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KRAMER-NEJM-2012 by ندىهوست


									                             The   n e w e ng l a n d j o u r na l   of   m e dic i n e

     H e a l t h L a w, E t h i c s , a n d H u m a n R i g h t s

           Regulation of Medical Devices in the United States
                          and European Union
      Daniel B. Kramer, M.D., Shuai Xu, M.Sc., and Aaron S. Kesselheim, M.D., J.D., M.P.H.

Millions of patients worldwide depend on an ever-
widening array of medical devices for the diag-               Approval Sys tems for Medic al
nosis and management of disease. In the United
States, the Food and Drug Administration (FDA)            United States
requires manufacturers of high-risk devices such          The Medical Device Amendments of 1976 gave
as heart valves and intraocular lens implants to          the FDA primary authority to regulate medical
demonstrate safety and effectiveness before the           devices and required the FDA to obtain “reason-
devices can be marketed. However, some policy-            able assurance of safety and effectiveness” before
makers and device manufacturers have character-           marketing.13 This legislation has been updated
ized U.S. device regulation as slow, risk-averse,         several times, including the Medical Device User
and expensive.1,2 Other experts, such as those at         Fee and Modernization Act of 2002, which estab-
the Institute of Medicine, have suggested that cur-       lished sponsor user fees for application reviews
rent premarketing procedures may not be com-              and set performance targets for review times.14
prehensive enough and may be particularly dan-                Each device type is assigned by the FDA into
gerous for devices that have been cleared by the          one of three regulatory classes on the basis of its
FDA on the basis of substantial similarity to an          risk and the evaluation necessary to demonstrate
already marketed device.3                                 safety and effectiveness.15,16 Most class I devices
   A frequent point of comparison for device reg-         (e.g., stethoscopes) are low-risk and subject only
ulation in the United States is regulation in the         to “general controls,” such as tests of sterility.
European Union.4-6 Reports suggest that Europe-           Class II devices (e.g., computed tomographic
an patients have access to some high-risk medi-           scanners) meet general controls as well as “spe-
cal devices, such as coronary stents and replace-         cial controls,” such as additional labeling require-
ment joints, earlier than American patients. This         ments. These moderate-risk devices generally
system has been touted as being better for pa-            pass through the 510(k) review pathway, which
tient care,7 as well as supporting good-paying            refers to the section of the Food, Drug, and Cos-
jobs and a positive trade balance.8 However, the          metic Act dealing with premarket notification.
E.U. system has drawn criticism for conflicts of          In this process, the FDA and the manufacturer
interest in its evaluation process,9 and a recent         rely on similarities between the device at issue
recall of a popular silicone breast implant that          and a previously cleared device. If a manufac-
was approved only in the European Union has               turer can show that its device is “substantially
reinforced European concerns about the clinical           equivalent,” additional clinical data are usually
evaluation of high-risk devices.10-12                     not required, although requirements for perfor-
   As policymakers in the United States and Eu-           mance standards and postmarketing surveillance
rope weigh these critiques, it is an opportune            may be imposed. Class III products (e.g., deep-
time to compare the two systems and consider              brain stimulators and implantable cardioverter–
what evidence exists on the performance of each           defibrillators) require clinical studies evaluating
device-approval system.                                   the safety and effectiveness of the device, called a

                                         10.1056/nejmhle1113918                                                    1
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                                         The   n e w e ng l a n d j o u r na l   of   m e dic i n e

