Document Sample
					Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 65 No. 6 pp. 641ñ645, 2008                                                 ISSN 0001-6837
                                                                                                                 Polish Pharmaceutical Society

                                                 TERESA BRODNIEWICZ-PROBA

                    MTZ Clinical Research Sp. z o.o., 5 PawiÒskiego St., 02-106 Warsaw, Poland

              Abstract: The article presents an outline of the requirements concerning the planning of preclinical and clini-
              cal studies, necessary for the legal approval of a medicinal product. It describes the clinical research plan of
              innovative and generic pharmaceutical products, taking into account the specific situations in which the assess-
              ment of biological equivalence of a generic product is not possible based on pharmacokinetic parameters. The
              article also discusses the guidelines which determine the scope of studies which are necessary in the process of
              registration of biotechnological and biosimilar products.

              Keywords: preclinical studies, clinical studies, innovative medicinal product, generic medicinal product, bio-
              logical products, similar biological products

Introduction and definitions                                                   lence studies) together with a comparative assess-
       A number of basic concepts must be defined                              ment of the pharmacokinetics or the therapeutic
before we describe the scope and requirements of                               effect, with the aim to prove similarity. No preclini-
preclinical and clinical studies which must be car-                            cal research is carried out on generic products.
ried out in order for the pharmaceutical product to                                  Biopharmaceuticals ñ are pharmaceuticals pro-
gain a legal approval and the marketing authoriza-                             duced according to biotechnological methods,
tion.                                                                          although no widely accepted definition exists. This
       Innovative medicinal product ñ i.e. an original                         group of products includes:
one, is a product whose effects are based on either                            recombinant proteins, (monoclonal) antibodies, vac-
new, unknown or previously unused active compo-                                cines, blood and plasma-derived products, products
nents or on components which, in comparison with                               obtained from the cells of: bacteria, yeasts, insects,
the products available on the marked, improve the                              plants, and mammals, as well as of genetically mod-
effectiveness, safety, or comfort of the therapy.                              ified plants and animals; products used in gene ther-
       Such a product is registered on the basis of a                          apy (vaccines based on DNA, oncological treatment,
complete set of registration documents including, in                           Parkinsonís disease and other neurodegenerative
addition to the chemical, biological and pharmaceu-                            diseases), somatic cell therapy, tissue engineering.
tical part, the results of original research, as well as                       Registration of these medicinal products is based on
pharmacological and clinical assessment. To fulfill                            a complete set of registration documents including
these requirements it is necessary to carry out a bat-                         preclinical and clinical data.
tery of preclinical studies, as well as studies of phase                             Medicinal biosimilar products ñ (terms used:
I, II, III, and IV.                                                            similar biological medicinal product/biosimilar,
       Equivalent medicinal product ñ i.e. a generic                           biotechnological generics, biogenerics, follow-on
one, is a product therapeutically equivalent to the                            biologics ñ the terminology is not synonymous due
innovative product. It is assumed that a product is                            to a great variety of products) medicinal products of
therapeutically equivalent if it is pharmaceutically                           biotechnological origin whose quality, safety and
equivalent and biologically equivalent.                                        efficacy in relation to the original (referential) prod-
       Such a product is registered on the basis of a                          uct has been proven, and which have obtained mar-
set of registration documents including, in addition                           ket authorization. The concept of biogenerics was
to the chemical, biological and pharmaceutical part,                           introduced by EMEA in 2004 (the review of the
the results of original clinical studies (bioequiva-                           European pharmaceutical law ñ Pharma Review).

* Corresponding author: e-mail:

642                                     TERESA BRODNIEWICZ-PROBA

This gives the basis for submitting the so-called sim-     the first in men administration, another part is con-
plified registration applications. It is necessary to      tinued parallelly with the studies of subsequent
prove the similarity to biological products registered     phases.
under the centralized procedure. There is no need to             The set of toxicity tests includes a test for local
carry out a whole battery of studies as it is in the       tolerance, in which the way the product is adminis-
case of original products.                                 tered must be identical to the one in the planned study
      Europe has worked out a system of recommen-          involving human subjects. Another type of study is
dations concerning the scope of preclinical and clin-      genotoxicity testing, whose purpose is to detect any
ical studies (general and detailed, prepared by            potential mutations or chromosomal damage by
CHMP ñ Committee for Medicinal Products for                means of tests performed on cells. The results must be
Human Use). The USA has been working on the                known before the start of phase II studies. Similarly,
legalization of this system.                               before the start of phase II studies, an assessment of
                                                           the effects of the product on the male and female
Research and development in the pharmaceutical             reproductive systems must be carried out. In some
industry and the risks associated with them                cases, an additional study on the potential carcino-
     It takes on average 13.4 years from the discov-       genic effects is performed. This study may be con-
ery of a compound to the registration. The process of      ducted after the registration of the product. If there are
developing a new medicinal product is very expen-          doubts concerning the safety of the product, the scope
sive and the risk of failure is very high. The risk for    of the study shall be appropriately extended (1).
various phases of the research is estimated as fol-
lows: preclinical phase ñ 61%, phase I / II ñ 78%,         Clinical studies of medicinal innovative pharma-
phase IIIó51%.                                             ceutical products

