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Medical Devices
Europeans are left to their own devices
Deborah Cohen
investigations editor
Matthew Billingsley
editorial intern
    BMJ, London WC1H 9JR, UK
Correspondence to: D Cohen
, doi:10.1136/bmj.d2826
, doi:10.1136/bmj.d2973
, doi:10.1136/bmj.d2905
, doi:10.1136/bmj.d2839
When it comes to medical devices, it seems that Europeans get a worse deal than US patients,
and even that their safety could be being compromised. Deborah Cohen and Matthew
Billingsley compare the regulatory systems

    Slick and efficient or opaque and patchy—these     implemented by each member state‘s national
are two of the views about the European medical        regulator. But the EU claimed earlier this year that
device regulatory system expressed during a recent     there was a need to ―adapt the European regulatory
US Congress debate. But unlike the case with say,      framework in order to secure patients‘ safety while
consumer drug advertising or other marketing           favouring innovation.‖(5) However, it is uncertain
incentives, the devices industry argues that           how much its proposals will actually change the
conditions are more favourable in Europe.              current system—financial constraints may mean
    ―European regs are driven by one key goal:         that only superficial tweaks are made.
innovation,‖ one industry report suggests.(1) And
another says that the conditions in Europe favour      Unknown quantity
medical technology companies—they can obtain               The UK regulator, the Medicines and
regulatory approval more quickly, generate             Healthcare Products Regulatory Agency (MHRA),
revenues faster, and ―engage patients and providers    also has concerns about the current system, saying
in the cycle of innovation to advance their products   that ―the evidence on safety and efficacy of new
and services.‖(2)                                      devices and new procedures at the time they are
    John Wilkinson, chief executive of Eucomed (a      introduced into UK practice is very variable.‖ It has
European medical device industry trade                 also suggested that the evidence base for most
association), said in a report: ―The current EU        devices was poor.(6)
regulatory system makes innovative medical                 The number of different types of devices on the
technology available to people the fastest in the      market is about 80<thin>000(7) in the UK and there
world while ensuring the highest safety                are over 200<thin>000(8) in Europe. We can‘t be
standards.‖(3)                                         certain about the numbers because not only is there
    But although the conditions might be more          no publicly available list of devices being used day
favourable to industry, not everyone agrees that       to day in healthcare settings but the MHRA does
this is the best for patients—and that includes the    not know precisely which class III devices (the
director of the US Food and Drug Administration‘s      most risky) have been cleared for use in the UK or
centre for devices and radiological health, Jeffrey    Europe. Such devices include stents, prosthetic
Shuren. Quoting a plastic surgeon as saying that       heart valves, hip implants, and pacemakers.
under the EU system, the public are being used as          One reason for the lack of knowledge at both
guinea pigs, he gave a stinging rebuke to the          UK and European level is that the decision on
Europeans. ―We don‘t use our people as guinea          market authorisation of high risk devices is made
pigs in the US,‖(4) he said.                           by privately run notified bodies rather than
    A similar debate is being conducted within the     government agencies (box). They, together with the
European Commission—and on some levels the             manufacturers, are therefore the most fundamental
Europeans agree. Medical device regulation falls       part of devices market approval and monitoring.(9)
under EU directives, which in turn are                 Notified bodies issue a certificate when a device

has been approved. Companies can then affix a CE            The FDA takes a different tack. Each class III
[Conformité Européenne] mark, the EU safety             device that has either been approved or cleared
standard.                                               through its regulatory mechanisms is on its website
                                                        together with the scientific rationale for the device
                                                        being on the market. In the US, devices can only be
Notified bodies and EU approval                         marketed for a clinical claim that is included in
process                                                 labelling that has been reviewed by the FDA.
    Decisions about marketing a new medical
device are made by notified bodies. These
                                                        Variable standards
                                                            There are agreed European standards for
organisations are accredited by national
                                                        medical devices. But there‘s concern that these
regulators—the MHRA in the UK—as being
                                                        standards are not uniformly applied. A MHRA
competent to make independent judgments about
                                                        meeting noted that there were discrepancies
whether a product complies with the CE marking
directive. Currently, there are 76 notified bodies in   between the notified bodies: ―Although the UK
                                                        Notified Bodies are accredited to EN 13485
Europe and six in the UK, including BSI, SGS, and
                                                        [conformity to the EU quality and safety standard]
                                                        by UKAS [United Kingdom Accreditation
    A manufacturer must demonstrate to the
                                                        Service], there are some Notified Bodies in Europe
notifying body that the safety of the device
                                                        with only two or three staff, and these may be
complies with the legal requirements in the EU
medical device directives(11) and submit a precise      operating to different standards.‖(13) In other
                                                        words, some of the key organisations appointed to
definition of the intended use of a device.
