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					 M e d t e c h                  I n t e l l i g e n c e
 Issue 1364 June 2010




Gene genie
Medtech plays leading role
in successful gene delivery

INSIDE
Beckman Coulter – one year on
from the Olympus Diagnostics buy
CEN’s Anna von Groote on
EU medtech standards writing
Japan: Setting up clinical trials
in the No 2 medtech market
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raising standards worldwide™
Clinica // June 2010                                                                                                     EDItor’S commENt




                    T
                            his year marks the 20th anniversary of the initiation of the Human
                            Genome Project and the 10th anniversary of publication of the draft
                            genome. The project had set out to identify all the 20,000-25,000
                    genes in the human genome and determine the sequences of the three bil-
                    lion base pairs that make it up. All this information would revolutionise the
                    way we diagnose and treat the myriad disorders that affect us.
                        Indeed, since the project was completed in 2003, we have seen a big
                    push in molecular diagnostics. This segment is the fastest-growing in
                    the in vitro diagnostics sector, driven particularly by the trend towards
                    personalised medicine. The use of companion diagnostics is set to
                    accelerate as healthcare providers begin to recognise the cost efficiencies
                    of testing patients to see if they are genetically predisposed to benefit – or
                    not – from a particular drug before putting them on a costly regime.
                        Mapping the human genome can also be useful in gene therapy, and
                    this is an area that has seen intense R&D activity. However, gene therapy
                    has had its fair share of ups and downs. 20 years after the first gene
                    therapy study was officially sanctioned, only two gene therapy products
                    have been approved for clinical use.                                                     Today, the
                        The biggest challenge here, as our cover feature (pp20-25) reveals, is        crossover between
                    the delivery of the modified genes to the target tissue.
                        Today, the crossover between devices and pharma in the drug delivery          devices and pharma
                    arena is no longer limited to syringes, inhalers, patches and pumps. The
                    cutting-edge technologies these days include advanced biomaterials,                in the drug delivery
                    nanoparticles and biopumps. Our in-depth report looks at some of the
                    interesting techniques under development for delivering gene therapy.               arena is no longer
                    These range from relatively straightforward methods such as jet injection,
                    electroporation and sonoporation, to the use of biological complexes such
                                                                                                       limited to syringes,
                    as virosomes and liposomes.                                                      inhalers, patches and
                        A therapy can only work if it is delivered effectively, and these
                    techniques could help accelerate the adoption of gene-based treatments            pumps...techniques
                    and grow this potentially lucrative market.
                        One company that has been working hard at growing its presence and             for delivering gene
                    consolidating its leadership position as a pure-play IVD firm is Beckman
                    Coulter, the subject of our Market Leader Focus (pp 32-33). Last year,
                                                                                                       therapy range from
                    the group bought Olympus’ clinical diagnostics business for around                electroporation and
                    $800m and has been quietly focused on integrating the acquisition into
                    its operations. With the integration complete, I spoke to Helmut Koehler,         sonoporation to the
                    Beckman Coulter’s new vice-president of global R&D for the much bulked
                    up clinical chemistry and automation business, about the company’s new               use of biological
                    offerings, and to Marc Meyer, clinical diagnostics marketing director in
                    Europe, about the firm’s strategy for growth.
                                                                                                            complexes
                        Continuing the IVD theme, we have a profile of Bioventix (p43).
                    This UK concern pioneered the use of sheep cells to create monoclonal
                    antibodies for the immunodiagnostic market. The company works with
                    the giants of IVD, such as Roche, Abbott, Siemens and Beckman Coulter,
                    and supplies them with its engineered sheep monoclonal antibodies,
                    which it says bind to their targets for “100 times longer” than rodent
                    antibodies, allowing for more sensitive and specific immunoassays.




                    Tina Tan
www.clinica.co.uk                                                                                                  © Informa UK Ltd 2010   1
coNtENtS                                                                                                                                               Clinica // June 2010



 EDITORIAL
 EDITOR:
 Tina Tan (via switchboard extn 4090) •
 DEPUTY:
 Elizabeth Cairns (6863) •
 EUROPEAN REGULATORY AFFAIRS:
                                                                               Contents
                                                                               Clinica 1364 June 2010
 Editor: Amanda Maxwell (+44 20 8546 1518) •
 INTERNATIONAL MARKETS &
 INVESTIGATIONS:
 Editor: Bernard Murphy (6972) •
 BUSINESS:
 Senior reporter: Joseph Harvey (6499) •
                                                                               News                                           International
                                                                                                                              India set for “comprehensive medtech
 SCIENCE & TECHNOLOGY:
 Editor: Elizabeth Cairns (6863); •
 Senior reporter: Madeleine Armstrong (6958) •
                                                                               Top Story                                      regulation” by the end of 2010                  12

 MULTIMEDIA:                                                                                                                  Canada approves industry fees hike              13
 Editor: Salina Christmas (7621) •                                             Study suggests clinicians may be
 DESIGNER:                                                                     overscreening for cervical cancer         4    brazil aims to increase domestic
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 PUBLISHER:
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 2        © Informa UK Ltd 2010                                                                                                                                  www.clinica.co.uk
Clinica // June 2010                                                                                                                              coNtENtS




                                              Features
                                              Gene genie: the role of devices in gene therapy delivery                                                       20
                                              Gene therapy has been hailed as the future of medicine, but has yet to fulfil its promise. Despite increased
                                              understanding of the genetics of various diseases, the problem of how to deliver therapeutic genes to their
                                              target tissues remains. Peter Charlish looks at some of the most intriguing gene therapy delivery techniques
 Gene genie: the role of devices in gene
 therapy delivery                        20
                                              How to get involved in EU medtech standards writing: the latest                                                26
                                              Standards are a lynchpin of the European medtech regulatory system. They may be voluntary, but complying
                                              with them avoids the difficulty of proving compliance via other routes. It is in each company’s interest that
                                              when standards which impact their products are written, they become involved in ensuring factors that might
                                              affect their business are taken into account adequately. So how do companies become involved? Anna von
                                              Groote of the European Standardisation Committee (CEN) explains.


                                              A smoother ride: streamlining medtech clinical trials in Japan                                                 29
                                              The stringent Japanese approval process for medical devices can be tricky – and expensive – to negotiate.
 How to get involved in EU medtech            Here, Tomoki Hasegawa, head of the medical device CRO business at Emergo Japan in Tokyo, provides an
 standards writing: the latest          26    overview of the clinical trial process for medical devices


                                              beckman Coulter: more solutions, more markets, more global                                                     32
                                              In August last year, Beckman Coulter closed its acquisition of Olympus’ lab-based diagnostics division. Nearly a
                                              year on and the integration is now complete. In an exclusive interview with Clinica, Marc Meyer, Beckman’s
                                              clinical diagnostics marketing director in Europe, and Helmut Koehler, vice-president of global R&D for
                                              chemistry and automation, tells Tina Tan how the new Beckman Coulter is moving forward


                                              UK banking on success with 500,000-person “reference library”                                                  38
                                              The UK Biobank is about to reach its target of 500,000 participants, making it one of the biggest health studies
 A smoother ride: streamlining medtech        in history. Madeleine Armstrong spoke to the project leader, Rory Collins, about how the resource could help
 clinical trials in Japan              29
                                              unravel the genetic and environmental causes of many different diseases


                                              Sheep give bioventix the advantage in immunodiagnostic market                                                  43
                                              Rodents have long been used to provide monoclonal antibodies for the diagnostic testing market. However, UK
                                              firm Bioventix has pioneered the use of sheep cells to create more effective antibodies. Joseph Harvey met the
                                              firm’s CEO Peter Harrison to find out why sheep are the way forward for diagnostics




 Beckman coulter: more solutions,
 more markets, more global               32
                                              Regulars
                                              In the industry’s words                                                                                   31
                                              IVD Insight                                                                                               34
                                              Patent Watch                                                                                              40
                                              Medtech Ventures                                                                                          44
                                              People                                                                                                    47
 UK banking on success with
 500,000-person “reference library”     38
                                              Five minutes with....                                                                                     48
www.clinica.co.uk                                                                                                               © Informa UK Ltd 2010     3
top Story                                                                                                                 Clinica // June 2010




News & Analysis
                                Study suggests clinicians may be
                                overscreening for cervical cancer
                                Scientific advances are intended to improve clinical care, but this aim
                                is not always achieved. The introduction of human papillomavirus
                                (HPV) testing in cervical cancer was intended to reduce the
                                frequency of screening. However, researchers have found that this
  Madeleine Armstrong
                                may not be happening, reports Madeleine Armstrong


A
         dding human papillomavirus (HPV)        appears that they are adopting HPV               Medicine, a JAMA journal. The study was
         testing to Pap tests does not lead      co-testing, but this does not seem to be         funded by the US National Cancer Institute,
         to less frequent cervical cancer        decreasing the frequency of screening.           the Centers for Disease Control and
screening as had been hoped, a study has             The investigators surveyed 1,212             Prevention, and the Agency for Healthcare
suggested.                                       US primary care physicians, 950 of               Research and Quality.
    DNA testing for HPV, which can               whom performed Pap testing and had                   In an accompanying editorial, George
eventually lead to cervical cancer, can be       recommended the HPV test for their               Sawaya of the University of California,
used in conjunction with the traditional         patients. The physicians were given various      San Francisco, described the latest results
Pap test to detect precancerous changes.         patient scenarios and asked when they            as “discouraging”: “The major benefit of
In women over 30, this approach could            would recommend the next round of                adding HPV DNA testing to cytology…is to
allow longer intervals between screening         screening.                                       obviate the need for three normal cytology
than with Pap testing alone. This is because         For example, for a 35-year-old woman         test results before [screening] interval
women with a negative HPV test have a            with three normal Pap test results, 31.8%        lengthening.”
low risk of developing cervical cancer in the    said they would recommend the next Pap               Dr Sawaya also pointed out that the
next few years.                                  test in three years, as recommended by           approach creates another challenge:
    Less frequent screening would reduce         the ACS and ACOG. 31.7% said they would          identifying women with a positive HPV
healthcare costs. Many women in the US           recommend the next test in one year.             DNA test result and a normal cytology
are currently tested annually or biennially,         For a 35-year-old woman with one             finding. “The optimal management and
but the American Cancer Society (ACS)            normal Pap and HPV test, only 19% of             counselling of these women is unclear.
and American College of Obstetrics and           clinicians would recommend screening             Contemporary guidelines suggest that
Gynecology (ACOG) has traditionally              in three years, as per the guidelines. 60.1%     these women be placed under surveillance
recommended that women over 30 with              would recommend the next test in one year.       and colposcopy be performed in those who
three consecutive normal Pap tests can be                                                         remain HPV positive.”
tested less often (every two to three years).    Wasting money?                                       He cautioned that the study’s approach
    Both the ACS and ACOG have slightly          “The practice patterns we found in our           may not accurately reflect clinical practices,
different treatment guidelines depending         study are likely to increase costs with little   and called for evidence from actual clinical
on whether a patient has received HPV            improvement in reducing cervical cancer          settings. However, he added that the group
testing. In women over 30 who have one           incidence and increasing survival,” the          has “shown that there is still much work to
negative result with both Pap and HPV            authors wrote.                                   be done to ensure that rational approaches
testing, the organisations recommend                  “Many physicians reported                   to screening are adopted”.
screening every three years. Neither             overscreening women by using both the                Some experts have suggested going
organisation recommends HPV co-testing           HPV and Pap tests annually. Until measures       further and making HPV testing the primary
in women under 30 – in this age group            are in place to reinforce extended screening     screening tool in women aged 35 and older.
it can lead to the overdiagnosis and             intervals among women with negative HPV          Pap testing would be reserved for the triage
treatment of precancerous lesions that may       and normal Pap test results, there is no         of HPV-positive women, who would then be
have eventually regressed.                       advantage gained with HPV co-testing, and        referred for colposcopy if they had positive
    However, the latest findings have            it is more expensive,” they concluded.           results. An Italian study has suggested that
suggested that, at least in the US, clinicians        The findings were published in the          this approach could be effective (www.
are not following these guidelines. It           June 14 issue of the Archives of Internal        clinica.co.uk, 22 January 2010).

 4     © Informa UK Ltd 2010                                                                                                    www.clinica.co.uk
Clinica // June 2010                                                                                                                            US




FDA’s data falsification rule raises
industry concerns
T
         he US medtech industry has              excluded from future studies because of a         what information, if any, the FDA would
         expressed serious concerns about        sponsor’s fear that they would draw special       share from the sponsor’s report with the
         a new rule proposed by the FDA,         FDA scrutiny and raise review issues that         clinical investigator who is the subject of
which, if finalised, would require device        could delay a review decision.                    the report. “It is unclear whether the report
sponsors to report to the agency about any           While it is becoming increasingly difficult   itself would be provided to the investigator
individual who is suspected of falsifying        to recruit and retain clinical investigators in   who is suspected of falsifying data,” it says.
data in studies involving human or animals.      the US (one of the reasons why clinical trials        Also, there is no clarity on the type of
    As sponsors could face criminal sanctions    are moving off-shore), the rule, AdvaMed          information, if any, that the FDA would
(including fines and imprisonment) for           says, would make investigators more               share with the institutional review board at
failure to submit such reports within 45 days    reluctant to carry out the job as they would      the centre where the accused investigator is
of them becoming aware of the information,       be faced with a greater possibility of being      conducting the study, or with other sponsors
the rule could have a negative impact on the     reported to the FDA even in the absence of        for whom the investigator is conducting or
relationship between sponsors and clinical       actual wrongdoing.                                has conducted clinical trials.
investigators.                                       Additionally, the potential liabilities           As the FDA’s investigation of a
    The threat of criminal sanctions, industry   facing both sponsors and investigators            sponsor’s report may form the basis of an
association AdvaMed says, could result in        under the proposed rule, the association          administrative action (eg placing a trial on
sponsors “erring on the side of caution” and     says, may result in a system that could           hold, disqualification, etc), this could have
reporting marginal and barely supportable        only survive with indemnification as a            implications far beyond the single study
suspicions of possible falsification. This       condition of conducting a clinical trial.         in which possible falsifications are alleged,
could tarnish an innocent investigator’s         As indemnification would most likely be           AdvaMed notes.
reputation and credibility.                      addressed through insurance, this would               It wants to know if the FDA would, solely
    AdvaMed’s views are supported by the         greatly increase the expense of clinical trials   on the basis of an allegation of “possible
University of Pittsburgh, which notes that       and, ultimately, patient costs.                   falsification” of data in an ongoing trial, stop
the FDA’s proposed rule does not offer any                                                         the pre-market approval application for a
guidance on the level of evidence needed for     Confidentiality issues                            different device.
the sponsor to submit such a report, except      AdvaMed has several questions about how               Because such an approach could result
that falsification “may” have occurred. Such     these reports of “possible falsification” would   in multiple product reviews coming to a
a standard, it says, will result in numerous     be treated by the FDA. For example, it wants      halt, the association wants the agency to
“false alarms” that would only increase the      to know if the reports would be subject to        clarify the rights of an applicant (with a
work load of the FDA and potentially subject     disclosure under the Freedom of Information       pending PMA) to defend its submission
wholly innocent clinical investigators to        Act and if so, whether the reports would          in the face of allegations of fabrication
serious allegations.                             be made available immediately or after a          of a clinical trial that is not part of the
    Even if cleared by the FDA, such             prescribed time period.                           applicant’s submission.
investigators, AdvaMed says, may be                  Of particular concern for AdvaMed is          Read the full story at www.clinica.co.uk


FDA to start policing lab-developed tests
T
        he US FDA has indicated that it          disadvantage and potential disincentive to        and the need for education and outreach
        plans to begin regulating laboratory-    innovation by other manufacturers whose           programmes.
        developed tests (LDTs) in order to       tests are approved or cleared by the agency           Following the public meeting and the
assure the public that all in vitro diagnostic   for similar indications. This, and other          close of the public docket, the FDA says it
tests used in the provision of healthcare,       factors such as the growing complexity            will “move forward expeditiously to develop
whether developed by a laboratory or by          of in-house tests, has led the FDA to             a draft oversight framework for public
other manufacturers, are safe and effective.     reconsider its policy for enforcement             comment to provide predictability as soon
    Until now, the FDA has been exercising       discretion over LDTs.                             as possible”.
“enforcement discretion” with regard to              The FDA will hold a public meeting                The proposed framework will follow a
such products, as a result of which most         on 19 and 20 July to seek stakeholder             risk-based approach, ie it will be phased
LDTs (ie manufactured and offered within a       feedback on its plan to develop an oversight      in over time, based on the level of risk
single laboratory) are currently not actively    framework for LDTs. Stakeholders can also         of the test. The FDA understands that
regulated by the agency. This is in contrast     submit written comments until 15 August.          there are issues unique to the laboratory
to the FDA’s approach to diagnostic test             Specifically, the FDA is looking for          community and these, it says, will be taken
kits sold by medical device manufacturers,       feedback on issues around LDTs that               into account when drafting the framework
which are subject to strict pre- and post-       present the “greatest concern to public           to ensure that it fosters innovation in this
market oversight.                                health”, such as: direct-to-consumer              area, while assuring that such tests are safe
    The absence of a level playing field,        marketing of such tests; patient                  and effective.
the FDA says, creates a competitive              considerations; challenges for laboratories;      Read the full story at www.clinica.co.uk

www.clinica.co.uk                                                                                                      © Informa UK Ltd 2010   5
US                                                                                                                              Clinica // June 2010




Heads of FDA and NIH outline plan for
personalised medicine
T
         he leaders of the US FDA and                respond to the drug, by looking for variations       Drs Hamburg and Collins noted that
         National Institutes of Health are           in the FCGR3A gene.                              researchers have identified many genetic
         working together to improve the ap-             But Drs Hamburg and Collins wrote:           variants that are linked with disease risk, and
proval process for companion diagnostics.            “The FDA has not reviewed the scientific         could represent new drug targets; however,
The organisations hope to establish a level          justification for this claim, but healthcare     private companies can be reluctant to follow
of regulation that “both protects patients           providers may use the test results to guide      these leads as there is insufficient evidence of
and encourages innovation”.                          therapy. This undermines the approval            a downstream market.
     “There has been an explosion in the             process that has been established to protect         The regulators have proposed a “more
number of validated markers but relatively           patients.”                                       integrated pathway” to fill this void, linking
little independent analysis of the validity of           They stressed that the agency has            the steps between identification of a potential
the tests used to identify them in biologic          an important role in ensuring that such          therapeutic target and approval of a new drug.
specimens,” wrote FDA commissioner                   biomarkers are used appropriately. They gave     They intend to do this is via schemes like the
Margaret Hamburg and NIH director Francis            examples of problems caused by non-FDA-          Therapeutics for Rare and Neglected Diseases
Collins, in a perspective article published          approved tests – such as women wrongly           programme, and by developing tissue
online in the NEJM on 15 June, called “The           being told that they were negative for a         banks that are linked with patients’ clinical
path to personalised medicine”.                      mutation that confers a high risk of breast      outcomes.
     Around 10% of the labels on FDA-                cancer, or an ovarian cancer test that led to        The FDA also aims to improve the
approved drugs contain pharmacogenomic               unnecessary removal of women’s ovaries.          regulatory process through its Genomic Data
information, which is “a substantial increase            “The FDA is co-ordinating and clarifying     Submission programme, where companies
since the 1990s”, Drs Hamburg and Collins            the process that manufacturers must follow       can discuss genetic information with the
noted.                                               regarding their claims, including defining       agency separately from the product review
     Several FDA-approved companion                  the times when a companion diagnostic            process. “The goal is to help companies
diagnostics are already available, such as           must be approved or cleared before or            integrate genomics into their clinical
HER2 gene testing to identify HER2-positive          concurrently with approval of the therapy,”      development plans,” the authors wrote.
breast cancer patients, who are more likely to       said Drs Hamburg and Collins. “The agency            In addition, the NIH is setting up a
respond to the drug Herceptin (trastuzumab).         will ensure claims that a test will improve      voluntary genetic testing registry for the
EGFR mutation status is also analysed to             the care of patients are based on solid          genetic tests currently available through
identify colorectal cancer patients who will         evidence.”                                       clinical labs – thought to be over 2,000. This
benefit from Erbitux (cetuximab).                                                                     will include information on whether the tests
     However, some companion diagnostics             Scientific obstacles                             have been cleared or approved by the FDA, to
currently on the market have not been                There are “myriad obstacles” to improving        help consumers make informed decisions.
reviewed by the FDA, and their clinical value        the current situation, the authors                   Drs Hamburg and Collins predicted that in
is uncertain. For example, Clinical Data’s           acknowledged. The challenges include             future, clinical trials will be based on a better
subsidiary PGxHealth markets a test that it          scientific concerns, such as determining         understanding of the genetic basis of disease,
claims predicts response to the non-Hodgkin’s        which genetic markers are most important         making them more efficient. Drugs that have
lymphoma drug Rituxan (rituximab). The test,         clinically, and identifying variants that are    previously failed might also be found to be
PGxPredict:Rituximab, is designed to identify        correlated with patients’ responses              safe and effective in subgroups of patients
the subset of patients who will strongly             to drugs.                                        with certain genetic markers.


FDA asks advisory panel to examine dental amalgam safety

T
         he US is asking its external experts        classified dental amalgam as a class II device   said in its petition.
         to examine several scientific issues        and designated special controls for dental           Other petitions too raised concerns
         that may affect the regulation of           amalgam, mercury and amalgam alloy.              regarding the adequacy of the risk
dental amalgam, used for direct filling of               Since that time, the International Academy   assessment method used by the FDA
carious lesions or structural defects in teeth.      of Oral Medicine has called for a complete ban   in classifying dental amalgam, the
    The advisory panel, the agency said, will        on the use of encapsulated mercury fillings as   bioaccumulative effect of mercury, the
meet on 14 and 15 December. The meeting              a dental restorative material.                   exposure of paediatric populations to
will focus particularly on the potential risk            If these products cannot be banned, they     mercury vapour and the adequacy of the
to vulnerable populations, such as pregnant          should be categorised as class III (high-        clinical studies on dental amalgam.
women, foetuses and children.                        risk) and the FDA should place restrictions          In advance of the meeting, the FDA is
    In July last year, the FDA issued a final rule   (not special controls) on their use in young     inviting feedback from stakeholders on these
that reclassified dental mercury from a class        children, women of childbearing age and          issues. Comments will be accepted until 3
I (low-risk) device to class II (medium-risk),       other susceptible categories, the academy        December.

  6     © Informa UK Ltd 2010                                                                                                         www.clinica.co.uk
Clinica // June 2010                                                                                                                           EU




IVDD revision: consultation starts here
T                                                 Classification                                   Scope: Genetic tests
         he European Commission is in the
         process of initiating the public con-    Would a risk-based classification, mirroring     Should the scope of the Directive make it
         sultation on the revision of the IVD     the GHTF principles, be an improvement           clear that it covers all genetic tests that
Directive, 98/79/EC and inviting comments         compared with the current listing for high-      have a direct or indirect medical purpose,
by 19 September.                                  risk IVDs covered by Annex II?                   while clarifying that tests without any
    Although a draft is circulating, the              A majority of stakeholders who               direct or indirect medical purpose remain
actual consultation document has not              responded to the public consultation on          outside the scope of the Directive 98/79/
yet been launched on the internet, but is         the proposed recast of the medical device        EC? Should the scope be extended to
imminent, Clinica understands.                    directives two years ago had indicated that      cover all genetic tests, unless specifically
    The directive has not been substantially      such a system would improve robustness to        mentioned in a negative list ( for example
amended since its adoption in 1998,               technological change.                            paternity tests?). And should there be
but the sector has “significantly evolved                                                          additional requirements or restrictions for
technologically”.                                 Conformity assessment                            direct-to-consumer tests?
    In its draft public consultation paper, the   If a risk-based approach is taken, should
Commission makes reference to the fact that       the current conformity assessment                Scope: Diagnostic services
the Global Harmonisation Task Force for           procedures for IVDs be amended, and if           Is there a need to amend the definition of
medical devices (the GHTF) has elaborated         so which and why? And should all IVDs,           “putting into service” to make it clear that it
new guidelines in the field of medical            with the exception of those in class A of        also covers IVDs not placed on the market,
devices. Indeed, in the interest of further       the GHTF classification (lowest risk) be         but used for the delivery of results within
global convergence in IVD regulations, the        required to have the premarket control of        the community? And should additional
                                                  the manufacturer’s quality management            specific requirements be introduced
European Commission has taken these on
                                                  system overseen by a third party as laid         for tests used for diagnostic services,
board and invited comments on many of the
                                                  down in the GHTF document, GHTF/SG1/             especially when the results are provided
GHTF-driven policies.
                                                  N046:2008?                                       directly to consumers, such as minimum
    The proposal is for specific issues
                                                      Also, which IVDs should be subject           requirements for advertising?
contained in the IVD Directive to be
                                                  to batch control and should each batch
revised, rather than a whole-scale overhaul.
                                                  be controlled? How and by whom should            Clinical evidence
    When it comes to possible amendments
                                                  these controls be performed?                     Is there a need to further clarify the
of general aspects, such as designation and
                                                                                                   requirements regarding clinical evidence
monitoring of Notified Bodies, vigilance,         Scope: Specific exemption for                    for IVDs – should the requirements
market surveillance, and the need for further
                                                  in-house tests                                   for clinical validity (demonstration of
centralisation, these are currently under         Should the current exemption for tests           performance characteristics) be extended,
discussion in the framework of the recast         manufactured “in house” ( for example            and should the IVD Directive require the
of the Active Implantable Medical Devices         within a hospital for use in that hospital) be   demonstration of clinical utility (ie the
Directive (90/385/EEC) and Medical Devices        maintained, clarified or limited?                demonstration of the potential usefulness
Directive(93/42/EEC), and will also apply to         Specifically, should all high-risk            and added value to patient management
the revision of the IVD Directive.                in-house tests be excluded from the              decision-making)?
                                                  exemption and have to fulfil the Essential
Specific issues                                   Requirements of the IVD Directive,               Conditional CE marking
The public consultation questionnaire             including the involvement of a Notified          Should a “conditional CE marking” route
covers the following areas specific to IVDs:      Body? Or should the health institutes and        be introduced for speedier market access
classification; conformity assessment             premises that manufacture in-house tests         for unmet clinical needs, such as for rare
procedures; scope – in-house tests, genetic       be subject to accreditation based on ISO         diseases, or for pandemics, allowing rapid
tests and diagnostic services; clinical           15189:2003 Medical laboratories - Particular     market access in certain conditions? If so,
evidence – clinical validity and clinical         requirements for quality and competence?         in which situation and which conditions?
utility; rapid market access to IVDs; and            If the exemption for in-house tests is
point-of-care testing.                            not maintained, would it be necessary to         Point of care/near-patient IVDs
    In inviting responses from interested         exempt IVD medical devices intended for          Do you see a need for specific requirements
parties, the Commission is calling for the        rare diseases from the scope of the IVD          for “point-of-care” or “near-patient” IVDs,
replies to include social and economic data       Directive and why?                               and if so, regarding which aspects?
and an evaluation of actual or estimated
costs of making the changes.                                                   Table 1: EU classification of IVDs
    As a reminder for readers, IVD tests fall      classification Notified Body involvement?                    types of test
into one of four different risk groups under       General         No                                           Haematology, cancer markers
the EU’s IVD Directive (see Table 1).
                                                   Self-test       Review of suitability of design and labelling Home tests
    This is a summary of the questions
contained in the draft public consultation         Annex II,       Yes, to audit technical documentation and    Rubella, prostate-specific
paper:                                             List B          quality system                               antigen

www.clinica.co.uk                                                                                                     © Informa UK Ltd 2010   7
EU                                                                                                                         Clinica // June 2010




Acquisitive BSI designated to audit IVDs
T
        he British Standards Institute (BSI)     Mrs Spencer once worked); SFS UK;                 advances, the divisions between the three
        has been notified to audit diag-         Amtac Certification Services; and UL              medical device directives becomes finer
        nostics manufacturers and their          International.                                    and products may cross over,” explains
products under the EU’s In Vitro Diagnostic          In Europe, there are 23 Notified Bodies       Paul Brooks, vice president BSI Healthcare.
Medical Devices Directive.                       in all that are accredited under the IVDD,        “It is essential that a Notified Body can
    The announcement comes nine                  including one in Switzerland under its MRA        support clients across all device categories,
months following the appointment of Sue          with the EU; five of them are in Germany.         and by extending our scope to include the
Spencer as head of BSI’s IVD business                BSI has been accredited with a                IVD Directive, BSI will enable customers
last September. Mrs Spencer has over 20          comprehensive scope which includes all            to work with one organisation for all their
years’ experience in the sector, in a range      IVDs listed in Annex II List A (high risk)        certification needs.”
of different organisations, most recently        and List B (moderate risk) as well as self            BSI will be offering IVD webinars and
running her own consultancy business             tests. Not many Notified Bodies have this         training in the future.
although she has worked at Notified Body         wide a notification.                                  The organisation has been on a major
level before too.                                    It is working with two of the world-          growth and acquisitive strategy over the
    The news means that BSI now offers           leading test laboratories, Paul Ehrlich           last year, having acquired German Notified
testing to all the EU medical device             Institut in Germany and Sanquin in the            Body, Eurocat (www.clinica.co.uk, 15
directives.                                      Netherlands to provide Annex II List A            September 2009) and also hired Dr Gert
    The other bodies notified in the UK to       verification of manufactured product testing.     Bos, formerly of the Dutch Notified Body,
test under the IVD Directive are: Lloyds             Growing the IVD business has been part        KEMA, last summer (www.clinica.co.uk,
Register Quality Assurance ( for whom            of a wider strategy for BSI. “As technology       14 August 2009).



