although each ¡division possesses
registration data are being prepared        its own research organisation, both
and compiled has led to a huge in-          divisions work together on an interdis-
crease in the amount of time and            ciplinary basis, for example in the field
money needed and in the number of           of oncology, since diagnosis and treat-
investigations required. The task of        ment will become much more closely
assembling registration documenta-          intertwined in the future than in the
tion for worldwide use is further com-      past. Pharmaceutical research focuses
plicated by the fact that government        on inflammatory diseases, bone dis-
requirements can differ widely from         eases, disorders of the central nervous
country to country regarding both the       system, cancer, metabolic and viral
content and format of the application       illnesses. The ¡Pharmaceuticals Divi-
dossier. There are also differences in      sion’s main research centres are located
official procedures and the criteria        in Basel (¡parent company), ¡Nut-
applied. In most countries drug regis-      ley, ¡Palo Alto and ¡Penzberg.
tration applications are assessed solely    ¡Chugai has three additional research
on objective, scientific criteria. It can   centres in Japan. In 2004, the Roche
take anywhere from just a few months        R&D Center China was established in

Roche from A to Z                                                               133
 Research expenditure


¡Shanghai. ¡Genentech, Inc. has its        model also includes Roche spin-offs
own research organisation in San           like BioXell, set up in 2002, and the
Francisco. ¡GlycArt Biotechnology          biotech company Basilea Pharma-
AG in Switzerland is also incorporated     ceutica as potential drug development
in the research network.                   partners. Licensing agreements that
   The ¡Diagnostics Division has re-       give Roche access to new drug candi-
search centres in Switzerland, Ger-        dates and technologies are another im-
many, Austria and the United States        portant part of its strategy. Alliances
(¡Diagnostics research).                   and licensing are also a key component
   Given the many diseases for which       of innovation management in the
there is still no cure, the need for new   Diagnostics Division, which in 2002,
and better treatments remains enor-        for example, acquired a broad port-
mous. Research and development are         folio of human papillomavirus (HPV)
therefore the engine that drives the       patents from Institut Pasteur. Roche is
company. Roche is pursuing an inno-        considered a partner of choice in the
vation strategy in which size alone is     healthcare industry.
not what counts. It believes that
having too large an organisation can       Research expenditure. Global spend-
actually slow innovation and reduce        ing by the Roche Group on research
productivity in healthcare research. So    and development (R&D) for new
Roche has taken a different approach,      products and manufacturing processes
one that relies on a network of highly     amounts to some CHF 5.7 billion an-
motivated centres of excellence that       nually. Around CHF 5 billion are spent
collaborate closely on research, ex-       every year on pharmaceutical R & D
changing information and technolo-         alone (including ¡Genentech and
gies across geographic and organisa-       ¡Chugai). Approximately two thirds
tional boundaries, while maintaining       of R&D costs are staffing costs, chiefly
a large measure of scientific and oper-    wages and salaries. The remaining
ational independence.                      third is needed for materials and stud-
   Roche’s own pharmaceutical and          ies. A growing proportion of research
diagnostics research units occupy cen-     expenditure is spent on acquiring the
tre stage in this innovation strategy,     licences for new substances in clinical
with Genentech and Chugai, the two         and preclinical development.
most important strategic allies, also         Research funds are channelled not
playing a leading role. Complementing      only into innovative ¡research, but
and strengthening the Group’s dy-          also into the development of ¡quality
namic R & D capabilities are over          control processes or ensuring the
50 scientific and commercial collabo-      safety of an established product.
rations with biotech companies and            The greatest challenges in pharma-
universities. The Group’s innovation       ceutical R & D are posed by the rela-

134
                                                                     Rheumatism


tively low success rate – few candidate     tion tanks at all of its chemical pro-
drugs selected for clinical testing actu-   duction facilities to hold runoff from
ally make it onto the market – and also     firefighting operations and spillage
by the long development times. The          until it can be analysed and treated.
total time from the discovery of a new
active substance to its launch as a mar-    Rheumatism. Umbrella term for vari-
ketable drug is usually around eight        ous painful diseases of the musculo-
years. However, since ¡patents must,        skeletal system that are now known
wherever possible, be submitted at the      to be different entities. These diseases
beginning of development, over half a       include rheumatoid ¡arthritis, anky-
product’s patent life may have expired      losing spondylitis, osteoarthritis, and
by the time it reaches the market. In       soft-tissue rheumatism. Osteoarthritis
the time that remains until patent ex-      is a degenerative disease, most often
piry and the appearance on the market       seen in the elderly, that affects the joint
of ¡generics, the R & D costs of ap-        cartilage of the hips, knees, fingers and
proximately USD 2 billion per prod-         toes or the intervertebral discs of the
uct, plus the compound interest for the     spine. Rheumatoid arthritis (RA) is
development phase, have to be re-           a progressive, systemic autoimmune
couped through sales. For this reason,      disease characterised by inflammation
and also for the benefit of potential       of the membrane lining in joints. This
patients, Roche is making considerable      inflammation causes a loss of joint
efforts to shorten development times        structure and function, resulting in
and increase the R&D success rate.          pain, stiffness and swelling, and ulti-
                                            mately leading to irreversible joint
Restriction enzymes. ¡Enzymes ob-           destruction and disability. Character-
tained from ¡bacteria that cleave           istic symptoms of RA include swelling,
¡DNA molecules at specific sites.           pain, and movement limitation around
They are important tools in ¡molecu-        joints of the hands, feet, elbows, knees
lar biology, particularly ¡genetic en-      and neck. In more severe cases of RA,
gineering.                                  the eyes, lungs or blood vessels may be
                                            affected. There can also be systemic
Retention tanks. Watertight concrete        symptoms such as osteoporosis, ane-
tanks (usually underground) or open         mia, or generalised weakness. RA is
basins, each with a capacity of several     thought to be caused by an abnormal
thousand cubic metres. Accidents and        immune reaction that results in the
fires can result in large quantities of     destruction of body tissue (¡auto-
contaminated water, which could             immune diseases, ¡immune system).
cause significant damage if allowed to      There is no cure for most forms of
enter natural watercourses untreated.       rheumatism, and patients are treated
Roche has therefore constructed reten-      by physiotherapy, exercise, and with

Roche from A to Z                                                                 135
 Rhine


pain-relieving drugs. However, pa-           senger RNA molecules (the “working
tients are now undergoing courses of         copies” of genes).
treatment that are increasingly suc-
cessful in inhibiting inflammation.          Risk management. A structured
The more modern forms of these               approach to managing risks and
therapies can even stop the process of       opportunities. Risks (opportunities)
joint destruction. The very first anti-      are events that can negatively (or
inflammatory drug, acetylsalicylic           positively) affect the achievement
acid, was discovered about one hun-          of our objectives. The approach can
dred years ago and is still in use today.    be applied to a variety disciplines and
It has been joined by numerous other         consists in assessing risks and oppor-
types of drug. Roche has contributed         tunities, deciding risk attitude and re-
several non-steroidal anti-inflamma-         sponse, assigning and then monitoring
tory drugs, such as Tilcotil. Roche          the implementation of adopted ac-
Group research centres in ¡Palo Alto         tions and the residual risk itself. Roche
and at ¡Genentech are currently              has established an in-house function
investigating specific aspects of the        that provides assistance in adopting
inflammatory process and studying            this methodology. This function also
various compounds which it is hoped          coordinates the Group risk assess-
will have a more selective effect on auto-   ment process, which involves compil-
immune reactions and the resulting           ing the various risks into a Group Risk
tissue destruction.                          Inventory. The approach is designed
                                             to improve proactive, factual and
Rhine. A river that rises in the Swiss       consequential decision making and
canton of Grisons and flows through          accountability throughout the Group.
Basel. The Roche headquarters are               One specific application of the risk
situated directly on the banks of the        management methodology is known
Rhine, as are the Roche facilities at        as “business continuity planning”.
¡Grenzach-Wyhlen and ¡Mannheim.              This involves the systematic assess-
Its water is an essential resource used      ment of the organisation’s exposure to
for cooling purposes at all of the pro-      disruptive events and the preparatory
duction sites in the region.                 implementation of appropriate meas-
                                             ures (controls, inventory, crisis organ-
Ribosome. Molecular complex con-             isation or redundancy) to ensure a
sisting of ¡RNA molecules and sev-           satisfactory level of resilience. Often
eral dozen different ¡proteins. Ribo-        applied to physical hazards like fire or
somes are cells’ “protein factories”.        IT/communications failures.
They synthesise proteins from amino
acid building blocks by reading the          Risk management planning. Impor-
genetic information carried by mes-          tant factor in assuring ¡safety, health

136
                                                   Risk management planning


and ¡environmental protection. Risk        – fire safety inspections;
management planning is required for        – compiling special emergency re-
those cases in which the preventive           sponse documents such as hazard
measures prove ineffective.                   and building registers;
    Prevention includes all technical,     – undertaking precautionary plan-
organisational and personnel controls         ning and studies to create an opti-
which can be sensibly adopted to              mum framework for all response
reduce or eliminate potential risks.          units;
If, despite all preventive measures, an    – conducting exercises and training
accident or incident does occur, the          sessions.
company must have invested reason-            The size and composition of the
able resources in implementing com-        team vary from one production or
prehensive precautions to minimise         warehouse site to another and are
the impact on human life and the envi-     geared to the hazards or potential risks
ronment.                                   at each. Fire service, local emergency
    Part of risk management planning       response team and Group emergency
involves documenting the potential         response team are deployed on the
hazards that exist in all Roche sub-       principle of subsidiarity. The unit
sidiaries with their own production        leader assesses the situation and enlists
facilities, mixing plants or warehouses,   the help of the next highest unit as
and defining and implementing the          appropriate.
procedures needed to manage an inci-          Where the potential risk is great,
dent or event.                             physical asset values high and the pub-
    All active response units are          lic fire service unable to respond
grouped together in the emergency          quickly enough or with adequate re-
response team, which is comprehen-         sources, a site fire service is operated.
sively equipped to deal with any inci-     Where the local fire service is respon-
dents. The fire brigade is the primary     sible for fire fighting, regular site visits
unit and can be supplemented by a cri-     ensure that fire fighters are familiar
sis management team if circumstances       with both the site and its hazards.
require. The main tasks of the emer-          When incidents and accidents oc-
gency response team include:               cur, it is the responsibility of the first
– fire fighting, rescue services and       aid and rescue service or the company
    dealing with spills and building       medical service to offer first aid and
    evacuation;                            tend to the injured.
– making staffing, equipment and ad-          The emergency response team is
    ministrative arrangements to en-       also responsible for alarm procedures.
    sure optimum response efficacy;        The emergency response team and
– maintaining and inspecting com-          medical service can be alerted round
    pany-owned equipment;                  the clock.

Roche from A to Z                                                                 137
 RNA


   A further aspect of risk manage-      fit analyses have shown that Roce-
ment planning is training staff in       phin’s once-daily dosing regimen
the correct way to behave if an event    reduces overall costs – fewer infusion
occurs. Building evacuation drills are   sets are needed, hospital waste is
conducted regularly in all Roche         reduced, patients spend less time in
companies. At sites where chemical       hospital and the workload for nursing
production takes place, emergency        staff is reduced. Once-daily adminis-
response facilities include equipment    tration also has significant advantages
for measuring pollutant levels on site   in outpatient treatment.
and in the surrounding area.
                                         Roche. Shortened form of the maiden
RNA (ribonucleic acid). Biological       name of the wife of Fritz ¡Hoffmann,
molecules that perform various tasks:    Adèle La Roche. It was only by chance
messenger RNA provides “working          that this name came to be used as a
copies” of genes, ribosomal RNA and      designation for the Group as a whole.
transfer RNA serve as tools in protein     Around 1900, the firm’s general
synthesis, and various RNA com-          agent in France expressed his opposi-
pounds have enzymatic functions.
RNA is made up of nucleotides formed
with the bases adenine, guanine,
cytosine and uracil; it forms single-
stranded, chainlike molecules. Chemi-
cally, RNA is very closely related to
¡DNA, the principal carrier of genetic
information.