                                                        control what enters the European market might not
    For the highest risk devices (class III), the
                                                        be rigorous enough in checking how safe or well a
manufacturer must conduct some human clinical
                                                        device works.
investigations, but these don‘t have to be
randomised clinical trials or even evaluate                 It‘s something that concerns the Association of
                                                        British Healthcare Industries. ―We need to improve
effectiveness.(8) And we have no way of knowing
                                                        the performance of the notified bodies so that they
what they have done. A manufacturer can also just
                                                        are all checking these requirements to the same
produce a comparative literature review if they are
                                                        high level,‖ it said.
arguing that their device is similar to an existing
                                                            Manufacturers can choose the notified body to
(predicate) product.(8)
    The national regulator is responsible for           which they submit their application. In his
                                                        testimony to Congress, Dr Shuren said that the
auditing the notified body. If a medical device
                                                        system allows them to pick the notified body that
needs to be removed from the market, it is the
                                                        they think will put their device through the least
responsibility of the notified body to suspend its
                                                        stringent checks.
certificate and of the notified body and the
                                                            Despite these concerns, the decision making
manufacturer to let the regulator know.
                                                        process is kept behind closed doors. There is no
                                                        publicly available summary describing the basis for
     In the UK the knowledge problem is                 granting a CE mark and neither is this available to
compounded by the fact that NHS procedures are          genuine clinical academic researchers.
poorly coded(12) — although in future all medical           When we contacted 192 manufacturers
devices should have a barcode.(6) So, while we can      requesting evidence of the clinical data used to
get detailed information about which drugs are          approve their devices,(14) they denied us access,
being used in the NHS, the same does not apply to       claiming that ―clinical data is proprietary
devices.                                                information,‖ that it was ―company confidential
    The MHRA told the BMJ and Channel 4                 information,‖ and that they could discuss only
Dispatches that a ―list of class III devices would      ―publicly available information.‖
not be helpful or beneficial.‖ But MHRA                     Likewise, when we asked the relevant notified
documents suggest otherwise.                            bodies for the scientific rationale for approval of
    ―Once CE marked, devices can enter                  various devices that had been recalled, the results
widespread use without any organised monitoring         were stark. This information was classed as
of the outcomes of their use. Long term outcomes        confidential because notified bodies were working
of implanted devices are a particular concern,‖ it      as a client on behalf of the manufacturers—not the
says.(6)                                                people who have them implanted in their
    Instead, the MHRA told us that it relies on a       bodies.But, as Dr Shuren put it: ―For the public in
―statutory vigilance or voluntary adverse incident      the EU, there is no transparency. The approval
reporting system‖ to regulate—in other words,           [requirements] are just what deal is cut between the
governmental regulation really starts when devices      device company and the private [notified
are already on the market.                              body].‖(15)

     But is this an acceptable situation? It‘s not a    told Congress: ―I can‘t help but wonder why
line that the FDA follows.                              clinical trials are widely accepted by the
     The FDA publishes information on its               pharmaceutical industry as essential to ensure
website about the basis for its approval                patient safety, but not by the device industry.‖(17)
decisions. The Office of In Vitro                       Drug regulation is a much older discipline than
Diagnostics publishes a summary of the basis for        device regulation—any legislation on device
its 510(k) clearance decisions for in vitro             regulation came into being only in the early 1990s.
diagnostic tests. It also publishes a summary of        Yet in the past 10-20 years the number and
safety and effectiveness data for original              complexity of medical devices has exploded,
postmarket approvals. The Office of Device              particularly in cardiology and orthopaedics. Dr
Evaluation, which reviews all other medical             Redberg added: ―In contrast to most devices in the
devices, is moving towards providing the same           1970s, the newer products pose substantially
information                                             greater risks—even life threatening risks—to
     “We find great value in being as transparent as    patients. For example, many new medical devices
possible. It helps patients and health care             are permanently implanted in a patient‘s body and
practitioners use a device safely and                   can be moved or changed, if at all, only with great
correctly, and it builds trust between patients,        risk to the patient.‖(17)
practitioners, and the government. Clinicians need          In the US here are currently two ways for a
to be able to evaluate a device’s risks and benefits,   class III device to get on to the market—through
how to use it appropriately, and for which patients.    the premarket authorisation route (PMA) or the less
It can help clinicians and patients make better         stringent 510(k) process (box).
informed decisions,” Dr Shuren told the BMJ.
