Confidential: For Review Only - BMJ · 2016. 6. 29. · Confidential: For Review Only Safety, trial outcomes reporting, and regulatory approval of medical devices in Europe and the

Confidential: For Review O

nly

Safety, trial outcomes reporting, and regulatory approval of

medical devices in Europe and the United States: cohort study

Journal: BMJ

Manuscript ID BMJ.2016.032105

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 22-Feb-2016

Complete List of Authors: Hwang, Thomas; Harvard University, Faculty of Arts and Sciences Sokolov, Elisaveta; National Hospital for Neurology and Neurosurgery Franklin, Jessica; Brigham and Women’s Hospital and Harvard Medical School, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine Kesselheim, Aaron; Brigham and Womens Hospital, Pharmacoepidemiology and Pharmacoeconomics

Keywords: medical device, Conformité Européenne, interventional cardiology, neuromodulation, regulation, health policy

https://mc.manuscriptcentral.com/bmj

BMJ


nlySafety, trial outcomes reporting, and regulatory approval of medical

devices in Europe and the United States: cohort study

Thomas J. Hwang, researcher,1,3 Elisaveta Sokolov, neurologist,2 Jessica M. Franklin, assistant

professor of medicine,3 Aaron S. Kesselheim, associate professor of medicine 3

1 Faculty of Arts and Sciences, Harvard University, Cambridge, MA, USA

2 National Hospital for Neurology and Neurosurgery, London, United Kingdom

3 Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology

and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and

Harvard Medical School, Boston, MA, USA

Correspondence to: [email protected], [email protected]

Date: February 22, 2016

Word Count (Main Text): 3,937

Word Count (Abstract): 357

Abbreviations: CE: Conformité Européenne; CI: confidence interval; FDA: Food and Drug

Administration; HR: hazard ratio; PMA: premarket approval; RR: risk ratio.

NB: In the US, devices are “approved” through the premarket approval, humanitarian device

exemption, and premarket supplement pathways, or “cleared” through the 510(k) process. For

simplicity, we use ‘approval’ to refer to both types of authorization, unless otherwise denoted.

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nlyABSTRACT

Objectives: To evaluate safety issues, publication of key trial outcomes, and subsequent US

approval of high-profile medical devices introduced in the EU.

Design: Cohort study.

Setting: Novel cardiovascular, orthopedic, and neurologic devices approved in the EU through

the Conformité Européenne mark between 2005 and 2010.

Data Sources: Public and commercial databases searched up to January 2016 for press

releases and announcements of approvals; public FDA and European regulatory authority

databases for US approvals and safety alerts and recalls; Medline, EMBASE, and Web of

Science for peer-reviewed publications.

Main Outcome Measures: We categorized the novelty of the devices in our sample as a “major

innovation” or an “other change,” and extracted descriptive data about the devices: therapeutic

category, sponsor size, dates of EU and (if any) US market authorization, safety alerts and

withdrawals. Linear regression models examined factors associated with differential EU and US

approvals. Cox proportional hazards regression models were used to evaluate factors

associated with safety alerts and recalls and to evaluate factors associated with trial outcomes

publication for devices categorized as major innovations. Models controlled for time, therapeutic

category, regulatory pathway, firm size, and indicator variables for devices approved first in EU

and devices approved only in EU.

Results: Most devices (67%, 206/309) were approved in both the US and EU, and approved

first in EU (63%, 129/206) at a median of 8.3 months before the US. Time to US approval of EU-

approved devices was longer for devices approved through the US premarket approval process.

The unadjusted rate of safety alerts and recalls for devices approved first in EU was 27%

(62/232) versus 14% (11/77) for devices approved first in the US. The adjusted hazard ratio for

safety alerts and recalls was 2.9-fold (95% CI, 1.4 to 6.2) greater for devices approved first in

EU. The pivotal trial results were published for 49% (37/75) of the devices categorized as major

innovations, with an overall publication rate five years post-approval of 37%.