Rocephin (antibiotics). First cepha-
losporin antibiotic in the Roche prod-
uct range. Thanks to its outstanding
therapeutic benefits and cost advan-
tages, Rocephin was for many years
the ¡Pharmaceuticals Division’s top-
selling drug. Rocephin is effective in
a wide range of severe infectious
diseases, including meningitis, and in
patients with weakened immune
defences (as seen in patients being
treated for cancer). Rocephin is used
to guard against infection in patients   Early advertisement for Sirolin (Paris,
undergoing major surgery. Cost-bene-     turn of the 20th century).

138
                                                  Roche Charter on Genetics


tion to the brand name ¡Sirolin,          and promise of using genetic informa-
which had been proposed by Roche          tion for the discovery and delivery of
Basel, and used the name “Sirop           new and improved diagnostics and
Roche” for the product in France. This    therapeutics, and the legitimate inter-
was awkward for Fritz Hoffmann-           est of society in applying the aggregate
La Roche, since it complicated world-     results of genetic studies to the im-
wide promotion of Sirolin. As a way       provement of the human condition,
out of the problem, he added the          genetic research is an essential and
words “La Roche” to the Sirolin trade-    indispensable element in our quest to
mark in all countries; this was later     provide better healthcare.
shortened to “Roche”. In this form, the      To achieve this goal, genetic re-
word refers to the Roche Group as a       search must be implemented in accor-
whole and is also the brand name used     dance with a number of scientific,
by the ¡Pharmaceuticals and ¡Diag-        ethical, societal and legal principles:
nostics Divisions (¡trademarks).          – the commitment to the pursuit of
                                             research according to the highest
Roche Biomarker Programme, RBP.              standards of scientific rigour and
Led by an interdisciplinary matrix of        excellence;
experts in our ¡Pharmaceuticals and       – the right of every individual to self-
¡Diagnostics Divisions, the Roche            determination, privacy and confi-
Biomarker Programme (RBP) supports           dentiality regarding the procure-
and promotes the incorporation of            ment and use of genetic information
¡biomarker concepts such as ¡pro-            with regard to both research and
teomics, ¡genomics and imaging               personal healthcare;
techniques in the discovery, develop-     – the obligation to abide by national
ment and marketing of healthcare             and international research stan-
products. Identification of disease-         dards and applicable laws, and the
related biomarkers in key therapeutic        need to respect specific social,
areas can potentially lead to improved       moral, ethical, religious and other
diagnostic ¡tests, more efficacious          values affecting the procurement
treatments and enhanced disease              and use of genetic information;
monitoring and thus improve the           – the responsibility to prevent the
medical outcome.                             misuse of genetic information ob-
                                             tained in the course of its research
Roche Charter on Genetics. The set           activities towards discrimination or
of principles according to which             exploitation of individuals and
Roche conducts its genetic research.         groups, as well as to oppose any
Roche recognises that, based on the          such misuse as a matter of policy;
importance of genetic predisposition      – the mandate to not pursue the de-
for complex disorders, the necessity         liberate creation of genetically iden-

Roche from A to Z                                                             139
    Roche Connect


    tical human beings (often termed        the procurement of ADRs (American
    “human cloning”);                       Depositary Receipts). One ADR is
–   the communication of research re-       equivalent to one Roche non-voting
    sults to the scientific community in    equity security.
    a timely fashion and the support of
    general educational activities in the   Roche Forum Buonas. The com-
    area of genetics;                       pany’s own training and conference
–   the concept of providing appro-         centre. Roche Forum Buonas was
    priately considered benefits to         opened in January 2002 and comprises
    communities contributing genetic        the Fritz Gerber Center – with confer-
    material for research purposes;         ence and seminar facilities, a hotel
–   the duty to integrate the principles    wing and restaurant – and historic
    enumerated above into a pro-            Buonas Castle, The Club and an im-
    gramme of scientifically and so-        pressive park. In addition to the 300-
    cially responsible, accountable and
    transparent use of genetic infor-
    mation for the development of
    new diagnostics and therapeutics,
    and
–   the value and importance of guid-
    ance and counsel from an inde-
    pendent scientific and ethics advi-
    sory group (SEAG) of acknowledged,
    outside experts representing the
    fields of biology, ethics, sociology,
    law as well as the community.
                                            seat auditorium, the centre offers 10
Roche Connect. Staff profit-sharing         seminar rooms and 50 hotel rooms.
scheme introduced worldwide in 2002.        With its clear and simple lines, the
Roche allows all its employees to share     building, designed by Lucerne archi-
in the success of the company on the        tects Scheitlin & Syfrig, has been care-
stock market on preferential terms and      fully integrated into the unspoiled
to receive company dividend pay-            landscape of the Buonas peninsula, in
ments. Staff can invest a certain pro-      the municipality of Risch on Lake Zug
portion of their salary in Roche non-       (Switzerland). Roche Forum Buonas
voting equity securities at a 20 percent    provides a central venue where people
discount. In the USA, where Roche           from Roche Group companies around
Connect cannot be offered for legal         the world can meet (¡training and
reasons, employees have the option          development).
of participating in a local plan for

140
                                                                                    Roferon-A


Roche Institute of Molecular Biol-          Roche. The RSR will help researchers
ogy. An institute for basic research in     to identify possible links between
Nutley, New Jersey (United States),         genetic variations and differences in
founded in May 1967 by Hoffmann-La          treatment response and the occur-
Roche Inc. This institute was the first     rence of drug side effects.
centre for basic molecular biological
research to be founded and financed         Roferon-A.     Genetically engineered
by the pharmaceutical industry on           interferon alfa-2a (¡interferons, ¡cy-
a non-product-oriented basis. It at-        tokines) from Roche; first approved
tracted more than a hundred highly          in June 1986 by the US Food and
qualified scientists to Nutley. The re-     Drug Administration (¡FDA) and in
search work undertaken by the Insti-        Switzerland for the treatment of hairy
tute focused on unravelling basic bio-      cell leukemia. This is a rare but hith-
chemical mechanisms such as protein         erto invariably fatal form of blood cell
synthesis in the cell, research into gene   cancer that, in about 90 percent of
expression and genetic recombination
and the characterisation of various
                                                    Roferon-A (interferon alfa-2a)
¡receptors and biologically active
¡proteins in the ¡immune system
and central nervous system.
   Despite its strong basic research ori-
entation, some of the work done at the
institute paved the way for major
achievements in product-related re-
search at Roche Nutley. For example,
work by Dr Sidney Pestka on the isola-
tion of ¡interferons began in 1969,               Amino acid sequence
                                                      Phenylalanine     Threonine    Glycine
and by the end of the 1970s the essen-                Tryptophan        Histidine    Alanine

tial groundwork had been completed                    Aspartic acid     Tyrosine     Valine


for genetically engineering a pure alfa               Methionine        Proline      Leucine

                                                                        Lysine
interferon (¡Roferon-A). In 1995 the
                                                      Glutamine                      Serine

                                                      Isoleucine        Arginine     Cysteine

institute in Nutley was closed down
after a Roche subsidiary was founded        Sequence of the 165 amino acids in
in ¡Palo Alto.                              interferon alfa-2a. Also shown, the
                                            disulfide bridges joining two pairs of
Roche Sample Repository, RSR. A             cysteine units; these links cause the pro-
collection of blood and ¡DNA sam-           tein to fold into a characteristic shape.
ples from patients being treated in         This structure determines the biologi-
phase II or phase III clinical ¡trials      cal properties and actions of interferon
with new medicines developed by             alfa-2a.

Roche from A to Z                                                                               141
 Rotkreuz


cases, responds to treatment with         longer than Roferon-A and can con-
Roferon-A. Most of these patients can     tinue fighting the virus for longer.
resume a normal life and even return      Patients are given Pegasys as an injec-
to work.                                  tion just once a week. In combination
   Roche began testing the effective-     with Copegus (ribavirin), Pegasys
ness of Roferon-A in ¡AIDS patients       achieves much higher response rates
as early as 1984. People with HIV in-     than Roferon-A. Pegasys is approved
fection suffer progressive deteriora-     for a broad range of patients with
tion of their immune system. About        hepatitis C, including those patients
one quarter of patients with AIDS         who have cirrhosis, are coinfected with
develop a potentially fatal form of       HIV or who have “normal” ALT levels.
metastatic cancer known as AIDS-          In addition, Pegasys is the only pegy-
related Kaposi’s sarcoma. Roferon-A       lated interferon that is approved for
brings about marked improvement in        the treatment of patients with chronic
about 25–40 percent of AIDS patients      hepatitis B.
with Kaposi’s sarcoma; the disease
regresses or even disappears. These       Rotkreuz. Located in the Canton of
patients are also less often subject to   Zug (Switzerland), Rotkreuz is home
life-threatening infections.              to the Diagnostics Division’s instru-
   Roferon-A was approved in Switzer-     ment centre, Roche Diagnostics AG,
land in this indication in 1986 and       the Roche Diagnostics Ltd. (Switzer-
subsequently in all other countries       land) sales company, the head office of
where AIDS occurs. Over the last ten      the ¡Professional Diagnostics busi-
years various improvements have been      ness area and the Roche Microtechnol-
made to the manufacturing methods         ogy Centre, a centre of excellence for
and product quality of Roferon-A. The     applied microtechnology.
drug’s clinical applications have been       Roche Diagnostics AG currently
widened through the addition of vari-     employs over 700 people from around
ous important indications: chronic        30 different countries. It is one of the
myelogenous leukemia, cutaneous T-        world’s leading design, development,
cell lymphoma and non-Hodgkin’s           production and service centres for
lymphoma, renal cell carcinoma and        ¡analytical systems for ¡Molecular
malignant melanoma (skin cancer). It      Diagnostics, ¡Professional Diagnos-
has also been used in combination         tics and ¡Applied Science. The highly
therapy for some solid tumours and        sophisticated ¡Cobas analytical sys-
has been employed extremely success-      tems that have revolutionised diagnos-
fully in hemangiomas (benign tumours      tic technology on more than one occa-
consisting of blood vessels) in new-      sion, include the Amplicor, TaqMan
born infants and young children.          and AmpliPrep instruments (molecu-
Pegasys is designed to stay in the body   lar diagnostics), the Cobas Integra

142
                                          Rx


product line for ¡clinical chemistry,
the LightCycler instruments for life
science and the Cobas software range
for hospitals. All the systems manufac-
tured in Rotkreuz (consisting of hard-
ware, software, disposable articles,
service IT solutions) comply with the
relevant international quality specifi-
cations (e. g. FDA, ISO standards) and
regulatory requirements (¡in vitro
diagnosis or research).
   Roche Diagnostics Ltd. (Switzer-
land), which employs over 150 people,
is responsible for selling and servic-
ing the whole Roche Diagnostics prod-
uct range – instruments, software,
¡reagents, tests and ¡test strips – to
patients, laboratories, hospitals, med-
ical practices and research institutes
throughout Switzerland.

Rx. Common abbreviation for pre-
scription medicines. In the United
States the symbol Rx, with the x
formed by a line across the extended
down-stroke of the R, is equivalent
to the Rp (from Latin recipe: take)
commonly used in prescriptions in
Europe.