     Nor does the same apply to medicines approved
by the European Medicines Agency. The EMA has           FDA processes
come under attack in the past for being secretive       Premarket authorisation (PMA)—The most
and opaque, but at least scientific rationale and       stringent type of approval of devices and similar to
study summaries are published along with                processes for drug regulation. Manufacturers must
submitted updates about the evidence detailing          submit their product to extensive testing to prove it
clinical claims for a drug.                             is both ―safe and effective for its intended use.‖ It
     Doctors and patients should know what a            was developed as a pathway for the approval of
device has been approved to do. And here‘s the          devices that ―support or sustain human life, are of
rub—in Europe the highest risk devices have to go       substantial importance of preventing impairment of
through tests to establish their safety and             human health, or which prevent a potential,
performance. They do not have to prove any effect       unreasonable risk of illness or injury.‖(18)
on clinical outcomes, even when a new technology
is being introduced.                                    510(k)—This is sometimes referred to as the
     As Dr Shuren told the US Congress: ―If a           ―substantial equivalence‖ route for class III
manufacturer wishes to market a laser to incise         devices. Initially intended for the likes of surgical
heart tissue to treat arrhythmia (abnormal heart        gloves and less invasive instruments, it is now used
rhythm) in the EU, the manufacturer must show           to enable manufacturers to make tweaks to existing
that the laser incises heart tissue only. In the US,    products without having to go through the
however, the manufacturers must show that the           extensive PMA route. Companies also use it if
laser incises heart tissue and also treats the          there is an existing product on the market (known
arrhythmia.‖(16)                                        as a predicate device). In this case manufacturers
     This is also something that the EU has raised as   have only to show that their new product is
an issue. A 2005 report says: ―Questions have           ―substantially equivalent‖ to the predicate
arisen on the evaluation of the design of a product     device.(19)
and, in particular, the absence of clear rules on
design evaluation, including verifying the
sufficiency and adequacy of clinical data.‖(9)              Although 90% of devices in the US are
     Again this is unlike the expectations before       approved through the 510(k) route,(2) Dr Shuren
drugs gain market approval—and some                     says that the FDA approach is more protective to
commentators argue that manufacturers of devices        the public that the European one. ―The US system
used in medicine ―have the same ethical                 has served patients well by preventing EU
responsibilities to the individual patient as those     approved devices that were later shown to be
companies which manufacture and sell drugs.‖(8)         unsafe or ineffective from harming American
                                                        consumers,‖ he said in his testimony to Congress.
Safety questions                                            The BMJ and Channel 4 Dispatches were sent a
   Earlier this year, Rita Redberg, editor of           document listing six devices that were recently on
Archives of Internal Medicine and a cardiologist,       the market in Europe but were rejected by the FDA

after going through the PMA approval process—so         In May 2007, Johnson and Johnson announced that
contrary to some opinion in Europe premarket            a pivotal clinical study of the device had failed to
clinical studies in a small number of people can        find a significant difference on the primary end
pick up problems (box).                                 point, possibly because patients got a suboptimal
                                                        therapeutic dose of paclitaxel. The trial did not
                                                        identify safety issues. As a result of this trial,
EU approved devices that the FDA                        Conor terminated ongoing clinical trials and chose
rejected                                                not to conclude the submission of its US
                                                        premarketing approval. Conor discontinued the sale
Covidien PleuraSeal lung sealant system
                                                        of the stent in Europe, Asia, and Latin America.
     This device went on the EU market in
November 2007 and is used during elective
pulmonary resection as an adjunct to standard               Most of the problems in the US have been with
closure techniques for visceral pleural air leaks. It   devices approved through the 510(k) route. During
has been approved for use on the dura and spine in      2005 to 2009, there were 113 device recalls that the
the US. However, the Investigational Device             FDA classified as high risk. Eighty (71%) of these
Exemption (IDE) study (a clinical study for FDA         were cleared through the 510(k) route—although
regulatory purposes) produced unexpected interim        only 13 (12%) were class III devices. However,
results. In October 2010 Covidien announced a           some major devices, such as hip and knee implants,
worldwide recall of all PleuraSeal lung sealant         fell into class IIb.(23)
systems                                                     The FDA also maintains a database of reported
Medtronic Chronicle                                     adverse events and device malfunctions (called
     The Chronicle is an implanted system designed      MAUDE). The reports are stripped of any
to measure and record haemodynamic variables            information related to the individual patient or
continuously. In March 2007, an FDA panel               physician involved in the report, but the device and
refused to approve the device, citing statistically     its manufacturer are included. This database
insignificant results as ―lack of clinical              has some limitations, but it provides the agency
effectiveness.‖ It was nonetheless approved in          with safety signals, which can indicate the need for
Europe, raising questions about the cost and            further and deeper investigation.