Committee welcomes                               NBOG focus turns to
                                                                                                           Other EU news on
new waste rules                                  revised regulations                                       www.clinica.co.uk:
One of the European Parliament’s
                                                 After publication in March of key
committees has said that it welcomes the                                                             - UK devices authority: better
                                                 documents related to how notified bodies
recent 5% increase in the targets for reuse                                                            device registers needed but
                                                 should audit their medical device clients,
and treatment of electrical and electronic                                                             challenges ahead
waste stipulated in Article 11(1) of the         the Notified Bodies Operations Group
Waste Electrical and Electronic Equipment        (NBOG) is now anticipating the planned
Directive (2002/96/EC). Moreover, it             revision of the IVD Directive. It is looking at     - CAT gives opinion on
welcomes the fact that these targets now         conformity assessment and related Notified            experimental data for first SME
also include medical devices.                    Body issues within this context.
    There is much sensitivity around the            NBOG is also looking at the role of              - Deadline looming: are the
reuse of medical devices intended for single     Notified Bodies within the regulation on              chemicals in your product on
use and a strong industry lobby against          Advanced Therapy Medicinal Products                   the ECHA list?
reuse in these cases. However, much of the       incorporating one or more medical devices.
medical equipment that would be covered             Additional work items on the agenda at           - Denmark tightens up public
by the WEEE is machinery that would be           present include:                                      procurement rule breaches
intended for multiple use, and so has the           •	 the implementation of 2007/47/EC,
potential for refurbishment and reuse.                  the revision of the Medical Devices
    The Committee of the Regions also                                                                - Smoking prostates mean extra
                                                        Directive, and the related review
called for the introduction of a separate 5%                                                           protection needed during
                                                        of existing scopes of designated
re-use target, in accordance with the waste                                                            surgery
                                                        Notified Bodies according to the
hierarchy. The committee views this as
                                                        NBOG BPG 2009-3 “Guideline for
helpful in removing the current deterrents                                                           - Why I know governments must
                                                        Designating Authorities to Define
to reusing recovered products, and ensure                                                              invest in healthcare now or pay
                                                        the Notification Scope of a Notified
the quality reuse of appliances.                                                                       massive price
    Article 11 (2) says that to facilitate the          Body Conducting Medical Devices
reuse and the correct and environmentally               Assessment”;
                                                    •	 the NBOG annual report 2009, which            - Changes afoot at the CEN
sound treatment of WEEE, “including
                                                        should be published in the second              Advisory Board for Health
maintenance, upgrade, refurbishment
                                                        quarter of 2010; and                           Standards
and recycling, member states shall take
the necessary measures to ensure that               •	 NBOG has planned more than 12
producers provide reuse and treatment                   observed assessments in the context          - Eucomed highlights heart
information for each type of new EEE put                of its peer review programme for               disease figures during World
on the market within one year after the                 2010, following the eight that were            Health Rhythm week
equipment is put on the market”.                        performed in 2009.

  8    © Informa UK Ltd 2010                                                                                                     www.clinica.co.uk
Clinica // June 2010                                                                                                                            EU




Introducing UDI: step-by-step global
progress being made
D
          ecision-makers should not underes-         Indeed the GHTF has set up its AHWG             based approach should determine “the level
          timate the importance of introduc-     on UDI, known as the UDI AHWG (and not              of specificity and granularity of the UDI”.
          ing unique device identification       to be confused with the AHWP, the Asian                 There is a need, he added, for the
(UDI) to harmonise the array of existing         Harmonisation Working Party - a liaison             GHTF to develop guidelines for direct
tools used to trace devices and which com-       body member of the GHTF), to specifically           part-marking of certain devices (such
plicate the work of regulators, industry and     focus on the global implementation of UDI.          as reusable surgical instruments and
healthcare professionals.                            This will now work with the regulatory          reprocessing).
    This was one of many messages                authorities on the results of the public
conveyed to delegates at a recent meeting        consultation to develop a global UDI                A workable system
on traceability issues, held in Paris, France,   system that will work for all countries, as         Also speaking at the Snitem meeting,
and they underlined the urgent need for          well as setting up a pilot group composed           Ulrike Kreysa, director of healthcare at the
action in the area of device identification.     of representatives of the EU member states,         GS1 Global Office, discussed the issue of
    The meeting, entitled “Global UDI: Can       to help move this forward.                          whether the same level of identification
we make it straightforward and simple?”,                                                             should be used for every medical device.
was organised by French medtech trade            Static yet dynamic                                      GS1 is an international, not-for-profit
association Snitem in conjunction with           Mr Sellès explained UDI as containing               association dedicated to the development
EuroPharmat, an organisation involved            partly static, partly dynamic information:          and implementation of global standards
in device nomenclature and traceability.             •	 UDI – Device Identifier (static). This       and solutions to improve the efficiency
EuroPharmat, also based in France,                       is a unique numeric or alphanumeric         and visibility of supply and demand chains
aims to help countries meet the national                 code specific for a medical device,
                                                                                                     globally and across many industrial sectors.
traceability requirements, for instance in               also used as the “access key”
                                                                                                         In Ms Kreysa’s view, due to the extreme
the area of medical implantables.                        to information stored in a UDI
                                                                                                     diversity in size, materials, processing, use
    During the event, Laurent Sellès,                    database; and
                                                                                                     and risk, different levels of information
deputy head of the cosmetics and medical             •	 UDI – Production Identifier
                                                                                                     should be required according to the type
devices unit at the European Commission’s                (dynamic). This is a numeric or
                                                                                                     of devices.
Health and Consumer Affairs Directorate                  alphanumeric code providing
                                                                                                         The examples she proposed are
General, Sanco B2 and chair of the Global                information reflecting how the
                                                                                                     summarised in Table 1 (she added that
Harmonization Task Force Ad Hoc Working                  device is controlled. It can include
                                                         any combination of serial number,           examples would vary on specific devices,
Group (GHTF AHWG) on UDI, revealed how                                                               usage and packaging levels).
developments are moving forward apace.                   lot/batch number, manufacturing or
                                                         expiration date.                                GS1 and GS1 Healthcare are currently
    Mr Sellès told delegates that the AHWG                                                           developing and enhancing standards
has received 45 responses to its public              There is no legal foundation requiring
                                                 any particular form of automatic                    specifically for healthcare, Ms Kreysa told
consultation which finished on 31 March                                                              the meeting, and the European medtech
2010. It is currently analysing them.            identification technology, but the aim of
                                                 the GHTF is to promote the use of a global          industry association, Eucomed, and its
    He also noted that the US FDA, which                                                             eBusiness and Supply Task Force are
is also active in the GHTF AHWG, intends         UDI among all stakeholders: including
                                                 regulatory agencies; medical device                 supporting this initiative actively.
to finalise its UDI feasibility study in the
                                                 manufacturers; distributors; hospitals; and             She added that Eucomed and ETF:
autumn. And the FDA website indicates
                                                 medical professionals.                                  •	 recommend introducing the use
that the UDI will be implemented in
                                                     Mr Sellès also reminded delegates that                 of global GS1 standards at any
September 2013.
                                                 the UDI system should be implemented                       opportunity deemed appropriate
    Many other parts of the world are also
                                                 according to the level of risk of the device               from a cost-efficiency and quality
developing local systems, he added, for
                                                 – with the most risky being dealt with                     point of view; and
example China and several EU member
                                                 first. He noted that the introduction of                •	 believe that companies
states, or individual regions within EU
                                                 UDI should allow sufficient timeframes to                  implementing these standards will
countries, as for example with Spain.
                                                 allow manufacturers to comply with the                     be best positioned to meet customer
    With so much happening all at once,
                                                 requirements. Moreover, he said a risk-                    expectations now and in the future.
the main objective should be to now avoid
a “rampant fragmentation” of the UDI, he                            Table 1: Proposed levels of device identification
said, stressing how frustrating and resource
intensive it would be if manufacturers had        Device                                         Information to be required
to input their device identification details      Pacemakers, hip replacements                   Device ID + serial number + lot number
into a myriad of different systems.               Catheters, needles                             Device ID + lot number
    The GHTF is working to avoid this
                                                  Syringes, stopcocks                            Device ID
outcome, he stressed, and encourage the
global uptake of a single system.                 Single use commodity devices                   No UDI

www.clinica.co.uk                                                                                                       © Informa UK Ltd 2010   9
EU                                                                                                                              Clinica // June 2010




ENVI committee to vote on devices
inclusion RoHS directive
The European Parliament’s Committee on                The plenary vote, being made during the         devices and control and monitoring
the Environment, Public Health and Food           first reading, had originally been due in June      instruments in the scope, the main
Safety (ENVI) is due to vote next month           but was postponed.                                  modifications in the Commission proposals
on the adoption of a draft report on the              The vote is being made on the European          are: maximum concentration values for
amendment of the RoHS Directive. The              Commission’s recast version of the original         the banned substances; extension of
legislation relates to the restricted use of                                                          permission to use non-compliant spare
                                                  Directive which aims to eliminate certain
certain hazardous substances in electrical                                                            parts to equipment benefiting from
                                                  hazardous substances from electrical
and electronic equipment.                                                                             an exemption; and a mechanism for
   This is a matter of key importance to the      and electronic equipment; where this is
                                                  temporarily not possible, exemptions are            introducing new substance bans in line
medtech industry since the Commission                                                                 with the REACH methodology, among
now intends to introduce medical devices          granted - as was the case with medical
                                                                                                      other things.
into the scope of this Directive. To date,        devices in the original version of the Directive.
medical devices have been exempt.                     Apart from the inclusion of medical             Read the full story at www.clinica.co.uk


RoHS recast: industry hammers case
for medtech exemptions
T
         he European electromedical indus-               obtain market approval to comply             been subject to any assessment.
         try association COCIR has once                  with the Medical Devices Directive.               It also calls for scientific evaluation on
         again stressed the need for medical         If such exemptions are not validated,            the basis of a comprehensive and consistent
equipment to remain out of the scope of           COCIR fears that the availability of medical        methodology before any new substance
the recast RoHS Directive, which concerns         devices and the future development of new           restrictions are introduced. Setting new
restricting the use of certain hazardous sub-     technologies will be compromised. The trade         restrictions without a proper assessment
stances in electrical and electronic devices..    association adds that it has been proven that       “bears unforeseeable risks and negative
    In view of the upcoming European              none of the apparent substitutes are suitable       consequences, especially at the level of
Parliament’s Committee on the Environment,        as of today.                                        product reliability and safety”.
Public Health and Food Safety (ENVI)                                                                       A RoHS Directive which is
vote on the proposal for a recast of Directive    Joint response                                      complementary to REACH needs to be
2002/95/EC, COCIR has worked together with        Together with the other associations,               fully consistent with the EU’s horizontal
other trade associations in the electrical and    COCIR also calls for support to:                    chemical management law to avoid double
electronic industries to draft a joint position       •	 clarify RoHS scope exclusions;               regulation and conflicting requirements,
paper, as well as issuing one on its own.             •	 introduce formats, timelines and             the joint industry statement says.
    In its position paper, COCIR, which                   grace periods for RoHS exemptions                REACH provides a fully harmonised
represents the electronic, radiological and               case by case;                               framework for chemicals management
IT industries, says that it fully supports            •	 establish a structured stakeholder           across the EU and includes in its scope
“essential additional exemptions for medical              consultation mechanism;                     substances used by the electrical and
devices”. The association warns that because          •	 assess the added value of the RoHS           electronic industries. So, to provide legal
its members manufacture highly innovative                 Directive during the REACH review           certainty, “it is vital that any additional
and complex healthcare technologies with                  process and in the meantime align           substance restrictions introduced
comparably long life cycle expectation                    RoHS with REACH to the maximum              under RoHS follow REACH criteria and
and many potential failure mechanisms                     extent; and                                 procedures”: in particular, they should use
(associated with substitutes), including              •	 align RoHS with the New                      all information produced within REACH’s
medtech within the scope of RoHS could affect             Legislative Framework, and in               chemical risk assessment.
long-term reliability of medical equipment.               particular to make use of European               The joint statement also expresses the
    In COCIR’s view, it is vital to:                      Standardisation Committees to               view that the RoHS Directive is not the
    •	 provide the EU market with safe                    harmonise relevant standards.               appropriate framework for nanomaterials,
        and effective medical devices that            The joint industry statement, meanwhile,        since these are used in a wide range of
        contribute to a better healthcare         issued just ahead of COCIR’s position, calls for    different applications far beyond the electrical
        system and improve citizens’ quality      “a thorough representative impact assessment        and electronics equipment industry.
        of life; and                              at EU level and scientific evidence for any              Indeed, nanomaterials are covered by
    •	 ensure sufficient time to find             major change to the existing Directive”.            the REACH Regulation and many related
        alternative components (research),            It warns the concept of an open scope is        activities are currently ongoing in the
        re-design products, conduct               “particularly unjustified” and that the impact      Commission with a view to the REACH
        validation and reliability testing and    of such far-reaching modifications have not         review 2012.

 10     © Informa UK Ltd 2010                                                                                                         www.clinica.co.uk
Clinica // June 2010                                                                                                                                     EUropE



Assobiomedica advocates                                                             Sicily forms first medtech
greater cost-effectiveness                                                          purchasing committee

T                                                                                   T
        he Italian medtech industry has advocated increasing the                           he health authorities of the Sicily region are to establish a
        cost-efficiency of the health system. The suggestions are well                     permanent committee on purchasing policy – a first for Italy’s
        timed; this week the Italian government announced austerity                        medical technology industry.
measures worth €24bn ($30bn) over 2011-12, or about 1.6% of GDP.                       Under an agreement with national trade federation
   Pending an assessment of any impact on the health services, given                Assobiomedica and local supplier groups, among other bodies, the
the planned cuts in general funding to regional authorities, national               purchasing committee will seek to “guarantee a minimum level of
biomedical products industry association Assobiomedica is clear                     healthcare product quality”, according to the association.
about what can or will not work to make medtech purchasing more
cost-effective.
                                                                                    “An example to other regions”
Creation of a national purchasing                                                       Its first task will be to produce best-practice guidelines on cost-
observatory is “crucial”                                                            effective purchasing, said Assobiomedica. The committee is expected
                                                                                    to consult regional and national suppliers, as well as clinical experts
   Speaking at the recent national medical devices conference                       and health economists.
(Rome, 14 April), Assobiomedica president Angelo Fracassi was                           The association welcomed the creation of the committee with the
adamant that the creation of a national purchasing observatory was                  hope that it would “act as an example to other regions”, especially in
“crucial to the development of a rational spending [policy]”.                       terms of how “it will demonstrate how to keep spending in check,
   He rejected, however, the idea of either applying single reference               according to the principles of appropriate product selection”.
prices to devices, or of centralising purchasing. “It has finally become                The move “will put quality and savings at the service of the
clearly evident [that] reference prices, purchase centralisation and                citizenship”, said Luigi Boggio, president of Assobiomedica’s
any excessive attempt to save at any cost, are pointless,” said                     “Assobiomedicali” division, which represents manufacturers and
Dr Fracassi.                                                                        distributors of devices.
   Moves to centralise purchasing were described by Dr Fracassi as
“perplexing” to medical technology manufacturers. “Without careful
planning, this could great harm. In general terms, the tendering
process must at least guarantee complete accessibility to all players,”
he added.
   Citing research conducted by the health ministry itself, Dr
Fracassi said that “average unit prices are not valid indicators of cost,
and can actually create distortions of the market”.
   “The time has come to realise that medical devices are ‘factors’ in
the care that they help provide,” said Assobiomedica in a statement.
“We must therefore accept as inevitable that in order to guarantee
appropriate care, we must first define the diagnostic and therapeutic
pathways involved,” said Dr Fracassi. “Only in such a system can
health technology assessment [HTA] deliver its full potential.”


                                                                                        Is NICE looking at a procedure
Portugal cuts spending on                                                               involving one of your devices?
glycaemia strips                                                                       NICE makes recommendations about
                                                                                       whether interventional procedures



P
       ortugal has introduced – “with immediate effect” – a 10% re-                    used for diagnosis or treatment are
                                                                                       safe enough, and work well enough,
       duction in the cost of glycaemia strips reimbursed through the                  for routine use in the NHS. Some
       national health service. The move is part of a 10-point package                 of the procedures we look at may
of healthcare-specific austerity measures that seek savings of at least                involve the use of a medical device.
€50m ($61.5m) by the end of 2010.                                                      Visit the NICE website to comment on
                                                                                       draft guidance or register to receive
    The measures, which were announced by the government on                            e-alerts on the new procedures just
24 May, also oblige state hospitals to, among other things, present                    taken on to the programme.
within 20 days a cost-cutting plan of action. The health ministry is                   This month NICE is consulting on
aiming for a 2% across-the-board cut in “supplies” spending, and a 5%                  draft guidance on the following
overall reduction in health system costs, among other savings.                         procedures:

    Although these “initial measures” are expected to result in a
€50m cut in spending this year, the health ministry said it is actually                                                        www.nice.org.uk
seeking to save “more than €100m” by the end of this year.

www.clinica.co.uk                                                                                                                © Informa UK Ltd 2010     11
                                                                            NICEClinicaFeb2010.indd 1                                                18/2/10 08:39:10
EUropE/INtErNAtIoNAl                                                                                                      Clinica // June 2010




India set for “comprehensive medtech
regulation” by the end of 2010
I
     ndia is set to enact its medical tech-       Controller General, Surinder Singh said,        Harmonization Working Party, so as to
     nology regulatory legislation later          according to a statement issued by FICCI.       “foster best practices on medical device
     this year, according to health minister                                                      regulations from various economies”.
Dinesh Trivedi. The Bill is expected to be        Medtech self-reliance                               Mr Trivedi set out a number of other
introduced to Parliament over the next few        Dr Singh also said that “the role of            planned healthcare modernisation
months (during the monsoon session) and,          government would be to enforce the law          initiatives. The government is proposing
subject to the approval of the state govern-      and facilitate the growth of the indigenous     to establish a National Health Portal to
ments, passed during the winter session,          industry”. The comments are reminiscent of      provide the public with information on
he said.                                          the self-reliance policies being adopted by     “standardisation and protocols”, and an
    The plans to enact “comprehensive             other fellow-BRIC states, especially Brazil.    e-records system for “all citizens”, he said.
                                                     Underlining the mutual benefits of
legislation to ensure standards, safety,                                                              Noting the rising demand for healthcare
                                                  bolstering the domestic medtech industry,
quality and effectiveness of medical                                                              from India’s growing population, the
                                                  FICCI advisor VK Topa said that “both
devices” were announced by Mr Trivedi at                                                          citizens’ greater awareness and the
                                                  industry and regulators want a safe, reliable
the National Workshop on Medical Device                                                           country’s changing disease profile, he also
                                                  and dependable system”, and that both
Regulations in India, held in New Delhi,          parties “need to be in sync” to achieve this.   spoke of plans to expand and modernise
on 11 June.                                          “Industry and the government will            the health system. The health ministry has
    The event was co-hosted by the                have to team up to work out a practical         signed an MOU with the Railway Ministry
Federation of Indian Chambers of                  implementation approach,” Mr Topa               for the sale of land to build diagnostic
Commerce & Industry (FICCI) and the               added. FICCI is proposing the creation of a     centres and hospitals at or near railways
national regulatory body for all healthcare       roadmap for training medtech regulators,        stations, he said.
products, the Central Drugs Standard              and has also called for the creation of             Emphasising the “need to address
Control Organisation (CDSCO).                     an “institutional development plan”             basic issues of healthcare”, Mr Trivedi
    “The proposed law will be specific            that cultivates links with the global and       said that the legislation will be key to the
to India, to cater to the country’s               regional harmonisation groups, the Global       government’s aims of sustaining GDP
socioeconomic conditions,” India’s Drugs          Harmonization Task Force and the Asian          growth at 9% per annum.



Spain: Osteoporosis                               EU’s ultrasound market                           Other Europe and International
fractures set to treble                           “saturated” but evolving                          news on www.clinica.co.uk
The incidence of osteoporosis-related             Elastography, therapeutic and contrast-           - Canada delays use of STED
fractures is set to treble in Spain over the      enhanced ultrasound are to offer new and            format for class III & IV devices
next 50 years, an expert said at the 11th         more effective means of diagnosis and help
                                                                                                    - Pandemic flu vigilance remains
national congress of AEEM, the country’s          drive growth in an otherwise mature market,
                                                                                                      critical – WHO
leading menopause research association,           according to analysts at Frost & Sullivan.
and the menopause division of SEGO,                  The segment, comprising urology,               - Antenatal ultrasound under
the national society for gynaecology and          obstetrics/gynaecology and surgical                 scrutiny in Ireland
obstetrics. The meeting took place in             ultrasound, is said to have generated             - Ireland launches major review
Malaga on 1-4 June 2010.                          revenues of $371m in 2008, and is estimated         of miscarriage diagnoses
    Around a half of all women are at risk        to grow to $438m by 2015, according to
of some form of bone fracture caused by           Shriram Shanmugham, author of the report          - New Zealand extends Smiths
osteoporosis, and one in three women              European ultrasound market: lower body              Medical’s syringe driver
will suffer a fracture specifically of the hip,   applications.                                       replacement deadline
according to Santiago Palacios, president of         “While the ultrasound market in                - Brazil maps mammography,
the AEEM’s scientific committee.                  Europe is saturated and is primarily a              aiming for 46% growth by 2011
                                                  replacement one, the therapeutic and
                                                                                                    - Irish reforms promise better
€120m per year                                    contrast-enhanced ultrasound segments
                                                                                                      access to stenting
Osteoporosis is currently the cause of            are nevertheless projected to experience
around 90,000 hip fractures and 500,000           stable growth,” he believes.                      - Vietnam meningitis burden
vertebral fractures every year, according to         He also notes that “as clinical research         offers “considerable scope” for
Dr Palacios. The direct healthcare costs of       becomes more intensive, research facilities         diagnostics
osteoporosis-related fractures is estimated       and ultrasound companies are forming              - Fresh concern over PIP omitting
to be around €120m [$147m] per year,              associations in order to accelerate                 protective envelope since 2005
he added.                                         ultrasound development”.

 12     © Informa UK Ltd 2010                                                                                                   www.clinica.co.uk
Clinica // June 2010                                                                                                               INtErNAtIoNAl




Canada approves industry fees hike
T
         he Canadian Senate adopted on 26          of programme costs for medical devices            to support the submission, and added up
         May proposals by Health Canada to         and pharmaceuticals. Under the proposal,          to determine the total fee payable for any
         allow it to increase user fees to medi-   annual revenues from user fees would              given submission.
cal device and pharmaceutical companies            increase to Can$112.4m (US$107m) from                 The proposal, if finalised, would
to cover its growing costs and workload            Can$47m.                                          establish a flat fee for different categories,
delivering regulatory services. The propos-            Other Western country regulatory              reflecting the average activity cost and level
als are expected to come into force in April       agencies have higher user fees to cover           of effort associated with those groups of
2011, officials have indicated.                    more of their costs: the UK (100%),               submissions. Health Canada believes that
    The proposal will now go to the                Australia (100%), the European Union              applying a flat fee structure to medical
Treasury Board, with which Health                  (70%) and the US (50%), for instance.             device and drug submissions would not
Canada will liaise to ensure there is no               Health Canada says the extra money            only simplify the determination of the fee to
clawback of existing funds. If the proposal        will support key regulatory services that         be charged, but would also more effectively
proceeds, it will be published in the              benefit Canadians and the industry,               align that fee to respective costs and
Canada Gazette Part I for a 75-day public          such as product review, compliance and            provide an increased level of cost certainty
comment period; publication is expected            enforcement and post-market surveillance          for fee payers.
in the second half of this year and this will      of adverse reactions. Revenues would also
set the implementation date.                       assist in conducting scientific assessments       Industry opposition
    Canada introduced user fees in                 within internationally comparable                 The Canadian medtech industry
the 1990s, but claims to be the only               timelines.                                        association MEDEC has previously told
international jurisdiction that has not                                                              the government that the proposed fee
increased them since their implementation.         Fee structure                                     increases were “too high and too fast”. In
It hopes that the revised fees will cover 50%      The current fee structure for medical device      a submission to the Senate on 13 May, the
of the cost of regulatory services compared        and drug submission evaluations is linked         group expressed concern that the proposed
to the current situation where fees only           to the submission type and is component-          increases could put at risk future patient
cover about 25% of costs. When fees were           based, where individual fees are identified       access to innovations (www.clinica.co.uk,
first introduced they covered about 50%            based on the type of information provided         17 May 2010).