Preclinical studies of innovative pharmaceutical           Phase I
products                                                          The aim of phase I of clinical studies is solely
     Preclinical studies are conducted only for inno-      a research (exploratory) one, rather than therapeutic.
vative products. Their aim is to discover the toxic        The participants of the study are essentially healthy
effects, especially their impact on particular organs.     volunteers (10 ñ 20 persons), unless administration
Moreover, the studies have to examine the relation         of the medicinal product to healthy people would be
between the impact of the toxic effect and the length      unethical, regarding its profile.
of the exposure to the tested product, as well as the             The aim is to make initial estimates as to the
reversibility of the impact.                               safety after a single and repeated administrations,
                                                           discovering the pharmacokinetics of the product
Pharmacological studies of safety                          (absorption, distribution, metabolism, and excre-
      These studies assess the impact of the product       tion), and discovering the pharmacodynamic effect
on the functions of, for example, the cardiovascular       (i.e. the effects of the product on the organisms of
system, the central nervous system, and the respira-       healthy or sick people). Sometimes it is possible to
tory system.                                               plan the study in such a way as to preliminarily esti-
                                                           mate the potential therapeutic effect.
Toxicokinetic and pharmacokinetic studies
      These studies help to obtain information on          Phase II
absorption, distribution, metabolism, and excretion.             The aim of phase II clinical studies is to dis-
The results of these studies are analyzed before the       cover the therapeutic properties of the product. The
start of phase I studies.                                  study is carried out on a selected group of patients.
                                                           A typical participantsí group in this study phase is
Toxicity tests                                             small and very homogeneous, (typically up to 100
      The first step are studies of acute toxicity after   participants in 1 ñ 3 research centres). During the
the administration of a single dose or increasing          study, the size of the doses (through an increase in
doses to two species of mammals. In the next step          dosage) which will be used in phase III is deter-
there are the so-called chronic toxicity tests, which      mined. An important aim of phase II is to verify the
must be adequate to the planned manner of adminis-         end points that will be used in phase III.
tration to humans. The product is given to two             Phase III
species of mammals, of which only one may be a                   The aim of phase III studies is to prove the
rodent. A part of the study must be completed before       expected therapeutic benefits. The selection of par-
                               The scope and requirements related to preclinical and clinicalstudies of...            643

ticipants is not as strict as in phase II, although cer-           product and reference product they should fall
tain criteria for acceptance or exclusion apply.                   between 80 ñ 125%.
Studies of this phase are usually multi-centre, there
may be even a few thousand participants. During the                Comparative clinical studies of pharmaceutical
study, a further assessment of the relation between                products based on pharmacokinetic parameters
the size of the dose and the therapeutic effect is per-                  Comparative clinical studies of pharmaceutical
formed, moreover, the effects of the medicine                      products based on pharmacokinetic parameters are
applied together with other medicinal products is                  carried out when the concentration of the active
assessed. The results of phase III studies will serve              component in the body fluids is sufficient. The sub-
as the basis for the registration of the product.                  jects of such studies are a limited number of healthy
                                                                   (with some precisely described exceptions) partici-
Phase IV                                                           pants. This number, depending on the intersubject
     During this postregistration phase further stud-              variability (CV), usually varies between 24 and 110.
ies on the administration safety and the relation                  After the administration of the product under strict-
between the administration and the effects of the                  ly specified conditions, samples of body fluids are
product are carried out. The participating patients do             taken at set times, and then, the concentration of
not undergo any selection; the only criteria are the               these products is measured. Obtained pharmacoki-
indications / contraindications written on the prod-               netic parameters: the AUC, Cmax and Tmax are ana-
uctís information leaflet. This phase of the study                 lyzed, and then, as a result of comparison, a conclu-
involves thousands of participants.                                sion on the biological equivalence can be drawn.