Conclusions: Devices approved first in the EU are associated with an increased risk of post-

market safety issues. Given poor trial publication rates, patients and clinicians need greater

regulatory transparency to make informed treatment decisions.

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nlySTUDY SNAPSHOT

What is already known on this topic

• In the EU, medical devices are approved by private Notified Bodies if they meet

performance criteria and are likely to be safe, but do not require evidence of

effectiveness

• Many high-risk devices are approved faster in the EU than in the US, which usually

requires clinical trials of such devices

• Controversy over the safety of implanted devices approved without rigorous

clinical testing have led to calls for regulatory reforms in both the EU and the US

What this study adds

• Most high-profile medical devices approved in the EU (devices for which the

approvals are publicly announced), including most devices identified as major

innovations, are eventually also approved in the US

• Medical devices available in the EU before the US are at higher risk for safety

issues

• Evidence that could guide treatment decisions remains unpublished or unavailable

for many new medical devices

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nlyINTRODUCTION

Medical devices play an important role in patient care, but their approval and regulation are

handled differently in the EU and US. In the EU, devices can be marketed if they perform “as

intended” and are likely to be safe; by contrast, in the US, most high-risk devices must

demonstrate reasonable assurance of safety and effectiveness usually through the conduct of

clinical trials before they can be used by patients (Box 1).1

The public health consequences of these diverging device regulation paradigms have come

under increasing scrutiny.2 3 4 5 On the one hand, approving devices without first requiring

evidence of safety and effectiveness can reduce the time to market of new technologies. For

example, transcatheter aortic-valve replacement was developed as an alternative to aortic valve

surgery for treatment of symptomatic aortic stenosis, and has been associated with higher rates

of survival than surgical aortic-valve replacement.6 The first transcatheter aortic-valve

replacement was approved for use in Europe in 2007, four years earlier than the first approval

by the US FDA in 2011 (although it was not until 2010 that evidence of its effectiveness was

established by the published randomized controlled trial).7

On the other hand, widespread use of new devices without adequate testing limits the ability of

patients to make informed treatment decisions and can slow the ability of investigators to

generate this information for future patients; in addition, it may expose patients to increased risk

of harms from devices with uncertain utility. For example, a report by the FDA highlighted twelve

devices that were approved in Europe (but not the US) and later found to be unsafe or

ineffective.8 The recent emergence of safety issues involving implanted devices in Europe9 10 11

and the US12 13 14 has renewed calls to revisit the appropriate trade-offs between device access

and risk. Indeed, the EU has been debating an overhaul of its device regulations, a process that

was first proposed in 2008 and was ongoing as of January 2016.

There is limited evidence on the safety and performance of different countries’ approaches to

device regulation.15 Previous studies have focused on the quality and reporting of evidence

supporting device approvals in the US3 16 17 18 19 20 21 22 and safety record of devices approved

with less clinical testing.23 24 25 Little is known about the European record. Attempts to study EU

device regulation have been hampered by the lack of a publicly available register of approved

devices in Europe (as there is in the US); the confidentiality of information submitted to the

regulatory bodies; and the decentralized nature of approval decisions made across individual

member states.1 15 26

In our study, we identified high-profile new cardiovascular, neurologic, and orthopedic devices

approved in the EU between 2005 and 2010 and evaluated factors associated with safety

issues and publication of key trial outcomes.

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nlyMETHODS

Study Cohort

We used public and commercial sources to construct a novel dataset of medical devices

granted marketing approval (Conformité Européenne [CE] mark) in Europe between January 1,

2005 and December 31, 2010 and indicated for the treatment of cardiovascular, neurologic, and

orthopedic conditions (Figure 1). We focused on “high-profile” devices, defined as those with

publicly-announced regulatory approvals.

First, we searched Factiva (Dow Jones, New York) for company press releases and news

articles mentioning devices granted CE marks as well as the dates of the regulatory decisions.