            Premarket Approval (PMA) application.17 How-              ignated Notified Body in a country of the manu-
            ever, class III devices that arise from changes to        facturer’s choosing. For approval by a Notified
            previously PMA-approved devices may not need              Body, devices are subject to performance and re-
            additional clinical studies.18,19 In addition, some       liability testing linked to the risks of their in-
            older class III devices for which the FDA has not         tended use.27 For most devices, the standard is
            specifically called for PMAs can receive clearance        met if the device successfully performs as in-
            through the 510(k) pathway.17 Devices that treat          tended in a manner in which benefits outweigh
            rare disorders (fewer than 4000 patients annu-            expected risks.23,28 The specific requirements
            ally) may receive a Humanitarian Device Exemp-            for premarketing clinical studies are vague, and
            tion and be approved on the basis of “probable”           details of trials are typically not made available
            benefits, a more flexible standard that recog-            to the public. Although clinical data are required
            nizes the difficulty of studying patient popula-          for high-risk devices, guidelines for the nature of
            tions with small numbers and limited treatment            these studies are not binding on manufacturers
            options.20                                                or Notified Bodies.29
                Sites where cleared or approved devices are              In the postmarketing phase, manufacturers
            used must report related serious adverse events           are required to report all serious adverse events
            to the FDA and the manufacturer.21,22 These re-           to the Competent Authorities. Since 1998, each
            ports are stored in a searchable, publicly avail-         Competent Authority (but not the public) has had
            able database called Manufacturer and User Fa-            access to the European Databank on Medical De-
            cility Device Experience. In addition, the FDA            vices (EUDAMED). This database stores informa-
            may conduct inspections, require manufacturers            tion on manufacturers, data related to approvals
            of high-risk devices to conduct postapproval              and clinical studies, and details on postmarket
            studies, and initiate recalls.                            events. Manufacturers have been required to di-
                                                                      rectly report events to EUDAMED since May
            European Union                                            2011. However, coordination and analysis of
            Until the 1990s, each country had its own ap-             postmarketing reports are highly variable, and
            proach to device evaluation.6 To regulate an un-          EUDAMED has limited utility even to Competent
            even and complex market, E.U. directives that             Authorities. A few E.U. member states provide
            outlined requirements under which a medical               the majority of adverse-event reports and field-
            device (as well as other commercial goods) could          safety notices, which are public notifications of
            be marketed across all E.U. member states after           device-related safety concerns.30 In 2004, the
            earning a Conformité Européenne (CE) mark in              guidelines published by the European Commis-
            any one member country.23,24 These directives             sion urged manufacturers to include both general
            categorize devices into four classes (I, IIa, IIb,        and device-specific follow-up as part of their
            and III) on the basis of increasing risks associ-         quality-assurance programs.31 These programs,
            ated with their intended use.25,26                        which the guidance document suggests might in-
               Device approval in each E.U. country is over-          clude registries or more formal prospective post-
            seen by a governmental body called a Competent            marketing studies, are left to the discretion of
            Authority, such as the Medicines and Healthcare           manufacturers.
            Products Regulatory Agency in the United King-
            dom and the French Agency for the Safety of                   Prominent Differences be t ween
            Health Products. The lowest-risk devices are de-                      the Sys tems
            clared to the Competent Authority, which may
            conduct inspections to confirm manufacturing              Mandate
            standards and review the technical file for the           Emerging from a public outcry over adverse
            device. Approval for more complex devices is di-          events, the FDA was given a mandate to provide
            rectly handled by Notified Bodies, independent            reasonable assurance of the safety and effective-
            companies that specialize in evaluating many              ness of medical devices32,33 (Table 1). Thus, the
            products, including medical devices, for CE               FDA may consider the severity of the disease and
            marks and are designated by Competent Authori-            available alternatives when evaluating high-risk
            ties to cover certain types of devices. First, a          devices. For example, a new system for catheter
            manufacturer of a device selects a properly des-          ablation of atrial fibrillation, which had been

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                                            The New England Journal of Medicine
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                                 Health Law, Ethics, and Human Rights

 Table 1. Prominent Points of Comparison between the United States and European Union for Approval of Medical Devices.*