Brazil aims to increase                                                                              China and Brazil to
                                                                                                     strengthen collaboration
domestic competitiveness                                                                             China’s SFDA and Brazil’s Anvisa healthcare
                                                                                                     regulatory agencies have met in Brasilia



B
        razilian regulatory agency Anvisa          domestic medtech industry and to raise            to further their collaboration in areas
        has launched an initiative to              the certification-related standards of            such as manufacturing inspections and
        “promote and strengthen” domestic          manufacturers, especially those classed as        information-sharing related to regulatory
production and market entry of medical             micro-sized or small”, said Anvisa.               processes and standards.
technology, with an emphasis on the needs              “A large proportion of Brazil’s medtech           The SFDA’s visit follows that of Anvisa
of the high proportion of micro-sized and          manufacturing sector consists of micro-           to China at the end of 2009 (www.clinica.
small manufacturers.                               sized and small enterprises, which creates        co.uk, 21 December 2009), and is being
    This month, the agency held in Brasilia        a need for guidelines that are specific           billed by the latter as “part of a politico-
the first of six regional conferences aimed        to this industry segment,” said Sebrae            strategic definition by both countries of
at raising awareness among manufacturers           representative Rosana Melo.                       how to strengthen our joint activities in the
and trade associations of the “legal and               Small-, medium- and micro-sized               area of healthcare [regulation]”.
operational considerations” involved in            firms jointly account for 78% (2009) of               The visit featured the signing of a
the production, registration and trade             Brazil’s medtech industry, according to the       memorandum of understanding related
of medical equipment and orthopaedic               leading trade association, ABIMO (www.            to the sharing of information between the
implants, especially.                              clinica.co.uk, 24 May 2010). According to         technical departments of both agencies.
    The initiative is the result of a              Anvisa, the small and micro-sized segment         The Chinese delegation was said to include
collaboration between Anvisa, the national         accounts for almost 26% of the total, with        the Chinese vice-minister for health and
industrial development agency (ABDI) and           medium-sized firms accounting for the             SFDA commissioner Shao Mingli.
Sebrae (Servicio Brasileiro de Apoio a Micro       remaining 52% of the total.                           The visit also sought to improve the
e Pequenas Empresas), an organisation that             The first of this series of conferences       SFDA’s knowledge of Anvisa’s structure,
supports and represents the interests of           took place on 9 June at Anvisa’s Brasilia         systems, processes and regulations. Anvisa
micro-sized and small enterprises across all       headquarters; the others were scheduled           already inspects Chinese manufacturers of
industries.                                        to take place in Manaus (17 June), Porto          medtech imported into Brazil. According to
    The aim of the initiative is to                Alegre (24 June), Rio de Janeiro (1 July), Belo   Anvisa, China is the fifth-largest exporter of
“improve the competitiveness of the                Horizonte (8 July) and João Pessoa (15 July).     medtech products to Brazil.

www.clinica.co.uk                                                                                                       © Informa UK Ltd 2010   13
BUSINESS                                                                                                                   Clinica // June 2010


SonoSite strengthens
ultrasound offering
                                                Covidien rearranges
with Visualsonics deal                          portfolio with two buys
H                                               C
         and-held ultrasound specialist                  ovidien has secured two acquisitions      acquired. Somanetics (Troy, Michigan)
         SonoSite is poised to purchase                  in the space of one month, highlight-     specialises in cerebral and somatic
         Visualsonics, a firm that develops              ing its desire to diversify its product   oximetry and recorded revenue of $50m in
ultra high-frequency micro-ultrasound           portfolio and pursue markets with higher           2009, with double-digit sales growth for the
technology, for around $71m net of cash         growth potential.                                  last 12 years. Prior to the merger deal, the
and debt.                                           In the largest of the two deals, Covidien      two firms had a long-standing relationship,
    Visualsonics (Toronto, Canada) claims       signed a definitive merger agreement worth         under which Covidien was the exclusive
that its micro-ultrasound technology            $2.6bn which will see ev3 become a part of         distributor of Somanetics´ INVOS (in vivo
uses five times the centre frequency range      Covidien’s vascular products business.             optical spectroscope) in Europe.
currently used in conventional ultrasound           Wide vascular portfolio Plymouth,                 INVOS is a noninvasive patient monitor,
systems, thus enabling the visualisation        Minnesota-based ev3 specialises in the             which continuously measures blood oxygen
of superficial anatomy with microscopic         treatment of peripheral vascular and               levels in the brain and in the body of
detail.                                         neurovascular diseases, with a portfolio           patients who are at risk of restricted blood
    SonoSite is aiming to integrate             of over 100 products including peripheral          flow, so that clinicians are able to detect
Visualsonics’ technology into its own           angioplasty balloons, stents, plaque excision      and correct a variety of complications. The
products, which include portable                systems, embolic protection devices, liquid        device can be used in surgery (both adult
ultrasound systems, mountable ultrasound        embolics, embolisation coils, flow diversion       and paediatric), anaesthesia, perfusion and
systems, catheter guidance technology and       products, thrombectomy catheters and               vascular procedures. It is currently in use in
ultrasound tools used in cardiovascular         occlusion balloons. Mr Meelia said that            more than 700 US hospitals.
procedures.                                     there was no overlap with Covidien’s                  Under the terms of the deal, which is
    Visualsonics’ technology is used to         product offering, ensuring a smooth                expected to close before the end of July,
aid research rather than for diagnostic         integration.                                       Covidien will purchase all outstanding
or therapeutic applications. However,               In fiscal 2009, ev3 recorded revenues          Somanetics shares for $25 each. Covidien
according to SonoSite, the technology           of $449.1m and a net income of $41.9m.             forecasts that the deal will be neutral to
could be used in diagnostic radiology,          Covidien reported vascular sales of $574m          earnings-per-share in fiscal 2010 and slightly
                                                in fiscal 2009; this represented only 5%           accretive to fiscal 2011 earnings-per-share
neonatology, paediatric cardiology,
                                                of the group’s overall sales and 9% of its         on a non-GAAP basis.
orthopaedic medicine, tissue regeneration
                                                medical device revenues.
and dermatology for clinical disease
                                                    Covidien’s vascular business includes          Sleep therapy sale
management. “We also see solid potential
                                                products under the firm’s Kendall brand,           The acquisition of ev3 is part of Covidien’s
to continue expanding in preclinical
                                                including vascular compression and                 strategy of becoming a leader in the
markets, such as cardiovascular research,
                                                vascular therapy products.                         endovascular market, “with strong
gene therapy, cancer and the overall
                                                    Under the terms of the acquisition,            positions in both the peripheral vascular
evaluation of drug therapies”,” said Kevin                                                         and neurovascular markets”. In a further
                                                Dublin, Ireland-based Covidien will pay
Goodwin, SonoSite president and CEO.                                                               move to achieve this goal, the company
                                                $22.50 in cash per ev3 share. The deal is
    Bothell, Washington-based SonoSite                                                             has signed a definitive agreement to sell
                                                expected to dilute 2010 earnings-per-
said that the research market is estimated                                                         its sleep therapy products to PH Invest, a
                                                share by 5-8 cents (with the underlying
to exceed $350m “with a projected double-                                                          private company located in Luxembourg,
                                                strength of Covidien’s existing business
digit annualised growth rate”. The company      offsetting this loss). The firm also expects       for an undisclosed fee.
said that it expects the acquisition to add     fiscal 2011 Non-GAAP earnings-per-share                PH Invest will receive Covidien’s
$17m in second-half 2010 revenues. One-         to be diluted by around 10-15 cents. The           continuous positive airway pressure
time charges related to the deal are forecast   transaction is scheduled to close before           (CPAP) and Bi-level products, as well as a
to be $5m.                                      the end of July.                                   manufacturing facility in Nancy, France. It
    SonoSite will update its 2010 revenue           Covidien chairman, president and CEO,          will acquire brands such as GoodKnight
and earnings-per-share guidance when            Richard Meelia, told investors that the ev3        and Sandman but will not gain the Adam,
announcing its Q2 results on 26 July 2010.      acquisition would “accelerate our growth,          Breeze and Dreamfit lines, which will
    Following the closing of the deal, which    improve our gross margins and provide              continue to be sold by Covidien.
is expected before the end of the second        new products”. He said the deal expands                Covidien expects the deal to close in
quarter, SonoSite will pay off $8m of debt      the company’s presence in the $3bn                 the third quarter of 2010. The transaction
owed by Visualsonics.                           peripheral vascular market and gave it a           is not expected to have a material effect on
    Last year, SonoSite expanded its            point-of-entry into the $1bn neurovascular         operating income or earnings-per-share for
cardiovascular disease management               industry.                                          2010 and 2011.
offering by purchasing haemodynamic                                                                    Mr Meelia said that despite the firm
monitoring firm CardioDynamics for              Somanetics purchase                                having a “small presence in a good market”,
around $12.3m net of cash and debt (www.        Covidien has also signed a merger deal             the sleep therapy segment was “difficult to
clinica.co.uk, 10 June 2009).                   with Somanetics worth $250m, net of cash           compete in”.

 14    © Informa UK Ltd 2010                                                                                                     www.clinica.co.uk
Clinica // June 2010                                                                                                                  BUSINESS




Bosch takes telehealth a stage further
with UK PCT project
B
        osch Healthcare is stepping up the      subject of some 30 peer-reviewed studies         has much to do with the fact that it places
        pace of its involvement in remote       over the last ten years. The key findings for    a focus on patients self-managing their
        patient monitoring with its first       the company are a high compliance rate           own conditions. Users can also engage in
major independent project in the UK.            of 85%, a QoL improvement, reduction             a question-and-answer process over their
    The Stuttgart, Germany-based group has      in mortality and morbidity, and cost             condition via the device, which enables
selected Barnsley Primary Care Trust (PCT)      reductions “across the board”. Moreover,         physicians and care staff to detect and
to host and operate a trial of its Telehealth   care providers’ acceptance of the service        analyse health changes, thereby potentially
Plus system in patients with long-term          is reportedly “very high”. In all, 86% of        avoiding acute complications.
conditions.                                     patients say they better understand their            Ulrich Behner, vice-president of Robert
    The remote monitoring system                chronic conditions through using the             Bosch global healthcare, says that Bosch
measures vital signs on a daily basis. The      Telehealth Plus.                                 Healthcare has been able to integrate its
technology has been conceived to help                                                            expertise in sensor technology from diverse
patients live independently, giving greater     Demographics point to higher                     parts of the group’s industrial, automotive
quality of life (QoL), while also cutting the   uptake of remote tech                            and consumer divisions. Speaking
cost of providing healthcare.                   The trials have been valuable in                 to Clinica, he said: “We understand
    The three-phase trial will start in         demonstrating that the technology is not         consumers, and we are focused on the long-
September and involve 150 patients living       for everyone, and there are issues yet to be     term view of making improvements to the
at home with congestive heart failure           resolved over reimbursement.                     technology.”
(CHF). The findings will shape the second           But the demographic changes that lie             The Barnsley trial will expand Bosch’s
phase, which will extend to patients with       ahead provide a compelling reason for the        knowledge or remote tech needs. The PCT,
chronic obstructive pulmonary disease           greater and faster integration of remote         in West Yorkshire, was chosen by Bosch
and diabetes. The third phase will bring the    technologies for chronic and other patients.     as it is seen as a progressive adopter of
trial population up to the target of 2,500          Peter Fouquet, the president of Bosch        telehealth. Some 60,000 of the population
patients.                                       UK, notes that the number of over-65s            of over 222,000 live with chronic conditions,
    Bosch, which came into UK and Ireland       will have doubled within 50 years, and the       said the PCT’s director of intelligence,
healthcare markets only two years ago, has      incidence of chronic conditions continues        innovation and quality Brian Hughes.
been on a steep learning curve. In January      to rise. The UK spent £125bn ($185bn) on
this year, it started up a 40-patient trial     healthcare in 2008 (including private sector     Chronic and social care needs
of the Telehealth Plus system in Dundalk,       care) – equivalent to 8.4% of GDP. The           The partnership is expected to advance
County Louth, Ireland, in CHF and diabetes      predicted shortage of nursing staff in the       knowledge of how chronic care can be
patients who were recurrent users of A&E        future also makes for a strong argument for      managed, bearing in mind the social as well
and hospital services.                          telehealth.                                      clinical aspects. “Admissions to hospital are
    Among the findings from the ongoing             The case for the Bosch technology is         often for non-healthcare reasons,” Ms Welte
Irish trial, which will be used to inform the   well established in the US, where, known         pointed out.
Barnsley project, five hospital admissions      as the “Health Buddy”, it has been used in           Mr Behner added: “The premise is that
have been spared and all patients have          150,000 patients in the last ten years. Some     the technology works; what is different
reported a higher QoL.                          33,000 US patients are currently connected       about the UK project is scale-up.”
    Clinician satisfaction is also reported     to Bosch devices. The Telehealth Plus                The trial, the findings of which will
to be high, said Bosch global head of           system is also used in Germany and the           be independently evaluated by Sheffield
healthcare sales Ileana Welte, at last week’s   Netherlands.                                     University, is another step towards greater
launch of the UK project, in London.                The improved QoL and reduced hospital        understanding and wider adoption of
    Bosch’s telehealth devices have been the    admissions among users of the technology         telehealth systems.



Accuray and Siemens in CyberKnife collaboration
Accuray has boosted the global sales reach      create a research and development alliance to    to non-invasively treat tumours anywhere in
of its CyberKnife robotic radiosurgery          explore potential synergies between the two      the body. The system automatically tracks,
system in the radiation oncology market by      firms’ capabilities. Siemens will purchase and   detects and corrects for tumour and patient
signing a strategic alliance with Siemens.      incorporate elements of Accuray’s technology     movement in real-time with the use of
    The collaboration will see Siemens sell     in its linear accelerators. Financial terms of   image guidance technology. The device also
CyberKnife globally; Accuray will continue      the partnership were not disclosed.              delivers high-dose radiation to minimise
to sell the device through its own worldwide        Sunnyvale, California-based Accuray says     damage to surrounding healthy tissue, thus
distribution network.                           that the CyberKnife device is the world’s        eliminating the need for invasive head or body
    As part of the deal, the companies will     only robotic radiosurgery system designed        stabilisation frames.

www.clinica.co.uk                                                                                                   © Informa UK Ltd 2010   15
BUSINESS                                                                                                                   Clinica // June 2010




Tissue Regenix eyes AIM listing
through reverse merger with Oxeco
T
        issue replacement specialist Tissue      into a patient for vascular repair. York,        executive chairman Michael Bretherton
        Regenix is seeking to become a pub-      UK-based Tissue Regenix intends to start         will be finance director. Alan Miller and
        lic company with a proposed reverse      marketing this product in the second half        Alex Stevenson, non-executive directors at
takeover of Oxeco, a holding and manage-         of 2010.                                         Tissue Regenix, will retain their positions at
ment company listed on the London Stock              The firm will also dedicate “a significant   the new firm.
Exchange’s Alternative Investment Market         proportion of the new funds” towards the            Alan Aubrey, CEO of university
(AIM). The acquisition will see around 240       development of its dCELL meniscus device         commercialisation firm IP Group, will also
million shares issued at a price of 5p each,     for repairing damaged knees. According to        become a non-executive director. Tissue
giving the deal a value of around £12m           Tissue Regenix, the priority markets for the     Regenix is currently a portfolio company of
($17.3m).                                        dCELL platform are vascular, cardiology          IP Group.
    Tissue Regenix says that it expects to       and orthopaedics.                                   Oxeco (London, UK) listed on the AIM
raise around £4.5m by placing shares of              Tissue Regenix managing director,            in December 2006. It was established to
the combined group on the AIM, giving the        Antony Odell, said: “The successful              acquire and manage businesses in the
new firm net funds of approximately £7.4m.       completion of the listing in difficult market    technology and science sector. In June
New shares in the combined company,              conditions will highlight the strength of our    2007, it acquired Oxray, a start-up focused
to be named Tissue Regenix Group, will           technology and the size of the market.”          on developing X-ray crystallography
commence trading on the AIM on 29 June.                                                           structure determination software.
    Proceeds from the share placement            New group details                                However, Oxeco decided to stop investing
will be used to develop Tissue Regenix’s         Mr Odell will become the managing                in Oxray after it failed to build up its
dCELL platform technology. The firm’s lead       director of Tissue Regenix Group, while          portfolio and customer base. Oxeco
product is the dCELL vascular patch, which       John Samuel, current chairman of Tissue          recorded a loss of £0.1m in the year to
is designed to be permanently implanted          Regenix, will be executive chairman. Oxeco       January 2010.


                                                                                                        Other business news
BD set to divest medtech businesses                                                                     on www.clinica.co.uk
to private equity firm                                                                               - Qiagen to develop molecular
                                                                                                       tests with Genome Diagnostics


B
        D is to sell a portion of its medical       The Franklin Lakes, New Jersey-based
        devices segment to private equity        company said that the assets being sold             - USHIFU grows portfolio with
        company RoundTable Healthcare            represented around $200m in estimated                 SB500 and Sonatherm tech
Partners.                                        revenues. This is around 3% of the group’s
   BD will divest its ophthalmic systems         overall revenues and 5% of the firm’s               - Covidien rearranges portfolio
unit, as well as its surgical blades, critical   medical segment sales. Estimated earnings-            with ev3 purchase
care and extended dwell catheter product         per-share for the divested assets is predicted
platforms of its medical surgical systems        to be $0.20-0.24 for full fiscal 2010.              - Sorin acquires Gish
business to Lake Forest, Illinois-based                                                                Biomedical for ECC focus
RoundTable. Financial terms of the               Asset sale “in line”
divestment were not disclosed.                   Morgan Stanley analyst David Lewis                  - Medline ups surgical offering
   BD’s assets will join RoundTable’s            suggested in a research note that more                with Proxy meshes for hernia
medtech portfolio, which already includes        divestments could be coming from BD.                  repair
single-use vascular access and patient           “BD’s asset sale within medical systems
                                                 is in line with activity we expect to see           - Brainlab teams up with
monitoring medical devices firm ACI
Medical Devices, disposable medical              across many large-cap device players, as              Toshiba for surgical suite
products company Aspen Surgical, and             companies more aggressively manage
                                                                                                     - Defibtech AED battery recall
medtech instruments, delivery systems and        their segment portfolios to adjust for
                                                                                                       given class I notice
precision machining specialist                   changing growth and profitability
Avalign Technologies.                            dynamics,” he said.                                 - Mediwatch collaborates with
   BD said that this sale would allow it to          Mr Lewis also pointed out that                    GE for urology pact
switch its resources to the core areas of its    historically, BD has been more used to
medical devices business, which focuses          buying than selling. “In 20 years, BD has           - Salient sues Bovie in
on parenteral medication delivery products       only divested six times – this asset may              electrosurgical patent case
such as syringe and needle systems.              prove the largest.”

 16    © Informa UK Ltd 2010                                                                                                     www.clinica.co.uk
Clinica // June 2010                                                                                                    ScIENcE & tEcHNoloGy




Can CUPID cure a broken heart? Trial
success for heart failure gene therapy
A                                                                                                    Muscle repair
         small-scale phase II trial of a gene      Society of Cardiology, held in Berlin,
         therapy for heart failure has had         Germany this month. They showed that the          Average levels of N-terminal pro-brain
         “encouraging” results.                    study met its primary efficacy endpoint:          natriuretic peptide (NT-proBNP), a serum
    Six-month data from the CUPID trial,           a composite including the simultaneous            biomarker found in elevated levels in heart
which is assessing the Mydicar therapy             assessment of patients’ clinical outcomes,        failure patients, increased by 5,540pg/ml
developed by Celladon and is sponsored             exercise tolerance, heart failure symptoms,       in the placebo group, and decreased by
by the company, indicate improvements in           biomarkers, and cardiac function.                 13.5pg/ml in the Mydicar group. Cardiac
clinical outcomes and disease markers in the           The 39 patients enrolled in the study had     function worsened in the placebo group,
34 advanced heart failure patients in the trial.   New York Heart Association (NYHA) class           with the left ventricular end-systolic
    Celladon (La Jolla, California) calls          III or IV heart failure and ejection fraction     volume (ESV) increasing by 18.2ml; ESV
Mydicar a “genetically targeted enzyme             of less than 35%, meaning that the pumping        decreased by 9.6ml in the Mydicar group.
replacement therapy”. Mydicar delivers             function of their hearts was severely             This indicates reverse remodelling – in
the gene for SERCA2a, an enzyme that               impaired.                                         other words, repair – of the damaged heart
improves myocardial relaxation and                     Patients treated with high-dose Mydicar       in the Mydicar-treated patients.
contractility, using a viral vector. SERCA2a       had a statistically significant reduction             Additionally, patients who received
levels decrease in all forms of late-stage         in cardiovascular events (defined as              Mydicar had significantly improved heart
heart failure resulting in deficient heart         death, the need for left ventricular assist       failure symptoms, exercise tolerance, serum
function, Celladon says.                           device or cardiac transplant, worsening           biomarkers and cardiac function.
    Mydicar is delivered in a single dose          of heart failure or heart failure-related             Dr Barry Greenberg, professor of
directly to the heart muscle in a short            hospitalisations). Patients given Mydicar         medicine at the University of California,
outpatient procedure that is performed             had a 50% reduction in their risk of these        San Diego, presented the results. “I am
in the cath lab. Celladon says the therapy         events compared with patients who                 very encouraged by these results and
acts in synergy with current heart                 received a placebo.                               optimistic that larger studies will confirm
failure treatments, including drugs and                The mean duration of hospitalisation          these data. Confirmation of these findings
biventricular pacing devices.                      in the Mydicar group during the six-              in larger trials would provide us with a
    Data from the CUPID trial were                 month period was 0.2 days per patient,            much-needed new approach for treating
presented at the annual meeting of the             substantially shorter than the 2.1 days per       patients with advanced heart failure,”
Heart Failure Association of the European          patient seen in the placebo group.                said Dr Greenberg.




Photocure’s acne therapy fails
R
         esults of a phase II study released       1.5 hours. The cream induces an increase          treatment site with a plastic film after
         today show that Photocure’s Visonac       in photoactive molecules called porphyrins        application of the cream, to enhance skin
         acne therapy has failed to outper-        in affected cells; the porphyrins are then        absorption.
form placebo.                                      activated by light, leading to selective tissue
    Furthermore, results with the therapy          destruction.                                      Still hope?
were not as good as those from a                       However, the latest results call Visonac’s    There is a glimmer of hope for Visonac – in
previous phase II trial, which used a more         efficacy into question. The primary               the latest study, there were “promising”
complicated treatment protocol. The latest         endpoints of the 107-patient study were           results in patients who had previously failed
study was carried out because the US FDA           reduction in lesion count and treatment           to respond to oral antibiotics, compared
requested more data on paediatric patients,        success six weeks after the last treatment.       with treatment-naïve patients. “For these
and included patients aged under 15.               The Visonac group showed a 39.8%                  patients…there is a clear need for a new
    The Norwegian company had hoped                reduction in inflammatory lesions and             treatment such as Visonac,” Photocure said.
that the product would be approved in              a 36.3% reduction in non-inflammatory                 “While we are disappointed that the
the US and Europe in 2012, but is now              lesions, which was not significantly better       results recorded in previous studies were
“considering the options for further               than with placebo. Patients in the trial were     not confirmed in the [latest] phase II study,
development of Visonac”. It plans to release       treated four times at two-week intervals.         we remain confident in the future potential
more details in the third quarter.                     A previous phase II study reported a          of Visonac,” said the firm’s president and
    Visonac comprises a photosensitising           57% and 47% reduction in inflammatory             CEO, Kjetil Hestdal.
cream containing methyl aminolevulinate,           and non-inflammatory lesions, respectively,           The firm also has the “resources and
which is applied to the patient’s acne, and        which was significantly better than with          commitment” to continue the Visonac
a full face lamp that is used to illuminate        placebo. This trial had included the              programme, its CFO, Christian Fekete,
the skin after an incubation time of around        additional step of occlusion, covering the        told Clinica.

www.clinica.co.uk                                                                                                      © Informa UK Ltd 2010   17
ScIENcE & tEcHNoloGy                                                                                                     Clinica // June 2010



Abbott’s                                      Philips launches first
bioresorbable DES
“extraordinary”                               mobile 3T MRI in Europe
                                              P
The dissolving drug-eluting stent under               hilips has launched the first mobile 3       This is because the Achieva 3.0T TX
development by Abbott could become “the               Tesla MRI system in Europe.              can transmit multiple radiofrequency
new standard of care for treating coronary                The firm’s Achieva 3.0T TX was       signals, as opposed to conventional 3T
artery disease”, according to a leading       showcased at the UK Radiology Congress           MRI devices that only use a single source.
cardiologist.                                 (UKRC), held this month in Birmingham.           “In other devices, the magnetic field
    Dr Patrick Serruys, professor of          The first unit has been sold to UK medical       that generates the images is delivered
interventional cardiology at Erasmus          charity Cobalt, which provides diagnostic        through one body coil. What we’re doing is
University Hospital in Rotterdam, the         services to the National Health Service,         dividing that body coil into two, delivering
Netherlands, presented data from the          including cancer screening.                      the energy through two amplifiers,” a
ABSORB trial, for which he is principal          As the Achieva 3.0T TX system is              spokesperson told Clinica.
investigator, at the annual EuroPCR           mobile, it can be taken to different                 “It’s like an extra lightbulb – if you use a
meeting, held in Paris, France, last month.   hospitals, giving them access to a 3T            single lightbulb to illuminate an object, you
    These data showed that Abbott’s device,   system without them having to buy and            will get shading on the far side of the object.
known as the bioresorbable vascular           install it themselves. Currently, most           If you have two lightbulbs opposite each
scaffold (BVS), was associated with a 4.4%    hospitals’ MRI systems operate at 1.5T, but      other, you don’t get any shading at all.”
rate of adverse cardiac events.               the 3T strength increases resolution and
    The BVS also demonstrated an average      improves image quality.                          40% faster
in-stent late loss – the amount by which                                                       The technology also allows the system
the vessel has re-narrowed in the six                                                          to scan up to 40% faster than other 3T
months since implantation – of 0.19mm.        The system employs                               machines, Philips claims. “Traditional 3T
“These extraordinary findings signal that     technology to reduce                             systems have a higher field strength, so you
Abbott’s disappearing scaffold may become                                                      need more energy to create the images, and
the new standard of care for treating         artefacts, which have                            therefore you hit the safety limits much
coronary artery disease”, said Dr Serruys.                                                     more quickly. This means that you have
    The BVS is composed of polylactic         limited the uptake of 3T MRI                     to slow the scan down to stop yourself
acid, and elutes everolimus, the same drug                                                     from going above these,” the spokesperson
                                                  A static version of the system is already
released by Abbott’s cobalt-chromium                                                           explained. These safety limits are calculated
                                              available – Philips launched it at the 2008
Xience V stent. It is not yet approved for                                                     using a model, which is the same for all
                                              RSNA conference (www.clinica.co.uk, 16
sale anywhere in the world.                                                                    patients, regardless of their size. “We have
                                              December 2008). But there have been
                                                                                               to take the worst-case scenario in order to
                                              challenges with creating a mobile version
                                                                                               manage safety limits properly.
 Other science & technology                   for the European market, the company
                                                                                                   “But with MultiTransmit, we can map
                                              explained: “3T systems have historically
 news on www.clinica.co.uk                    only been available in static sites because of   out the energy needed on a patient-by-
                                              the weight of the magnet and the shielding       patient basis, and can see where the energy
  - Trial data confirm that women             associated with it. But we have been             is distributed. Where there are inequalities,
    benefit more from CRT-Ds                  able to make the magnet so light that, in        we can adjust the transmission to even
    than men                                  combination with lighter shielding, it’s now     these out. We know how much energy we’re
                                              feasible to put this system into a European      using for each patient, so don’t need to be
  - Study: Iridex’s “tissue-sparing”                                                           so conservative and can scan faster. This is
                                              trailer, which wasn’t possible previously.”
    laser as good as standard of                                                               especially relevant in whole body imaging
                                              Mobile 3T systems are already available in
    care for diabetic eye disease                                                              where a large area is being scanned – it’s
                                              the US, where bigger trailers are available to
                                              accommodate heavier magnets.                     not so important with small extremities.”
  - Vital’s cellular liver therapy
                                                  The device is also the first mobile 3T           Philips believes that the advantages
    enters clinical trial
                                              MRI system in the world to employ the            3T technology offers over 1.5T devices are
  - More testicular cancer risk               firm’s MultiTransmit technology. This can        such that 3T will become the dominant
    genes raise possibility                   reduce the artefacts that are associated         modality: “Around 10-15 years ago we
    of screening                              with 3T, particularly in certain applications    moved from 0.5T to 1.5T systems. Now we
                                              such as full-body imaging. These artefacts       are seeing a move towards 3T, and this is
  - Biosensors launches BioMatrix             can lead to non-uniform images, and this         happening much more quickly than we
    Flex stent; trial data positive           has limited the uptake of 3T MRI so far.         thought it would. I think in a couple of
                                                  Philips believes that its technology gets    years’ time, 3T will be the gold-standard
  - Could trial data mean 2010                around these problems: “MultiTransmit will       MRI application. This mobile system is
    launch for Signature’s                    address these issues, and the device will be     an opportunity for people to have a taster
    colorectal cancer tests?                  able to do any imaging application, just like    of 3T before they make a commitment to
                                              the mobile 1.5T systems.”                        buying a device themselves.”