Roche from A to Z                         143
 Safety

                                           facilities. To cope with these tasks, it
                                    S      can call on the services of experienced
Safety. The concept of industrial          chemists, biologists and engineers, as
safety encompasses a wide spectrum         well as specialists in ¡occupational
of issues that have to be given top        hygiene, accident prevention and envi-
priority in the chemical industry.         ronmental protection. In addition,
   At Roche, safety questions are ac-      the department plays a part in the
corded the same degree of care as          advanced training of production and
chemical operations and the manufac-       research personnel in the fields of
ture of new products; in fact, they are    safety, health and environmental pro-
an integral part of each project. The      tection, as well as sharing know-how
beginnings of an active safety policy      with the authorities and other compa-
can be traced back to the 1930s. In line   nies.
with the technology used at that time,
the initial emphasis was on accident       Safety data sheet. Internationally
prevention. Since then the enormous        harmonised system for providing in-
progress made in the fields of science     formation on chemical substances or
and technology has opened up a wide        mixtures to professional users. Safety
range of possibilities, but it has also    data sheets primarily include infor-
created new dangers and given rise to      mation on identifying a particular
the need for additional safety regula-     substance or mixture and its physical,
tions (¡biosafety). The first (initially   chemical, toxicological and environ-
part-time) safety engineer was ap-         mentally relevant properties. They
pointed in 1954. At the same time a        also list characteristics and provide
safety committee was formed, with the      safety advice in the form of hazardous
initial task of examining the problems     substance and international danger-
involved in technical safety in produc-    ous goods transport classifications.
tion and accident prevention. This task    Instructions on handling, storage and
is now carried out by the Corporate        disposal in everyday and emergency
Safety, Health and Environmental           situations are also provided. Roche’s
Protection department (CSE) and by         safety data sheets are prepared by the
similar units at Group companies.          Corporate Safety, Health and Environ-
   CSE issues regulations and direc-       mental Protection department.
tives as circumstances require and
assesses procedures and processes with     Sapac Corporation, Ltd. Sister com-
regard to occupational safety and envi-    pany of Roche from 1926 to 1989,
ronmental compatibility. By means of       with headquarters in New Brunswick
periodic audits it monitors the status     (Canada). During that time, the Roche
of safety, health and environmental        Group had a twin structure: each
protection in the various production       Roche shareholder was automatically a

144
                                                                  Sequencing


Sapac shareholder as well. All Roche      Screening. A selection or test proce-
companies located in continental          dure based on clearly defined criteria
Europe and the Mediterranean region       for recording data within a particular
were members of the Roche Group.          group. In medicine, screening is a di-
Sapac comprised all the Roche compa-      agnostic measure for the early detec-
nies situated in North and South          tion of specific illnesses within a risk
America, Asia, Oceania, the central       group for the purpose of identifying
and southern parts of Africa, Australia   pathogens and initiating effective
and Great Britain.                        treatment as soon as possible.
   This complex corporate structure
was a product of international ten-       Sepsis test. Sepsis is one of the oldest
sions between the two world wars. As      known clinical conditions, and, despite
far as possible, the company’s material   huge advances in many other areas of
and intellectual capital was to be kept   medicine, still a major challenge to
from falling into the hands of an         every doctor. Because of the lack of
aggressor. Against this background,       detailed information about the actual
management decided to expand Roche’s      pathogen involved, the standard treat-
American operations into an inde-         ment in the first 72 hours of sepsis has
pendent unit. It also examined ways of    to rely on broad-spectrum antibiotics.
conferring a legally independent status   As a result, the fight against “blood
on those members of the Group that        poisoning” is increasingly being lost in
were located in countries not directly    this era of growing antibiotic resist-
exposed to the risk of war, so they       ance. A new PCR-based (¡polymerase
could continue to be run as auto-         chain reaction) test developed by the
nomous units should Switzerland be-       ¡Diagnostics Division and known as
come involved in hostilities. Following   the LightCycler SeptiFast test is set
the annexation of Austria by the          to remedy this situation. Within six
German Reich in 1938, the companies       hours the test can reliably detect the
located outside continental Europe        pathogen or pathogens that are caus-
were consolidated into the existing       ing sepsis with much greater accuracy
(but hitherto “dormant”) Sapac hold-      and sensitivity than current tech-
ing company within a few days, and        niques.
Panama City was designated its head-
quarters. After the war Sapac moved       Sequencing. Determination of the
its legal domicile to Canada. In 1989     ¡DNA or ¡RNA sequence, i. e. the
Roche underwent a corporate restruc-      order in which the individual building
turing. As Sapac had largely ceased       blocks (nucleotides) are arranged in a
to serve its original purpose, it was     DNA or RNA molecule. DNA sequenc-
transformed into a pure ¡holding          ing has revolutionised the biological
company (¡share capital).                 sciences and ushered in the era of

Roche from A to Z                                                            145
 Seveso


                                          costs of sequencing and increase
                                          throughput. The US company 454 Life
                                          Sciences was the first in the world to
                                          bring one of these techniques to mar-
                                          ket. The latest representative of this
                                          technique, the Genome Sequencer 20
                                          system, is distributed by ¡Applied
                                          Science and is being further developed
                                          jointly by Roche and 454 Life Sciences.
Genome Sequencer 20 (GS20): Auto-            Applied Science’s Genome Se-
mated ultra-fast system for sequence      quencer 20 instrument sequences over
analysis (determination of the sequence   20 million bases in a four-and-a-half-
of bases in nucleic acids) based on an    hour run – sixty times the number
innovative microtechnology.               possible with Sanger technology,
                                          currently the most popular method.
genome research (¡genomics). Of           The nanotechnology-based special
the various sequencing techniques         technology developed by 454 Life
currently available, the most popular     Sciences incorporates the 454 picoliter
technology is the Sanger method,          technology with its patented light-
which is based on electrophoresis. This   emitting sequencing chemistry and
formed the cornerstone of the human       state-of-the-art informatics. The re-
genome project.                           sulting system is ultra-fast and cost-
   Scientists are increasingly relying    effective and suitable both for the
on Roche’s GS 20 and FLX genome           sequencing of whole ¡genomes (= all
sequencers for their work on medical,     of the genes in a cell) and individual
biological or evolutionary research       ¡genes. The high speed is achieved
issues. The range of applications for     partly through the parallel analysis of
these devices is growing all the time.    thousands of DNA or RNA molecules.
Whereas they were initially used to       The system can be used both to decode
decode the genes of simple fungi or       unknown nucleic acid sequences and
bacteria, they are now being used to      to identify known existing sequences.
analyse human ¡genomes. Doctors
hope to obtain new findings about the     Seveso. An industrial community in
genetic causes of complex illnesses       Lombardy about 30 km (19 miles)
such as cancer, about virus identifica-   north of Milan. The name Seveso has
tion and about the sites of action of     become a symbol for a number of rea-
new drugs.                                sons. First of all, Seveso stands for the
   A large number of research institu-    four adjoining communities (Seveso,
tions and companies are now working       Cesano Maderno, Desio and Meda)
on technologies designed to lower the     affected by a chemical accident that

146
                                                                       Shanghai


occurred on 10 July 1976 at the works      chemicals were spread over a relatively
of Icmesa S.p.A. (part of the Givaudan     wide area. In the end, the safest and
group) in Meda. Givaudan, the former       most expedient method proved to be
Roche subholding comprising the            that of clearing away the layers of earth
Fragrances and Flavours Division, was      that had been permeated by the chem-
spun off as a separate company in May      icals. The contaminated soil and
2000. Now a publicly traded company,       rubble from the demolished buildings
Givaudan is headquartered in Vernier,      were landfilled near the factory site
near Geneva (Switzerland).                 using an impermeable containment
   Following an abnormal reaction, a       system. Problems were also encoun-
mixture of chemicals escaped, affect-      tered during disposal of the residues
ing large areas of the surrounding four    from the reaction vessel. Disposal was
communities. As a result of this acci-     to have been carried out by a specialist
dent, Seveso came to symbolise the         company in an environmentally re-
environmental hazards inherent in the      sponsible manner and in accordance
chemical industry, and it revolu-          with legal requirements. But this plan
tionised the safety philosophy of the      failed, and the residues embarked on a
whole Roche Group.                         bizarre journey lasting several months,
   Today, we can thankfully say that       before ending up in Basel for tempo-
the damage caused was far less severe      rary storage. Ciba-Geigy Ltd (now part
than initially feared. There were no fa-   of the Novartis group) then offered the
talities. One hundred and ninety-three     use of its high-temperature incinera-
cases of chloracne – the characteristic    tor. The residues were incinerated un-
skin disorder caused by exposure to        der the supervision of the authorities,
dioxin – were confirmed by the inter-      without any technical or environmen-
national committee investigating the       tal problems, in June 1985.
accident, but all those affected have
since recovered and bear practically       Shanghai.      Both Shanghai Roche
no trace of these lesions. Two children    Pharmaceuticals Ltd. and Shanghai
sustained minor visible scarring as a      Roche R&D Center (China) Ltd. are
result of caustic soda burns. Neither      based in the Zhangjiang Hi-Tech Park
the feared fetal malformations nor an      in Shanghai. Shanghai Roche Pharma-
increase in the number of miscarriages     ceuticals Ltd. was founded in 1994.
actually materialised. It is now thought   Roche’s first joint venture in China,
that the quantities of dioxin released     Shanghai Pharmaceuticals Ltd. is dedi-
during the accident were less toxic for    cated to improving human health and
human beings than was at first sup-        quality of life by providing a wide vari-
posed.                                     ety of prescription drugs covering key
   Decontamination of the affected         therapeutic areas such as oncology,
areas posed complex problems. The          virology and transplantation. It brings

Roche from A to Z                                                              147
 Shanghai


to China not only state-of-the-art        ments in the fields of oncology, hepati-
technology and innovative products,       tis and transplantation. In 2002 Roche
but also a superior management sys-       invested nearly RMB 100 million so
tem. With an investment of USD 3.7        that eight Chinese hospitals could par-
million, Shanghai Roche Pharmaceu-        ticipate in the HERA project, a global
ticals Ltd. initiated a CRM (Customer     clinical trial of Herceptin breast cancer
Relationship Management) system in        treatment. In the transplantation field,
China, raising the bar to the highest     Shanghai Roche initiated a transplan-
level of practice internationally. This   tation follow-up care management
system earned the “Innovation Prize”      system and simultaneously founded
at the “First Asian One-on-One Inno-      a transplantation follow-up care co-
vator Awards”. It was also named one      ordination committee. These moves
of China’s top-ten CRM Systems in         aim to promote clinical research at the
2002 and given an award for being the     domestic transplantation centre, to
best implementation of CRM in China       strengthen the long-term follow-up
in 2003.                                  care of kidney transplant patients and
   A pioneer in the Chinese healthcare    to provide a foundation for the sharing
industry, Shanghai Roche has achieved     of transplantation resources in days to
tremendous accomplishments since its      come.
founding. It has enjoyed successive          Roche always maintains high moral
double-digit sales growth over the past   standards and strives to be a good cor-
ten years and has occupied a leading      porate citizen in all its business activi-
position in the IMS ranking for           ties. Shanghai Roche has so far organ-
domestic prescription drug sales to       ised donations of cash and medicine
hospitals for many years. The Shang-      with a total value of over RMB 22 mil-
hai Roche High-Potent Production          lion. Contributions have been made in
Plant held its inauguration cere-         response to earthquakes and floods
mony in October 2005. The plant, in       and in response to need for other char-
which a total of CHF 21 million was       ity programmes in China.
invested, manufactures ¡Xeloda and           The Roche R&D Center (China)
¡CellCept, two of Roche’s high-qual-      Ltd. (RRDCC) opened in October
ity innovative products.                  2004. It is one of Roche’s global phar-
   In addition to developing its own      maceutical R&D facilities and its first
business, Shanghai Roche plays an         wholly-owned R&D centre in Asia. Its
active role in supporting the develop-    activities focus on lead generation and
ment of the Chinese healthcare indus-     optimisation for medicinal chemistry
try. Roche has invested more than         research. Collaborating with other
RMB 10 million to sponsor local hos-      R&D facilities, the RRDCC will con-
pitals’ participation in international    tribute to the development of novel,
multicentre clinical trials for treat-    high-quality clinical candidates. The