We did a similar search through annual reports, financial regulatory filings (e.g., with the US

Securities and Exchange Commission), transcripts of earnings and investor relations calls, and

stock analyst reports using two commercial databases (S&P Capital IQ [McGraw Hill Financial,

New York] and Bloomberg [Bloomberg L.P., New York]). We then consulted market research

reports, trade publications, and search engines, and cross-checked our results with a

commercial database of marketed medical devices (Evaluate Ltd., London, UK). We also

reviewed companies’ websites and marketing materials to match product names as they may

differ between the US and European models. Finally, we supplemented these searches with a

manual review of the FDA review summaries for PMA devices approved between January 1,

2005 and January 31, 2016; these summaries typically include a section detailing “prior

marketing history.” All data were initially downloaded on May 30, 2015 and subsequently

updated through January 31, 2016.

Data Extraction and Coding

We extracted key demographic information, including generic (e.g., implantable electric

stimulator) and trade names (e.g., Brio Neurostimulation System), therapeutic area and sub-

category (Appendix Table 1), sponsor name, marketing status in the US and Europe, and date

of CE mark. We also matched devices approved in Europe to the FDA’s publicly available lists

of devices that have been cleared or approved for marketing in the US through the 510(k),

premarket approval, premarket supplement, or humanitarian use pathways. To identify devices

that may have been later withdrawn or discontinued, we cross-referenced public sources and

investor materials for mention of marketing or sales in the US. For devices also marketed in the

US, we extracted the date of clearance or approval, as well as the applicable regulatory

pathway, and identified whether devices were approved first in the US or Europe. We

categorized device sponsors as small- and medium-sized companies if they had gross revenues

less than US$1 billion at the time of device approval. We searched Medline, EMBASE, and Web

of Science for peer-reviewed publications of the pivotal clinical trial(s) used to support regulatory

approval and/or used to demonstrate safety and effectiveness of the device. We excluded small

case series reports (<25 patients).

Using a pre-specified protocol (see Appendix), we categorized the novelty of each device in our

sample as a “major innovation” or an “other change.” A major innovation was defined to be: (i) a

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nlydevice that was the first in an entirely new class of products; (ii) a device that involves new

technology and makes new claims with respect to its safety and/or effectiveness; or (iii) a device

that involves new technology and is intended to be used in a new or expanded patient

population. For example, the Melody Transcatheter Pulmonary Valve was categorized as a

major innovation, because it was the first transcatheter pulmonary valve that received regulatory

approval in the US or Europe (CE mark granted in 2006). “Other change” devices included

already marketed products as well as devices that differ from existing products due to minor

technical, mechanical, system, or manufacturing changes.

Finally, for each device in our study sample, we determined if the device had been subject to a

recall or a post-marketing safety alert. We searched for recalls, field safety notices (which are

issued when a device needs to be recalled for technical or clinical reasons), and other safety-

related corrective actions (e.g., software updates to prevent possible adverse patient outcomes

or device malfunction) using publicly available databases maintained by the FDA and national

regulators in the two largest medical device markets in Europe: Germany (Bundesinstitut für

Arzneimittel und Medizinprodukte) and the United Kingdom (Medicines and Healthcare Products

Regulatory Agency). We excluded recalls and safety alerts that were limited in scope (e.g., a

safety alert for a small number of lots because they had not been properly sterilized during

manufacturing) or that were unlikely to cause adverse health consequences or technical failure

(e.g., a field safety notice for misspellings in the product label). To be conservative, we also

excluded manufacturing-related recalls for three products (Confient ICD and Livian CRT-D in

201027; ConforMIS iDuo System in 201528), for which the manufacturers stated that patients

were unlikely to be harmed (including these recalls in our analysis strengthened our results).

Statistical Analysis

We calculated the unadjusted median time difference between approval in Europe (CE mark)

and the US (approval or clearance by the FDA), rate and relative risk of safety alerts and

recalls, and median time to pivotal study publication. Time to first safety alert and recall as well

as time to publication were calculated from the time of first approval in either setting.