 System Feature                  United States                           European Union                       Potential Implications
 Mandate             Oversight of public health                Device safety (overseen through         May influence dealings with industry
                                                                  Competent Authorities), device         clients, and attention paid to bal-
                                                                  approval (through Notified             ance between effectiveness and
                                                                  Bodies), and facilitation of trade     risk of safety concerns
 Centralization      Oversight of all device regulation by     Directives outline processes carried    Standardization and coordination of
                        the FDA                                   out by Competent Authorities            premarketing and postmarketing
                                                                  and Notified Bodies                     evaluation are theoretically sim-
                                                                                                          pler and easier to enforce in the
                                                                                                          United States
 Data requirements   Reasonable assurance of safety and        Generally performance-based analy-      E.U. assessment made by manufac-
                        effectiveness for approval of high-       sis, requiring proof that device        turers and Notified Bodies; pro-
                        risk devices, “substantial equiva-        works as intended                       vides less insight into clinical
                        lence” for 510(k) clearance                                                       end points for high-risk devices
 Transparency        Proprietary limits with public reporting Review of Notified Bodies not made       Greater public access to evidence in
                        of premarketing review of ap-            public; postmarketing data               the United States
                        proved devices, recalls, and             shared among Competent
                        adverse events                           Authorities but not with the public
 Funding             Combination of federal appropriations Funding of Competent Authorities            Notified Bodies may be vulnerable to
                       (80%) and user fees (<20%)             variable among countries;                   conflict of interest with industry
                                                              Notified Bodies paid directly               client; the FDA may be influ-
                                                              by sponsors                                 enced by changes in federal
                                                                                                          funding and political climate
 Access              Clinical premarketing testing of high- E.U. patients may have access to           E.U. patients have faster access to
                         risk devices delays patient access    certain high-risk devices sooner           certain devices, but these prod-
                         to these devices (no differences for  than in the United States, subject         ucts are marketed with less rigor-
                         low- and moderate-risk devices)       to limitations by payers                   ous proof of effectiveness and
                                                                                                          may have a greater chance of
                                                                                                          later-identified adverse events

* FDA denotes Food and Drug Administration.

marketed in the European Union since 2006 on                  medical devices.23 For example, a distal protec-
the basis of pilot data, was presented to the FDA             tion system for coronary-artery interventions re-
in 2011 on the basis of a clinical trial involving            ceived a CE mark after a single-group study involv-
210 patients.34 An FDA advisory panel recommend-              ing 22 subjects showed that the device worked as
ed against approval owing to safety questions                 intended.37,38 In the United States, FDA approval
raised by the study, the existence of established             came several years later on the basis of a ran-
alternatives, and the fact that the treatment large-          domized study involving 800 subjects, in which
ly targeted quality of life rather than survival.             a clinical end point of major adverse cardiac
    By contrast, the E.U. system is part of a frame-          events was used.39
work for commerce, which originated as a means
of streamlining trade and coordinating manu-                  Centralization
facturing, safety, and environmental standards                Central coordination in the United States allows
within the European Union.35,36 Notified Bodies               postmarket phenomena in one generation of de-
are not designed to work as public health agen-               vices to inform later applications and study de-
cies. The most important public health role in the            signs. For example, specific criteria for trial design
system is played by Competent Authorities, which              and end points have been developed to standard-
primarily oversee device safety, although the com-            ize the development of artificial heart valves40
position, funding, and responsibilities of Com-               and devices to treat congenital heart disease.41,42
petent Authorities vary widely among member                   These criteria also informed novel methods and
states. These features in part explain why proof              statistical approaches to studying devices.43 A
that the device works as intended may be suffi-               central registration system also provides publicly
cient to permit marketing of even high-risk                   searchable listings and databases of adverse events

                                         10.1056/nejmhle1113918                                                                      3
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                                         The   n e w e ng l a n d j o u r na l   of   m e dic i n e