148
                                                                  Share capital


centre has cooperated with top Chi-           From 1928 to 1931 Roche’s share
nese research institutes on genetics       capital was reduced from 8 million to
research projects. Its establishment       CHF 16,000 in a series of repayments
represents a key strategic decision that   to shareholders. During the same pe-
will allow Roche to continue to en-        riod a stock split doubled the number
hance its capabilities in medicinal        of bearer shares to 16,000, and a total
chemistry at a global level. In addition   of 48,000 non-voting equity securities
to its role as part of Roche’s global      in bearer form were issued. In 1943 the
R&D operations, the centre also pro-       last franc outstanding on each share
vides key support to Roche’s business      was also repaid to the shareholders.
development strategy in China.             Capital stock was raised to the statu-
                                           tory minimum of CHF 50,000 solely
Share capital. Incorporated as a lim-      by drawing on net reserves, resulting
ited company in 1919, F. Hoffmann-La       in a nominal value on paper of CHF
Roche & Co. Ltd, Basel, originally had     31/8 per share. In 1971, to mark the
a capital stock of CHF 4 million,          75th anniversary of Roche’s founding,
divided into 4000 shares with a nomi-      and again in 1984, one new non-voting
nal value of CHF 1,000. In 1920 the        equity security was issued for every
company’s capital stock was doubled        10 shares or non-voting equity securi-
to CHF 8 million.                          ties, bringing the total of outstanding
   In 1927 various parts of the com-       non-voting equity securities to 61,440.
pany were combined to form a sepa-            In 1989 the Board of Directors ap-
rate corporation, ¡Sapac Corpora-          proved a far-reaching capital restruc-
tion, Ltd. The Sapac shares, which had     turing. All outstanding shares in the
a nominal value of CHF 50, were            sister company, Sapac, were redeemed,
paired with shares in F. Hoffmann-La       and it and F. Hoffmann La-Roche &
Roche & Co. Ltd. As twin companies,        Co. Ltd, which until this time had been
Sapac and Roche underwent all the          the operating parent, were trans-
same changes in capital structure until    formed into a pure holding company
1989.                                      under the name Roche Holding Ltd.
                                           The former parent’s operating busi-
                                           nesses and related assets and liabilities
                                           were transferred to a newly established
                                           Swiss operating subsidiary, F. Hoff-
                                           mann-La Roche Ltd, Basel. The previ-
                                           ous twin corporate structure was thus
                                           terminated, and Sapac became a
                                           Group subsidiary.
Non-voting equity securities of F. Hoff-      On completion of the various trans-
mann-La Roche Ltd.                         actions, Roche Holding Ltd had a

Roche from A to Z                                                              149
 Sirolin


share capital of CHF 80 million,           cleotides) distributed randomly across
divided into 800,000 bearer shares         the ¡genome. SNPs can be located
with a nominal value of CHF 100.           at any position inside or outside the
In addition, there were 3,330,134 non-     ¡genes and thus produce widely
voting equity securities with no nomi-     differing effects. Since they can play a
nal value, but conferring the same         role in the differing degrees of efficacy
rights as shares to participate in net     and tolerability of drugs (¡pharma-
profits and any liquidation proceeds.      cogenetics, ¡pharmacogenomics) SNPs
   In November 1991 the capital stock      are the subject of intensive research
of Roche Holding Ltd was doubled to        efforts.
1,600,000 bearer shares with a nomi-
nal value of CHF 100. The number of        Social benefits. Benefits, primarily of
issued and outstanding non-voting          a financial nature, but also those
equity securities was raised to            promoting the social wellbeing of
7,025,627.                                 employees, that are provided by a
   Following the revision of the Swiss     company in addition to contractually
Code of Obligations in 2001, Roche         agreed wages and salaries. Such social
Holding Ltd took the opportunity to        benefits may originate as voluntary
lower the nominal value of its shares.     initiatives on the part of the company,
The shares and non-voting equity           or they may be in response to gradual
securities were split one hundred-for-     changes in public opinion and the
one in May 2001. The existing share        needs of society as a whole. The extent
capital of CHF 160 million was re-         of social services depends, of course,
structured into 160 million shares         on the commercial success of the com-
with a nominal value of CHF 1. The         pany. Internationally operating com-
company now has 702,562,700 non-
voting equity securities.

Sirolin. Launched by Roche in 1898,
this was the company’s first big-selling
product. Earnings from this product
formed the basis for the development
of the firm up to World War I. It is a
syrup based on guaiacol, which was
thought to have antibacterial proper-
ties.

SNPs. Single nucleotide polymor-
phisms (SNPs) are individual varia-
tions in ¡DNA building blocks (nu-

150
                                                         Sternbach, Leo Henryk


panies offer different social benefits      Stem cells. Precursor cells that are
from country to country in accordance       constantly being formed in the bone
with local value systems, government        marrow. They give rise to differenti-
regulations or priorities resulting from    ated daughter cells, which in turn un-
employer–employee agreements.               dergo further differentiation to form
                                            blood cells and cells of the body’s
Social    responsibility. Responsible       ¡immune system.
safeguarding of the interests of society
in connection with the company’s            Sternbach,    Leo   Henryk     (1908–
operations. Over and above its pri-         2005). Father of the ¡psychotropic
mary role as an innovative healthcare       drugs Librium and Valium Roche. Leo
business, Roche also has a long her-        Sternbach was born in the then Aus-
itage of wider community involve-           trian town of Abbazia and studied
ment – in humanitarian and social           pharmacy and chemistry at Jagiellon-
projects centred mainly in least            ian University in Cracow, where he
developed countries, and through its        obtained his doctorate. He worked
support for scientific research, devel-     under Professor Karol Dziewonski as
opment opportunities for young              a postdoctoral researcher until 1937,
scientists and contemporary music           and spent the next four years working
and arts. All these activities are an ex-   with Professor Leopold Ruzicka of the
pression of an autonomous, innova-          Federal Institute of Technology in
tion driven corporate culture that has      Zurich in the field of chemical synthe-
developed over a period of more than        sis. Sternbach then joined Roche Basel
a century. Roche seeks to fulfil its
social obligations in all countries in
which it operates. Wherever the opera-
tions of the company affect the envi-
ronment or local, national or inter-
national communities, Roche aims to
meet the highest standards of respon-
sible business practice. Its contri-
butions to society range from human-
itarian aid, via educational and
information campaigns and various
aspects of ¡health (¡Phelophepa) to
¡environmental protection and the
promotion of ¡art. As a healthcare
company, Roche can make a special
contribution at the interface between
health and illness (¡AIDS Walk).

Roche from A to Z                                                             151
 Studies, clinical


as a research chemist. In 1941, he was     of their key evaluation criteria. There-
posted to the American subsidiary in       fore, sustainability reporting is inte-
¡Nutley where, in 1956/57, he discov-      gral to our annual report (¡ecology,
ered the ¡benzodiazepines, which           ¡environmental protection, ¡social
soon became hugely important as            responsibility, ¡Corporate Gover-
medicines for the treatment of mental      nance).
disorders and various physical ill-
nesses. The best-known of these is         Synthesis. The amalgamation of vari-
Valium Roche, but they also include        ous individual parts to form a whole.
an extensive range of anxiolytic, anti-    Within medicine, a distinction is made
epileptic and sleep-promoting com-         between two different types of syn-
pounds. Sternbach’s scientific findings    thesis – artificial synthesis, which
are presented in over 120 publications     normally involves the production of
and resulted in 240 patents. In 2005       chemical compounds ¡in vitro (“in
Sternbach was inducted into the US         glass”), and biochemical synthesis in
National Investors Hall of Fame for his    biological tissues. Biosynthesis can
contributions to medicine.                 involve either the formation or con-
                                           version of endogenous substances
Studies, clinical. ¡Trial, clinical.       such as carbohydrates, fats or proteins
                                           in the living organism or the technical
Sustainability. Sustainable develop-       manufacture or complete synthesis of
ment is development that meets the         drugs in the laboratory.
needs of the present without compro-
mising the ability of future genera-       Systems biology. A new discipline
tions to meet their needs. Sustainabil-    that addresses the analysis of entire
ity is an ongoing process that aims        biological systems in dynamic inter-
to achieve responsible innovation and      action with their environment. Rather
progress. The principle of ecoeffi-        than analysing individual components
ciency is particularly important if        of a cell, systems biology focuses on all
progress is to be made in sustainable      components and their interacting net-
development. At Roche we are com-          works at the level of genes, proteins,
mitted to sustainability and thus run-     biochemical reactions and physiologi-
ning our business in a way that is ethi-   cal processes. It is based on the grow-
cal, responsible and creates long-term     ing understanding of how biological
value. Roche strives to create sustain-    systems interact dynamically to give
able value for all major stakeholders      rise to physiological functions. Under-
and has been included in various rat-      standing complex biological and phys-
ings, investment funds and indexes         iological interactions can help scien-
(e. g. Dow Jones Sustainability Index)     tists find new ways to detect, prevent
that have defined sustainability as one    and treat multifactorial and polygenic

152
                                            Systems biology


diseases such as cancer or type 2 dia-
betes. Individually tailored health care
solutions can then be offered to very
specific patient groups. SystemsX, the
Swiss initiative in systems biology was
created to enhance and extend trans-
disciplinary research and education at
the highest level in the field of systems
biology. Scientists from Roche and
SystemsX’s Competence Center for
Systems Physiology and Metabolic
Diseases are collaborating in a joint re-
search project entitled “Systems biol-
ogy of the beta-cell-application to type
2 diabetes progression”. The project
aims to identify novel pathways for
drug development in diabetes as well
as new biomarkers of beta cell failure
for diagnostics. Beta cells are located
in the islets of Langerhans in the pan-
creas and produce and release the hor-
mone insulin, controlling the level of
glucose (sugar) in the blood. If the
project identifies suitable biomarkers,
the chances of finding a genuine cure
and not merely a symptomatic treat-
ment for diabetes will increase.




Roche from A to Z                                        153
 Tamiflu


                                            all clinically relevant strains of in-
                                      T     fluenza virus. By blocking neurami-
Tamiflu. The first orally administ-         nidase, these compounds prevent the
ered neuraminidase inhibitor; a novel       ¡virus from spreading and thus stop
medicine launched in 1999 to treat          the infection. For maximum effect
infections caused by influenza viruses      Tamiflu needs to be taken within
(¡influenza). The enzyme neurami-           48 hours of the onset of symptoms.
nidase in these viruses plays a crucial     Tamiflu was developed as an oral med-
role in viral replication. Acting like a    icine to offer patients the advantages
pair of “molecular scissors” it cuts        of simple, reliable dosing. Another
newly formed virus particles free, en-      benefit of oral use is that the drug
abling them to spread and infect new        reaches the virus in every part of the
host cells. In the 1980s scientists found   body where it can do harm. Tamiflu
that a tiny piece of the neuraminidase      has been tested in clinical ¡trials in-
protein was virtually identical in all      volving over 7,000 patients, and over
influenza viruses. This major discov-       40 million people have already been
ery paved the way for the development       treated with the drug. In clinical trials
of the neuraminidase inhibitors, a          in influenza patients, Tamiflu reduced
class of compounds effective against        the severity and duration of illness,
                                            with patients who received the drug
                                            recovering faster than those who did
                                            not. Tamiflu also helped reduce com-
                                            plications of the disease. Tamiflu is ad-
                                            ministered to adults and children one
                                            year and older for the treatment of
                                            influenza and also for prevention fol-
                                            lowing contact with a patient suffering
                                            from influenza. Tamiflu can also be
                                            employed as a preventive measure dur-
                                            ing a general flu epidemic. The prepa-
                                            ration is available in capsule form or as
                                            a powder for the preparation of an oral
                                            suspension. Tamiflu supplements, but
                                            does not replace, flu vaccination.