 18    © Informa UK Ltd 2010                                                                                                   www.clinica.co.uk
Clinica // June 2010                                                                                                      ScIENcE & tEcHNoloGy




New autism gene discovery could allow
risk testing in five years
A                                                   Early treatment best
         genetic test to identify children                                                            by whatever means, then they should be
         at high risk of developing autism          Early identification of at-risk children          assessed by a professional. We know that
         spectrum disorders may be available        could allow earlier intervention, which           early intervention typically means better
in just five years’ time, after researchers         leads to better clinical outcomes. Current        prognosis.”
identified dozens of new genes linked to the        treatments include applied behavioural
condition.                                          analysis, which teaches children with             New drug targets
    The findings came from the second phase                                                           The discovery could also aid the
                                                    autism spectrum disorders how to interact
of the Autism Genome Project, funded by                                                               development of new drugs, Dr Shih said:
                                                    in social situations, by “breaking down the
scientific advocacy group Autism Speaks.                                                              “We might be able to address the deficits by
    “The research is very exciting,” Andy Shih,     components into more digestible parts”,
                                                                                                      developing medications that target some of
vice-president of scientific affairs for Autism     Dr Shih explained.
                                                                                                      the pathways we have identified.”
Speaks, told Clinica. “We’re piecing this               However, he stressed that the
                                                                                                          The genes’ different functions might
puzzle together, bit by bit. But I don’t think it   information should not be used to develop
                                                                                                      represent different pathways to the disease,
would be too optimistic to say there might          prenatal screening which, in combination
                                                                                                      or different forms of the disorder, Dr Shih
be something available within five years.”          with selective abortion, could reduce
                                                                                                      believes. “The reason that’s important is
    The researchers analysed the genomes            the prevalence of autism spectrum
                                                                                                      because we know that individuals with
of 996 people with autism spectrum                  disorders. “That would be akin to aborting        autism are all very different in their clinical
disorders and 1,287 matched controls. They          a child with genetic risk factors for high        presentation and deficits,” he said. “We’re
found that people with the disorders were           cholesterol or blood pressure, just because       moving towards more of a personalised
more likely to carry more copy number               we’re worried about them developing               medicine approach to treating autism.”
variations in their genes – submicroscopic          cardiovascular disease in later life. It would
insertions and deletions. Some of these are                                                           New drugs targeting specific genetic
                                                    be equally wrong,” he said.                       variants could also be available in five
thought to be inherited, while others arise             “We’re hoping to use the technology
spontaneously.                                                                                        years, he believes.
                                                    to identify children at risk of developing            The study also supports a hypothesis
    The group also identified many new
                                                    autism – it doesn’t mean that they                which is becoming more popular – that
autism susceptibility genes, including:
                                                    definitely will. It’s similar to how you          autism is caused in part by many rare
SHANK2, SYNGAP1, DLGAP2 and the
X-linked DDX53-PTCHD1 locus. Some of                get your blood pressure and cholesterol           genetic variants, with each risk factor
these genes are involved in synapse-related         checked to estimate your risk of developing       affecting 1% or less of the total population.
pathways, while others are important in             cardiovascular disorders. Then by                     “The long-term goal is to understand
cellular proliferation and motility, and            modifying your behaviour, you might be            the genetic architecture of autism,” Dr Shih
intracellular signalling.                           able to manage your risk effectively.             said. “So far we feel like we’ve scratched
    The findings were published online                  “The main lesson is that if a child is        the surface. But the research is also very
in Nature on 9 June.                                identified as being at high risk for autism,      encouraging.”



STARFlex trial fails; NMT Medical’s shares drop

T
        he STARFlex heart implant devel-            as safe as drug therapy, with a low rate          discussed at the American Heart Association
        oped by NMT Medical has failed in a         of complications and a very low rate of           meeting in November 2010,” he said.
        clinical trial, causing the company’s       thrombus formation. Closure rates in the              NMT is seeking FDA and CE mark
share price to plummet to an all time low.          trial were 86.5%, which is consistent with        approvals for the STARFlex device to treat
   STARFlex is designed to close a hole in          NMT’s previously reported results for the         two congenital heart disorders: ventricular
the septum of the heart. The hole, called           STARFlex implant, and in line with other          septal defect and atrial level shunt. The
a patent foramen ovale (PFO), may be a              transcatheter closure devices.                    results of CLOSURE I are not expected to
causative factor in conditions including                NMT’s share price plunged 80% to close        affect these processes.
embolism, migraine, stroke and transient            at $0.56 on the Nasdaq yesterday. President           PFOs can allow venous blood, unfiltered
ischaemic attack (TIA).                             and CEO Frank Martin said the firm was            and unmanaged by the lungs, to enter the
   The CLOSURE I trial was assessing the            “disappointed” with the trial’s failure, but      arterial circulation and reach the brain,
device in the prevention of recurrent strokes       was “in discussions with the US FDA to            possibly triggering a cerebral event or brain
and TIAs. Preliminary results showed that           evaluate our possible next steps relating         attack.
STARFlex was marginally better than drug            to the stroke/TIA indication”. He said that           In January 2008, the company’s share
therapy, but the benefit was so small that it       further data analysis was ongoing to guide        price tanked when it closed another trial
could have been due to chance.                      the firm’s clinical and regulatory options. “It   of STARFlex, this time in migraine patients
   Trial data indicated that STARFlex was           is anticipated that full data results will be     (www.clinica.co.uk, 1 February 2008).

www.clinica.co.uk                                                                                                        © Informa UK Ltd 2010   19
coVEr FEAtUrE                                                                Clinica // June 2010




Gene genie: the role of devices in gene
therapy delivery
Gene therapy has been hailed as the future of medicine, but has yet to fulfil its promise.
Despite increased understanding of the genetics of various diseases, the problem of
how to deliver therapeutic genes to their target tissues remains. Peter Charlish looks
at some of the most intriguing gene therapy delivery techniques




20    © Informa UK Ltd 2010                                                       www.clinica.co.uk
Clinica // June 2010                                                                                                               coVEr FEAtUrE




I
     t is now over 20 years since the first         regulatory clampdown. However, optimism          down a negative opinion on Cerepro that
     patient was enrolled into an officially        was restored the following year by the           Ark initially appealed, but, following a
     sanctioned gene therapy study, and in          results of a study carried out at the Hôpital    determination by the EMA’s Scientific
that time the field has been through a series       Necker in Paris. In that study, CD34+            Advisory Group on Oncology that the
of triumphs and setbacks. Only two gene             cells harvested from the bone marrow of          pivotal trial supporting the approval
therapy products have so far been approved          infants with X-linked SCID were infected         application was subject to bias, and that an
for clinical use, but interest in gene therapy      with a viral vector carrying the γc cytokine     additional trial would therefore be needed,
remains keen.                                       receptor gene, which is non-functional in        the company pulled back and instituted a
    The first patient to take part in a             this variant of the disease. The cells were      review of its business.
formal gene therapy study, in 1989, was a           then reinfused into the patients. The results
four-year-old girl with severe combined             were described at the time as “spectacular”:     Non-viral delivery
immunodeficiency disorder (SCID) caused             not only was the gene expressed in the           A long-term aim is to develop gene therapy-
by an inherited adenosine deaminase                 infants, but they were apparently cured of       based treatments that can be administered
deficiency. Her treatment involved                  the disease.                                     directly to the patient. One of the biggest
separating T-lymphocytes from her blood,                The euphoria in this case did not last       challenges is how to deliver the genetic
genetically modifying them to produce               long. By 2003, a number of children taking       material to the target tissues. Viral vectors
adenosine deaminase, and reinfusing them.           part in the French trials had developed a        are extremely useful, but they are not
The aim was to replace the faulty gene and          leukaemia-like illness, and at least one died.   suitable for all situations. Non-viral delivery
restore production of the enzyme.                   The trial was suspended in 2002 (and all gene    methods, though, are still a relatively
    SCID is an ideal target for gene therapy,       therapy trials in the US were suspended not      inefficient way of delivering genetic material.
as it is the result of a defect in a single gene.   long afterwards), although it recommenced            Since the object of gene therapy is to
The adenosine deaminase gene is regulated           in 2004 with a number of modifications to        deliver genetic material to individual cells,
in a straightforward ‘always on’ fashion,           the protocol. Another case of leukaemia-         the simplest approach is to use naked
unlike many other genes, and the ‘dose’ of          like disease led to the French trial being       DNA itself. However, DNA molecules are
adenosine deaminase is not critical – even          suspended for a second time in 2005.             fragile, and may be damaged during cell
small amounts are beneficial, while large               Despite these setbacks, research into        penetration. Because simple injection
amounts are well tolerated.                         gene therapy has continued. Among the            of DNA into a tissue has proved to
    The success of this first gene therapy          most important developments during the           be of limited usefulness, other ways
experiment (it can hardly be described as a         past five years or so was the treatment of       of administering naked DNA have
‘trial’) led to a large number of gene therapy      two patients with metastatic melanoma            been explored, including jet injection,
studies being initiated in the early 1990s.         using killer T cells genetically modified to     electroporation and sonoporation, among
The target of many of these studies was             attack the cancer cells. This study, carried     others.
either cystic fibrosis or haemophilia, which,       out in the US in 2006, was the first to
like SCID, are monogenetic diseases. At the         provide evidence that gene therapy may be        Jet injection
same time, researchers were beginning to            useful in the treatment of cancer.               Jet injection has gained an increasing
study the role of gene therapy in treating              Later the same year, research into           acceptance as a delivery method for naked
other disorders, such as certain cancers.           the first use of a lentiviral vector in gene     DNA because it allows gene transfer into
    The first major setback for gene                therapy was published. Researchers at            a variety of tissues with relatively deep
therapy came in September 1999 with the             the University of Pennsylvania described         penetration – up to 10 mm – and causes
death of 18-year-old Jesse Gelsinger, who           the use of lexgenleucel-T (VRX496), a fully      minimal tissue damage. Furthermore,
suffered from a deficiency of ornithine             gutted HIV-based vector that delivers an         it is unaffected by the length of the
transcarbamylase. This enzyme is involved           anti-HIV antisense sequence targeted to          DNA molecule being administered, and
in the breakdown of ammonia produced                the HIV env coding sequence. Of the five         transfection is as efficient as with other
by protein catabolism, and its deficiency           HIV patients who had failed two or more          techniques. Perhaps most importantly,
renders the patient intolerant of protein.          HAART regimens, three showed significant         DNA delivered in this way remains intact
It was hoped that replacing the ornithine           decreases in viral load one year after           throughout the delivery process, despite its
transcarbamylase gene would effect a cure.          dosing, while the other two had stable viral     physical fragility.
    The question here was how to deliver            loads at three and six months.                        One company that has used jet injection
the gene to the patient’s liver, the principal          Another success was the treatment in         as a delivery method is Japanese gene
site of ammonia metabolism. The                     the UK of a patient with Leber’s congenital      firm AnGes MG. In 2004 it entered into a
technique employed in this case has since           amaurosis, an inherited form of blindness        research partnership with Shimadzu to
been widely used in gene therapy studies:           caused by mutations in the RPE65 gene.           explore the use of the latter’s Shima Jet
the ornithine transcarbamylase gene was             Subretinal delivery of a recombinant adeno-      needleless hypodermic pressure injector
incorporated into an adenovirus vector,             associated virus carrying the gene caused a      for the delivery AnGes’s NF-κB decoy
which was then delivered to the liver.              modest increase in vision with no apparent       oligonucleotides, which are designed
Unfortunately, the six trillion adenovirus          side-effects.                                    to treat dermatological disorders such
particles administered during the trial                 But there have also been                     as psoriasis. The Shima Jet injector was
provoked a massive immune response that             disappointments, the most recent of which        originally introduced in 2001 for the
proved fatal.                                       was the withdrawal of Ark Therapeutics’          delivery of insulin to diabetic patients.
    The Gelsinger incident led to a great           EU filing for its brain cancer gene                   The Shima Jet was the subject of another
deal of introspection by scientists involved        therapy product Cerepro (sitimagene              Japanese study, this time into the use of
in gene therapy research, as well as a              ceradenovec). Last year the CHMP handed          gene therapy in wound healing. This study

www.clinica.co.uk                                                                                                       © Informa UK Ltd 2010   21
coVEr FEAtUrE                                                                                                             Clinica // June 2010


found that gene expression increased            gene therapy in the treatment of atopic           be achieved by adjusting the pulsing
about a hundredfold when jet injection          dermatitis. Interleukin-10 is overexpressed       conditions such as the number, voltage and
was compared with normal hypodermic             in this condition, so Japanese researchers        duration of pulses.
injection. Using the Shimadzu device to         have investigated the effects of                      A company that makes electroporation
deliver the hepatocyte growth factor (HGF)      iontophoretic delivery of an antisense            instruments specifically for use in
gene, the researchers reported an increase      oligonucleotide to inhibit IL-10 production.      transferring genetic material is China’s
in cellular proliferation of the epidermis      In a mouse model of atopic dermatitis, the        Ningbo Scientz Bio-tech Co Ltd, which is
and the number of microvessels in the           treatment was effective in causing skin           based in Zheijang, with branches in the
granulation tissue around a healing wound.      lesions to disappear while decreasing the         US. The company manufactures a range
Transfer of the prostacyclin synthase (PGIS)    concentration of IL-10 and its mRNA in            of laboratory and medical equipment
gene also resulted in increased blood flow      the lesions.                                      including a number of dedicated gene
around the wound. Furthermore, transfer                                                           electroporators.
of the HGF gene promoted actual healing,                                                              Another specialist in this area is Inovio
especially when it was combined with the                                                          Pharmaceuticals, whose MedPulser
PGIS gene.                                                                                        DNA delivery system consists of a pulse
    Another device that has been used for                                                         generator and needle electrode applicator,
the enhanced delivery of gene therapy is                                                          designed to deliver DNA vaccines into
the Swiss injector, which was manufactured                                                        muscle cells for immunisation. The vaccine
by EMS Medical Systems. This hand-held                                                            is first injected via the needle assembly
device employs pressurised air to force                                                           into the selected muscle tissue, and the
small volumes of naked DNA solution into                                                          pulse generator switched on. Low-voltage
the target tissues. German researchers                                                            electrical pulses are delivered into the
have used it to insert the β-galactosidase                                                        injected tissue through an electrode-needle
(LacZ) reporter gene construct and tumour                                                         array on the applicator. The company’s
necrosis factor alpha-expressing vectors                                                          Elgen DNA delivery system is a newer
into xenotransplanted human tumours.                                                              generation of electroporation system,
Both genes were efficiently expressed in the                                                      consisting of a pulse generator and needle-
tumour tissue.                                  Only two gene therapy                             electrode applicator that incorporates two

Iontophoresis
                                                products have so far been                         syringes/needles. The needles are inserted
                                                                                                  into selected muscle or skin, the DNA is
If the disease being treated by gene therapy    approved for clinical use,                        injected, and electrical pulses are delivered
affects the skin, topical delivery of the                                                         into the same selected tissue through the
genetic material may be preferable. The         but interest in gene therapy                      electrode-needle pair on the applicator,
ability of oligonucleotides to penetrate
the skin has been investigated, but even        remains keen                                      effectively co-localising the DNA and the
                                                                                                  porating electric field.
with the use of chemical enhancers, this                                                              Inovio’s CELLECTRA electroporation
approach has not been very successful.             Iontophoresis is also being developed as       device can deliver DNA intramuscularly
    This has led some researchers to            a gene delivery system for the treatment of       and intradermally. The device measures
investigate non-chemical ways of enhancing      eye diseases.                                     tissue resistance and adapts electrical
skin penetration. Iontophoresis is an              While a number of companies, including         output to the individual conditions, such
attractive technique in this context as it is   Alza, Dynatronics, Iomed and Vyteris              as fat content in the muscle, skin thickness,
ideally suited to a highly charged molecule     manufacture iontophoresis systems for             or changing tissue resistance during the
such as DNA and avoids the risks and            drug delivery, iontophoretic gene therapy         electroporation process. This is claimed to
discomfort associated with injections.          has not yet reached the stage where               optimise DNA uptake and result in uniform
The technique is characterised by the           there is a significant number of dedicated        expression of the target protein with
application of small, low voltage, continuous   equipment manufacturers.                          minimal tissue damage.
currents to propel oligonucleotides through                                                           Another manufacturer is Bio-Rad
a biological membrane.                          Electroporation                                   Laboratories, whose range includes the Gene
    Studies in animals have shown               Electroporation differs from iontophoresis        Pulser Xcell and MXcell electroporation
that iontophoresis can enhance local            in that it depends on the use of high voltage     systems. Others include Cyto Pulse Sciences
concentrations of oligonucleotides              electrical currents of very short duration        (Columbia, Maryland), Protech International
when applied to the skin. In fact, the          (microseconds to milliseconds) to achieve         (San Antonio, Texas) and Tritech Research
charged nature of DNA molecules means           the same aim. In fact, it has been proposed       (Los Angeles, California).
that their delivery can be fine-tuned           that electroporation is better suited for gene
by careful control of the iontophoretic         delivery since it enhances the permeability       Sonoporation
parameters. The amount of oligonucleotide       of the stratum corneum, the main barrier to       Electricity is not the only physical modality
transported is dependent on the length and      topical gene delivery. It may also increase the   that has been used to deliver gene
conformation of the oligonucleotide, the        permeability of underlying tissues.               therapy: sound waves, or more specifically
concentration in which it is administered           In one study, electroporation increased       ultrasound waves, have also been used
and the duration of the iontophoresis.          the amount of oligonucleotide penetrating         for this purpose, mainly in isolated cells
    Other studies have looked at the            viable skin a hundredfold. Furthermore,           but increasingly in the whole body. The
potential of ionotophoretically applied         control of oligonucleotide delivery could         process of using ultrasound to facilitate the

 22    © Informa UK Ltd 2010                                                                                                    www.clinica.co.uk
Clinica // June 2010                                                                                                                coVEr FEAtUrE



                                         Figure 1. Selected gene therapy patents (2009-2010)

 Number                  Title                                                               Applicant                        Publication date
 US20100120155A1         Construction of fully-deleted adenovirus-based gene delivery        Isogenis Inc                      2010-05-13
                         vectors and uses thereof
 US20100055080A1         Bioadhesive directed somatic cell therapy                           S U Song, Y Yi                    2010-03-04


 US7655468               Stable lipid-comprising drug delivery complexes and methods for University of Pittsburgh              2010-02-02
                         their production
 US7648495               Apparatus for the delivery of drugs or gene therapy into a          Global Gene Therapies Inc         2010-01-19
                         patient’s vasculature and methods of use
 EP2130912A1             Pestivirus replicons providing an RNA-based viral vector system     Institut für Viruskrankheiten     2009-12-09
                                                                                             und Immunprophylaxe
 US20090298917A1         Non-viral vector system for the delivery of nucleic acid into the   T Kissel, E Kleemann et al        2009-12-03
                         lung
 US7592320               Cancer gene therapy based on translational control of a suicide     A Debenedetti, R J Defatta        2009-09-22
                         gene
 US20090221684A1         Molecules for gene delivery and gene therapy, and methods of        Trustees of Boston                2009-09-03
                         use thereof                                                         University
 US20090214637A1         Novel gene therapy approach for treating the metabolic disorder     Neurologix Inc                    2009-08-27
                         obesity
 US7576058               Method for importing biologically active molecules into cells       Vanderbilt University             2009-08-18


 US20090203768A1         Nucleic acid-containing complex                                     H Mori, Y Tabata et al            2009-08-13


 US20090169485A1         Gene therapy and pharmaceutical composition for prevention          Seoul National University         2009-07-02
                         and treatment of lung cancer                                        Industry Foundation
 Source: Delphion



delivery of DNA molecules is referred to as       liver cells in vitro. If these studies are        which offers the SP100 sonoporator as
sonoporation.                                     successful, the technique will be tested in       well as a polymer-stabilised, lipid-based
    The technique of sonoporation grew out        animals before clinical evaluation, although      microbubble product. The SP100 uses
of the use of ultrasound contrast agents          that is probably some years away. In some         continuous and pulsed ultrasound to
in diagnostic imaging. These agents are           ways, this is an idea system in which to          achieve transient membrane permeability
gas-filled microbubbles that are usually          evaluate the efficacy of sonoporation:            for applications including delivery of
administered intravenously. When                  the ultrasound contrast agent will be             plasmids to cells and tissues for gene
exposed to ultrasound of the appropriate          administered concurrently with the G6PC3          therapy-based applications and studies and
frequency the microbubbles oscillate and          gene, which means that its progress               delivery of nucleic acids to cells and tissues
the energy released during this process           towards the liver can be observed directly        for studies on control of gene expression
can temporarily increase the permeability         using the same ultrasound scanner that is         and gene therapy. Sondel also supplies
of cell membranes. This phenomenon                used to energise the microbubbles; also, the      electroporation equipment.
can be used to increase the delivery of           effectiveness of the technique will be easy           Other devices available include the
                                                                                                    SoniTron 2000 from the German company
molecules, such as drugs, DNA or other            to follow by measuring systemic glucose
                                                                                                    Heinemann and the SonoPore KTAC-4000
large molecules, into cells.                      concentrations.
                                                                                                    from Japanese manufacturer NepaGene.
    This technique is being developed by              Other groups are planning to take this
companies like Philips and biotech concern        technique a stage further. The ultrasound         Intravascular delivery
GlyGenix for clinical use. Last year, the         contrast agent could be targeted, by              An attractive route for the delivery of gene
two firms entered a research collaboration        conjugating a peptide such as a monoclonal        therapy is via intravascular administration.
to assess the role of sonoporation in the         antibody to the shell of the microbubbles.        It is attractive because the gene can
treatment of glycogen storage disease             Another possibility is to attach the genetic      be disseminated locally in the target
type 1a (GSD-1a), which is caused by a            material to the microbubbles directly, to         tissue or systemically throughout the
defect in the gene G6PC3, which encodes           give precisely controlled local delivery.         body, depending on the precise route of
the enzyme glucose-6-phosphatase. The                 A number of companies offer dedicated         administration. In the case of gene delivery
gene is primarily expressed in the liver.         sonoporation devices mainly for use in in         to a particular organ, local intravascular
    Initially, Philips and GlyGenix are           vitro studies. One of the leading companies       delivery could avoid the necessity for
studying the effects of sonoporation on           in this area is the Irish firm Sonidel,           multiple injections to the target tissue.

www.clinica.co.uk                                                                                                        © Informa UK Ltd 2010   23
coVEr FEAtUrE                                                                                                             Clinica // June 2010


    Studies in animals have shown that           cystic fibrosis, which has also reached          for example, during one of the delivery
intravascular delivery of DNA, either            phase III.                                       processes already described.
complexed with lipid or incorporated into           A similar fate has greeted an aerosolised         One of the most popular approaches
an appropriate viral vector, results in gene     gene therapy treatment for cystic fibrosis       involves the use of liposomes. Liposomes
expression in many cells accessible from         under development by GenVec and                  are relatively straightforward to produce,
the vasculature, especially endothelial cells.   Genentech and an inhaled adenovirus-             easy to handle, and have low immunogenic
The transfection rate can be improved            associated therapy being developed by            potential. Nevertheless, there are a
by injecting the genetic material in             Targeted Genetics.                               number of issues associated with their
hyperosmotic solution or by restricting                                                           use, including compartmentalisation in
blood flow from the target organ.                                                                 the blood, binding to plasma proteins or
Rapid administration of a large bolus                                                             cellular blood components, the risk of
overloads the capacity of the heart to                                                            enzymatic degradation en route to the
handle the fluid, which therefore backs                                                           target (admittedly less with liposomal DNA
up into the liver. This technique has been                                                        than naked DNA), the uptake of liposomes
found to enhance the efficiency of gene                                                           by the reticuloendothelial system, the
transfer into hepatic tissue – transfection                                                       necessity of transversing the target cell
rates of up to 40% of the total number of                                                         membrane, and the various intracellular
hepatocytes have been reported.                                                                   processes that may affect the fate of the
    Although this technique, which is also                                                        liposomes.
known as hydrodynamic gene therapy,                                                                   One example of this approach to
has not yet been applied to the clinical                                                          gene delivery is Protiva Biotherapeutics’
situation, it is possible that it could be                                                        SNALPs (stable nucleic acid-lipid particles):
                                                                                                  specialised lipid nanoparticles that fully
replicated in humans by delivery directly
                                                                                                  encapsulate and systemically deliver a
into one of the vessels supplying the liver,
via an indwelling catheter, for example.         Simple injection of DNA                          variety of nucleic acid molecules such as
                                                                                                  siRNA, aptamers and plasmid DNA. The
    Direct intravascular delivery of gene
therapy may also be suitable for the
                                                 into a tissue has proved to                      technology utilises a mechanism referred to
                                                                                                  as the enhanced permeability and retention
treatment of genetic disorders that affect       be of limited usefulness,                        effect, which occurs because these nucleic
striated muscle. Muscle has a high density
of capillaries which can potentially bring       so other ways of                                 acid-containing particles have a long
                                                                                                  circulation time in the blood, resulting
the genetic material into contact with
a large proportion of muscle cells. One
                                                 administering naked DNA                          in accumulation at sites of vascular leak
                                                                                                  such as those found at sites of tumour cell
company exploring this route is the French       have been explored                               growth, infection, inflammation and in the
firm Transgene, which is developing                                                               normal, healthy, liver. Once at the target
MyoDys, a muscular dystrophy gene                    Another company, UK-based Electrosols,       site, cells take up the SNALP and the lipids
therapy that uses the Pathway intravenous        took a different approach, but this too seems    of its bilayer interact with the endosomal
delivery system developed by Mirus, a            to have come to nothing. The company was         membrane to release the nucleic acid inside
nucleic acid company that was acquired by        developing a gene therapy for cystic fibrosis    the cell’s cytoplasm. The released DNA
Roche in 2008. Meanwhile AVI BioPharma           delivered by pulmonary inhalation based          enters the nucleus, where it is expressed.
is carrying out phase II clinical trials with    on the company’s proprietary electric field          A number of other companies and
an intravenously administered antisense          technology. The technology used electric         research groups are investigating the use
gene therapy for Duchenne muscular               fields to create charged or uncharged particle   of liposomes for gene therapy. One of
dystrophy.                                       mists of uniform and controllable size from      the most successful has been Regulon,
                                                 liquids or powders.                              whose LipoVIL12 is an interleukin-12
Inhalation                                           Although most companies carrying             gene immunotherapy product under
In cases where the genetic disorder being        out trials of inhaled gene therapy               development for the treatment of cancer.
treated affects the lungs, such as cystic        targeted cystic fibrosis, one company,           The interleukin-12 gene is expressed
fibrosis or certain types of cancer, direct      Houston, Texas-based CytoGenix has               from an encapsulated non-pathogenic
delivery of genetic material via aerosol         used its proprietary single-stranded DNA         Semliki Forest virus vector. LipoVIL12 has
inhalation may be appropriate.                   expression system to develop an aerosol          completed a Phase I study and is moving
    A number of companies have explored          therapy against a cancer gene common to          into phase II studies in a variety of cancers.
this option, but progress to date has been       metastatic tumours, for the treatment of             Also in clinical trials is Synergene
limited. For example, in collaboration           lung metastases. However, the status of this     Therapeutics’ SGT-53, a gene therapy
with the University of Alabama in the US,        research is not clear.                           complex composed of wild-type p53 gene
and the Royal Brompton Hospital in the                                                            plasmid DNA encapsulated in a liposome,
UK, Genzyme was developing a cationic            Liposomes                                        for the treatment of cancer. In addition,
lipid-mediated gene therapy for cystic           There are various methods of delivering          the US company Gradalis is developing a
fibrosis using one of its proprietary cationic   naked DNA. There is also a lot of interest       bifunctional short hairpin RNA construct
lipids. The project had reached Phase III        in the use of ‘protected’ DNA, that is, DNA      directed at the gene for stathmin 1, a
before being discontinued. There is also         that has been treated in some way to             microtubule-destabilising protein with
some doubt over the future of an inhaled         enhance its diffusion into cells or to protect   a critical role in mitosis regulation, for
adenoviral-mediated gene therapy for             its structure, from degradation by nucleases     patient-specific treatment of cancer. It is