            and postmarketing reports, which are useful to            510(k) pathway,18 although the FDA has a stated
            independent researchers evaluating specific de-           goal of correcting these cases by the end of 2012.56
            vices.44-46                                               Studies in the European Union regarding the pre-
               Directives and guidance documents provide an           market features of devices that are subject to re-
            overview of the evaluation process in the Euro-           calls have proved impossible to conduct.57
            pean Union, but the system defers significant
            authority to Competent Authorities and even more          Transparency
            to nongovernmental Notified Bodies. Though in-        The FDA has several mechanisms for making its
            dividual Notified Bodies may be motivated to pro-     decision-making process accessible, even though
            vide a predictable and streamlined approach to        much of a sponsor’s application for a new device
            attract customers, there may be inconsistency in      may remain proprietary. Open presentations to
            the process for approving similar devices among       advisory committees describe particularly novel,
            Notified Bodies.47 Such differences in interpret-     complex, or high-risk devices, and committee pan-
            ing and applying European directives may allow        elists can publish their views.58,59 At the time of
            manufacturers to identify the most conducive path     approval of high-risk devices, a “Summary of Safe-
            toward earning the CE mark. Decentralization          ty and Effectiveness Data” provides the justifica-
            also hinders collection and analysis of safety data   tion for approval as well as discussion of adverse
            and does not aggregate large numbers of patients      events. Public postmarket data have been used in
            to help identify potential rare but life-threatening  the United States to quantify the risks for sev-
            adverse events.9,48                                   eral devices, including implantable cardioverter–
                                                                  defibrillator leads44 and generators60 and cardiac
            Data Requirements                                     septal-closure devices.45 In contrast, in the Euro-
            In the United States and the European Union, data pean Union, Notified Bodies have no obligation
            requirements for high-risk devices can differ sub- to publish their decision-making process or the
            stantially. For example, a device for left atrial ap- evidence provided by sponsors.9,47,61
            pendage exclusion for prevention of stroke in
            atrial fibrillation received a CE mark in 2009 on Funding
            the basis of pilot data but was rejected by the In the United States, user fees account for less
            FDA on the basis of safety concerns, including pro- than 20% of the budget for the medical-device
            cedural complications and high rates of stroke, approval process, and the government supplies
            emerging from a 700-patient study conducted as the remainder.62 Relying on centralized funding
            part of a PMA.49-51 Notably, researchers have crit- subjects the FDA to resource limitations, partic-
            icized the data that have been collected in some ularly in postmarketing surveillance.63,64 How-
            PMAs.46,52 One group showed that about two ever, public funding also promotes the indepen-
            thirds of the PMA applications were approved on dence of regulators. In the European Union, the
            the basis of a single study and that trials were funding of Competent Authorities varies with dif-
            rarely randomized or blinded.52 Trials may lack ferent combinations of public support and fees
            sufficient representation of women53 and have levied on manufacturers or Notified Bodies, and
            inconsistencies in the way they report data.54        this variability may exacerbate differences among
                Differences in data requirements between the the resources focused on device safety in each
            United States and the European Union are less country. The system of Notified Bodies is for-
            stark for devices that do not require a PMA. De- profit, with funds derived from the review fees.
            vices that are cleared through the 510(k) process This sets up a dynamic in which Notified Bodies
            in the United States generally do not require clin- view manufacturers as clients or customers and
            ical trials, which remains a point of substantial compete with one another for business. As one
            controversy. For example, one study investigating Notified Body writes in its advertising brochure,
            a cohort of high-risk recalls in the United States “Our aim is to provide a high quality, fast, reliable
            showed that 71% of such devices had previously and stress-free service to meet your deadlines.”65
            been cleared through the 510(k) process and an-
            other 7% had been exempt from review.55 In an- Access
            other report, approximately 25% of high-risk de- Patients in the European Union have access to
            vice submissions during a 4-year period were some new, complex technologies earlier than pa-
            found to be inappropriately evaluated through the tients in the United States (in some cases, sev-