                                            Taq   (Thermus      aquaticus)     poly-
                                            merase. This ¡enzyme is a key factor
                                            in PCR and thus responsible for the
                                            ¡synthesis of genetic material in the
Tamiflu packaging line.                     form of ¡DNA or ¡RNA. The isola-

154
                                                             Technology transfer


tion of this enzyme from the bac-            Technology transfer. Apart from re-
terium Thermus aquaticus helped              search results protected by ¡patents,
make the ¡polymerase chain reaction          the chemical and pharmaceutical
process more robust and more suitable        industries are constantly developing
for daily use.                               technology and know-how that have
                                             their own value as intellectual prop-
Tarceva. Tarceva is a type of drug called    erty because they are essential to the
a ¡tyrosine kinase inhibitor (TKI) that      development and maintenance of
is designed to block tumour cell growth      industrial production. Technology
by targeting HER1/EGFR, an important         transfer means putting such knowl-
protein for cell growth. Tarceva was first   edge at the disposal of partners in
introduced in 2004 for the second-line       other countries. The transfer between
treatment of patients with advanced          industrial nations covers an extraordi-
non-small cell lung cancer and is            nary range of technologies. The devel-
comarketed in the United States by           oping countries – intent on building
Genentech and OSI Pharmaceuticals. In        up industries of their own – have the
2005 it was also approved by the FDA         greatest need for such transfers.
for the treatment of advanced pancre-        Whenever Roche establishes a produc-
atic cancer in combination with gem-         tion centre in one of these countries
citabine and a variation application is      or contracts out production to a local
currently being reviewed by EMEA.            manufacturer, there is a corresponding
Tarceva is the only tyrosine kinase in-      transfer of technology.
hibitor that has demonstrated an overall        The technology required and devel-
survival benefit in non-small cell lung      oped by the pharmaceutical and
cancer, improving overall survival by        chemical industry is extremely de-
42% and increasing one year survival by      pendent on know-how, and if suitable
45%. Significantly, because of Tarceva’s     personnel and technical facilities are
unique mode of action, these benefits,       not available in the recipient country,
while equivalent to traditional chemo-       the transfer will not make economic
therapy, were achieved without the de-       sense. Thus, technology transfer al-
bilitating side effects often caused by      ways entails some degree of adaptation
¡cytostatic agents. Tarceva is available     to the specific needs and circum-
as a tablet, freeing patients from the       stances of the recipient country.
need for complicated intravenous regi-          Technology transfer is not, as its
mens. Roche and Genentech are contin-        name might suggest, restricted to tech-
uing to explore the use of Tarceva in        nical aspects of production. In addi-
earlier lines of therapy as well as in nu-   tion, the products manufactured must
merous other tumour types, including         be used correctly, and this calls for ad-
ovarian, renal and many other kinds of       equate communication of knowledge
cancer (¡oncology).                          and skills. In the pharmaceutical field

Roche from A to Z                                                                155
 Tender


the recipients of this know-how must        the pharmaceutical industry calls for
understand the indications, effects and     tender are often issued when a country
side effects of drugs. Access to new        – particularly one with a state-run
technology almost always results in         national health service or one in the
the creation of new jobs. This does         Third World – wishes to buy bulk
not necessarily result in a loss for the    quantities of a drug needed to fight
country passing on the technology,          a particular disease. Deals involving
however, since additional demand is         tenders are significant from the point
created by the spread of this expertise.    of view of quantity, but prices usually
The aim of technology transfer must         have to be kept very low.
always be to create a mutually benefi-
cial partnership between the originat-      Test strips. Preferred tool for carrying
ing and recipient countries.                out rapid diagnostic tests. They consist
   As part of its ongoing commitment        of a narrow strip to which one or more
to increase access to HIV drugs and         reagent fields are fixed. In these
address the growing need for second-        reagent fields, all the substances – such
line treatments in sub-Saharan Africa,      as chemicals, ¡enzymes, ¡antigens,
in 2006 Roche launched its “AIDS            ¡antibodies and excipients – that are
Technology Transfer Initiative”.            needed to detect a particular substance
   The aim of this initiative is to share   are impregnated on an absorbent car-
the knowledge that Roche has ac-            rier material or incorporated into a
quired in the manufacture of second-        film. On urine test strips up to ten con-
line HIV treatments and provide             stituents can be detected in the urine
hands-on guidance to local manufac-         at the same time. The test is carried out
turers in countries within sub-Saharan      by dipping the strip in a urine sample
Africa or those defined by the United       and then performing quantitative or
Nations as “least developed”. The ini-      qualitative assessment, either auto-
tiative is currently being implemented      matically using ¡analytical systems or
in 63 countries and revolves around         with the naked eye by means of colour
the production of saquinavir, Roche’s       comparison. In the case of test strips
HIV protease inhibitor that is recom-       for blood analysis, the specimen is ap-
mended by the World Health Organi-          plied to the reaction field. Nowadays,
zation (WHO) as a second-line treat-        the results are assessed almost exclu-
ment in resource-limited settings.          sively by reflectance photometry and
                                            only very seldom by inspection.
Tender. An invitation, usually issued
by an official body, for bids for the       Tests, diagnostic. Analyses per-
supply of bulk quantities of specific       formed as part of laboratory diagno-
goods, sometimes including the serv-        sis. An exactly defined procedure is
ices necessary for their distribution. In   followed for each particular diagnostic

156
                                                                Tinguely, Jean




Test strips and other diagnostic prod-    West facade of the Museum Tinguely,
ucts offering quick results are among     as viewed from Solitude Park. In
the mainstays of medical diagnostics      the foreground, Tinguely’s “Floating
today. Such products are available for    Water Sculpture”.
a wide array of blood and urine pa-
rameters.

test (¡Diagnostics research), entailing   brought him worldwide renown. From
the use of ¡analytical systems (¡Am-      the 1970s on he worked increasingly
pliChip CYP450 test) and diagnostic       in Switzerland and exhibited his work
¡reagents. The screening of donated       in major international shows.
blood (¡blood-screening) for infec-          To mark its centenary year, F. Hoff-
tious pathogens is important for en-      mann-La Roche Ltd presented the city
suring the perfect quality of blood       and region of Basel with the Museum
products. A modern diagnostic test for    Tinguely, which was designed by the
identifying the causative agents of       Ticino architect Mario Botta and built
blood poisoning (¡sepsis test) has        in Solitude Park, on the right bank
been available since 2006.                of the Rhine. The museum exhibits
                                          works by Jean Tinguely that reflect the
Tinguely, Jean (1925–1991). Artist        development of art in the second half
who became famous as the creator of       of the 20th century.
machine sculptures. Jean Tinguely was        In the 1950s Tinguely’s sculptures
one of the outstanding artists of his     – many of them in black and white –
time. Born in Fribourg in 1925, he        were characterised by severity and
grew up in Basel and found his true       great clarity. In 1959 he created the
vocation as an artist in Paris. Along     first of the drawing machines; these
with Alexander Calder, he introduced      Méta-Matics were a significant inno-
movement into art and created highly      vation.
individual, motor-driven machine             In 1960 he enjoyed great interna-
sculptures. His spectacular displays of   tional success with the self-destructing
self-destructing machines in the 1960s    machine Homage to New York. How-

Roche from A to Z                                                            157
 Toxicology


ever, Tinguely’s style changed rapidly.   trial may entail just a single dose or
He began to work with scrap iron and      may continue throughout the animal’s
arc welding, and his sculptures became    life (about two years in the case of
more provocative.                         rats). During the trial the same blood
   In the 1970s, among other works,       chemistry analyses are carried out as in
he produced the Carnival Fountain, in     hospital laboratories. At the end of the
Basel.                                    trial about thirty of the dead animals’
   The final phase of Jean Tinguely’s     organs are subjected to histological
work, in the 1980s, was associated with   examination. This reveals the dosage
a number of major projects, including     level that would be tolerated without
large-scale altars such as the Lola       harmful effects by the species in ques-
retable.                                  tion and indicates the organ systems
                                          that might be damaged at higher
Toxicology. A subdivision of ¡ phar-      dosages. Even if the results obtained
macology dealing with the effects         in the animal experiments indicate
of poisons on the body. In any drug       that the substance is suitable, or even
treatment the desired action against      highly suitable, for use in human be-
the disease is likely to be accompa-      ings, this does not mean that it can
nied by other effects. These may be       subsequently be given to humans
merely inconvenient in some cases,        without further investigation.
but highly undesirable or absolutely
unacceptable in others. Pharma-           Trademarks. A visible sign or device
cologists study the desired effect of     that indicates that a product or service
a drug on a pathological condition,       originates from a particular enter-
while toxicologists seek to establish     prise. Trademarks are extremely im-
whether the medication produces any       portant for companies, which use them
undesirable side effects. The fate of     to identify their products and distin-
a chemical compound depends on            guish them from those of their com-
whether the risk of side effects is       petitors. Registered trademarks are
acceptable when measured against          identified by the following symbol: ®.
the expected benefits.                    Since they reassure customers that a
   This risk-benefit ratio must be de-    certain level of quality will be main-
termined before the drug can be given     tained, trademarks are an important
to humans, hence the importance of        factor in marketing. For this reason a
¡animal experiments. In experimen-        trademark may be used only by the
tal toxicology a compound is adminis-     owner or a licensee authorised by the
tered to different kinds of laboratory    owner. Any vehicle manufacturer may
animals in exactly the same way, but at   call his product a car, but only the
higher doses and over a longer period     owner of the Cadillac trademark may
than envisaged for human beings. The      call his car a Cadillac.

158
                                                                     Trademarks


   Similarly, a ¡pharmaceutical prod-       to the nature of the product or to the
uct’s trademark must be distinguished       manufacturer, but they may also be
from the ¡generic name of its active        purely fanciful.
ingredient. The trademark Pegasys              For pharmaceuticals fanciful, in-
denotes the Roche pharmaceutical            vented names with no relation to the
containing the active ingredient pegy-      product concerned and names that do
lated interferon alfa-2a. Pegylated         indicate the type of product are both
interferon is the generic name of the       used. Where possible, Roche prefers
active ingredient.                          invented names that can be used in the
   Trademarks must also be distin-          same form worldwide. Care is taken to
guished from ¡patents. While a patent       ensure that the word is linguistically
guarantees the inventor of a new prod-      compatible and has no objectionable
uct or process exclusive rights for a       connotations in any language.
specific period, with trademarks it is         Trademark rights are usually ac-
immaterial whether the product is new       quired through a process of registra-
or not. A trademark is protected for an     tion at the trademark office in each
indeterminate period, since in princi-      country. Since Roche operates world-
ple it can be renewed as long it is still   wide, this means that Roche trade-
being used.                                 marks often enjoy legal protection
   Trademarks can take various forms.       in over 150 countries. Roche owns
They may be words, symbols or com-          over 35,000 trademarks (registered
binations of words and symbols, for         or pending), which represent a very
example. The Roche logo, which must         substantial material investment, quite
appear in a precisely specified shade of    apart from their incalculable value as
blue, is an example of a combined           intellectual property.
word-symbol trademark. It is used on           Roche wants to protect its trade-
all packaging, stationery and business      marks. Accordingly, it monitors the
cards, as well as in the company’s          trademark activities of other compa-
advertising. In the case of pharmaceuti-    nies, objects to the registration or use
cal products it is used in conjunction      of marks similar to its own, and takes
with a second ¡hexagon, which con-          legal action where necessary. It keeps
tains no wording and is colour coded to     a special eye out for misuse of its
indicate the product’s therapeutic area.    trademarks by others in order to pre-
This double hexagon is a key feature        vent good, well-known brand names
of the Roche family design, helping         from suffering the same fate as Vase-
to clearly distinguish Roche products       line or Frigidaire. Both were once
visually from those of the competition.     legally protected brand names but
   Trademarks are a product of human        degenerated over the years into
imagination. They may be geographi-         generic terms, thus losing their value
cally descriptive or contain references     as trademarks.