 24    © Informa UK Ltd 2010                                                                                                    www.clinica.co.uk
Clinica // June 2010                                                                                                             coVEr FEAtUrE


still undergoing animal toxicology studies      of Buffalo in the US used nanoparticles           target tissue. A number of methods have
using a clinical-grade plasmid vector           fashioned out of Ormosil, a type of               been used to accelerate the metal particles,
delivered via targeted liposome-based           organically modified silica, to deliver genes     including compressed gas, magnetic and
nanoparticles.                                  to the brains of living mice. Ormosils            electrostatic systems.
    Meanwhile, CytRx is developing              permit the creation of a wide variety of              One of the best-known examples of
TranzFect, a synthetic polymer-based            tailored nanoparticles whose surface              a gene gun is Bio-Rad’s Helios system, a
(poloxamer) system for the intracellular        functionality can be carefully controlled so      hand-held device that uses an adjustable
delivery of genes. Other companies              that they target specific cells.                  low-pressure helium pulse to sweep DNA-
reportedly involved in this area include            Copernicus Therapeutics, of Cleveland,        or RNA-coated gold microcarriers from
Fujimoto, Genzyme, Mitsubishi Tanabe            Ohio, has discovered a technique to               a small plastic cartridge directly into the
and SkyePharma.                                 compact DNA into complexes containing             target. The microcarriers accelerate as they
                                                only a single molecule of DNA, resulting in       move through the barrel of the device, while
Virosomes and other complexes                   a volume 30-1,000 times smaller than other        the helium pulse diffuses outward. A spacer
A variation on the liposome theme is            complexes. The company has established            maintains the optimal target distance for
virosomes, phospholipid bilayer vesicles        proprietary processes to produce DNA              in vivo applications (the system can also
based on reconstituted empty influenza          nanoparticles using raw materials readily         be used in vitro) and vents the helium
virus envelopes. In contrast to liposomes,      amenable to pharmaceutical quality control        gas away from the target to minimise cell
virosomes contain functional viral              measures: such compacted particles can            surface impact. Bio-Rad sells the Helios
envelope glycoproteins such as influenza        be stably stored at 4°C for a number of           gene gun as a system that includes the
virus haemagglutinin and neuraminidase          years. By adding targeting ligands to DNA         gene gun, a tubing prep station and tubing
intercalated in the phospholipid bilayer        nanoparticles, Copernicus believes the            cutter, in addition to a special helium
membrane. This confers structural stability     complexes can be directed to specific             regulator and hose assembly. A number of
and homogeneity to virosome-based               tissues, including the liver, epithelial cells,   other manufacturers also supply gene guns,
formulations.                                   endothelial cells and tumours.                    including China’s Ningbo Scientz Bio-tech.
    One of the leading companies working            Another variation is the use of magnetic          Impalefection is another technique
with virosomes is Crucell. Its patented         nanoparticles to deliver gene therapy.            used for in vitro gene transfer. In this
virosome technology is a broadly                Researchers at the Children’s Hospital of         approach, needle-like nanostructures
applicable delivery system with prospective     Philadelphia, for instance, have used iron-       such as carbon nanofibres, nanotubes or
applications in antigen-based vaccines          containing nanoparticles and a magnetic           nanowires are attached to a substrate,
as well as for the delivery of DNA or RNA.      field to deliver DNA to muscle cells. The         and DNA is attached to the surface of the
The company’s virosome technology has           technique uses a biodegradable polymer,           nanostructure. Arrays of these devices are
been used in a number of vaccine products       polyethyleneimine, impregnated with iron          then applied to the cells or tissue, and the
                                                oxide to create nanoparticles with a surface      DNA is delivered to cells that are impaled
and is exclusively licensed for a number
                                                coating of DNA, which can then be directed        on the nanostructures.
of indications to Pevion Biotech, a joint
                                                to the desired site. Magnetic nanoparticles
venture company with Bachem, and is
still available for licensing for a number of
                                                have a number of potential uses: for              Strong innovation flow
                                                example, they could deliver gene therapy to       Since gene therapy became a reality two
infectious disease areas.
                                                implanted stents, where it could be used to       decades ago, this field has witnessed
    Another company involved in virosomes
                                                inhibit the overgrowth of cells that can lead     many setbacks and a disappointingly
is Virosome Biologicals, based in the
                                                to restenosis of the stent.                       small number of gene therapy treatments
Netherlands. Since last year, it has been
                                                    Before leaving this area, it is worth         that have actually made it to market.
owned by US biotechnology concern
                                                mentioning the potential use of                   Nonetheless, this has not diminished
Mymetics. Virosome Biologicals focuses on
                                                artificial chromosomes in gene therapy.           interest in the potential of this technology.
the use of virosomes as vaccine adjuvants
                                                These represent a way of introducing              Research into improved methods of
and delivery vehicles, and has vaccine
                                                heterologous DNA into mammalian                   delivering gene therapy continues to be the
candidates in development for HIV/AIDS          cells, where they are able to maintain
and malaria.                                                                                      subject of intense activity. Figure 1 (p 23) is
                                                gene expression without integrating into          just a small selection of patents filed and
    The use of dendrimers, highly branched      the host genome. There are a number of
macromolecules with a spherical shape,                                                            approved over the past two years.
                                                potential areas of application for artificial         If innovation and improvements in gene
to encapsulate genetic material is another      chromosomes, but one that is of particular
technique with considerable similarity to                                                         therapy and its delivery methods continue
                                                interest is their application to stem cells,      to flow at a significant pace, it will only be a
liposomes. Dendrimers are straightforward       particularly haematopoietic stem cells.
to produce and, compared with liposomes,                                                          matter of time before we see its widespread
permit greater control over molecular                                                             adoption.
                                                Ex vivo gene therapy
structure, and therefore size. In addition,     There is still considerable interest in ex
the surface of the particle may be              vivo gene therapy, and a number of devices
functionalised in many ways, which could        have been developed to facilitate it. Perhaps                            Peter Charlish is a
provide targeted delivery.                      the best known is the so-called ‘gene gun’,                              principal analyst at
    Other types of material have been used      which is designed to deliver particles of                                 Informa business
as carriers in gene therapy. For example,       a heavy metal (usually tungsten or gold)                                   Information, the
nanoparticles made out of a variety of          coated with DNA. Originally developed                                    publisher of Clinica
materials have been found to be effective       for the delivery of genes to plant cells, the                           Medtech Intelligence.
for delivering DNA to specific cells. In        device accelerates the coated particles
one study, researchers at the University        through a partial vacuum towards the

www.clinica.co.uk                                                                                                     © Informa UK Ltd 2010   25
rEGUlAtory – EU                                                                                                             Clinica // June 2010




How to get involved in EU medtech
standards writing: the latest
                                Standards are a lynchpin of the European medtech regulatory system.
                                They may be voluntary, but complying with them avoids the difficulty
                                of proving compliance via other routes. It is in each company’s interest
                                that when standards which impact their products are written, they
                                become involved in ensuring factors that might affect their business
                                are taken into account adequately. So how do companies become
                                involved? Anna von Groote of the European Standardisation Committee
                                (CEN) explains
      Anna von Groote


Clinica: How do you propose a new standard or a                        Clinica: How do you become involved in a TC or
standard amendment?                                                    working group? What do you need to qualify to
Anna von Groote: Any company or individual that wishes to propose      become involved?
a new standard or an amendment to a standard should submit their       AVG: You become involved through approaching the national
proposal to their national standards body.                             standards body whose responsibility it is to put together a delegation
   A national standards body mirror committee – that is, a             to go forward to CEN technical committee level.
committee which monitors and mirrors work ongoing at European             The type of qualification needed to become involved in standards
and international level – will then examine the proposal and decide    work depends on the CEN national member’s conditions. But in any
whether to put it forward to CEN.                                      case you clearly have to prove a certain level of expertise in the subject.
   During this stage, the proposal will also be checked against work
already existing or ongoing at CEN and at the international level to   Clinica: How much of a commitment is involved in
avoid unnecessary duplication.                                         being active in standards writing at working group
                                                                       level? How many meetings are there in all – face to
Clinica: How does this fit with the context of what                    face or telephone links – during the development
is going on at the International Standards                             process of a standard?
Organisation (ISO)?                                                    AVG: This will depend on the nature of the project, and whether the
AVG: The committees at European and international level are            standard is just being developed at EU level or whether it is being
closely linked. Most European representatives on the ISO Technical     developed in conjunction with the ISO. There is normally only one
Committee (TC) or working group for a standard will also be on the     CEN plenary meeting a year, but the number of other meetings
CEN TC or working group for the same standard, or their colleagues     depends on the individual project. A more urgently needed standard
are. There is plenty of co-ordination.                                 will require more frequent meetings. An alternative and easier way to

 26     © Informa UK Ltd 2010                                                                                                     www.clinica.co.uk
Clinica // June 2010                                                                                                             rEGUlAtory – EU


participate is at national level through the CEN national members –        Implantable Medical Devices (AIMD), Medical
this will cost less and mean they can work in their own language. A lot    Devices (MD) and the In Vitro Diagnostic Devices
of work is being done remotely. CEN technical bodies are very much         (IVD) Directives. But often other Directives may
encouraged to make use of electronic means of communication, such          apply, like the Machinery Directive, or the
as teleconferencing, as much as possible in order to minimise costs
                                                                           Electromagnetic Compatibility (EMC) Directive. How
and efforts linked to the development of a standard.
                                                                           do companies work out which standards under
Clinica: How long does the process take?                                   these other Directives may apply to their products?
AVG: Essentially, there are seven steps to the approval of a standard:     AVG: The manufacturer knows their own product best and it is up
    •	 proposal – evaluate and decide;                                     to the manufacturer to determine which directives apply. We cannot
    •	 draft and build agreement;                                          give exhaustive advice on such questions.
    •	 public enquiry – generate comments;                                     Nevertheless, there is much guidance on the application of
    •	 consider comments;                                                  individual Directives and Regulations available on the European
    •	 approve the final draft;                                            Commission’s website, and we suggest that companies contact the
    •	 publish the standard; and                                           Commission, national competent authorities or notified bodies if
    •	 review the standard.                                                they have questions.
The timeframe for developing a European standard foresees 36                   This is not an easy area – from a technological point of view, there
months between the proposal of a project and the publication of            are so many different medical devices to which different standards
the standard by CEN. A review is carried out by the responsible            apply, but which may also fall under other Directives, and we cannot
technical body after a maximum of five years, to determine whether         predict what technologies will emerge next.
the standard is still up to date or whether it should be revised or            There is always a sentence within the Annex ZA of European
withdrawn.                                                                 standards which advises users of that standard that other Directives
    After the closure of the adoption procedure, the definitive text       and other Essential Requirements may apply.
in the official language versions of an approved CEN publication               Annex ZA is an informative yet compulsory annex to a
is distributed by the CEN-CENELEC Management Centre to the                 harmonised standard. It shows which elements of the standard are
national members for publication at national level.                        the basis for meeting the corresponding Essential Requirements of
    Stakeholders can obtain copies of the CEN documents once these         the relevant Directive.
have been published as national standards by the CEN National
members. CEN itself does not sell standards – only the CEN national
                                                                           Clinica: To what extent are standards drafted under
members do. The list of CEN national members is available online at:       the Machinery Directive relevant to the medical
http://www.cen.eu/cen/Members/Pages/default.aspx                           device and diagnostic sectors?
                                                                           AVG: There is still much uncertainty in this area. For medical device
Clinica: How do you comment on a standard in                               manufacturers, the leading Directive is the MDD. Nevertheless,
development if you are not on a TC?                                        where a relevant hazard exists, if the Essential Requirements in
AVG: During the public enquiry, which is effectively a five-month          the new Machinery Directive are more specific, then these have
comment period for anyone to comment, the draft can be obtained            to be met as well. The European Commission has produced an
through the national member bodies, and comments sent back                 interpretative guidance document on this matter.
to these members. The comments will be examined by a national
standards body mirror group and, where appropriate, put forward to         Clinica: Have you completed the revision of all the
CEN level.                                                                 medtech standards to make sure they are in line
                                                                           with the revisions that Directive 2007/47/EC bring
Clinica: How many chances do you get to                                    to the AIMD and MD Directives?
comment?                                                                   AVG: CEN technical bodies have assessed all 200-plus standards
AVG: There is usually just one public enquiry. However, if there are a     which were cited under these two Directives to see if they needed
significant number of technical comments during the first enquiry,         updating to fall into line with the amendments introduced by
it is possible to hold a second enquiry. This is rare, as drafts that go   Directive 2007/47/EC.
to public enquiry tend to be technically relatively mature.                    About half needed amending, and most of these have been
                                                                           published now following a revision of the Annex ZA.
Clinica: How do you ensure you are kept up-to-date                             This has been an interim solution due to the short timelines, just
with progress on a standard?                                               providing information on which elements of the standard are the
AVG: Standards progress details are available on the CEN website.          basis for meeting which Essential Requirements of the amended
There you can see if a standard is at the proposal, public enquiry or      Directive. Evaluating whether more far-reaching technical changes
final approval stage.                                                      are needed will be the next stage.
   CEN also publishes a regular “snapshot” of standards in the             Very few standards still need their Annex ZA amending; we expect
medtech area (under the Active Implantable Medical Device, Medical         these to be amended very shortly.
Devices and In Vitro Diagnostic Medical Devices Directives). This is           By changing the Annex ZA, which is a Europe-only part of the
a summary at a given date of all the standards that have been made         standard, and none of the technical aspects, we have been able to
available to national members for publication within the last six          make the changes in a pragmatic way and with limited expense.
months, in addition to the work programme.                                     That said, now we have completed the review and amendments
                                                                           of the Annex ZA – a significant task – we are now looking at whether
Clinica: CEN provides a clear list of standards that                       we need to make changes of a more technical nature to cover
might apply to individual products under the Active                        additional aspects of the amended Directive.

www.clinica.co.uk                                                                                                       © Informa UK Ltd 2010   27
rEGUlAtory – EU                                                                                                        Clinica // June 2010


Clinica: When was this amended list submitted to
                                                                                                                                  NE
the European Commission?                                                                                                            W
AVG: The first list was sent at the end of 2009 and the references
to European Standards were republished in the Official Journal of
the European Union then. We hope the Commission will republish
the remaining standards (with the exception of the ones still to be
revised) imminently.



       CEN and European standards:
              an overview                                                                              Rajdevices.com
                                                                                                       Device regulatory guidance.
   CEN brings together the National Standardisation Bodies
                                                                                                       Your industry expert.
   of the 31 EU states and also of the European Free Trade
   Association (EFTA) member states. It is officially recognised                                       Visit the new site today
   by the European Commission and the EFTA as one of the
   three European Standards Organisations. CEN describes
   European Standards as an efficient way of finding a voluntary
   agreement whilst avoiding over-regulation and extra burdens
   on businesses.
   Under the New Approach, European standards for medical
   devices offer a recognised method of compliance with
   the strict regulatory requirements set out in the different
   European Directives that are applicable. They are in fact one
   of the key elements of the New Approach.
   CEN has been developing standards for medical devices
   since 1971, when the first TC in the healthcare sector was
   created.
   Nowadays, there are 22 active CEN TCs covering a wide
   range of products and technologies.
   Under the New Approach Directives, such as the MDD, the
   AIMD and the IVDD, the desired outcome in terms of device
   safety is laid out in the Essential Requirements, but not the
   method of how it should be achieved.
   European standards, therefore, specify how to meet the
   Essential Requirements, and if they are harmonised by the
   European Commission, any manufacturer that complies
   with the standard is presumed to be in compliance with the
   Essential Requirement(s) of the relevant Directive for which
   they have been drafted.
   Meeting these standards, however, is voluntary.
   Manufacturers can choose to develop their own company-               Our expert insight will help you:
   specific technical specifications, but must be sure that they          Minimise compliance costs
   can fully justify the use of these.
                                                                          Achieve faster time to market
   The following are a few more facts and figures on how CEN
                                                                          Mitigate risk
   operates.
   •	 The average timeframe to develop a European standard is
       36 months.
                                                                      V I S I T T H E N E W S I T E T O D AY -    RAJDEVICES.COM
   •	 In all, CEN has published 536 standards in the healthcare
       area, with 128 more underway. Of these, 314 are
       harmonised and published, with 83 ongoing.
   •	 Each European Standard replaces any conflicting national
       standard in 31 countries, giving access to 500 million
       consumers.
   •	 CEN works with the ISO to adopt international standards
       in Europe wherever possible and to avoid duplication of
       work, under a pact known as the Vienna Agreement.


 28    © Informa UK Ltd 2010                                                                                                www.clinica.co.uk
Clinica // June 2010                                                                                                     rEGUlAtory – JApAN




A smoother ride: streamlining medtech
clinical trials in Japan
The stringent Japanese approval process for medical devices can be tricky – and
expensive – to negotiate. Here, Tomoki Hasegawa, head of the medical device CRO
business at Emergo Japan in Tokyo, provides an overview of the clinical trial process
for medical devices


A
         significant factor shaping the          help beget new and sophisticated medical          additional safety measures for medical
         Japanese market – which is the          technologies. But first, the general regulatory   devices.
         second largest worldwide, following     landscape in Japan must be examined.                  The Japanese market is highly regulated
the US and ahead of Germany – is its                                                               and also competitive, adding to the
changing population. Japan’s demographics        Structure and organisation                        complexity of the process. This is especially
reflect an increasingly aging society: by 2015   The regulation of medical devices in Japan        harmful given Japan’s ageing society.
it is projected that one in four Japanese        is controlled by the Pharmaceutical and           An inherent device lag in the Japanese
                                                 Food Safety Bureau, a subdivision of the          market is one of the consequences of
citizens will be over the age of 65, compared
                                                 MHLW. Medical devices are classified              this complexity. In order to address some
to one in five today. The US Census Bureau
                                                 according to their risk to the human body,        of these issues Japan has implemented
also estimates that the population will
                                                 and range from class I (least risk) to class      a “Five-Year Strategy for Creation of
drop drastically over the next few decades,
                                                 IV (greatest risk). The risk to humans is         Innovative Drugs and Medical Devices”
from 127 million in 2007 to 97 million in
                                                 determined by the risk classification rules       (April 2007). Improvements in clinical
2047. Healthcare expenditure per capita
                                                 established by the Global Harmonization           trials and faster reviews and approvals
will continue to rise as Japan will have to      Task Force (GHTF), though in Japan,               by the Pharmaceuticals and Medical
provide for an older society that is likely      two distinct class II classifications exist:      Devices Agency (PMDA) and MHLW would
to be more dependent on medical devices.         Designated Controlled Medical Devices and         alleviate some of the burdens on foreign
The Japanese Ministry of Health, Labor,          Controlled Medical Devices, the latter of         manufactures, and are outlined in the
and Welfare (MHLW) has recognised these          slightly greater risk than the former.            five-year plan. However, some ambiguities
trends and issued its “New Vision for the            The Pharmaceutical Affairs Law is the         and complexities in the regulatory process
Medical Device and the Medical Technology        law governing medical device regulations; it      remain.
Industry” on 19 September 2008 in order          was amended in 2002, and enacted in 2005.
to accommodate these future needs.               Crucial aspects of the 2005 amendments            Device lag and its implications
Nonetheless, barriers still exit; namely, the    included a new classification system that         In Japan, the device lag impedes approval
cyclical notion of “device lag,” the stifling    associated the risk of medical device to the      of and access to sophisticated and high-
of innovative products, and the – albeit         human body, the allowance of third party          end foreign medical devices and in vitro
improved – cumbersome clinical trial             review bodies, or Certification Bodies, in        diagnostics. Keeping in mind that the
process. Breaking down these barriers would      low-risk medical device applications, and         Japanese market is the second largest

www.clinica.co.uk                                                                                                    © Informa UK Ltd 2010   29
rEGUlAtory – JApAN                                                                                                            Clinica // June 2010


worldwide, this issue seems particularly        MHLW Clinical Trial Protocol. Foreign                •	 Technical documents on clinical
acute, especially in comparison to the          clinical trials are now generally accepted if           studies are compulsory for new
availability of these products in the EU and    they are equivalent to the Japanese GCP. In             medical devices (those that have
US. Further confounding this issue is the       this way, the once-strict regulatory control            novel indications, performance,
fact that due to perceptions of the device      of clinical trials has lessened to some extent.         structure, etc and are clearly different
lag, foreign manufacturers are reluctant to         As stated above, foreign clinical                   from devices already on the Japanese
submit their products for approval in Japan.    data may be accepted in lieu of locally                 market).
    On this note, a 2008 survey by the          conducted Japanese trials. The information           •	 The number of cases in a clinical trial
American Medical Devices and Diagnostics        which the Japanese PMDA needs to                        must be appropriate for evaluating
Manufacturers’ Association (AMDD) polled        examine in order to accept the results of               the efficacy and safety of the medical
foreign medical device manufacturers on         foreign clinical trials include the following:          device by taking into account the
why they had not submitted their products           •	 the country and/or region where the              purpose and principal evaluation
for approval in Japan. They qualified the               clinical data is from;                          items of the clinical trial.
manufacturer-perceived barriers as:                 •	 the regulatory mechanism that was
    •	 high regulatory cost;                            used; and                                 Timeframe, costs, and hindrances
    •	 insufficient demand;                         •	 the standards to which the trials          In general, clinical trials in Japan require
    •	 anticipated time lag;                            conformed (this data will be used         between one and three years, depending
    •	 high cost of business;                           to ascertain whether or not the           on the medical device and its classification
    •	 unattractive reimbursement; and                  regulatory provisions are equivalent      and may cost between ¥50m and ¥200m
    •	 lack of resources.                               to Japanese standards and GCP).           ($550,000-$2.2m), not including the PMDA’s
    The two contributors to the device              If a clinical trial is conducted according    consulting fee.
lag, the regulatory barriers as well as         to standards that differ from Japan’s GCP,            One of the reasons for the high
manufacturer disinclination to market in        but upon PMDA review of the foreign               associated operational costs is that the
Japan, result in a deleterious cycle that       standards it is determined that the               fees are largely contingent upon the
                                                differences do not affect the reliability         individual clinical research organisations
worsens the device lag and further hinders
                                                of the clinical trial, this data may also be      (CROs) and site management organisation
the approval of innovative products.
                                                accepted. For this data to be accepted,           (SMOs) selected in medical device clinical
    As would be expected, the most
                                                however, technical documents that                 trials. Further, it seems that fees are often
prominent reason from the AMDD survey
                                                demonstrate that the clinical trial was           calculated based on the cost that would
for not submitting medical devices for
                                                conducted according to or comparably to           be incurred in performing a clinical trial
approval in Japan was the high regulatory
                                                Japan’s GCP and that the Japanese PMDA            on a pharmaceutical, despite the fact there
cost. The AMDD survey investigated
                                                determined that these documents were              are fundamental differences between
regulatory costs and found that the costs
                                                appropriate, should also be provided.             pharmaceuticals and medical devices,
stemmed from the following requests:
                                                    Additional points to consider in the          particularly as they relate to how clinical
additional clinical trials; additional data
                                                submission of clinical trial data include         trials are performed.
requirements; post-marketing trials;
                                                the implementation and management
application fees; and other regulatory                                                            Vast benefits
                                                of a clinical trial; and whether or not the
compliance costs including consultation                                                           The regulatory process in Japan can be
                                                essential documents are equal to or better
fees and QMS costs.                                                                               difficult to navigate, but once a medical
                                                than the Japanese standards.
    Clinical trials are required for any                                                          device has been approved by the MHLW,
“new product” – those for which there is        Validity of a clinical trial                      the benefits can be vast. Japan’s medical
no precedence on the Japanese market;           In 2008, a notification regarding the             device industry is the second largest
this includes new generation products           “Necessary Scope of Clinical Trial Data           worldwide, and according to The Market
that differ from their predecessors.            on Medical Devices” was released. The             Report: Medical Device Market Japan
Medical devices made from bio-materials         notice stipulated the scope of technical          2007, published by Swiss Business Hub
(human or animal tissue or organs), or          documents on clinical trial results for           Japan, imports account for 40% of the
the use of gene recombination technology        medical devices as follows:                       total market. It is essential for foreign
require clinical trials. Additional medical        •	 Clinical efficacy and safety of a           manufacturers to be knowledgeable
devices that require clinical trials include:         medical device can be evaluated             of Japan’s requirements, flexible, and
protective materials for wounds; surgical             based upon the results of non-clinical      patient, as the process and requirements
adhesives; implants; stents placed in an              trials (performance tests and animal        can be confusing, and the timeline
artery; blood purifying devices; and soft or          tests, existing literature, etc).           lengthy. With hope, many of these
hard contact lenses. The need for clinical         •	 Whether technical documents on              issues will be addressed with Japan’s
trials is evaluated on a case-by-case basis,          clinical study records are necessary        “New Vision for the Medical Device
so cooperation and communication                      will be determined using a number of        and the Medical Technology Industry”.
between the Marketing Authorization                   factors, including: the characteristics     Regulatory requirements are becoming
Holder and PMDA is crucial.                           of the particular medical device;           simpler, and the direction in which
    Clinical trials must be in accordance             equivalency with an existing medical        the population is moving foresees that
with the Good Clinical Practice (GCP)                 device; and non-clinical study results.     the medical device industry will be
ministry ordinance No 36 of 2005 by                   It is recommended that clinical             increasingly lucrative and remunerative
the MHLW Clinical Trial Protocol.                     evaluation consultation services            for foreign manufacturers.
Specifications for the clinical trial plan,           offered by the Pharmaceutical and
clinical data, informed consent, IRB review           Medical Devices Agency (PMDA)               For a full version of this article, go to
and clinical trial report are outlined in the         are used.                                   www.clinica.co.uk

 30    © Informa UK Ltd 2010                                                                                                        www.clinica.co.uk
Clinica // June 2010                                                                                                               INDUStry q&A




In the industry’s words
United States’ MDMA
                           On tenterhooks over the FDA’s reform of the 510(k) review process, the
                           US medical technology industry is warning that the potential changes
                           threaten its position as global leader in the supply of these products.
                           Mark Leahey, president and CEO of the Medical Device Manufacturers
                           Association (MDMA), explains the thinking behind what it sees as the
                           risk of a major weakening of medtech innovation
     Mark Leahey


Clinica: What are the most                      Clinica: How are you addressing                   determine which should be accessible
important issues for the US                     this?                                             by patients and their providers. Over the
domestic medtech market?                        ML: MDMA has been working closely with            coming years, MDMA and its members
Mark Leahey: Currently, the most                its members, elected officials, policy-           will be looking closely at the greater use of
                                                makers and others to communicate the              health technology assessments [HTAs] by
important issues the medical device
                                                concerns of the industry. We are working to       foreign payers, especially in the EU.
industry is facing are potential changes
                                                educate the public and interested parties so          In addition, our members are closely
to the FDA’s 510(k) review process. The
                                                they understand exactly what it takes to get      monitoring the implementation of the
US medical device industry has long
                                                a medical device product from an idea to          recently introduced medical device
been the global leader in designing and                                                           directive 2007/42/EC, which went into
                                                the marketplace, and just how detrimental
manufacturing products that enhance                                                               effect in March 2010. Among our concerns
                                                ill-guided policies could be to an industry
patient care and provide good quality jobs.                                                       is that there was never really a transitional
                                                that reports show was responsible for
This leadership position clearly is at risk     423,000 jobs, $24.6bn in payroll and almost       period put into place for implementation of
if government regulators institute policy       $136bn-worth of products in 2008. It is vital     the mandate, so the transition may be more
changes that will impede innovation             that the FDA’s review process is transparent      abrupt than is necessary.
and threaten the ability of engineers,          and predictable, so that innovators know
entrepreneurs and scientists to make life-      how their products will be measured, and          Clinica: What would you ask of
changing inventions.                            what the endpoints are, as they seek to           the national healthcare market?
    In addition, the recently enacted health    enter the marketplace.                            ML: MDMA believes it is essential that
reform legislation contains a provision that        Regarding the device tax, we continue to      we continue to encourage research and
will institute a 2.3% excise tax on most        work on a repeal of the tax, but if this is not   investment into cutting-edge technologies
medical devices sold in the US, starting        successful, there should be provisions that       and medical advancements. While access
in 2013. In response to this looming tax,       exempt small and mid-sized businesses –           to care is certainly a critical issue, it is just
every poll and study that we have seen          for example, those with less than $100m in        as important that the care being provided
shows that companies will either cut back       sales – as they are the ones that develop         utilises the safest, most effective products.
                                                the great majority of innovations and the         Recent studies have shown that private
on research and development, eliminate
                                                cutting-edge technologies of tomorrow.            investments in new medical technologies
jobs or, in extreme situations, go out of
                                                                                                  are being reduced due to the uncertainties
business. Unfortunately, the tax is on gross    Clinica: What are the most                        and lack of predictability in the regulatory
sales, regardless of whether or not you are     important issues for exporters?                   process. It is critical that we support the
profitable. As a result, this tax could prove   ML: The medtech industry is one of the few        medical device industry which is at the
to be a fatal blow to small and mid-sized       sectors in the US that is a net exporter of       core of patient care and innovation.
companies [SMEs] that are just beginning        goods. The EU has a very clear and efficient
to grow.                                        process for reviewing medical devices to          Mr Leahey was speaking to Bernard Murphy.