necessity of the procedure.                                 “By publishing device safety and effectiveness
PIP breast implants                                     information, experts, industry and the public can do
     In 1991, breat implants manufactured by Poly       their own analysis. In fact, it keeps the FDA in
Implant Prosthese (PIP) received a CE mark for its      check. Device problems have been highlighted to
silicone breast implants But in 2001 they changed       us by other people going through the reports and
the gel, so that it was different from the one          drawing our attention to an issue,” De Shuren says.
described in the CE marking file.(20) This                  However, in Europe, it‘s almost impossible for
modification led to rupture rates higher than           independent researchers to assess the extent of the
silicone implants made by other manufacturers.(21)      health problems posed by recalled devices.(14)
On 30 March 2010, the French regulator—                 Because information is confidential, companies
AFSSAPS— issued a recall of all pre-filled              would often not tell us where a device had got its
silicone breast implants manufactured by PIP,           CE mark or what class the device was approved as.
affecting an estimated 35<thin>000-45<thin>000          Furthermore, neither lists of devices on the market
women worldwide. In April 2011, the AFSSAPS             nor the number of adverse event reports for each
had found that there is no link between the PIP and     device is publicly available, meaning that rates of
genotoxicity but that ―test results have confirmed      safety problems cannot be accurately calculated.
that the gel inside can bleed through the pocket of         It‘s something that companies acknowledge—
the implant.‖(22)                                       although from a slightly different angle. A trade
                                                        group that lobbies for the medical device industry
Trilucent breast implants
                                                        said in a report: ―The reasonable question has been
     First marketed in the UK in 1995 by LipMatrix,
                                                        raised whether greater regulatory efficiency in the
Trilucent implants were recalled and withdrawn
                                                        EU has been achieved at the expense of patient
from the market in 1999. The filler of the implants,
                                                        safety. However, no information is available to
which was derived from soybean oil, broke down
                                                        suggest that patient safety in Europe has been
in the body and leaked through the shell, causing
                                                        compromised.‖(24) ―They don‘t have enough data to
ruptures. The breakdown of the filler was
                                                        make a firm comparison, but we do have evidence
significantly different from that predicted during
                                                        to suggest that our system provides great value,‖ Dr
preclinical testing, and many patients had to have
                                                        Shuren said.(15)
implants removed.
                                                            The Association of British Healthcare
Conor CoStar drug eluting stent                         Industries agrees that the lack of transparency leads
     CoStar is a cobalt, chromium, paclitaxel eluting   to misunderstanding and mistrust. ―Today it is very
coronary stent and received EU approval in 2006.

hard for anyone, even manufacturers and               directives, The MHRA currently relies on
authorities, let alone citizens, to find out what     manufacturers and clinicians to report problems to
products are approved to be on the market. We         it. But in the past manufacturers have been slow to
would like to see enhanced transparency and           respond to problems with a device.
information to patients, citizens, and all EU              In 2005, certain implantable cardiac
government authorities.‖ It proposes a central EU     defibrillators made by Guidant were recalled from
database to avoid the potential of 27 national        the market following deaths due to internal short
databases essentially all repeating the same thing.   circuiting. This resulted in failure to deliver a shock
    Even the Freedom of Information Act is of no      when needed.(27) However, following an
use in obtaining information on adverse events.       investigation, Guidant pleaded guilty to
The BMJ/Channel 4 Dispatches attempts to get          withholding information from the FDA regarding
access to adverse incident reports for the Pinnacle   ―catastrophic failures‖ in some of its lifesaving
and ASR hip implants and the HighRes 90k              devices four years later.(28) (29)
cochlear implants from the MHRA through the act            Recently, Medtronic has had lawsuits filed
were thwarted because it is overridden by medical     against it alleging that it delayed disclosing
device legislation. Article 15 of the EU Medical      information about lead fractures that occurred in its
Devices Directive states: ―Member States shall        Sprint Fidelis implantable cardiac defibrillators.(30)
ensure that all the parties involved in the           Medtronic settled for a total payment of $268m—
application of this Directive are bound to observe    although they did not admit any liability.(31)
confidentiality with regard to all information             Company reporting is supplemented by
obtained in carrying out their tasks.‖(25)            clinicians and patients reporting adverse reactions
    And future plans to share adverse event data      to any devices to the MHRA. But clinicians often
will be similarly opaque. The European                fail to report adverse reactions for all sorts of
Commission has plans to create a database to share    reasons. One systematic review found that the
this information between the national regulators—     median under-reporting rate across the 37 studies
but it will not be publicly available.                included in the review was 94% (interquartile range
                                                      82%–98%).(32) In other words, most adverse drug
Postmarketing problems                                reactions were not reported—although it‘s hard to
    This shroud of secrecy occurs despite the         know if this can be extrapolated to devices.