Roche from A to Z                                                              159
 Training and development


Training and development. Activities      partially centralised but that serve the
designed to prepare staff for future      interests of the local companies or are
assignments and problem- and task-        often performed especially for them.
based learning programmes to help         Thus, the prices of goods supplied to
them acquire competencies in new          subsidiaries by the parent company
technologies and methods in a rapidly     must take account not only of the
changing business environment. Em-        manufacturing costs but also of
ployees’ skills and work practices need   expenditures on additional services
to keep pace with continual changes in    such as research and development,
the workplace. At Roche employees are     medical and scientific information,
offered a range of training and devel-    ¡ quality assurance, general adminis-
opment opportunities geared to their      trative work and, last but not least,
individual needs. Based on Group ob-      financing.
jectives, programmes are developed
– and continually reviewed and up-        Trial, clinical. Studies using human
dated – which specifically address the    subjects with the aim of determining
needs of particular national markets or   the benefits and safety of a drug. Clin-
divisions or span a range of corporate    ical trials or studies are planned and
activities. Courses specially adapted     carried out to strict scientific and
to Roche’s needs are prepared by in-      medical standards and must satisfy
house specialists working in conjunc-     binding ethical and legal norms.
tion with leading educational institu-       By means of strict observance of the
tions in Europe and the United States     detailed experimental design (close
(¡Roche Forum Buonas).                    medical supervision, in addition to
                                          detailed, mandatory test protocols)
Transfer prices. The prices of goods      the safety of the test subjects and pa-
and services transferred within a cor-    tients and the quality of the results are
porate group are called transfer prices   guaranteed. Prior to the start of any
or internal charges. There is a regular   clinical study, moreover, approval
and fairly intensive exchange of goods    must also be obtained from independ-
and services between the companies        ent ethics committees and, in most
that make up the Roche Group. These       countries, from the national health
internal transactions are paid for like   authorities as well. Observance of
any other business transaction. A sim-    ethical and legal norms is monitored
ilar internal price system to that used   by the ethics committees and in many
at Roche is practised by all other        countries also by the authorities, by
pharmaceutical firms operating inter-     means of independent inspections.
nationally. These internal charges are    With the “Helsinki Declaration” of
set against the costs arising from        1964, the World Medical Association
Group activities that are wholly or       established for the first time the prin-

160
                                                                     Trial, clinical


ciples according to which clinical trials    ten substances tested in animal studies
are to be run. These have been clarified     makes it to the clinical stage.
and expanded in the course of several           All data from the various human
revisions. Additionally, the responsi-       and animal tests are presented to the
bilities of investigating physicians and     health authorities for review and
the pharmaceuticals industry have            comment, and a summary, called the
been precisely set out and codified in       “Investigational Drug Brochure”, is
¡good clinical practice (GCP) regula-        sent to ethics committees and investi-
tions.                                       gating physicians.
   Every clinical trial is preceded by ex-      Clinical testing proceeds in four
tensive chemical and drug formulation        phases. Except for Phase I (see below),
experiments, not least for the purpose       clinical studies are usually performed
of developing a preliminary dosage           outside the drug company in hospitals
form for administering the test sub-         and, in some cases, in specialised med-
stance to humans and animals. More-          ical practices. The investigating physi-
over, the drug is subjected to detailed      cian, who is also responsible for the
animal or in vitro testing for toxicity      test subjects and patients, is required
and pharmacological effects, both de-        to inform them in advance of the
sirable and undesirable (¡pharmacol-         purpose and goals of the trial and of
ogy, ¡toxicology). In particular, the        possible effects and risks. The main
metabolites of the test substance pro-       concern of the investigating physician
duced in the body and their effects on       in carrying out a clinical study must
important organ systems must be              always be to protect the patients from
identified in animals before clinical        physical injury (the medical principle
trials in humans can begin. But many         of “first do no harm”) and respect their
drugs behave differently in humans           right of privacy (doctor–patient confi-
than in animals; certain effects and         dentiality). Participation in a study is
side effects occur only in humans and        voluntary and the consent of the test
not in animals, or vice versa. Based on      subjects or patients to participate must
experience, however, hypothetical mod-       be documented by their personal sig-
els of the behaviour of drugs within         nature on the informed consent form.
the human body can be obtained.              Participants have the right to quit a
These must be painstakingly reviewed         clinical trial at any time.
(¡pharmacokinetics). Another pre-               Phase I trials test for tolerance in
condition for proceeding to clinical         healthy volunteers (test subjects) by the
testing in humans is a well-founded          administration of gradually increasing
expectation that the new substance           doses until the proposed therapeutic
will meet therapeutic requirements           level is attained (tolerance test).
more effectively than those already in          In the next step, Phase II, the thera-
use. That is why no more than one in         peutic effect at various dosage levels is

Roche from A to Z                                                                161
 Trial, experimental


determined in controlled, randomised        Federation of Pharmaceutical Indus-
tests in a small group of patients. This    tries and Associations (EFPIA), Roche
permits the appropriate dosage range        launched a website in 2005, www.roche-
to be established. If the results of this   trials.com, which gives patients and
step are also positive, that is, if the     healthcare professionals a publicly
drug is well tolerated by patients and      accessible register for clinical trial
leads to cure of the disease or at least    preparations and a database with
to alleviation of symptoms, the drug        study results.
enters Phase III for broader testing.
In this phase, the drug – again under       Trial, experimental. Systematic ex-
controlled conditions and depending         perimentation designed to examine
on the type of illness – is administered    the biological and pharmacological ef-
to anywhere from several hundred to         fects of a substance. In rare cases, the
several thousand patients to test its       therapeutic effectiveness of a sub-
effectiveness under different condi-        stance is first discovered in clinical
tions, as well as its interactions with     practice; as a rule, however, it is the
other medications.                          experimental trial that leads to the
   Long-term treatment is carried out       discovery of therapeutic effects.
exclusively in Phase III, after which an       Such experiments are carried out in
application for ¡registration is sub-       vitro – that is, in the test tube, in cell
mitted to the health authorities. Phase     cultures and in isolated organs – then
IV can begin once approval has been         in animals. The type of screening usual
obtained. The aim of continued testing      in the past – that is, using animals to
of the medication is to discover any        test substances about which only rudi-
unusual side effects, which may not         mentary knowledge was available – is
appear until a drug has been used in        now rarely practised. To identify phar-
many more patients, and to explore          macological and chemotherapeutic
possible additional uses. In any case,      effects that are worth pursuing, a sub-
even after the conclusion of the clinical   stance will first be tested in therapeutic
trials programme, the drug is subject       models (e. g. computer simulations).
to continuous monitoring, since side        Most compounds fail to pass these
effects (but also positive developments     initial trials. The few that remain are
such as effectiveness in treating other     subjected to further testing to sort out
illnesses) are occasionally discovered      the range of effects in detail. This also
only after prolonged clinical experi-       permits the identification of undesir-
ence (¡Drug Safety Monitoring).             able effects. Once all these details are
   With the aim of increasing trans-        known, animal experiments are indis-
parency, and in accordance with the         pensable for clarifying effects and side
guidelines on the disclosure of in-         effects in the intact organism. Pharma-
formation issued by the European            cokinetic and metabolic tests examine

162
                                                         T lymphocytes (T cells)


the distribution and chemical changes         a healthy body. Tumour markers are
the substance undergoes in the body.          primarily used to monitor the progres-
Only after comprehensive experimen-           sion of cancers (¡oncology).
tal testing has demonstrated the safety,
as well as the desired effectiveness, of a    Tyrosine kinase inhibitor. A type of
potential new medicine can it be tested       chemical compound that blocks a pro-
in humans.                                    tein critical for cell growth. Human
   The experimental testing conducted         cells contain more than 900 types of
during the course of product develop-         kinase and these can malfunction to
ment also includes tests to investigate       drive uncontrolled cell division, lead-
behaviour, degradability and possible         ing to cancer. This has been seen in
harmful effects on organisms in the           several kinds of cancer and inhibition
environment.                                  of such faulty kinases can help bring
                                              the cancer under control. Roche’s drug
Tumour markers. Substances or cellu-          ¡Tarceva is an example of a tyrosine
lar changes whose presence, or in-            kinase inhibitor that has been shown
creased concentration, in sample ma-          to be effective in lung and pancreatic
terials – e. g. stools, blood or urine – is   cancer (¡oncology).
directly connected with the presence
or progression of malignant tumours.          T lymphocytes (T cells). Class of
They are produced either by the tu-           white ¡blood cells that are part of
mour cells themselves or by other             the ¡immune system; they mature in
¡cells that are triggered to do so.           the thymus (¡autoimmune diseases).
However, their significance is limited        T cells have two main functions: con-
since such tumour markers can also
occur in association with inflamma-
tory processes in the body and even in




Immunoassay CA-15-3: identifies a
specific protein – a tumour marker –
in the body of breast cancer patients.

Roche from A to Z                                                               163
 T lymphocytes (T cells)


trolling immune responses (helper
T cells) and eliminating cells that are
abnormal or have been invaded by
viruses or parasites (cytotoxic T cells
or killer T cells).




164
                                            Ultra-High-Throughput Screening


                                     U
Ultra-High-Throughput       Screening,
UHTS. Automated, high-performance
test systems which facilitate efficient
drug discovery. In the quest for new
drugs, drug targets (proteins that play
a key role in disease) are systematically
screened for interactions with poten-
tial active drug ingredients from           Roche’s multichannel screening system
Roche’s extensive compound libraries.       speeds up the discovery of new active
The aim of screening large compound         ingredients.
libraries is to find suitable drug candi-
dates quickly and make them available       between potential active drug ingredi-
for development as medicines.               ents and drug targets (fluorescence,
   Roche and Carl Zeiss Jena have           luminescence, and absorption meas-
jointly developed a new UHTS system         urements). It thus meets today’s exact-
that sets new global standards for          ing requirements for high-throughput
screening systems. The new system can       efficiency in drug discovery.
test up to 200,000 samples a day, per-         ¡Applied Science, a business unit
forming up to ten measurements per          of Roche Diagnostics, develops and
sample. The centrepiece of the new          supplies generic assays and reagents
technology is a novel detection system      for UHTS and offers tailor-made solu-
(a multichannel reader), combined           tions for customers’ needs.
with newly developed equipment and
control software for processing the
microtitre plates in which the tests
are performed. Miniaturisation of test
volumes, using microtitre plates with
384 or 1,536 wells, dramatically re-
duces the amounts of biochemical
reagents and chemical samples re-
quired. The custom-designed 96-
channel reader permits high-precision
analyses of 384 samples in four steps,
or of 1,536 samples in 16 steps, within
a matter of seconds. The Zeiss reader
employs all the optical detection
methods customarily used in biologi-
cal screening to detect interactions

Roche from A to Z                                                             165
 Viruses