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                                           CLINICAL RESEARCH



www.clinica.co.uk                                                                                                      © Informa UK Ltd 2010   31
mArKEt lEADEr FocUS                                                                                                     Clinica // June 2010




Beckman Coulter: more solutions,
more markets, more global
In August last year, Beckman Coulter closed its acquisition of Olympus’ lab-based
diagnostics division. Nearly a year on and the integration is now complete. In an
exclusive interview with Clinica, Marc Meyer, Beckman’s clinical diagnostics marketing
director in Europe, and Helmut Koehler, vice-president of global R&D for chemistry and
automation, tells Tina Tan how the new Beckman Coulter is moving forward



A
         s far as medtech acquisition deals    of global R&D for chemistry and clinical         DxC moderate- to high-throughput
         went last year, Beckman Coulter’s     automation. “All the products, when              systems. The company also gained
         purchase of Olympus Diagnostics,      brought together, offer much higher              Olympus’ OLA’s automated pre-analytical
at ¥76bn ($800m), would not be consid-         value to the customers,” says Dr Koehler.        instruments, which have been renamed
ered the biggest. However, the reward that     This value does not come from having             AutoMate 1200/2500 and AutoMate
the world’s largest standalone IVD player      additional hardware, but from finding the        1250/2550. These, together with Beckman’s
expects to reap from its greatly extended      most appropriate and efficient solution for      AutoMate 800 and with the Power
portfolio – particularly in chemistry and      the customer and meeting their needs as          Processor automated sample-handling
clinical automation – is manifold.             they evolve over the years. “It’s not ‘1+1=2’,   system, enable the company to offer full
    Beckman’s top line is already benefiting   but rather ‘1+1=3’.”                             automation of pre-analytical, analytical and
from the additional business. Just a few                                                        post-analytical processes.
months following the acquisition, the                                                              Did the company come across any
Olympus products contributed $180m to
full-year 2009 revenue. This year, in the
                                                                 “All the                       challenges when rebranding an established
                                                                                                product like the OLA? “We haven’t really
first quarter alone, they brought in $116m                       products,                      faced resistance from the name change,”
and Beckman is expecting Olympus-
related sales for 2010 to be $480-500m.                          when                           says Mr Meyer. “We have been working
                                                                                                with the customers and it has been quite
The acquisition has propelled Beckman to
joint leading position with Roche in the
                                                                 brought                        a smooth process. We’ve only changed the
                                                                                                OLA to AutoMate, and have kept the AU
worldwide clinical chemistry market, while                       together,                      product name.”
in Europe it has doubled its market share to
become number two in this region.                                offer much                     Portfolio harmonisation
    The integration of the Olympus clinical
chemistry operations – which encompasses
                                                  Helmut Koehler higher                         At next month’s annual meeting of the
                                                                                                American Association of Clinical Chemistry
instrument R&D and manufacturing               value to the customers. It’s                     (AACC), Beckman Coulter will be unveiling
capabilities in Japan, lab automation
                                                                                                the latest addition to the AU series – the
competencies in Germany and reagents           not 1+1=2, but rather 1+1=3”                     AU5800. The new analyser has better
know-how in Ireland – has been carried
                                                                                                capabilities than the AU5400, says Dr
out with little fanfare over the last 10
                                                   Through the acquisition, Beckman             Koehler, offering a throughput of 2,000
months and is now complete, leaving what
Beckman says is a “very different” company     Coulter has significantly expanded its reach     to 8,000 photometric tests an hour, in a
from a year ago.                               in the high-throughput and low-volume            combination of up to four instruments. The
    First and foremost, the products. “We      segments of the clinical diagnostics market      AU5800 is pitched exclusively at the high
provide more solutions to the customers        with Olympus’ AU series of automated             throughput sector .
and we have more flexibility to adapt to       clinical chemistry analysers. At one end             “We’re seeing the development of
their requirements,” says Marc Meyer,          of the series is the AU480, designed for         international lab networks. These networks
clinical diagnostics marketing director at     small to medium-sized laboratories with          will include labs ranging from the very big
Beckman Coulter’s Eurocentre.                  the capacity to hold about 60 different          to the very small, and the beauty of our
    But the effect of combining the Olympus    reagents on board (and a throughput of           portfolio is that we have solutions for all
and Beckman portfolios is not simply           400 photometric tests an hour), while at         these labs. Labs from the same network
additive, elaborates Helmut Koehler.           the other end is the AU5400, the ultra-high      will get the same attention from the same
Formerly Olympus Europe’s executive            throughput analyser with the capacity            company and product portfolio. In terms
managing director for life science, Dr         to hold up to 96 reagents and an hourly          of training logistics and service for the
Koehler has joined Beckman Coulter in          throughput of up to 4,800 tests . These          customer, this is real value,” says
the newly created role of vice-president       analysers sit alongside Beckman’s UniCel         Dr Koehler.

 32    © Informa UK Ltd 2010                                                                                                 www.clinica.co.uk
Clinica // June 2010                                                                                                  mArKEt lEADEr FocUS

    The integration of the two companies’        reagents and all the software solutions.        clearance for the tests during the first half
technologies is one of Dr Koehler’s key          When you look at Roche, Siemens and             of 2011 (www.clinica.co.uk, 14 May 2010).
objectives in his role at Beckman. “We           others, they often have to depend on OEM            Nonetheless, Beckman Coulter
started the process in August with our           providers for software or hardware. It is       continues to be bullish about the prospects
positioning strategy, how we position the        important to have these capabilities in-        of its overall immunoassay business, which
business as we combine the portfolio.            house, especially when you want to provide      it says, is its fastest-growing business
Then we have been targeting the low-             high-end integrated solutions, which is         segment. “We’re still growing much faster
hanging fruit, such as integrating the           a combination of automation software,           than market rate. For Q1 our immunoassay
existing technologies, and connecting            analysers and chemistry. It is better to have   business grew worldwide more than twice
the AU5400 to the Power Processor.               this all under one roof, than having outside    as fast as the market, and in Europe the
We are now moving on to the next-                providers for certain products.”                rate is also in double-digits. This is because
generation chemistry systems like the                                                            [as with the clinical chemistry business] we
AU5800 (which will ultimately replace the        Immunoassay a key element
                                                                                                 propose a set of solutions for the very low-
AU2700 and AU5400), in order to achieve          While the benefits of the Olympus
                                                                                                 to the very high-volume customers and we
harmonisation in our portfolio,” he              acquisition for Beckman Coulter’s clinical
                                                                                                 have a very competitive product portfolio
tells Clinica.                                   chemistry business are clear, synergies
                                                                                                 menu,” says Mr Meyer. To help accelerate
    True harmonisation, though, will             between the chemistry and immunoassay
                                                                                                 this growth, the company ensures it brings
come when the company streamlines its            businesses were significant drivers that
                                                 motivated the purchase in the first place.      to the market a steady flow of new and
instrument and reagent portfolio, so that
                                                    Globally, Beckman is the number              novel markers.
it can offer “one instrument family with
                                                 four company in immunoassay, behind                 Areas in which the firm has decided
the same design and specifications as
                                                 Roche, Siemens and Abbott. It is hoped          to invest particular resources are cancer,
one reagent family being used on these
systems.” He believes that this can be           that Beckman will boost its immunoassay         high-risk pregnancy and reproductive
achievable in three to four years.               market share by cross-selling its               endocrinology. “We are specifically
                                                 immunoassay products to Olympus’                interested in prostate cancer, for which
Wider global reach                               chemistry customers, either as standalone       we have a new PSA isoform called p2PSA.
Another change brought about by the              products or through an integrated               This assay is available on the immunoassay
acquisition of Olympus Diagnostics is            chemistry and immunoassay platform.             platform and on the consolidated
that it has enabled Beckman Coulter to                                                           platforms, and will help the urologist
expand its infrastructure globally, giving the                                                   to significantly decrease the number of
Brea, California-headquartered company
a new set of “centres of excellence” across
                                                                    “Our assay                   unnecessary biopsies, which is a real issue,”
                                                                                                 explains Mr Meyer. When PSA is slightly
three continents. In addition to Beckman                            business                     elevated, the patient typically undergoes
Coulter’s traditional sites in the US, it has                                                    a biopsy but 75% of biopsies are negative
further strengthened its existing European                          grew                         so there is a significant need to improve
presence with new lab automation
competencies in Germany (Dr Koehler is                              worldwide                    the management of these patients with
                                                                                                 elevated PSA. “With our assay, it will help
based in the recently opened €15m R&D
centre in Munich) and gained a reagents
                                                                    more than                    to significantly reduce the number of
                                                                                                 unnecessary biopsies.”
facility in County Clare, Ireland, and                              twice as                         Beckman Coulter is also working on two
an instruments manufacturing base in                  Marc Meyer
Mishima, Japan.                                                     fast as the                  markers for pre-eclampsia and has an AMH
                                                                                                 (anti-Müllerian hormone) assay available –
    “Because of our wider geographic
presence, we are now closer to customers         market, and in Europe the rate                  a marker to help assess ovarian reserve in
                                                                                                 women.
in all regions of the world, and this makes it   is also in double-digits”
easier to get more complete feedback from
                                                                                                 “Never-ending story”
them when we discuss new products,” says
                                                                                                 So, with the integration of Olympus
Mr Meyer.                                           “In Europe, many deals are closed via
                                                 tenders and this takes some time to go          complete, is the new Beckman Coulter
    But there are also challenges. Dr Koehler
                                                 through, but we are definitely working in       back on the acquisition trail again?
concedes that managing R&D projects
                                                 that direction,” Mr Meyer tells Clinica.            Says Mr Meyer: “For the core lab, the
and different product portfolios can be
complex. “However, it is important for the          Beckman’s immunoassay business was           company is very well equipped now. As
portfolio, going forward, to maintain the        recently subject to a product corrective        Helmut said, it is all about harmonisation
existing expertise and capabilities. We are      action on its troponin test performed on its    of the methods and offering one single
continuing with these sites because, in the      UniCel DxI system, after it was discovered      product line, one single menu, so we can
end, you benefit from the local know-how,”       that tests performed on this analyser were      go a step further into the standardisation
he says.                                         more likely to return a positive result than    of our methods. This is really the most
    Having such significant in-house R&D         with its Access system (www.clinica.co.uk,      significant point. And to continuously
and manufacturing operations is also one         26 March 2010). At the time, the US FDA         refine our offering for all market segments
of the key factors that differentiate the        also indicated that modifications to the test   so that we match the market needs and
new Beckman from its competitors, adds           had been made without obtaining proper          customer needs. It’s a never-ending story.
Dr Koehler. “We develop and manufacture          clearances. The company announced               The market is always evolving and we have
across all product areas – instruments,          last month that it will seek updated US         to be ahead of where the market is going.”

www.clinica.co.uk                                                                                                   © Informa UK Ltd 2010   33
IVD INSIGHt                                                                                                            Clinica // June 2010




Point-of-care testing: the bedside drugs
of abuse market
R
        apid drugs of abuse tests employed       the industrial setting. These are used for    2007. A number of smaller suppliers have
        at the point of care (POC) in hospi-     pre-employment screening and routine          entered the industrial POC testing segment,
        tals emerged in the early 1990s. Their   monitoring of employees involved in           competing primarily on price. Although
development was pioneered primarily by           certain high-risk occupations. Customers      new drug screening programmes are still
Biosite Diagnostics in the US, now a unit        in the industrial segment include             being established, other programmes have
of Inverness Medical. Biosite developed a        government agencies, corporations with        been scaled back (eg, in the US military)
family of multianalyte urine drug screening      employee screening programmes, and            because of the low rate of positives. Overall,
test cards that allowed physicians to quickly    law enforcement agencies that monitor         based on data from Medtox, the positivity
determine if a patient had taken any of up       individuals in parole and probation           rate for regulated drugs (amphetamines,
to seven abused drugs. Biosite’s product,        programmes. Other customers include           cocaine, opiates, phencyclidine and
called Triage, was particularly attractive to    student health clinics, hospital-based        cannabinoids) in 2005 was 2.1%.
hospital emergency departments to help           occupational health clinics, and reference    Nevertheless, overall sales in the industrial
decide if treatment should be altered due to     laboratories. The industrial POC drugs        market are increasing, including expansion
potential drug interactions, or to rapidly di-   of abuse testing market is continuing         of sales outside the US in areas such as
agnose drug-related illness. Although Triage     to expand, as indicated by sales trends       roadside drugs of abuse testing.
was designed for POC use, it is now used         for leading suppliers such as Medtox              The market for rapid drugs of abuse
in the laboratory during late shifts, as an      Laboratories and American Bio Medica.         screening in hospitals is highly competitive,
alternative to running low volumes of tests      Sales of Medtox’s collection kits increased   although there has been a considerable
on automated systems that require more           at an 11.6% compound annual rate between      degree of consolidation over the past two
highly-trained operators. The POC drugs          2003 and 2008, increasing by 6.9% between     to three years as a result of acquisitions
of abuse testing market grew rapidly in the      2007 and 2008. American Bio Medica’s          made by Inverness Medical. Biosite was
early- and mid-1990s but has since matured       sales more than doubled between fiscal        essentially the only company in this
significantly, with growth rates now under       1999 and 2005, with sales of POC drugs of     market in the mid-1990s. Now at least five
4% per year.                                     abuse testing products reaching $12.9m.       companies, including Inverness (which
    Another segment of the drugs of abuse        However, these have since been flat and       includes the Biosite, Applied Biotech,
screening market is made up of tests for         declined by 8.8% in 2008 compared with        Instant Technologies and SureStep

 34    © Informa UK Ltd 2010                                                                                                 www.clinica.co.uk
Clinica // June 2010                                                                                                                                  IVD INSIGHt


            Figure 1. Number of US emergency department visits involving                                            Existing products
                                illicit drug use in 2006                                                            There are a wide variety of products
                                                                                                                    available in this area: the US FDA has
 Drug                                                      Number of ED visits                  percent of total*   cleared more than 280 drugs of abuse
 Cocaine                                                   548,608                              57.3%               testing products for both clinical and
                                                                                                                    physician office labs. The Biosite unit of
 Heroin                                                    189,780                              19.8%
                                                                                                                    Inverness Medical, the current market
 Cannabis                                                  290,563                              30.3%               share leader, has a comprehensive line of
 Amphetamines                                              32,240                               3.4%                tests, encompassing 11 different classes
                                                                                                                    of drugs in five different screening panels.
 Methamphetamines                                          79,924                               8.3%
                                                                                                                    Cost per panel or per test is quite high for
 MDMA (Ecstasy)                                            16,749                               1.7%                many POC products compared with the
 GHB                                                       1,084                                0.1%                costs of reagents for tests performed in the
                                                                                                                    central lab. List prices for Biosite’s products
 Flunitrazepam (Rohypnol)                                  –                                    0.0%
                                                                                                                    range from $20-39.95 per panel in low-
 Ketamine                                                  270                                  0.0%                volume testing, or $2.91-3.63 per individual
 LSD                                                       4,002                                0.4%                analyte tested. Although there are typically
                                                                                                                    significant discounts from list price, the
 PCP                                                       21,960                               2.3%
                                                                                                                    consumables cost per test remains well
 Miscellaneous hallucinogens                               3,898                                0.4%                above that for tests performed on high-
 Inhalants                                                 5,643                                0.6%                volume analysers in the central lab, which
                                                                                                                    can be as low as $0.15 per test.
 Combinations not listed above                             2,055                                0.2%
                                                                                                                        However, since most drugs of abuse
 Total ED visits, illicit drugs                            958,164                              –                   testing is performed in large reference
 *Some visits involve more than one illicit drug. Source: Drug Abuse Warning Network, 2006 survey report            laboratories, where charges can be up to
                                                                                                                    $50 for a drug panel and $33 for a single-
                                                                                                                    drug assay, the cost of having the test
                                                                                                                    performed by a reference lab is similar to
product lines, not all of which address                              information for the treatment of some          the cost of a hospital performing a POC test
the hospital POC market), American Bio                               patients. Physicians confronted with a         itself using a product like Biosite’s Triage.
Medica, Medtox and LifeSign/PBM supply                               patient in a coma may have no other means      Labour costs for newer POC tests are not
hospital products. Many of these firms also                          of determining if drug abuse is a causative    significantly different than the cost of
target the industrial testing market. With                           or contributing factor, and such tests         collecting a urine sample and sending it to
the recent wave of consolidation in the                              become vital for guiding therapy. Testing in   a reference lab.
POC drugs of abuse segment, the market                               pregnancy is also an important application.        Biosite’s Triage is the most widely-used
has become more rationally structured,                               Based on data from the most recent             rapid drugs of abuse test in the hospital
although still competitive, with five major                          National Institute on Drug Abuse (NIDA)        setting, being employed in more than 2,300
players in a market totalling about $106m                            survey on drug use in pregnancy, more than     US hospitals (63% of hospitals nationwide)
worldwide.                                                           5% of the four million women who gave          and over 50 countries worldwide. To carry
                                                                     birth in the US in 1992 used illegal drugs     out the assay, the technician adds 140uL
Trends in bedside/POC drugs of                                       while they were pregnant. This figure could    of urine to the device, waits 10 minutes,
abuse testing                                                        be as high as 31% depending on geographic      then transfers the reaction mixture to the
According to data from the Drug Abuse                                location. Over 100,000 babies are born         detection area and washes off unbound
Warning Network (DAWN) in the US,                                    annually to mothers who use cocaine.           reagents. Results for each of the drugs
there where approximately 1.88 million                                   The worldwide market for laboratory-       are read visually by the user. Biosite has
visits to US emergency departments that                              based drugs of abuse testing in 2008 was       also added the Express test cartridges to
were drug or alcohol-related in 2007. Of                             approximately $612m. The majority of           its product line, which feature a higher
these, 55% or 958,164 cases involved illicit                         testing is carried out at large centralised    cut-off level for opiates. The most recent
drugs, either alone or in combination with                           reference laboratories. However, testing at    Biosite product is its second-generation
pharmaceuticals or alcohol. The number                               the POC using qualitative rapid screening      test, Triage TOX, which can provide a
of episodes appears to be stable over time                           devices has grown more rapidly than            documentable result that can be printed
based on 2004-2006 data, in spite of a 3.9%                          lab-based testing. Both in the hospital        out or transmitted to the lab or hospital
increase in total emergency room visits                              emergency department and the workplace,        information system.
over the same period. The majority of                                there is a demand for more rapid                   Other products in this segment include
drug-related emergency department visits                             turnaround time. In the hospital, there is     Medtox’s Profile-II/II ER; the Rapid Drug
involve multiple illicit drugs. According to                         a need to begin treatment as quickly as        Screen, Rapid TOX, and Rapid InCup tests
data from suppliers, 25-50% of all visits to                         possible, while in the industrial setting, a   from American Bio Medica; and LifeSign’s
US emergency departments are related to                              rapid result can avoid the 24-48-hour wait     Status Stik and DS tests. All suppliers
alcohol or drug abuse, and illicit drug use                          typical of lab-based testing. This could       offer tests for most of the standard drugs
leads to 20,000 deaths each year.                                    potentially prevent an employee from           required by federal mandates, and some,
    In the hospital emergency department,                            performing a high-risk activity under the      such as Alfa and American Bio Medica,
drugs of abuse tests provide critical                                influence of drugs.                            provide additional drugs that are of interest

www.clinica.co.uk                                                                                                                      © Informa UK Ltd 2010   35
IVD INSIGHt                                                                                                                                   Clinica // June 2010



            Figure 2. Worldwide market for laboratory versus POC drugs-of-abuse testing products (hospital segment)
 year                      lab sales ($millions)             Growth (%)       poc sales ($millions)      Growth (%)      total sales ($millions)     Growth (%)
 2008                      510                               –                102                        –               612                         –
 2009                      536                               5.0              106                        4.3             642                         4.9
 2010                      566                               5.6              110                        3.2             675                         5.2
 2011                      599                               5.8              114                        3.6             712                         5.4
 2012                      634                               6.0              118                        3.7             752                         5.6
 2013                      673                               6.1              122                        3.9             796                         5.8
 2014                      716                               6.3              127                        3.9             843                         5.9
 CAGR                      6.0%                                               3.7%                                       5.6%
 2009-2014
 Numbers may not add due to rounding. Source: InteLab Corporation



for some hospitals, such as oxycodone. List                         morphine, opiates, phencyclidine and              12-panel test cartridge along with a reader,
prices range from $1.00-4.00 per analyte                            tricyclic antidepressants). Alfa is also          barcode scanner and printer. Profile-V
tested. American Bio Medica claims a                                developing the Saliva DOA test cartridge          will provide higher detection sensitivity
99% correlation between its Rapid Drug                              which will screen for seven drugs of              for certain drugs, as well as instrumented
Screen panel and laboratory-based testing                           abuse (cocaine, cannabis, amphetamine,            readout with result storage and
methods. Up to nine drugs can be detected                           methamphetamine, morphine, methadone              documentation. The Profile-V will replace
with a single test card. LifeSign’s Status DS                       and benzodiazepines) in oral fluid with a         the Profile-III and Profile-IV products in the
is designed in a test card format, but has                          read time of 5-7 minutes.                         Medtox line.
the advantage of offering essentially any                                                                                 The heART2 unit of Nano Entek is
combination of tests from a single analyte                                                                            developing drugs of abuse tests for its
card up to a 10-drug panel.                                         Growth will be due                                FREND analyser, which can also run tests
    A relatively recent development in                                                                                for cardiac markers such as troponin I,
the market is the introduction of drugs                             primarily to expansion in                         CKMG, myoglobin, D-dimer and NT-
of abuse tests that use a saliva sample
rather than urine, marketed by companies
                                                                    the number of hospitals                           proBNP. The analyser employs fluorescence
                                                                                                                      analysis and uses less 20µL of whole blood
including American Bio Medica and                                   using POC drug testing,                           to generate results in five minutes. The
Cozart Biosciences. These are particularly                                                                            FREND is currently sold in Asia, but is not
useful for patients who are unwilling or                            particularly outside the US                       yet FDA-cleared.
unable to provide a urine sample. Cozart’s
RapiScan product is a fully integrated,                                 Concateno, the parent company of              Market analysis and forecast
on-site test that can also assess oral                              Cozart, has established a partnership             The market for POC drugs of abuse testing
fluid specimens for five drugs of abuse                             with Philips to develop a new handheld            in the hospital setting totalled $107m in
in a few minutes. Available tests include                           drugs-of-abuse detection device. The              2009. The market is forecast to grow at a
cannabinoids, amphetamines, cocaine,                                Concateno-Philips product will test               3.7% compound annual rate until 2014,
opiates, benzodiazepines, methadone,                                for five drug groups (cocaine, heroin,            with growth driven primarily by unit
methamphetamine and Ecstasy. However,                               methamphetamine, amphetamine and                  volume. Prices are expected to remain
drug levels are typically much lower in                             cannabis) in a saliva sample. The total           under considerable pressure due to the
oral fluid than in urine, meaning that tests                        time from sample collection to result will        high level of competition in the market.
need to have high sensitivity. In addition,                         be less than 90 seconds. This represents          Growth will be due primarily to expansion
the use of oral fluid to test for cannabis is                       a significant advance over products such          in the number of hospitals using POC drug
problematic since detectable levels persist                         as Biosite’s Triage test, which requires up       testing, particularly outside the US. Test
in saliva for only 48 hours after use.                              to 10 minutes to generate a result. The           volume is projected to grow at a 3.2% rate
                                                                    new device employs Philips’ Magnotech             while prices increase at only about 0.5%
Products in development                                             magnetic nanoparticle immunoassay                 per year. As shown in Figure 2, the hospital
Alfa Scientific Designs is developing the                           technology to concentrate the reactants           POC segment of the drugs of abuse testing
Vision Drugs of Abuse Test Cup, a urine                             and accelerate reaction time as well as to        market is expected to grow somewhat
sample cup that employs rapid lateral flow                          achieve high sensitivity. A 15-20µL saliva        more slowly the hospital laboratory
immunoassay technology for qualitative                              sample is required, and the technology            segment. The estimates for the hospital
screening for drugs of abuse. Test read                             is believed to be compatible with CLIA-           laboratory segment exclude sales of drugs
time is 5-60 minutes, and analytes in the                           waived requirements. Initially, Concateno         of abuse testing products for industrial
test panel include the 12 standard drugs                            will target the roadside drugs-of-abuse           and workplace applications. Sales in the
of abuse (cocaine, cannabis, methadone,                             testing market.                                   hospital laboratory segment are expected
amphetamine, methamphetamine,                                           Medtox is developing a new product,           to increase from $536m in 2009 to $716m
barbiturates, benzodiazepines, Ecstasy,                             the Profile-V, which will include a nine- and     by 2014.