European system relying more on post-marketing             One way to capture problems with devices is to
surveillance than it does on premarket testing. But   use a register. Although registers are not a
what exactly is required in terms of postmarketing    replacement for clinical trials, they can provide
surveillance? For drugs, extensive phase IV trials    data on long term safety, performance, and
and studies are usually mandated by the regulators,   reliability and allow early identification of
who help companies with their study design to         emerging problems. Registers have been central to
enable them to spot potential adverse reactions.      spotting problems with devices that have not gone
And the FDA mandates postmarketing surveillance       through adequate premarket clinical testing, such as
studies for class III devices and some class II       the problems with some metal in metal hip
devices as a condition of approval. In Europe,        implants.
however, manufacturers of devices are obliged to           Although no-one wants to halt the pace of
implement a ―medical device vigilance system‖ to      innovation—it has brought dramatic improvements
monitor their products once they are on the market.   to people‘s quality of life—the system needs fine
This is monitored by the notified bodies and          tuning. Given past problems and the rapid pace of
audited by the MHRA in the UK.                        innovation over the past 20 years, the EU‘s
    But how manufacturers do this is not mandated.    propensity to support innovation needs to be
Rather than have large postmarketing studies,         balanced with better means of protecting the
manufacturers may rely simply on feedback from        public.
users. Steve Owen, head of Devices Policy,                 An FDA style regulator for Europe has been
European and Regulatory Affairs at the MHRA,          advocated by some—but it‘s unlikely to happen.
has stated that he finds it ―staggering‖ how many     But having one agency that regulates devices and
manufacturers fail to fully fulfil their legal        drugs has had its benefits in the US—institutional
responsibility to collect product data once their     memory is collective and experts from both the
device is on the market.(26) And according to an      device and the drug centres can share expertise and
MHRA report: ―Post-market surveillance has not        information easily. And data obtained through
been addressed sufficiently in the past, as many      postmarketing studies, adverse event reporting, and
manufacturers do not focus on this area, and it is    premarket applications from other manufacturers
not ‗policed‘ vigorously enough by Notified           can inform the questions asked about new devices
Bodies.‖(6)                                           submitted for approval and the decision
    The MHRA had hoped that this would change         subsequently made. “It’s much harder to learn if
with the recent amendments of the medical device      you don’t get all the information,” Dr Shuren says.

    And there are calls for drugs and class to be put    6 Campbell B. Report on registers—for the
more on an equal footing in terms of evaluation.             MHRA. 2010.
Jürgen Windeler, director of the Institute for     
Quality and Efficiency in Health Care in Germany,            /Devicesregulatorynews/CON082083
agrees that the current process of device approval       7 How medical devices are regulated in the
does not address the same level of detail as that for        UK. Drugs Ther Bull 2010;48:82-4.
drugs: ―I agree with the CE marking, but it‘s not        8 Fraser AG, Daubert JC, van de Werf F,
enough,‖ he said. He also added that we need                 Estes NA, Smith SC Jr. Clinical evaluation
―some kind of proof of benefit before bringing               of cardiovascular devices—principles,
medtech products onto the market, just as for                problems and proposals for European
drugs.‖(33)                                                  regulatory reform. Eur Heart J
    As Dr Redberg said about the situation in the            (forthcoming).
US, this needs to be through the ―proper use of
                                                         9 European Commission. Commission staff
evidence-based medicine and well-designed
                                                             working document. Annex to the proposal
clinical tests before the devices are approved and
                                                             for a directive of the European Parliament
clinical registries to track outcomes in real time
                                                             and of the Council amending Council
after they are approved.‖(17)
                                                             Directives 90/385/EEC and 93/42/EEC and
Competing interests: All authors have completed              Directive 98/8/EC of the European
the unified competing interest form at                       Parliament and the Council as regards the (available on               review of the medical device directives
request from the corresponding author) and declare           impact assessment. 2005:8.
no support from any organisation for the submitted 
work; no financial relationships with any                    cal-
organisation that might have an interest in the              devices/files/revision_docs/entr_pe_dts_ia_
submitted work in the previous three years; and no           md_en.pdf
other relationships or activities that could appear to   10 European Commission Enterprise and
have influenced the submitted work.                          Industry. Notified bodies.
Provenance and peer review: Commissioned; not      
externally peer reviewed.                                    nando/index.cfm?fuseaction=directive.notif
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