                                           developed, including the HIV pro-
                                    V      tease inhibitors ¡ Invirase and Vira-
Viruses. Minute, often highly conta-       cept for AIDS viruses.
gious pathogens consisting of an inner        Certain viruses do not cause serious
core of genetic material, in the form of   disease in subjects whose ¡immune
¡DNA or ¡RNA, which is frequently          systems are functioning normally.
surrounded by one or more protective       These include the rhinoviruses (re-
shells (capsids). Retroviruses contain     sponsible for the common cold),
genetic information in the form of         cytomegalovirus (CMV) and various
RNA, which can be transcribed into         other herpes viruses. However, if the
DNA by the viral ¡enzyme reverse           immune system is impaired (as is the
transcriptase. HIV, the causative agent    case in AIDS patients or people who
of ¡AIDS, is a retrovirus. Viruses can     have undergone chemotherapy or
only replicate with the help of bio-       are immunosuppressed following an
chemical “tools” provided by the host      organ transplant), even these viruses
cells they invade.                         can pose a threat. CMV, for instance,
   Drug treatment of viral diseases        will then damage vital organs and
has so far proved very difficult, as       cause blindness.
substances intended to block viral            Many viruses are dangerous to
replication often also interfere with      everyone, either because they can seri-
important physiological processes in       ously damage organs even in healthy
human cells and thus provoke side          subjects or, in some cases, because they
effects. It is only recently, with the     can cause cancer to develop. Measles,
characterisation of entire ¡ genomes       mumps and polio viruses are danger-
of many viruses, that new specific tar-    ous mainly for infants and young
get structures have been identified.       children. Infection with the rubella
This characterisation of viral ge-         (German measles) virus during preg-
nomes coupled with PCR technology          nancy causes damage to the unborn
has also allowed development of            child. A number of other viruses pose
highly sensitive diagnostic tests that     a threat to adults too: type A and B in-
quantify the amount of virus in            fluenza viruses, meningitis viruses, the
blood, enabling monitoring of              various hepatitis viruses (A, B, C, D),
patient response to therapy as well        the AIDS viruses HIV-1 and HIV-2,
as detection of dangerous viruses in       and the Epstein-Barr and human
donated blood and organs before            papilloma viruses, which can cause
they are used in transfusions or           cancer. The Ebola virus and a number
transplantation. With the help of          of other viruses found in tropical
¡ genetic engineering and computer         countries can prove rapidly fatal.
modelling of active ingredients,              People can be protected against
highly effective drugs have been           viral infections by being inoculated

166
                                         Viruses


with killed or greatly attenuated
viruses or with virus capsid proteins
produced by genetic engineering.
Inoculation (also called vaccination)
stimulates the immune system to form
“memory” cells, which, in the event
of infection with an active pathogen,
trigger the production of specific
¡antibodies and T lymphocytes that
recognise the invader.
   Roche produces the following anti-
viral drugs: Cymevene/Cytovene (ganci-
clovir) for CMV infections, the HIV
protease inhibitors ¡Fuzeon, Invirase
(saquinavir) and Viracept (nelfinavir)
for the treatment of AIDS, ¡Roferon-
A (interferon alfa-2a) and Pegasys
(pegylated interferon alfa-2a [40KD])
for ¡hepatitis B and hepatitis C,
Copegus (ribavirin) for hepatitis C
and ¡Tamiflu for ¡influenza.




Roche from A to Z                             167
 Wastewater treatment


                                  W
Wastewater      treatment. Since the
early 1970s Roche has invested sub-
stantially in the construction of mod-
ern wastewater treatment facilities.
   Chemically polluted effluents are
treated for the most part at company-
owned facilities combining chemical
and biological treatment processes.
Up to roughly 90 percent of organic
pollutants are biologically degraded by
microorganisms. The resulting sludge
is separated, dewatered and then dis-
posed of by environmentally responsi-
ble incineration methods. Effective as
modern biological treatment systems
are, however, effluents generated by
Roche and other companies still con-
tain compounds, such as chlorinated
and aromatic hydrocarbons, which are
poorly biodegradable.
   Roche scientists are working to
develop and evaluate state-of-the-art
processes for pretreating poorly
degradable process effluents. This in-
house pretreatment ensures that prob-
lem compounds can then be readily
biodegraded by existing treatment
processes.

WHO (World Health Organization).
Agency of the United Nations,
founded in 1947 for the purpose of
promoting ¡health. Its headquarters
are in Geneva.




168
                                             Xeloda


                                      X
Xeloda. A chemotherapy agent (active
ingredient capecitabine) taken in tablet
form as a treatment for breast and
bowel cancer. Xeloda is converted into
the active cytostatic agent 5-fluoro-
uracil (itself a product originally devel-
oped by Roche as ¡Fluoro-uracil Roche
four decades ago) inside tumours, so it
has much less effect elsewhere in the
body, resulting in far fewer side effects
without sacrificing efficacy. Xeloda was
launched in 1996 and recently cele-
brated the milestone of the millionth
patient treated. In addition to its cur-
rently licensed indications, Xeloda has
also shown benefit in cancers of the
stomach and pancreas, where it is hoped
its use will shortly be approved. Studies
investigating Xeloda in other types of
cancer are in progress (¡oncology).




Roche from A to Z                                169
Index


Page numbers in italics refer to entries on the subjects listed in the index. Page
numbers in regular type refer to pages where indexed subjects are mentioned.

A                                         Antidepressants, 128
Accu-Chek, 48–49, 93                      Antigen, 12–13, 32, 34, 82, 92, 99, 130,
Accutrend, 130                               156
ACE inhibitors, 4, 33                     Antimicrobials, 5, 14, 23, 53, 63, 108
Activase (TNKase), 33, 68                 Antiparkinsonian agents, 16, 74, 98,
Adenine, 52, 138                             119
Adjuvant therapy, 31, 78                  Apothecary jars, historical, 16
Agonist, 4, 12, 26                        Applied Science, 16, 49, 82, 122, 142,
AIDS, 4, 15, 30, 60, 63, 86, 107–108,        146, 165
    116, 126, 130, 142, 151, 166          Apprenticeships, 17
AIDS Walk, 5, 151                         Architecture, 18, 24, 44, 74
Air pollution, control of, 5, 59          Art, 19, 44, 151
Airol, 6                                  Arthritis, rheumatoid, 20, 22, 38, 135
Alarm centre, 6                           Autoimmune diseases, 14, 20–21, 104,
Alternatives to animal testing, 6, 11        135, 163
Alzheimer’s disease, 7                    Avastin, 11, 19, 22, 65, 103
Amino acids, 7, 126
AmpliCare programme, 8                    B
AmpliChip CYP450 Test, 8, 49, 53, 64,     Bacteria, 13–14, 23, 28, 67, 82, 135
    157                                   BAN, 65
Amplicor, 95, 117, 142                    Barell, Emil Christoph, 18, 23–24, 30,
Analysis, 9, 66, 93, 102                     62, 79
Analytical systems, 9, 38, 40, 49, 56,    Basel, 6–7, 16–20, 24, 25–26, 44–46,
    78, 142, 156–157                         57, 72, 79, 81, 90, 97, 108, 111,
Anemia, 10, 20, 34, 60, 98, 103              133, 149, 151, 157–158
Angiogenesis, 10, 22                      Basic research, 22, 25, 62, 68
Angiotensin, 4                            Basilisk, 25, 78
Animal experiments, 11–12, 132, 158       Benzodiazepines, 25, 81, 98, 119, 128,
Antagonist, 4, 12, 26, 119, 131              131, 152
Antibodies, 5, 12–13, 21, 28, 30, 32,     Bioavailability, 9, 62, 66
    70, 81–82, 99, 103, 113, 122, 126,    Biologics, 26
    130, 156, 167                         Biology, 26
Antibodies, humanised, 13, 21, 77, 82,    Biomarkers, 26, 50, 139
    104                                   BioS, 26
Antibodies, monoclonal, 13, 21–22,        Biosafety, 27, 77, 122, 144
    32, 65, 77, 92, 104                   Biosimilars or follow-on biologics
Antibodies, polyclonal, 13                   (FOBs), 28

170
                                                                            Index


Biotechnology 23, 29, 33, 65, 93–94,      Coagulation self-monitoring, 39, 109,
    103                                      131
Biotransformation, 29                     Cobas, 9, 39, 79, 117, 142
Blood cells, 4, 21, 29, 34, 60, 73, 88,   Cohen, Stanley, 67
    98, 131, 163                          Communication, employee, 40
Blood-screening, 30, 115, 157             Communication, financial, 40
Board of Directors, 18, 23, 30            Communication, general, 41
Bondronat, 103                            Communication, product-related, 41
Bonviva/Boniva, 106                       Communications, 80
Boyer, Herbert, 67                        Competition, 41
Breast cancer, 22, 31, 77                 Copegus, 15, 77, 142, 167
Burgdorf, 32, 48, 83                      Copyright, 42
B lymphocytes, 13, 30, 32, 91             Corporate functions, 43, 90, 108
                                          Corporate Governance, 43, 152
C                                         Corporate Principles, 41, 43
Caflisch, Albert, 30                      Counterfeit drugs (cultural commit-
Capsules, 107, 123                           ment), 44, 62, 107, 124
Cardiac Reader, 130                       Cultural sponsoring, 44
Cardiology, 33                            Cystic fibrosis (CF), 46, 65
Cardiovascular, 4, 33                     Cytokines, 10, 46, 82, 84, 92, 113, 131,
CellCept 29, 33, 122, 148, 170               141
Cell, human, 34–35, 52                    Cytosine, 52, 138
Cell nucleus, 34, 131                     Cytostatic agent, 47, 102, 155
Cells, 60, 97, 163
Cells, dendritic, 30, 34                  D
Cephalosporins, 34                        Derivative, 48
C.E.R.A., 10, 34, 61                      Diabetes, 10, 22, 32, 48–49, 82, 93
Chemotherapeutic agents, 35               Diabetes Care, 32, 48–49, 82, 93
Child-proof drug containers, 35, 107,     Diagnostics Division, 5, 9, 16, 38–39,
   121                                       48, 50–51, 53, 56, 73, 76, 78,
CHMP, 35, 56, 133                            81–82, 94, 105, 108, 111, 114, 116,
Cholesterol, 35                              122, 125, 130, 134, 139, 145
Chromosomes, 34–35, 46, 67, 69            Diagnostics research, 49, 134, 157
Chugai, 21, 33, 38, 52, 78, 92, 97–98,    Dilatrend, 33
   106, 112, 133–134                      Distribution centres, 50
Clinical chemistry, 10, 38–39, 130, 143   Divisions, 40–41, 43, 51, 76, 112, 133
Clinical Research Ethics Advisory         DNA, 26, 29, 34–35, 46, 52, 62, 64,
   Group (CREAG), 38                         67–69, 94–95, 97, 114–115, 127,
Clone, 38                                    131, 135, 138, 141, 145, 150, 154,
CoaguChek, 39, 130                           166

Roche from A to Z                                                             171
Index


DNA chips, 9, 52                         G
DNA probe, 52, 68                        Gene, 7, 9, 14, 38, 64, 67–69, 82, 95,
Dormicum, 81                                127, 146, 150
Dosage forms, 62, 107, 113, 123–124      Gene chip, 9, 64
Dow Jones Sustainability Index, 152      Gene disruption, 68
Drug resistance, 53                      Gene segment, 66
Drug Safety Monitoring, 53, 121, 162     Genentech, Inc., 22, 32–33, 46, 52, 64,
                                            78, 82, 85, 92, 97, 103, 112, 134,
E                                           136
Early detection, 55                      Generic names, 65, 159
E-business (electronic business), 55     Generics, 42, 62, 66, 124, 135
Ecology, 55, 60, 74, 152                 Genetic engineering, 23, 26, 29, 66,
Elecsys, 9, 56                              85, 111, 131, 135, 166
EMEA, 34–35, 56, 133                     Genetic engineering techniques, 52,
Employee health service, 57, 76, 102        67–68
Employee representation, 57              Genetic information, 52, 64, 68
Energy supplies, 58                      Genetics, 69
Environmental protection, 9, 56, 58,     Genome, 34, 52, 64, 69, 96, 113, 127,
    76, 86, 122, 137, 151–152               146, 150, 166
Environmental risk assessment, 60        Genome Sequencer GS20, 146
Enzymes, 29, 38, 52, 60, 95, 126, 128,   Genomics, 17, 26, 69, 94, 115, 139,
    130, 135, 154, 156, 166                 146
Epidemiology, 60                         Gerber, Fritz, 31
EPO, 10, 60                              Glucose, 48, 69, 82, 109
Epogin, 38, 61, 98                       Glucose self-monitoring, 48, 69, 82,
Erythrocytes, 10, 29, 60                    109
Erythropoietin, 10, 60, 88, 98, 122      GlycArt Biotechnology AG, 69, 134
Escherichia coli, 28, 61                 Good Clinical Practice Regulations
Expression, 71, 104, 141                    (GCP), 71, 129, 161
                                         Good Laboratory Practice Regula-
F                                           tions (GLP), 72, 129
FDA, 5, 62, 65                           Good Manufacturing Practice Regula-
Fermentation, 35, 121–122                   tions (GMP), 72, 91, 122, 129
Fire service, 137                        Granulocytes, 30, 73
Fluoro-uracil Roche, 62, 169             Graz, 73
Formulation, 62, 66, 113, 121, 123       Grenzach-Wyhlen, 6, 74–75, 79, 96,
Foundations, scientific, 62                 132, 136
Fusion inhibitors, 5, 63, 119            Group, 74, 80, 108
Fuzeon, 63, 119, 167                     Guanine, 52, 138
                                         Guggenheim, Markus, 16, 74