 36      © Informa UK Ltd 2010                                                                                                                      www.clinica.co.uk
Clinica // June 2010                                                                                                                                                                   IVD INSIGHt



               Figure 3. 2008 worldwide sales and market share for leading suppliers of hospital POC drugs-of-abuse
                                                   testing products by region

 Supplier                                                                        2008 sales by region ($millions) and market share (%)

                                US                   Share                 Europe               Share                roW                  Share                 WW                   Share

 Inverness                      41.5                 55.6                  12.6                 77.1                 3.3                  30.8                  57.4                 56.4

 Medtox                         5.9                  7.9                   0.0                  0.0                  0.0                  0.0                   5.9                  5.8

 Other                          27.2                 36.4                  3.7                  22.9                 7.5                  69.2                  38.4                 37.7

 Total                          74.6                 100.0                 16.4                 100.0                10.8                 100.0                 101.8                100.0

 Other includes Alfa Scientific, American Bio Medica, Acro Biotech, LifeSign, Branan Medical, Aventir Biotech, Nano-Ditech and Tianjin New Bay Bioresearch. Numbers may not add due to rounding.
 Source: InteLab Corporation




    The total market for POC drugs of abuse                          Drivers and limiters                                                      POC tests are also becoming more
screening products, including the hospital                           The market for hospital POC drugs of                                  attractive as hospital labs consolidate and
and industrial (workplace and criminal                               abuse testing is being driven by increased                            drug testing is moved into a core lab or sent
justice) segments, was estimated at about                            numbers of emergency room visits coupled                              out to a reference lab. The resulting longer
$250m worldwide for 2009. Growth in the                              with the continued use of illicit drugs.                              turnaround times can be problematic
industrial segment will outpace growth                               According to the United Nations Office on                             in emergency situations. In addition, in
in the hospital segment, due to continued                            Drugs and Crime, the annual prevalence of                             hospitals that continue to perform drugs of
issues with drug use in the workplace, and                           illicit drug use was 208 million in 2006/2007                         abuse testing in the laboratory, POC tests
expanded adoption of testing due to new                                                                                                    may still be used as a back-up method on
                                                                     versus 200 million in 2005/2006. There
formats such as oral fluid testing – this is                                                                                               the late shift, or in emergency situations
                                                                     were 112 million monthly drug users in
a particularly important factor for smaller                                                                                                where physicians need a result in minutes.
                                                                     2006/2007 compared with 110 million in
                                                                                                                                               Limiters of the hospital POC drugs
companies, as well as in applications such                           2005/2006, and 26 million problem drug
                                                                                                                                           of abuse testing market include price
as roadside testing.                                                 users worldwide in 2006/2007 compared                                 competition as an increasing number
                                                                     with 25 million in 2005/2006. The increases                           of companies enter this segment, along
Product suppliers’ sales and                                         are primarily due to population growth,                               with the mature nature of the market
market shares                                                        since prevalence rates have remained stable                           with regard to penetration of available
Biosite/Inverness accounts for over half                             for the past four years. Drug abuse is a                              testing sites. While price declines are
of the worldwide hospital POC drugs of                               global problem, particularly in the US, Asia,                         expected to be limited mainly by the fact
abuse testing market, and has continued to                           the UK and Australia. POC drug testing is                             that the cost of alternative lab-based
dominate in spite of premium pricing for                             an important tool in patient management,                              testing is stabilising and may rise, there
its products. About 81% of the Biosite unit’s                        particularly in the hospital emergency                                will be continuing pressure to reduce costs
sales are realised in the US. Biosite’s growth                       setting where, in some cases, up to half of                           for POC testing products, particularly
in the segment has slowed as the number                              all visits may be drug- or alcohol-related.                           in the hospital setting. While there is
of available hospital POC testing sites has                               The market can be considered                                     some growth projected in the number of
saturated, with sales showing a declining                            technology driven in the sense that the                               hospitals performing POC drugs of abuse
trend since 2005. Biosite/Inverness believes                         need for rapid drug screening has existed                             testing, the hospital market has clearly
that its sales in this market may continue                           for some time. However, a significant                                 begun to approach saturation, at least in
to decline as it becomes more price-                                 market did not emerge until simultaneous                              the US. Outside the US, the hospital market
competitive. The other major player is                               multi-drug testing devices were developed.                            is considerably less saturated, but to date
Medtox.                                                              The ease of use of testing devices has been                           adoption of POC drug testing remains
    Concateno, which includes the                                    another factor in driving market growth,                              limited.
                                                                                                                                                               This article is an extract
former Cozart business unit, has recently                            and that trend is expected to continue as
                                                                                                                                                               from the report, Worldwide
emerged as a leading player in the drugs                             new products are introduced providing
                                                                                                                                                               Markets and Emerging
of abuse testing segment. The Cozart unit                            greater convenience for both users and test                                               Technologies for Point-of-
generated sales of £4m ($7.3m) in 2005 for                           subjects. In addition, new high-sensitivity                                               Care Testing, published in
its RapiScan POC drugs of abuse testing                              rapid test systems are about to enter the                                                 August 2009 by InteLab
products, and in 2008 its POC product                                market, such as Philips/Concateno’s device,                                               Corporation. For more
sales totalled £14.4m ($26.7m). Most (about                          providing improved performance and ease                                                   information about the
82%) of the company’s sales are realised in                          of use in addition to a more quantitative,                            report, go to www.intelabcorp.com. Intelab
Europe, and to date have been focused on                             definitive result. However, the new                                   has also launched a new report, The
the criminal justice and workplace testing                           Concateno analyser will not be sold in the                            Worldwide Clinical Diagnostics Market
market, not the hospital POC sector.                                 hospital market initially.                                            2009-2015.

www.clinica.co.uk                                                                                                                                                     © Informa UK Ltd 2010        37
r&D FocUS                                                                                                                Clinica // June 2010




                                                                                                         Copyright: Wellcome picture archive




UK banking on success with
500,000-person “reference library”
                               The UK Biobank is about to reach its target of 500,000 participants,
                               making it one of the biggest health studies in history. Madeleine
                               Armstrong spoke to the project leader, Rory Collins, about how the
                               resource could help unravel the genetic and environmental causes of
                               many different diseases
      Rory Collins




I
     f you’re aged between 40 and 69 and live   out more about the project and ask any          reference library, with a store of information
     in the UK, you might have been invited     questions of their own – they have to give      that’s ready to be tapped into in the future.
     to participate in the UK Biobank. You      written consent before the assessment           “We will only be looking at the people who
may even have decided to donate your            can be carried out.                             develop a certain disease and matched
personal data to the project, which aims            The volunteers provide information          controls, maybe two to three controls per
to improve the prevention, diagnosis and        on their lifestyle and environment using        case,” Prof Collins explained. “It’s much
treatment of serious diseases, including        a touch screen questionnaire that takes         more efficient that way, because you don’t
cancer, heart disease and dementia.             30-40 minutes to complete. It covers factors    have to measure all 500,000 people.
    If so, you’re in good company. Almost       like occupation, social circumstances,              “It also means that we’ll be doing
500,000 people have signed up so far, and       and whether they drink alcohol, smoke or        specific measurements for the disease of
the researchers expect to meet this target      exercise. The system also assesses cognitive    interest, and of course we’ll be doing it five,
in July. “We’re coming close to completing      function, psychological status and hearing.     10 or 15 years down the line, when we’ll be
recruitment nearly a year ahead of              Measurements taken include blood                able to do much more in terms of assays.”
schedule,” Rory Collins, CEO and principal      pressure, height, weight, waist and hip             Another advantage of the biobank is
investigator of the biobank, told Clinica.      circumference and bone density.                 that it can be used to study any disease
“The response has been very positive. We’ve         Biobank staff then collect blood, saliva    that occurs, if enough participants develop
had to open fewer assessment centres than       and urine samples from each volunteer.          the condition. “The beauty of this kind
we anticipated because people have been         These are aliquoted and stored at -80°C in      of project is that it doesn’t focus on any
willing to travel further to take part in the   a specially-designed automated facility,        particular disease,” Prof Collins said.
study than we anticipated.”                     which will allow researchers to access          Patients’ data will be linked with all of their
    At assessment centres in several cities     specific samples quickly. The blood sample      health records, not just death and cancer
including London and Birmingham,                is divided into different components, such      records, which is typical of many large-scale
volunteers spend two to three hours             as plasma, serum, red cells and white cells,    population-based studies. This means that
answering questions and having                  to allow a range of analytes to be measured.    the biobank could be used to explore the
measurements and samples taken.                     But these assessments aren’t being          causes of rarer disorders – the size of the
Participants also have a chance to find         carried out yet. The biobank acts more like a   project is another plus point here, as less

 38    © Informa UK Ltd 2010                                                                                                   www.clinica.co.uk
Clinica // June 2010                                                                                                                    r&D FocUS


common diseases can be overlooked in




                                                                                                                                                Copyright: Wellcome picture archive
smaller samples.
   “Within five years, we’ll have a very large
number of people who’ve developed more
common conditions, such as diabetes,
coronary disease and stroke,” he predicted.
“But as time goes by, more and more
individuals will have developed other, less
common conditions. And of course as they
get older they’ll start to develop conditions
associated with old age, such as dementia.”

Linking up
Once enrolment is complete, the next
stage of the project will be linking each
participant to a wide range of health
records. “That will generate a huge
amount of additional data on disease
outcomes that will need to be checked
and sub-classified,” Prof Collins said. “For
example, if a patient has had a stroke, is it
a haemorrhagic or ischaemic stroke? And
what kind of ischaemic stroke? The more
characterisation we can carry out, the more
valuable the biobank will be to researchers
around the world.” Researchers can apply
to use the information from the biobank,
as long as they put their findings back into                                         Robotic storage facility
the project.
    “During the next five years we’ll be         information about their physical activity.          the website will be “revamped”, according
linking to more and more kinds of records,”      We’re also looking at badges they can wear,         to Prof Collins, with more emphasis on
Prof Collins continued. “Linking to death        and meters in their houses, to measure              informing participants what the biobank
and cancer records and hospitalisations          exposure to various gases.” This could              is being used for and what findings are
is comparatively straightforward, so will        include radon, which Prof Collins says is           emerging from it. “Hopefully, these findings
happen earlier. But as we link more records,     the second most important cause of lung             will then influence the way in which
we’ll get a very large number of health          cancer in the UK, after smoking. “It leaks          participants and their children are cared for.”
outcomes for each participant.                   out of stone and accumulates in peoples’                 Other biobanks already exist, such
    “I think over the next few years the         houses. Even in the same neighbourhood              as the HUNT Databank in Norway,
project will start to produce findings, but      you can get big variations in radon levels,         which holds DNA samples from 200,000
the more mature it becomes, the more             so you need to measure exposure at the              individuals, and Icelandic company
findings that will emerge from it. It will       household level.”                                   deCODE genetics’ database on over 140,000
become more and more valuable as it                                                                  Icelanders. These projects are also similar
studies a wider and wider range                  Altruistic                                          to classic epidemiological studies like the
of conditions.”                                  Patients don’t receive any feedback about           Framingham Heart Study, which aimed
                                                 their data, apart from a summary of their           to identify risk factors for cardiovascular
Nature versus nurture                            body measurements and information about             disease, and the British Doctors Study,
The biobank also aims to untangle                how this compares to measurements taken             which linked smoking to lung cancer and
genetic and environmental causes of              from the rest of the population. “Because           other conditions.
disease. Using the answers from the              the samples aren’t going to be analysed                  “But what’s different with the UK
lifestyle questionnaire, along with body         yet, and because we don’t know what will            Biobank is the scale,” Prof Collins said. “The
measurements and genetic information,            be assessed, we agreed that individuals             [ first] Framingham Heart Study, which
Prof Collins believes it will be possible                                                            is still used by doctors in the UK today to
                                                 should not get details of their results,”
to tease out the different factors that                                                              determine people’s risk of having a heart
                                                 Prof Collins said. “When we explain this,
contribute to diseases: “Let’s say 10,000                                                            attack, only recruited 5,000 people. The
                                                 people are obviously curious about their
people have breast cancer. You can                                                                   British Doctors Study had 50,000. The UK
compare their data with 20,000 people who        individual findings, but the vast majority          Biobank has 500,000 people, with much
didn’t develop the disease but are otherwise     can understand why we don’t give feedback.          more information collected at baseline, and
similar.”                                        Only a few say they’re no longer interested         a much wider range of samples collected,
    Prof Collins plans to take the               in taking part.”                                    which will allow a huge range of assays to
environmental component a step further               So what do volunteers get out of                be done.
by gathering even more data. “For example,       participating in the biobank? “I think the               “I think it’s going to produce some
in the next six months, we will be asking        main motivation is truly altruistic,” he            incredibly important findings that should
participants to wear wristbands with             replied. “It’s like being a blood donor.”           lead to changes in treatment strategies,”
an accelerometer, which will give us                 During the next phase of the project,           he concluded.

www.clinica.co.uk                                                                                                       © Informa UK Ltd 2010   39
pAtENt WAtcH                                                                                                                               Clinica // June 2010




Hydrogel adhesive and shape-memory
mesh for vascular repair
Clinica’s Patent Watch looks at the previous month’s most interesting patent applications.
May’s choices include a “hydroswellable” cartilage, high-strength fibrous tissue glue and a new
“wrap-around” device for treating aneurysms and other vascular conditions. By Phil Greenfield


Orthopaedics
An implant and a surgical procedure developed by a Hawaiian company                    causes the membrane to swell and have a viscoelastic property similar
provides an alternative to conventional joint replacement procedures.                  to the body’s own articular hyaline cartilage. The material comprises
The procedure, which involves restoring a joint with an artificial cartilage,          polyoxyalkylene chains covalently interlinked with polyalkylene urethane
was developed by Kaiser Permanente-Hawaii orthopaedic surgeon                          chain segments, which are further interlinked with aliphatic urea chain
John Frauens, who formed a company, Soft Joint, to develop the device.                 segments. It exhibits more than a 50% increase in volume when placed
WO2010059495 describes the device: a cap made from a polyether-                        in the body. The intra-articular device can be made from a viscoelastic
urethane-urea material that absorbs the joint’s own synovial fluid. This               polyether-urethane-urea material by dip moulding.


                                                                         Orthopaedics

 Number and priority date         title                               Assignee                Description/application

 US20100121459                    Tetra calcium phosphate-             Stryker                A compound that is structurally similar to phosphoserine,
 WO2010056811                     based organophosphorus               Development            and which can be mixed with an aqueous solution to
 12 December 2008                 compositions and methods             (US)                   provide adhesive and cohesive strength in both wet and
                                                                                              dry environments and exhibit significant bond strength
                                                                                              upon curing. These compositions may be used to attach
                                                                                              bone to bone or bone to other materials, such as implants,
                                                                                              for example in fracture fixation.
 US20100121447                    Method for replacing a               Depuy Mitek            Improved methods and apparatus for anatomical
 10 October 2008                  ligament in a knee                   (US)                   replacement of an ACL ligament in a knee. The invention
                                                                                              relates to a method for replacing an ACL in a human knee
                                                                                              by cross-pinning opposite ends of one or more grafts in
                                                                                              respective femoral and tibial bone bores.
 US20100112032                    Bone/polyurethane                    Osteotech (US),        Injectable and/or mouldable composites comprising bone
 30 October 2008                  composites and methods               Vanderbilt             particles and polyurethanes which, when implanted or
                                  thereof                              University (US)        injected, promote cellular infiltration from adjacent osseous
                                                                                              tissues, thus accelerating the remodelling process.

 WO2010059783                     Reinforced biologic material         Lifecell (US)          Composite materials comprising biologic and non-biologic
 21 November 2008                                                                             components for ligament, tendon, and other soft tissue
                                                                                              repair and replacement.
 WO2010059495                     Device & method for                  Soft-Joint (US)        An intra-articular device comprising a membrane cap with
 19 November 2008                 restoring joints with artificial                            geometry similar to a head of a bone for a joint to be
                                  cartilage                                                   restored. The cap has an open end that is stretched over the
                                                                                              head of the bone and held in position on the bone interposed
                                                                                              between the head and the articular component of the joint.
                                                                                              The cap is made from polyether-urethane-urea with a property
                                                                                              of absorbing the joint’s own synovial fluid to swell and have a
                                                                                              viscoelastic property similar to the body’s own cartilage.
 US20100131064                    Bioresorbable polymer                University of          Composite comprising a porous, inorganic bone matrix
 5 April 2006                     reconstituted bone and               Nebraska (US)          structure, the pores of which are filled with bioresorbable
                                  methods of formation                                        polymers or copolymers of certain lactones, as a superior
                                  thereof                                                     bone replacement material.


 40     © Informa UK Ltd 2010                                                                                                                    www.clinica.co.uk
Clinica // June 2010                                                                                                                        pAtENt WAtcH



Surgery
Tissue adhesives have many potential medical applications, including              their effectiveness. However, a tissue adhesive in a fibrous form could
wound closure, supplementing or replacing sutures or staples,                     be more effective in absorbing blood to help control bleeding and
anti-adhesion barriers to prevent post-surgical adhesions, and as a               thereby being easier to apply. WO2010059280 describes a new tissue
haemostatic sealant. Conventional tissue adhesives are not suitable               sealant that may be particularly useful as a haemostatic sealant to
for a wide range of adhesive applications. For example, cyanoacrylate-            stanch bleeding from surgical or traumatic wounds. It is in the form of
based adhesives have been used for topical wound closure, but the                 a sheet comprising two parts: an a fibrous polymer with electrophilic/
release of toxic degradation products limits their use for internal               nucleophilic groups and a second component, also with electrophilic/
applications. Fibrin-based adhesives are slow to cure, have poor                  nucleophilic groups, capable of crosslinking the first component when
mechanical strength, and pose a risk of viral infection. Additionally, the        the sheet is exposed to blood, thereby forming a crosslinked hydrogel
fibrin-based adhesives do not bond covalently to the underlying tissue.           that adheres to biological tissue. The fibrous tissue sealant may also be
Several types of hydrogel tissue adhesives have been developed which              useful as a general tissue adhesive for wound closure, supplementing
have improved adhesive and cohesive properties and are nontoxic.                  or replacing sutures or staples in internal surgical procedures such as
However, these hydrogels typically swell or dissolve away too quickly,            intestinal anastomosis and vascular anastomosis, tissue repair, and to
or lack sufficient adhesion or mechanical strength, thereby decreasing            prevent post-surgical adhesions.


                                                                         Surgery

 Number and priority date title                                   Assignee              Description/application

 WO2010059280                   Fibrous tissue sealant and         Du Pont (US)          An anhydrous fibrous sheet comprising a first component
 WO2010059279                   method of using same                                     which is a fibrous polymer containing electrophilic or
 19 November 2008                                                                        nucleophilic groups and a second component capable of
                                                                                         crosslinking the first component when the sheet is
                                                                                         exposed to an aqueous medium, thereby forming a
                                                                                         crosslinked hydrogel that is adhesive to biological tissue.
 WO2010059234                   Soft tissue repair                 CR Bard (US)          A hernia repair device, which includes a soft tissue repair
 21 November 2008               prosthesis, expandable                                   prosthesis and an expandable device that can be
                                device, and method of soft                               connected with the soft tissue repair prosthesis.
                                tissue repair



Electromedical and diagnostics
Measuring blood perfusion can non-invasively identify the infarct core            the determined ischemic lesion and infarct pixels to determine the
and penumbra in acute stroke. This can provide important information              penumbra, where mismatched regions between the ischemic lesion
to a physician in order to determine an appropriate treatment regime              and the infarct core define the penumbra. Apollo Medical Imaging
for the patient, such as thrombolytic therapy for an acute ischaemic              Technology, based in Melbourne, Australia, develops advanced
stroke patient. Within hours of the onset of a stroke, an ischaemic               image processing software for clinical and research applications.
lesion can consist of an infarct core of irreversibly damaged tissue or           The company has been developing software focusing on emerging
a penumbra region with reduced blood flow that is at risk of further              functional imaging applications (CT/MR/NM whole body perfusion,
infarction, but tissue that can be salvaged by the rapid restoration of           molecular imaging, etc), and cross-modality solutions with automated
blood supply. However, existing techniques of measuring perfusion,                workflow. The company’s MIStar is a multi-modality, multi-module
including MRI and CT, have difficulty in determining which of these               and multi-purpose software package with a broad spectrum of
lesions is present. WO2010055405, from Apollo Medical Imaging                     functionalities ranging from the very basic image visualisation/analysis
Technology, describes a possible solution to this problem. According              to the most advanced functions such as whole body perfusion, multi-
to the patent application, ischaemic pixels can be determined from                modality image fusion and diffusion tensor imaging. It is sold as a
perfusion imaging data, and a cluster analysis is applied to all of               standalone product and on an OEM basis.


                                                          Electromedical and diagnostics

 Number and priority date title                                   Assignee              Description/application

 WO2010056624                   Long-term implantable             Isense (US)            An analyte-sensing assembly for blood glucose monitoring
 11 November 2008               biosensor                                                for long term implantation, comprising an electrode for
                                                                                         insertion below the epidermis and a reference electrode for
                                                                                         insertion below the epidermis, where the indicating
                                                                                         electrode and the reference electrode are coupled.


www.clinica.co.uk                                                                                                               © Informa UK Ltd 2010   41
pAtENt WAtcH                                                                                                                             Clinica // June 2010



                                                     Electromedical and diagnostics (cont)

 Number and priority date title                                   Assignee                Description/application

 WO2010056624                   Long-term implantable             Isense (US)             An analyte-sensing assembly for blood glucose monitoring
 11 November 2008               biosensor                                                 for long term implantation, comprising an electrode for
                                                                                          insertion below the epidermis and a reference electrode for
                                                                                          insertion below the epidermis, where the indicating
                                                                                          electrode and the reference electrode are coupled.
 WO2010055405                   Method and system for             Apollo Medical          A method of identifying ischaemic lesions. The method
 14 November 2008               mapping tissue status of          Imaging                 includes loading perfusion imaging data into an electronic
                                acute stroke                      Technology              memory element and deriving perfusion maps from the
                                                                  (Australia)             perfusion imaging data, where the perfusion maps include
                                                                                          a cerebral blood volume map and an arterial delay time
                                                                                          map, which utilise arterial delay and dispersion effects.
 WO2010052660                   Coupled antenna                   Physical Logic          Antenna coils that permit deeper penetration into tissue for
 6 November 2008                impedance spectroscopy            (Switzerland)           glucose detection, improving the signal-to-noise ratio and
                                                                                          expanding the spectral range for greater accuracy and precision,
                                                                                          to enable continuous non-invasive monitoring for either
                                                                                          improved patient or automated management of diabetes.
 WO2010049523                   Antenna arrangement and           Arbexa Industries       Antenna design for increasing signal to noise ratio for
 30 October 2008                apparatus for microwave           (Sweden)                microwave imaging of the physiologic properties of tissues
                                imaging                                                   and organs.




Cardiovascular and peripheral vascular
WO2010048671 describes a new device and methods for treating                       The mesh-like device can be made from Nitinol or another shape-
stenoses, aneurysms or other conditions that require a vessel to be                memory material, and can be delivered by minimally-invasive or
supported. The flexible device could be used for treating cerebral                 intravascular means. WO2010059563 describes another new way to
aneurysms as an alternative to clipping it at the neck (a procedure                treat aneurysms. In this case, the invention is a stent graft for treating
performed by a neurosurgeon). It could also be used in endovascular                abdominal aortic aneurysm that features drug-delivering polymer
repair by coiling, stenting or both (performed in a radiology suite); or           micelles that are stimulated by radiofrequency, ultraviolet or infrared
wrapping with material, such as muslin (performed by neurosurgeon).                energy to deliver blood clotting or other therapeutic agents.


                                                     Cardiovascular and peripheral vascular

 Number and priority date        title                                     Assignee                Description/application

 WO2010048671                    Vessel support device and                 Macquarie               Devices and methods for supporting a vessel in the
 30 October 2008                 methods                                   University              human body, such as a vessel from the vasculature,
                                                                           (Australia)             biliary tract, gastrointestinal system or genitourinary
                                                                                                   system. The device can support part or whole of the
                                                                                                   circumference of the interior or exterior of a vessel.

 WO2010059563                    Targeted drug delivery for                Medtronic Vascular      Localised treatment of aneurysms using polymer
 WO2010059561                    aneurysm treatment                        (US)                    micelles that release therapeutic agents when
 24 November 2008                                                                                  exposed to energy.

 WO2010056341                    Compositions and methods for              University of           Compositions comprising mesenchymal stem cells
 12 November 2008                tissue repair                             Vermont and State       or multipotent stromal cells, and methods using
                                                                           Agriculture College     these cells to repair or regenerate a damaged
                                                                           (US)                    tissue or organ, particularly in the prevention of
                                                                                                   tissue damage related to ischaemic injury (including
                                                                                                   cerebral or cardiac ischaemia).