Preclinical studies of generic pharmaceutical                      Comparative clinical studies of pharmaceutical
products                                                           products based on pharmacological parameters
     In the case of generic products, in principle, no                   Comparative clinical studies of pharmaceutical
preclinical studies are carried out.                               products based on pharmacological parameters are
                                                                   carried out when there is insufficient concentration
Clinical studies of biological equivalence of ge-                  of the tested (active) substance in the body fluids.
neric pharmaceutical products                                      Typical examples are studies of local effect of der-
      The aim of the study of biological equivalence,              matological preparations containing corticosteroids.
preceded by studies designed to demonstrate the                    The study avails itself of the fact that the preparation
pharmaceutical equivalence, is to demonstrate phar-                penetrates the epidermis and the stratum corneum,
macological equivalence, and thus therapeutic                      causes vasoconstriction and thus blanching of the
equivalence ñ and hence also therapeutic inter-                    skin. The above mentioned pharmacodynamic effect
changeability which provides the basis for the regis-              is proportional to the time which has elapsed from
tration of the generic product.                                    the application of the preparation and to the thera-
      In other words, biological equivalence indicates             peutic effect. The participants of this type of studies
pharmacological equivalence, and thus, on this basis               also comprise a relatively limited number of healthy
conclusions about biological equivalence can be drawn.             volunteers (between 60 and 100). The findings, i.e.
      An evaluation of the biological equivalence is               AUEC (area under effective curve), Cmax and Tmax,
carried out according to an analysis of the following              are compared using the same principles as in the
parameters: pharmacokinetic, pharmacological, the                  case of pharmacokinetic studies, and conclusions
results of comparative therapeutic studies                         concerning the biological equivalence are drawn.

Analyzed parameters                                                Comparative clinical studies of medicinal prod-
     Parameters of primary importance: AUC ñ area                  ucts based on therapeutic data
under the curve; Cmax ñ maximum concentration.                           Comparative clinical studies of medicinal prod-
Secondary parameters: Tmax ñ the time of maximum                   ucts based on therapeutic data are carried out when the
concentration from the administration; T1/2 ñ the                  tested substance is not present in sufficient concentra-
time of achieving half of the maximum concentra-                   tion in the body fluids, and when there is no pharma-
tion of the active component; MTR ñ mean resi-                     codynamic effect which could be easily compared.
dence time; % of extrapolated AUC value.                                 An example of such a study may be the study of
     When comparing these parameters a 90% con-                    a pharmaceutical product containing mesalazine
fidence interval is applied for the relation between               which practically does not leave the colon after
average AUC and Cmax parameters. For the tested                    administration. 280 patients participated in the cited
644                                     TERESA BRODNIEWICZ-PROBA

study. The comparative assessment of AUC, Cmax,            the reproductive system, as well as mutagenicity is
and Tmax was performed on the parameters of the ther-      not a routine requirement.
apeutic effect. The study lasted longer than 2.5 years.          In the case of biosimilar insulin, in vitro tests
                                                           are carried out first. Their aim is to detect any dif-
Preclinical studies of innovative and biosimilar           ferences in the bonding to the receptor. Then a test
biopharmaceuticals                                         for cell proliferation is performed. The in vivo stud-
      Preclinical studies of innovative biotechnolog-      ies are carried out in rodents (as the model here
ical products (biopharmaceuticals)                         serve rats deprived of the pituitary gland). They esti-
      Preclinical studies of innovative biotechnolog-      mate the weight increase or the length of the femur.
ical products have a different scope for products of       Toxicological studies involve administration of the
different origins. The scope of the studies is regulat-    product for 4 weeks at least 2 times a week. They
ed by EMEA directives.                                     assess the local tolerance. The studies that are not
      Products such as cytokines, recombinant coag-        required: assessment of safety pharmacology, repro-
ulation factors, enzymes, hormones, recombinant            ductive toxicology, mutagenicity, and carcinogenic-
proteins, and plasma-derived products are tested in a      ity (2-4).
different way than heparins, vitamins, DNA vac-
cines, or products for cell therapy.                       Clinical studies of innovative biotechnological
      The study begins with tests in the in vitro sys-     products
tem, during which the presence of receptors on cells            Clinical studies of innovative biotechnological
and the affinity to them is determined, the rules for      products are planned and carried out in a manner
pharmacological effects are set, and information           analogous to clinical studies of innovative medicinal
useful when selecting species of animals for phar-         pharmaceutical products.
macological studies is obtained (e.g. the animals               Due to the nature of the products, the safety,
used in studies on monoclonal antibodies have an           and particularly the immunogenic potential of the
epitope to which the tested monoclonal antibody has        products of biological origin, is thoroughly analyzed.
an affinity, and a cross-reactivity profile that is sim-
ilar to that of a human).                                  Comparative clinical studies of biosimilar prod-
      The next step is usually the safety test with two    ucts.
species of animals. The choice of animals with an                When planning clinical studies of biosimilar
epitope involved in a specific reaction is very impor-     products, designed to prove the similarities, the fol-
tant. The way of administering the product is the          lowing principles must be applied:
same as in the planned clinical study, and the size of     ● selecting the reference product and its character-
the dose is a multiplication of the dose administered      istics;
in the clinical study. The immunogenic profile of the      ● demonstrating the similarities in the in vitro and in
product is analyzed in a particular way. The               vivo models in preclinical studies;
immunogenic potential is checked by several highly         ● demonstrating the safety and efficacy through
specialized and selective methods.                         limited clinical studies (Phase I and III);
                                                           ● demonstrating the safety of the product through
Preclinical studies of biotechnological generic, i.e.      immunological research.
biosimilar products                                              The rules which apply to the planning of clini-
      Preclinical studies of biosimilar products are       cal studies of biosimilar products:
not as extensive as the studies of innovative prod-        ● demonstrating the physicochemical and biologi-
ucts. One can track them by looking at the examples        cal similarities to the reference product (preclinical-
of studies, recommended by the EMEA, of biosimi-           ly) are as follows:
lar erythropoietin and insulin.                            ● demonstrating the relation between the pharmaco-
      In the case of biosimilar erythropoietin in vitro    dynamic and therapeutic effect, and the dose;
tests examining the bonds to receptors and differen-       ● determining the possibility of using surrogate
tiation of cells should be carried out. The in vivo        endpoints and their relation to the dose and the con-
studies involve tests with the use of policystemic or      centration of the product in fluids and tissues;
normocystemic mice.                                        ● statistical proof of the efficacy at a 95% level of
      Toxicological studies involve a 3-month long         confidence in relation to the extent to which bioe-
administration of the product to animals, and assess-      quivalence is accepted, fulfillment of the test sensi-
ment of local tolerance in at least one specie. The        tivity requirements, taking into account the inter-
evaluation of safety pharmacology, toxicology of           changeability determined by standard deviation, and
                               The scope and requirements related to preclinical and clinicalstudies of...           645