172
                                                                               Index

H                                            In vitro diagnosis, 68, 87, 115, 130
Health, 76, 133, 151, 168                    In vivo, 72, 87
Health protection, 76                        In vivo diagnosis, 87
Hepatitis, chronic, 15, 77, 107, 116, 167
Herceptin, 32, 65, 77, 103, 122              J
Hexagon, 78, 159                             Jann, Adolf Walter, 30
Hitachi, 78                                  Jerne, Niels Kaj, 12–13, 98–99
HIV, 4–5, 8, 15, 30, 56, 60, 63, 67, 86,
   96, 100, 107, 115–117, 119, 126,          K
   142, 156, 166–167                         Kidney disease, chronic, 34, 61, 88, 98,
Hoffmann, Traub & Co., 6, 79                    172
Hoffmann-La Roche, Fritz, 6, 24,             Koechlin-Hoffmann, Albert, 30
   62–63, 74, 79–80, 96, 108, 112,           Köhler, Georges, 13, 98–100
   138–139                                   Kytril, 103
Holding company, 30, 80, 108, 145
Hormones, 80, 131                            L
Human interferons, 85                        La Roche, Adèle, 79–80, 138
Humer, Franz B., 31                          Landfills, 89
Hybridomas, 81                               Landscaping, ecological, 89
Hypnotics, 25, 81                            Languages, 90
                                             Leukocytes, 29–30, 73
I                                            Lexotan, 25
Immune system, 4, 12–13, 21, 30, 32,         Librium, 25, 151
    34, 46, 82, 85, 91–92, 104, 113,         LightCycler, 17, 143, 145
    131, 135, 141, 151, 163, 166             Logistics, 90, 93, 120
Immunoassay, 39, 56, 82                      Lymphocytes, 73, 82, 91–92
Immunoglobulin (Ig), 82                      Lymphokines, 91
Immunology, 82
Indianapolis, 82                             M
Indication, 83                               MabThera, 65, 92, 100, 103
Influenza (flu), 16, 83, 154, 167            Macrophages, 34, 92
Informed consent, 71, 161                    Madopar, 16, 119
INN, 29                                      MagNA Pure LC, 17
Insulin pump therapy, 32, 84                 Mannheim, 74, 92, 136
Interferons, 29, 46, 67, 77, 84, 91, 122,    Marketing, 93, 112
    126, 141                                 Measurement units, analytical, 93
Investment, 85, 123, 126                     Medicine, personalised, 76, 94
Invirase, 15, 86, 119, 166                   Metabolism, 94
In vitro, 6, 11, 68, 72, 85, 87, 115, 130,   Metabolites, 9, 161
    143, 152                                 Milstein, Cesar, 13, 98–99

Roche from A to Z                                                                   173
Index


Mircera, 34, 61                          P
Molecular biology, 26, 94, 99, 135       Packaging, 90, 107, 123
Molecular Diagnostics, 49, 53, 82, 94,   Palo Alto, 107, 133, 136, 141
   114, 116, 142                         Parent company, 24–25, 30, 108, 133
Molecular medicine, 94–95                Patents, 6, 44, 66, 85, 108, 135, 155,
Molecule, 26, 96                             159
Monitoring, 96                           Patient self-monitoring kits, 109
mRNA, 68                                 PCR, 15, 30, 50, 60, 68, 77, 109, 111,
Mullis, Kary, 100, 115                       114
Multinationality, 96                     Pediatric pharmaceuticals, 109
Museum Tinguely, 45–46, 157              Pegasys, 15, 29, 68, 77, 122, 142, 159,
Mutagenesis, 68                              167
Mutation, 7, 13, 46, 97                  Penzberg, 26, 70, 74, 111, 122, 133
                                         pH value, 94
N                                        Pharmaceutical formulation, 73
Nanotechnology, 146                      Pharmaceuticals, 51, 66, 71, 78, 83, 94,
NeoRecormon, 10, 29, 61, 98, 103,            104, 107–109, 111–112, 122, 133,
   122                                       138–139, 159
Neurotransmitters, 16, 98, 101, 131      Pharmaceuticals, Division, 51, 71, 76,
New Drug Application (NDA), 132              78, 107–108, 111, 122, 133,
Nobel Prize, 12–13, 25, 82, 98, 115          138–139
Non-Hodgkin’s lymphoma, 92, 100          Pharmacoeconomics, 112
Non-voting equity security, 140, 149     Pharmacogenetics, 112, 150
Nutley, 19, 24, 85, 100, 133, 152        Pharmacogenomics, 113, 150
                                         Pharmacokinetics, 113, 161
O                                        Pharmacology, 113, 158, 161
Obesity, 94, 101                         Phelophepa, 113, 151
Occupational hygiene, 9, 55, 76, 101,    Plasmid, 114
   144                                   Platelets, 29–30
Oncogene, 102                            Pleasanton, 95, 114
Oncology, 13, 22, 47, 62, 65, 78, 92,    Point of Care Testing, 115
   94, 100, 102, 115, 119, 155, 163,     Polymerase chain reaction (PCR), 49,
   169                                       68, 95–96, 100, 109, 115, 130, 145,
Organ transplantation, 13, 21–22, 33,        155
   63, 103, 108                          Predisposition, 76, 118
Orphan drugs, 105                        Prevention, 82, 118
Osteoporosis, 20, 56, 94, 105            Prices, 118
                                         Prix Galien, 63, 86, 119
                                         Product distribution, 120
                                         Product safety, 9, 120

174
                                                                           Index


Production, biotechnological, 29, 33,      Rheumatism, 22, 38, 135
   85, 121                                 Rhine, 74, 92, 132, 136
Production, chemical, 122                  Ribonucleic acid, 52, 64, 138
Production construction projects, 123      Ribosome, 136
Production, pharmaceutical, 123            Risk management, 136
Production sites, 86, 125                  Risk management planning, 137
Professional Diagnostics, 9, 39, 49, 56,   RNA, 26, 68, 136, 138, 145, 154, 166
   78, 81–82, 105, 115, 125, 130, 142      Rocephin, 16, 29, 34, 122, 138
Profit, 126                                Roche, 85, 138
Protease, 126                              Roche Biomarker Programme, RBP,
Proteins, 7, 12, 21, 26, 29, 35, 38, 46,       139
   52, 61, 64, 66, 68–69, 85, 111, 121,    Roche Charter on Genetics, 139
   126–127, 130, 136, 141                  Roche Commissions, 44–45
Proteomics, 17, 26, 50, 127, 139           Roche Connect, 140
Psychotropic drugs, 25, 119, 128, 151      Roche Forum Buonas, 140, 160
Pulmozyme, 46, 68                          Roche Foundation for Anemia
                                               Research, 63
Q                                          Roche Holding AG, 30, 74, 81, 108,
Quality assurance, 71–72, 121, 129, 160        149–150
Quality control, 9, 71, 121–122, 129,      Roche Institute of Molecular Biology,
  134                                          85, 141
                                           Roche ’n’ Jazz, 45
R                                          Roche Organ Transplantation
Randall, Lowell, 25                            Research Foundation (ROTRF),
Rapid diagnostic tests, 130                    63
Rating, 152                                Roche Research Foundation, 63
Reagents, diagnostic, 130, 143, 157        Roche Sample Repository, RSR, 141
Receptors, 5, 126, 131, 141                Roferon-A, 30, 67, 77, 85, 103, 113,
Recombination, 131                             141, 167
Recycling, 59, 131                         Rohn, Roland, 19
Reflotron, 130                             Rotkreuz, 142
Regio, 132                                 Rx, 112, 143
Registration, 35, 56, 60, 72, 108, 111,
    132, 162                               S
Research, 7, 25, 71, 76, 86, 108, 112,     Safety, 56, 60, 76, 102, 136, 144
    126, 133–134                           Safety data sheet, 144
Research expenditure, 7, 134               Salvisberg, Otto R., 18–19, 44
Research, genetic, 139                     Sapac Corporation, Ltd., 144, 149
Restriction enzymes, 135                   Science and Ethics Advisory Group,
Retention tanks, 135                           (SEAG), 140

Roche from A to Z                                                           175
Index


Screening, 76, 145                         Transformation, 68
Sepsis test, 145, 157                      Traub, Max Carl, 79
Sequencing, 50, 145                        Trial, clinical, 33, 54, 66, 71, 74, 78, 85,
Serology, 131                                  87, 121, 132, 141, 152, 154, 161
Seveso, 146                                Trial, experimental, 72, 87, 94, 162
Shanghai, 134, 147                         Tumour markers, 56, 103, 163
Share capital, 74, 79, 81, 145, 149        Tyrosine kinase inhibitor, 103, 155,
Sirolin, 80, 139, 150                          163
SNPs, 150                                  T cells, 4–5, 21, 30, 163–164
Social benefits, 150                       T lymphocytes (T cells), 21, 30, 34,
Social responsibility, 5, 8, 114,              91, 163
    151–152
Stem cells, 10, 151                        U
Sternbach, Leo Henryk, 25, 98, 151         Ultra-High-Throughput Screening,
Studies, clinical, 152                        UHTS, 165
Supply Chain Management, 90                Uracil, 138
Sustainability, 8, 56, 152                 USAN, 65
Synthesis, 152, 154
Systems biology, 152                       V
                                           Valcyte, 15, 104, 108
T                                          Valium Roche, 25, 151–152
Tablets, 35, 107, 111, 123, 125            Viracept, 15, 166–167
Tamiflu, 16, 60, 84, 154, 167              Viruses, 4, 13–14, 28, 67, 69, 82, 84,
TaqMan, 95, 117, 142                           86, 154, 166
Taq (Thermus aquaticus) polymerase,
    154                                    W
Tarceva, 103, 155, 163                     Waste, 6, 28, 58–59, 88–89, 122, 131,
Technology transfer, 124, 155                 138
Tender, 156                                Wastewater treatment, 59, 168
Test strips, 69, 82, 115, 143, 156         WHO, 44, 65, 71, 73, 76, 99, 101, 168
Tests, diagnostic, 9, 26, 139, 156         Wieland-Zahn, A., 30
Thymine, 52
Tinguely, Jean, 46, 157                    X
Tonegawa, Susumu, 13, 82, 99–100           Xeloda, 62, 102, 148, 169
Toxicology, 7, 9, 12, 72, 102, 113, 121,   Xenical, 101, 111
    130, 158, 161
Trademarks, 6, 25, 44, 78, 80, 85, 139,    Z
    159                                    Zenapax, 68, 104
Training and development, 140, 160
Transfer prices, 160

176

								
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