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                                            The New England Journal of Medicine
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                                Health Law, Ethics, and Human Rights

eral years earlier), though precise estimates vary        testing. There is some irony in criticizing the
among reports.66,67 The timing of approval of             FDA for delayed approval of technology, such as
low- and moderate-risk devices, which account             TAVI, in which the effectiveness has been shown
for more than 95% of devices reviewed by the              only in the studies performed to meet the FDA’s
FDA, is generally equivalent.67 For devices in which      safety and effectiveness requirements. One essen-
clinical data ultimately prove favorable, E.U. pa-        tial question that remains unanswered is wheth-
tients will have enjoyed these options before             er speedier access to some newer technologies in
similar patients in the United States. For exam-          the European Union has improved public health.
ple, two devices for transcatheter aortic-valve im-       Or does the more deliberative posture taken for
plantation (TAVI) have had CE marks since                 some high-risk devices by the FDA better serve
2007.68 Later, in a study involving patients with         patients overall? Certainly, swifter approval helps
inoperable severe aortic stenosis, TAVI was               generate revenue for manufacturers, and physi-
shown to reduce mortality in absolute terms by            cians may benefit from having more tools at their
20 percentage points at 1 year, as compared with          disposal. But the primary goal of bringing new
standard therapy,69 with a favorable effect on            devices to market should be to improve the treat-
quality of life.70 On the basis of these data, the        ment of specific diseases, and no current studies
FDA approved one TAVI model in late 2011. In              address this outcome.
the United States, truly new but high-risk devic-             The few studies that have evaluated the per-
es may be available at an early stage only through        formance of regulatory systems have relied on
a humanitarian exception or as part of a clinical         unconvincing outcomes such as recall rates. Be-
trial, and in both cases conditions of use include        cause recalls require a number of unpredictable
oversight by institutional review boards and typ-         steps (including device-malfunction recognition,
ically postapproval studies evaluating outcomes.          reporting, aggregation with other events, and reg-
   However, differences in timing are related to          ulatory action), low rates of recalls do not show
the need in the United States to conduct clinical         an optimally functioning system, and high rates
trials for high-risk devices. Although E.U. pa-           do not necessarily translate into patient harm or
tients may have earlier access to some devices,           identify regulatory flaws.
they also face the risk that subsequent studies               One way to address unresolved questions
will show no benefit to the new device or reveal          about the effectiveness of the two approaches to
important harms from adverse events that did              device regulation would be to perform more
not emerge from the premarket review. For ex-             comparative-effectiveness studies of device tech-
ample, the PleuraSeal Lung Sealant System for             nology or disease management in which outcomes
the treatment of air leaks after pulmonary re-            with new therapeutics could be compared with
section was approved for the E.U. market from             alternative approaches or devices. Yet the FDA and
2007 through 2011 but was withdrawn after an              Competent Authorities have limited power to re-
FDA-required study showed a higher complica-              quire these sorts of studies. Comparative technol-
tion rate than with standard care.71 Approval of          ogy assessment in the European Union is cur-
a device in the European Union does not neces-            rently handled by other government bodies or
sarily guarantee earlier access for patients, since       private organizations in an unsystematic manner,
insurance coverage and payers’ decisions vary             whereas policymakers’ attention to comparative-
widely.72                                                 effectiveness research for devices in the United
                                                          States remains in its infancy. More government
             Recommendations                              resources in the two settings need to be applied
                                                          to address both the effectiveness and cost-effec-
This review of device approval in the United              tiveness of new device technology.
States and Europe shows that both systems are                 In our view, the greatest challenge facing U.S.
facing problems requiring policy changes. Much            device regulation is the evaluation of high-risk
attention has been focused on the time to ap-             devices through pathways intended for lower-risk
proval and regulatory barriers in the United              devices, such as the 510(k) process. Although it
States,73 but we found numerous examples of               is worrisome that many PMA approvals in the
high-risk devices that were first approved in the         United States result from unblinded studies or
European Union but showed no benefit or dem-              other features of high-quality clinical trials, these
onstrated substantial safety risk in subsequent           study elements may be impossible in trials of

                                        10.1056/nejmhle1113918                                                     5
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            some of the highest-risk implantable devices. In                  This article (10.1056/NEJMhle1113918) was published on Feb-
                                                                              ruary 14, 2012, at
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               Supported in part by a grant from the FDA Center for Devices   ary 2009 (
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                                     Health Law, Ethics, and Human Rights

25. European Commission. Classification of medical devices         46. Kramer DB, Mallis E, Zuckerman BD, Zimmerman BA,
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