meeting the requirement concerning adequate test                   Phase III. Comparative study confirming efficacy
power;                                                             and safety
● an analysis of the potential immunogenicity and                        The scope of biological equivalence is relative-
the creation of neutralizing antibodies                            ly narrow and defined a priori. It refers to a signifi-
                                                                   cant therapeutic effect by setting clinically meaning-
     Examples of biosimilar products with legal                    ful endpoints. The power of statistical calculation is
approval and those in the course of development:                   usually fixed between 80-90%. The number of
recombinant growth hormone (EMEA recommen-                         patients, often determined on the basis of pilot stud-
dations are available); recombinant erythropoietin                 ies, may even be more than a thousand people. In the
(EMEA recommendations are available); recombi-                     case of various indications, separate studies are rec-
nant insulin (EMEA recommendations are avail-                      ommended to prove the therapeutic effects and safe-
able); recombinant hormone stimulating the growth                  ty for each indication.
of granulocytes (EMEA recommendations are avail-
able); monoclonal antibodies; genes; cells for cell                SUMMARY
therapy; vaccines.
                                                                         The nature and origin of a medicinal product
Rules for conducting clinical studies of biosimilar                determines in advance the scope and requirements
products                                                           concerning the clinical studies necessary to obtain
Phase I. Study showing pharmacokinetic equiva-                     legal approval of the product. In turn, the exactly
lence                                                              outlined clinical studies strategy imposes certain
       The purpose of the study is to demonstrate the              aspects of preclinical studies, although, in general,
pharmacokinetic equivalence, mainly in terms of AUC                their scope is defined by existing guidelines.
and Cmax (80 ñ 125%) or broader (in justified cases).              The aim of the performed studies is to create a prod-
       An example of applying the analysis of phar-                uct that is comprehensively tested, maximally safe
macodynamic parameters (PD) may be a compari-                      for the patient, and which has new therapeutic (or
son of the well-known PD effect such as measuring                  generic) possibilities of a medicinal product.
the concentrations of glucose for insulin, the meas-
urement of the anti-viral effect for interferon, meas-             REFERENCES
uring the IGF -1 for the growth hormone.
       Combined PK/PD studies are preferred where                   1. EMEA ñ CPMP/ICH, 286/95, November 2000,
one typically plans a double-crossed study for                         ICH Topic M3 (R1). Non-clinical safety studies
generic products. The studies typically involve                        for the Conduct of Human Clinical Trials of
about 30 or more participants (healthy or sick).                       Pharmaceuticals.
       After carrying out the Phase I study and ana-                2. EMEA.CPMP/ICH/302/95 ICH Topics S6. Pre-
lyzing the results, further study (or studies) of Phase                clinical Safety Evaluation of Biotechnology
III is performed. Sometimes, between phase I and                       ñDerived Pharmaceuticals.
III, study of phase II is carried out, although it is not           3. EMEA/CHMP/BMWP/94526/2005.
required.                                                           4. EMEA/CHMP/BMWP/94528/2005.