 42     © Informa UK Ltd 2010                                                                                                                  www.clinica.co.uk
Clinica // June 2010                                                                                                               compANy FocUS




Sheep give Bioventix the advantage in
immunodiagnostic market
Rodents have long been used to provide monoclonal antibodies for the diagnostic
testing market. However, UK firm Bioventix has pioneered the use of sheep cells to
create more effective antibodies. Joseph Harvey met the firm’s CEO Peter Harrison to
find out why sheep are the way forward for diagnostics


B
         ioventix specialises in developing        company, having launched its IPO in April           unlikely to run out of projects to work on:
         sheep monoclonal antibodies (SMAs)        this year. The firm floated around five million     “There are always new targets and new
         for use in immunodiagnostics, with a      shares on the PLUS-quoted stock market at           sciences to work on”.
particular focus on clinical diagnostics and       an opening price of 198p per share. Bioventix           The company first commercialised its
drugs-of-abuse testing.                            believes that it has reached an appropriate         own SMAs in 2009, launching monoclonal
    The Farnham-based company creates              point in its development to seek a public           antibodies for oestradiol and testosterone,
hybrid cells by fusing myeloma cells               listing for its shares and gain funds required to   both markers for fertility. Mr Harrison said
(abnormal plasma cells) with sheep cells.          finance future projects and possible strategic      that, although there were already similar
This process combines the antibody                 acquisitions, if the opportunity arises.            markers for testosterone on the market when
secreting properties of the sheep cell with             The company recorded sales of                  Bioventix launched its own, this product
the “immortality” of a myeloma cell.               approximately £1.6m in fiscal 2009, a 65%           was able to demonstrate the advantages
    SMAs are used as markers: they detect and      increase on the previous year’s revenue. Net        of the company’s technology and prompt
attach themselves to their target particles and    income for 2009 was around £0.6m, double            leading players to adopt their tests. An SMA
are then detected themselves. The ultra-high       2008’s figure.                                      for vitamin D deficiency is scheduled to be
affinity of this type of monoclonal antibody                                                           commercialised in 2013, while drugs-of-abuse
means that they remain bound to their target       Business strategy                                   antibodies are also planned.
for approximately 100 times longer than            The company has been commercialising its
rodent antibodies, allowing the development        SMAs since 2003 and has built a customer            Future prospects
of diagnostic immunoassays with increased          base that features Abbott Laboratories,             Despite having significantly expanded
sensitivity and precision.                         Beckman Coulter, Ortho-Clinical                     its product portfolio since 2003, Mr
    It is the high affinity SMAs have for their    Diagnostics, Roche and Siemens.                     Harrison said that the company has been
antigens that the company’s CEO Peter                  The firm’s first antibodies were created        experiencing modest revenue growth
Harrison believes gives Bioventix’s technology     via sponsored work for customers. It created        over the past 2-3 years. He believes the
a major advantage over other monoclonal            antibodies for hormone imbalance (T4) and           turning point will come in 2013, when the
antibodies on the market. Not only are they        for use as cardiac markers (NT-proBNP) in           firm expects to launch what it considers
able to bind to targets that are present in very   2004. The latter still provides the firm with       a premium product, the SMA for vitamin
low concentrations, they can also recognise        half of its revenue, according to Mr Harrison.      D testing. In addition, Mr Harrison
what Bioventix calls ‘difficult’ targets or            Currently, the firm is developing two           told Clinica that another new project is
closely-related molecules that rodent              SMAs to help detect cortisol ( for hormone          underway to develop an SMA to detect
antibodies have not been able to tell apart.       imbalance and stress) and troponin (another         troponin levels as a way of identifying
    Mr Harrison told Clinica that Bioventix        cardiac marker) as part of contract work            individuals at risk of heart disease.
is the only company using sheep cells to           for customers. These SMAs are set to be                 The firm’s short-term goals are to grow its
form monoclonal antibodies. However, this          commercialised in 2011 and 2013, respectively.      product pipeline and get these new SMAs to
doesn’t mean that the firm is alone in this            About half of Bioventix’s revenue stream        market, the CEO said. Bioventix also has an
field: “We compete with the in-house teams         is taken from contract services provided to         eye on possible mergers and acquisitions; Mr
at companies like Roche and Siemens who            diagnostics companies. As part of this service,     Harrison said that the company had money
are creating their own antibodies,” said           Bioventix creates SMAs that can be used             in the bank and it would “definitely consider”
Mr Harrison.                                       against an antigen of the customer’s choice.        purchasing a complementary business if the
    The company has been around since              Bioventix also receives a royalty from the          opportunity arose.
the early 1990s, when it was a laboratory          customer, once the SMA is commercialised.               When asked about the firm’s long term
owned by biotechnology firm KS Biomedix.           Mr Harrison told Clinica that “even a 2%            aspirations, the CEO said that the company
In September 2003, another biotech firm,           royalty would be enormous for [Bioventix]”.         is already profitable and expects modest
Xenova Group, bought KS Biomedix and, a                “The sponsored projects provide a               growth in profitability over the next few
few months later, sold the laboratory to a         guaranteed customer” said Mr Harrison.              years. And beyond that? “Who knows?” said
newly-created company called Bioventix for             Bioventix aims to produce two new SMAs          Mr Harrison. He explained that the company
£800,000 ($1.2m).                                  each year, through a 50-50 combination of           was firmly focused on its current operations,
    Fast forward seven years to the present,       working on its own antibodies and sponsored         but implied that greater success could not be
and Bioventix is now a publicly-listed             work. Mr Harrison said that the firm was            far away.

www.clinica.co.uk                                                                                                         © Informa UK Ltd 2010   43
pArtNErING                                                                                                                Clinica // June 2010




Medtech Ventures
Some 40 companies from Europe and the US presented their technologies to potential investors
at the second EuroMedtech partnering conference held in Leipzig, Germany, on 1-2 June. In this
month’s Medtech Ventures, we pick out three young firms, developing next-generation products
for the cardiovascular disease and brain trauma/stroke markets


 Hot pick of the month
 Miracor Medical SySteMS
Specialty area(s): Devices for improving         undergone PCI end up with suboptimal             heart muscle to build up, which pushes the
post-PCI perfusion                               microcirculation (i.e. scoring a myocardial      blood into the border zone of the ischaemic
Based in: Vienna, Austria                        blush grade of 0/1). In the longer term, this    tissue. When the coronary sinus pressure
Founded in: 2008                                 increases the risk of major adverse cardiac      plateau is reached, the balloon deflates.
No. of employees: 6                              events (MACE) and another heart attack           This effect, similar to a dam bursting,
Total investment received to date: €6m           occurring. “Even with ideal blood flow           causes a “washout” of the coronary veins.
Investors: Earlybird Venture Capital and         through the stent, studies show that 18.3% of    The technology may also have important
Delta Partners                                   patients with a blush grade of 0/1 will die at   regenerative effects.
                                                 12 months,” says Mr Hoem.                            The pressure plateau differs from patient
Since the first balloon angioplasty was             Miracor’s PICSO (Pressure-controlled          to patient, and Miracor’s proprietary Wien
performed over 30 years ago, the procedure       Intermittent Coronary Sinus Occlusion)           Algorithm – incorporated in the console –
has become the standard of care for acute        procedure redistributes the blood flow           calculates this plateau and each patient’s
coronary syndrome and heart attack                                                                inflation/deflation cycle.
patients. Some three million angioplasties                                                            The procedure will take place straight
were performed worldwide in 2009 and                                                              after a patient receives a stent or during the
this number is expected to grow in tandem                                                         stenting procedure; the treatment would
with the ageing population and the rise in                                                        typically last 90 minutes. However, if the
cardiovascular disease.                                                                           infarct is large, the treatment time could be
    Miracor Medical is targeting this pool                                                        longer.
of patients, but the technology it has                                                                Similarities have been drawn between
developed is not in competition with any                                                          Miracor’s PICSO technology and intra-aortic
angioplasty/stenting technologies. Instead,
the Austrian firm’s PICSO Impulse System                                                                    Did you know?
is designed to work in conjunction with
percutaneous coronary intervention (PCI)             The Miracor PICSO Impulse system               The founder of Miracor, Prof Werner
to revitalise the tissue damaged during the                                                         Mohl, came up with the concept for
heart attack by improving microcirculation       into affected areas of the heart, as well          the PICSO technology in 1979. He
in the myocardium.                               as flushing out microemboli in the                 had attended a lecture by a Polish
    The company believes, based on initial       venous circulation arising from the heart          surgeon who had expounded the idea
market research, that each year there            attack. This contributes to improved               of forcing arterial blood into the heart
are 410,000 patient candidates for its           microcirculation and has the potential to          to help regenerate muscle. While he
PICSO procedure in the US alone, and             reduce the infarct size. The technology may        agreed with the benefit of flushing
a further 240,000 in the EU. “There is a         also be used in heart failure and cardiac          out malfunctioning blood vessels to
clear consensus among interventional             surgery patients.                                  improve microcirculation, Prof Mohl
cardiologists in Europe and the US that              The PICSO Impulse system consists of           felt that this approach would not work,
they need a technology to improve                a low-profile, single-use balloon catheter         as the pressure of the blood being
outcomes in patients with large anterior         and an external console which controls             pumped out would be enormous.
infarcts – the so-called STEMI patients”,        the inflation and deflation of the balloon.        That set him thinking of a “back door”
says Miracor CEO Jon Hoem.                       The catheter accesses the coronary sinus           approach, where the pressure on the
    “Coronary stents help to open the arteries   either via the femoral vein, the internal          blood flow is much lower – in other
and restore blood flow, but they do not          jugular vein or the brachial vein. Once it is      words, the coronary sinus. This is also
help microcirculation in every patient,” he      placed in the coronary sinus, the balloon is       the approach that cardiac surgeons use
continues. Studies have shown that around        automatically inflated and acts like a dam,        every day for cardioprotection during
30% of the STEMI (ST-segment elevation           temporarily blocking the heart’s venous            cardiac surgery procedures.
myocardial infarction) patients that have        outflow. This causes the pressure in the

 44    © Informa UK Ltd 2010                                                                                                    www.clinica.co.uk
Clinica // June 2010                                                                                                                pArtNErING


balloon pumps (IABPs), which have been in       cardiac surgery patients, has much wider         strategy, Miracor will take a cautious
existence as far back as the 1960s. But Mr      application.                                     approach and sell the system directly
Hoem maintains that the two technologies            The PICSO technology was first               in select European countries. “The
have very different functions. An IABP          conceived some 30 years ago by Miracor           technology is advanced and our clinical
consists of a balloon that sits in the aorta    founder and chief scientific officer Prof        application specialists need proper skill
and actively inflates and deflates with         Werner Mohl (see Did you know?). A very          sets to teach the use of the product. In our
every heart beat. “It increases perfusion in    early version of the technology was tested       experience, this kind of technology does
the coronary arteries, in the arterial side,    clinically in the 1980s, on heart attack         not lend itself well to commercialisation
when the balloon is inflated, and it reduces    patients who were receiving thrombolytic         by third-party distributors. We’ll first target
afterload when the balloon is deflated. What    therapy. Results from these early trials show    German-speaking countries, Benelux and
the PICSO Impulse System does, sitting on       that PICSO-treated patients experience an        Scandinavia, and establish the technology
the venous side, is to intermittently block     86% reduction in risk of MACE and 96%            there, before expanding into other
outflow. This occlusion is held over multiple   reduction in risk of re-infarction.              European markets,” says Mr Hoem.
heartbeats to increase the pressure and             The current, new-generation PICSO                Miracor will not overlook the US, where
redistribute flow in the border zone and        Impulse System has already undergone             the PICSO technology will be approved via
washout of microemboli in the venous            preclinical trials and successfully              the premarket approval (PMA) route. But
circulation,” he tells Clinica. “The PICSO      demonstrated the procedure’s safety, says        for now, the company will focus its efforts
technology and IABPs are not competitive        Mr Hoem. The firm is now recruiting for a        on getting its technology through the CE
but rather complementary. The ideal device      multi-centre European clinical trial, called     mark process, the RAMSES trial and onto
is a combination of the two as documented       RAMSES, and expects to initiate the study        the European cardiology market.
in preclinical trials. One improves arterial    in the first quarter of 2011.
inflow, the other clears the microcirculation       The company is also confident it will be        Jon Hoem, CEO.
and redistributes blood flow.”                  able to CE mark the product early next year,        Tel: +43 1236 657 611.
    Mr Hoem adds that the indications           as it believes it has sufficient clinical data      Email: jhoem@miracormedical.com
are also different for the two technologies.    from trials of the early version of the PICSO       Miracor Medical Systems GmbH.
IABPs are indicated for haemodynamically        technology, as well as its preclinical safety       Mariannengasse 14/14, A-1090 Vienna,
unstable patients, while the PICSO, which       data, to gain European approval.                    Austria.
targets heart attack, heart failure and             In terms of its commercialisation               www.miracormedical.com


 Minnow Medical

Specialty area(s): Radiofrequency balloon       as stents and balloon angioplasty, or even       arterial plaque, the balloon is inflated at a
angioplasty                                     more recent technologies like atherectomy        low pressure – between 3-4 atm compared
Based in: San Diego, California, US             devices, are not able to successfully address.   to 10-12 atm for a typical angioplasty –
Founded in: 2003                                   “We are not replacing or competing            until it makes contact with the artery wall.
No. of employees: 12                            directly with stents. We’re targeting            Low-powered, nonablative RF energy from
Total investment received to date:              speciality areas such as the back of knee,       the generator is then delivered through the
Confidential                                    over the knee, the lower extremity arteries      balloon catheter electrodes to the plaque.
Investors: Neomed and private investors         – where stents can actually fracture and             The treatment time would vary,
                                                angioplasty balloons can dissect the             depending on the length of the lesion.
The ageing population, coupled with the         arteries,” Tom Steinke, president and CEO        Typically, a 20mm lesion would take around
rise in obesity and related diseases such       of Minnow, tells Clinica.                        10-15 seconds to treat.
as diabetes, are pushing the incidence of          Minnow’s ZCath System consists of a               The moderate heat generated from the
vascular disease. Peripheral artery disease     disposable balloon catheter and an external      RF energy not only reduces the volume of
(PAD) is the buildup of plaque in the large     RF energy generator. The catheter has            plaque, it also helps to inhibit artery recoil
arteries that carry blood to the arms and       micro-thin electrode strips mounted along        (when the artery returns to its original size)
legs. PAD in the leg is said to affect up to    the length of the balloon’s surface. When        and restenosis by preventing the disease
20% of Americans aged 65 or older and           the balloon catheter is placed at the site of    from progressing. This is achieved through a
results in over 250,000 amputations                                                              series of mechanisms, explains Mr Steinke.
each year.                                                                                       The moderate heat breaks down the collagen
    Minnow Medical has developed what                     Did you know?                          of the plaque irreversibly. The plaque then
it believes is a unique technology, which                                                        becomes more compliant, so that it can
combines radiofrequency (RF) energy with          The name of the company, Minnow,               reshape around the balloon catheter more
balloon angioplasty, to target the growing        was given by one of CEO Tom Steinke’s          easily, minimising stretching and injuring
PAD market. The San Diego, California firm        children. The firm says its name               the vessel. The changes to the collagen also
is specifically homing in on niche areas          reflects its position as “a small fish in      reduce the volume of plaque, by expelling
in which stenting should be avoided – for         a big pond”, swimming among the big            water. This results in a larger arterial lumen,
example, anatomically difficult locations         vascular intervention players such as          and the process does not lead to any debris
and disease at artery bifurcations – and          J&J, Boston Scientific and Medtronic,          (which could become potentially harmful
those which current interventions such            to name a few.                                 emboli). Proteins that cause artery recoil
                                                                                                                                             p46
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www.clinica.co.uk                                                                                                    © Informa UK Ltd 2010   45
pArtNErING                                                                                                                   Clinica // June 2010


are denatured as a result of the treatment,                                                       this year. By then, the firm hopes to be able to
and restenosis is reduced by inhibiting small                                                     have its next-generation ZCath system ready.
muscle cell proliferation and deactivating                                                        This new version will be a “more intelligent”
macrophage and foam cells.                                                                        system, and provide more feedback on how
    The company has completed a                                                                   to treat the lesion to the physician. The
prospective, open-label, non-randomised                                                           company plans to commercialise it directly
study across five sites in Germany,                                                               in the US, unless, it says, it can find a suitable
Argentina and Chile, involving 78 patients                                                        partner with a large distribution network
with a total of 83 lesions. The treatment                                                         across the country.
met its safety endpoint, with no major                                                                As for other indications, Minnow
adverse clinical events occurring within        The electrode-mounted balloon catheter of         believes the ZCath system can also be
30 days, no device-related serious adverse               Minnow’s ZCath system                    effective for treating in-stent restenosis.
events, nor any flow-limiting dissections.                                                        “We have already used the device in three
The results showed that on average, based       using energy to open total occlusions, but        in-stent restenosis patients with excellent
on visual assessment, stenosis was reduced      these arteries then need to be treated by         results. [Our technology] could provide
from 86% before treatment to 14% post-          something like Minnow’s ZCath system to           a solution to this vexing problem, that
treatment. In terms of the durability of the    finish the job,” he says.                         usually uses another stent inside the
treatment, nearly 73% of the 50 patients            The ZCath system was CE marked in             original clogged stent,” says Mr Steinke. It is
treated at the Leipzig clinical trial site      April 2010 and the company is currently           also exploring the use of the device in deep
showed no binary restenosis at six-month        seeking partners to distribute the device         vein thrombosis and other forms of PAD,
follow-up. “More importantly, we achieved       in Europe. It is also working to raise $10m       such as in the tibial artery.
these results without any use of adjunctive     to support their US regulatory activities,
therapy – no stents, athrectomy or laser,”      obtain reimbursement in various countries            Tom Steinke, CEO and president.
says Mr Steinke.                                and expand the device size offering.                 Tel: +1 858 217 0300.
    According to Minnow, there are no               The firm submitted its application for           Email: tsteinke@minnowmedical.com
other companies that are developing an          510(k) clearance to the FDA at the end of            Minnow Medical Inc. 10911 Technology
RF balloon angioplasty technology for use       February. If all goes well, Minnow expects to        Place, San Diego, CA 92127, US.
in arteries. “There are some companies          get the all-clear from the agency by the end of      www.minnowmedical.com

 eBS technologieS
Specialty area(s): Noninvasive electrical       improving their performance.”                     of the AlphaSynch on 20 patients with visual
brain synchronisation                               While there are already invasive deep         field loss caused by optic nerve damage.
Based in: Kleinmachnow, Germany                 brain stimulation (DBS) technologies that         Results showed that after 10 days, patients
Founded in: 2007                                are on the market for treating functional         were starting to see 36% improvement
No. of employees: 10                            loss of the brain, Dr Sabel stresses that the     in vision, accompanied by up to 30%
Total investment received to date: €4m          AlphaSynch is not positioning itself as an        improvement in brain wave activity in the
Investors: Earlybird Venture Capital, High-     alternative to DBS, but rather a new way          visual centres of the brain. One patient, who
Tech Gründerfonds, Brandenburg Capital          of treatment. “Besides, the AlphaSynch            had only 3% vision before the treatment and
                                                will be going for different indications than      was almost blind, showed 18% vision after 10
Stroke is not only one of top killers in the    DBS. And unlike DBS, AlphaSynch does not
rich world, it is also a leading cause of       focus on stimulating a particular area of
disability. Treatment and rehabilitation of     the brain, but it induces synchronisation of
                                                                                                             Did you know?
stroke victims is a heavy financial burden      brain wave activity as a network,” he adds.         EBS Technologies’ founders, chief
– in the US, the lifetime cost per patient          The key components of the AlphaSynch            scientific officer Bernhard Sabel and
averages at hundreds of thousands of dollars.   system are the electrical brain synchroniser        his wife Kornelia, who is CEO, had
    In Germany, where there are over one        and a cap, worn by the patient which has            previously started up another company
million stroke patients each year and the       electrodes mounted onto it. The electrodes          together, NovaVision, which developed
annual treatment costs are around €7.1bn,       deliver a very low electrical current – less        software for treating partial blindness.
Kleinmachnow-based EBS Technologies             than one milliamp – through the optic               Dr Sabel believes that their distinct
is developing a noninvasive device to           nerve and into the brain at a specific              strengths – his being in science and
resynchronise brain waves and treat             frequency. The current induces a pulse              technology and Mrs Sabel’s, an MBA
functional loss in language, vision, motor      that stimulates the nerve cells to fire. “The       holder, her business know-how – makes
performance and cognition resulting from        secret is the frequency at which the current        for a successful partnership. “Generally
stroke or brain trauma.                         is delivered – this is the key part of the          speaking, married couple businesses
    “Our device, the AlphaSynch, is like        technology” says Dr Sabel.                          are a ‘no-go’ area for investors. But
a brain pacemaker, but a noninvasive                The therapy is “completely painless”, and       Kornelia and I have successfully raised
one that does not require surgery,” chief       can be performed in the clinician’s office.         venture financing together,” says
scientific officer Bernhard Sabel tells         Each treatment lasts 20-40 minutes and is           Dr Sabel. “Our dinners often end up
Clinica. “We are targeting neuronal             administered once a day for 10 days.                being executive meetings. So married
networks in the brain that have been                The company has successfully completed          couple businesses can work!”
partially damaged, with the goal to             two small clinical trials, testing the efficacy

 46    © Informa UK Ltd 2010                                                                                                     www.clinica.co.wuk
Clinica // June 2010                                                                                         pArtNErING/pEoplE IN tHE NEWS


days of therapy. And the patient continued to     so they are predisposed to recover more           already enlisted three sales and marketing
show improvement even after therapy had           slowly and less fully from brain trauma,” Dr      partners and hopes to see the first revenues
stopped. “At 60 days post-treatment, vision       Sabel tells Clinica. This does not mean that      from initial sales of the AlphaSynch shortly
continued to improve to 23%,” says Dr Sabel.      the AlphaSynch would not be appropriate           after regulatory approval. The company is
    However, it appears that the AlphaSynch       in these cases, but that a different protocol     also now looking to raise additional capital
is not suitable for all patients. In one of the   may be needed to make it more effective.          to fund its market entry costs.
trials, where the AlphaSynch was compared             Meanwhile, EBS is also planning to
with a placebo, the company found that            carry out a multicentre trial involving              Bernhard Sabel, chief scientific officer.
over half of the patients did not respond         100 patients with visual field loss, and             Tel: +49 33203 50 380.
to EBS’ therapy. The firm is currently            has initiated a smaller trial to test the            Email: info@ebstech.de
investigating the reason for non-response.        AlphaSynch on patients with aphasia.                 EBS Technologies GmbH. Albert-Einstein-
“One possibility is that some patients do             The company is expecting to CE mark the          Ring 7, 14532 Kleinmachnow, Germany.
not have sufficient plasticity of the brain,      device by the second quarter of 2011. It has         www.ebstech.de


 People in the news
                      Leukocare has made         corporate vice-president and president          Kolls had worked in the same positions for
                     Wolfram Altenhofen           of eyecare and medical technology firm          another orthopaedic specialist, Orthofix
                     its new vice-president of    Allergan Medical. He has also worked in         International, since 2004. He has over 20
                     business development. Dr     several management positions at Lumenis,        years’ experience in corporate governance,
                     Altenhofen was previously    including executive vice-president of the       commercial transactions and employment
                     responsible for building     company’s ophthalmic unit. Andy Corley,         law. Wright (Arlington, Tennessee)
      Wolfram        up the firm’s sales forces   president of B+L’s surgical business since      specialises in devices and biologic
     Altenhofen      in Europe and India. This    2008, will become senior advisor to the         products for extremity, hip and knee repair
                     appointment comes as         group.                                          and reconstruction.
                     part of the company’s
   dynamic growth programme, whereby               Michael McNulty is to become chief             Molecular diagnostics company
   Leukocare also merged their R&D division       operating officer of molecular diagnostics      Predictive Biosciences has filled two
   in Frankfurt with its head office in Munich    firm Response Genetics. From 12 July, Mr        newly-created roles on its management
   and relocated to Martinsried on 1 June.        McNulty will be responsible for the firm’s      team. James Groves has become the firm’s
   Leukocare’s technology involves coupling       strategy and corporate development.             vice-president of lab operations, while Mark
   functional molecules to the surface of         Before joining Los Angeles, California-         Smith has been appointed vice-president
   medical devices, and stabilising these         based Response, Mr McNulty worked as            of information technology. Mr Groves
   molecules so that they are not destroyed       general manager, diagnostics at Agilent         was previously head of operations for SED
                                                  Technologies. He has also held the role of      Medical Laboratories and chief operating
   during sterilisation and other procedures.
                                                  vice-president, laboratory operations at        officer and vice-president of clinical
   It has a broad range of applications in the
                                                  Berkeley HeartLab, which now known as           operations at the Beijing International Heart
   fields of medical devices and diagnostics.
                                                  Celera Diagnostics. Response Genetics is        Hospital. Mr Smith most recently worked
                                                  focused on the development of PCR-based         for Athena Diagnostics as vice-president
    Satoshi Tsunakawa is to become
                                                  tests for detecting non-small cell lung,        of information technology. Predictive
   the new president and CEO of Toshiba
                                                  colorectal and gastric cancers.                 Biosciences (Lexington, Massachusetts) is
   Medical Systems. Mr Tsunakawa has
                                                                                                  currently developing molecular diagnostic
   been at the Toshiba group since 1979, in
                                                   Pedicle screw placement specialist            cancer assays and anatomic pathology
   various positions within the company’s                                                         laboratory products.
                                                  SpineGuard has elected orthopaedic
   medical business. From 2004 until 2008,
                                                  entrepreneur Alan Olsen chairman.
   he was president of Toshiba America            Mr Olsen has served as a director of             Molecular diagnostics specialist
   Medical Systems and, for the last year, he     SpineGuard since November 2009. He has          Myriad Genetics (Salt Lake City, Utah) has
   led the global sales, strategic planning and   in-depth knowledge of the orthopaedic           appointed Heiner Dreismann to its board
   corporate communications operations.           market – he was founder and president           of directors. Dr Dreismann has over 24 years
   He replaces Kenichi Komatsu, who will          of Danek Medical, which recorded more           of experience in the healthcare industry, and
   become an adviser to the firm’s board and      than $90m in orthopaedic sales in the           currently serves on the boards of several
   an advisor to the Toshiba group. Toshiba       early 1990s before merging with Sofamor         public and private companies in the sector.
   Medical Systems specialises in diagnostic      and, later, being bought by Medtronic.          He worked for Roche from 1985 until 2006,
   imaging systems, including X-ray, MRI, CT      Mr Olsen is also currently the CEO and          where he held several positions, including
   and ultrasound systems.                        chairman of Atlas Spine, a spinal implant       President and CEO of its molecular systems
                                                  company.                                        division, and head of global business
   Robert Grant will become CEO and                                                               development of Roche Diagnostics. He was
   president of eyecare specialist Bausch          Raymond Kolls has been appointed              one of the early adopters of polymerase
   + Lomb’s global surgical business on 1         to the positions of senior vice-president,      chain reaction (PCR) technology, which is
   August. Before joining Rochester, New          general counsel and secretary for               now one of the most widely-used techniques
   York-based B+L, Mr Grant was the               orthopaedic firm Wright Medical. Mr             in genetics research.


www.clinica.co.uk                                                                                                      © Informa UK Ltd 2010   47
q&A                                                                                                                             Clinica // June 2010




Five minutes with…
Martin Pickford of Accentus Medical
Martin Pickford joined Accentus Medical as managing director in 2000. Before joining
Accentus, he held positions at leading orthopaedic firms Corin and Zimmer. Accentus
claims to be the largest UK supplier of specialist coatings to the orthopaedic
manufacturing industry. The Didcot-based firm is currently developing its Agluna surface
modification technology for knee revision procedures
                                Clinica: Over the past decade, what         to normal, active lives. Also, because Accentus is very much in the
                                has been the single most important          manufacturing sector of the economy, we are providing employment
                                innovation in orthopaedics?                 for an increasing number of people in the communities around our
                                MP: During the last ten years, the          base at Harwell, south of Oxford. In the current financial climate, I
                                advent of newer, tougher materials          am personally very proud of that fact.
                                such as cross-linked polyethylene and
                                the arrival of new bearing couples such     Clinica: What is the worst part of your job?
                                as metal-on-metal and ceramic-on-           MP: The development and commercialisation of new technologies
                                ceramic have changed the situation for      in the medical device field is often a slow, methodical, and
                                orthopaedics dramatically. There are        sometimes tortuous process. As a naturally impatient person, I find
                                now literally hundreds of thousands of      this extremely frustrating. However, the challenge of overcoming
      Martin Pickford           patients around the world under the         technical problems and clearing the various obstacles which appear
                                age of 60 who have returned to full,        in our way is also intellectually very stimulating. I get a great deal of
active life after having received new generations of implants that may      satisfaction when the company’s goals are met as expeditiously as
very well continue to perform satisfactorily for the rest of their lives.   possible despite all of the hurdles that have to be jumped along
This has been a great step forward for orthopaedics.                        the way.

Clinica: What will be the next game-changing technology in the              Clinica: What sets Accentus’ technology aside from its
field of orthopaedics?                                                      competitors?
MP: Although the incidence of infection following primary joint             MP: There are many companies working on technologies aimed
replacement is only a few percent of the total number of cases              at reduction of infection rates following the implantation of
performed, they can be very serious and difficult to treat. Bone does       orthopaedic devices. We feel that our patented Agluna surface
not have a good blood supply and therefore it is difficult to target        modification has several advantages. It was the first technology of its
the infection by prescribing systemic antibiotics, and many of the          type to enter clinical evaluation at two major orthopaedic oncology
organisms which cause these infections are becoming increasingly            centres in the UK. We now have four years follow-up on the earliest
resistant to antibiotics. Many patients with implant-related infection      patients and the results are very encouraging for the future of Agluna.
end up in hospital for extended periods and often end up having their       In addition, it is a relatively inexpensive process to perform. With
implants removed and replaced by new ones.                                  increased pressures on reimbursement for medical procedures
Antibacterial coatings aimed at preventing such infections occurring        this will be a very important factor, not only in orthopaedics but
in the first place are currently being developed to address this urgent     also in other areas such as cardiac and dental implants where such
and very expensive clinical problem.                                        technology could be used in the fight against infection.

Clinica: What is the best part of your job?
MP: The products and processes we have developed continue to
help innumerable recipients of joint replacement implants to return         Martin Pickford was talking to Joseph Harvey



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