In adjusted analyses, we constructed: (i) multivariable linear regression models to examine

factors associated with greater time differentials between Europe and US approval; (ii) Cox

proportional hazards regression models to examine factors associated with safety alerts and

recalls; and (iii) Cox proportional hazards regression models to examine factors associated with

trial outcomes publication for devices categorized as major innovations. Models included all

variables of interest regardless of statistical significance: therapeutic sub-category, regulatory

pathway, firm size, an indicator variable for devices categorized as major innovations (except for

models predicting publication), an indicator variable for devices approved first in Europe (which

included devices not yet approved in the US), and an indicator variable for devices approved

only in Europe. To account for secular trends over time, we included indicator variables for year

of CE mark or year of first approval for the linear and Cox regression models, respectively. In

sensitivity analyses, we repeated our analysis of safety events using only recalls, using a

continuous time variable instead of an indicator variable for approval year, using indicator

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nlyvariables for both therapeutic area and sub-category. We also repeated our analyses using

logistic regression models and obtained substantively similar results.

Statistical analyses were performed using Stata version 12 (StataCorp). Two-tailed P values

<0.05 were considered statistically significant.

Patient Involvement

No patients were involved in setting the research question or the outcome measures, nor were

they involved in developing plans for design or implementation of the study. No patients were

asked to advise on interpretation or writing up of results. There are no plans to involve patients

in the dissemination of results, nor will we disseminate results directly to patients, beyond our

general media communications plan.

RESULTS

We identified 245 (79%) cardiovascular, 28 (9%) neurologic, and 36 (12%) orthopedic devices

that received CE marks between 2005 and 2010, a total of 309 new devices. Nearly a quarter

(75 of 309, 24%) was classified as major innovations. The majority was developed by large

companies (174 of 309, 56%).

Regulatory Approval in Europe and the United States

Most EU-approved devices in our sample were also approved for use in the US (206 of 309,

67%), of which most were approved first in Europe (129 of 206, 63%). Among the devices

approved in both Europe and the US, 44 (21%) were approved though the PMA pathway, 76

(37%) were approved as supplement PMA, 82 (40%) were cleared through the 510(k) pathway,

and 4 (2%) were approved as humanitarian use devices. Of the 75 devices categorized as

major innovations, a greater proportion was approved in the US (54 of 75, 72%), approved first

in Europe (40 of 54, 74%), and approved through the PMA pathway in the US (20 of 75, 27%).

Overall, CE mark was received 8.3 months before FDA approval (range, -46.8-94.5 months).

The median time difference between CE mark and FDA approval was -1, 11.0, 12.3, and 36.3

months for 510(k) clearance, PMA supplement, humanitarian exemption, and PMA approval,

respectively (P<0.001 for comparison across categories) (Figure 2). For devices categorized as

major innovations, the median time difference was 25.1 months. In multivariable linear

regression modeling adjusting for therapeutic sub-category, level of innovation, firm size, and

year, PMA and PMA supplement devices were associated with time differences of 38.0 (95%

confidence interval [CI], 30.0-46.1; P<0.001) and 20.5 (95% CI, 12.5-28.5; P<0.001) months,

respectively, between CE mark and subsequent FDA approval (Appendix Table 2).

Analysis of Safety Alerts and Device Recalls

There were 73 devices (24%) in our study cohort subject to a recall or post-marketing safety

alert as of January 31, 2016. Examples of safety events included the recall of an automated bi-

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nlyventricular support system due to a defect that could cause the device to shut down and stop

pumping without warning (Abiomed AB-5000 Console; 2010), and a safety alert and labeling

change for a neurostimulator warning that reducing or ceasing stimulation could cause

worsening of seizure frequency or severity compared with prior to implant (Medtronic Deep

Brain Stimulation; 2015).

The unadjusted rate of safety alerts and recalls in devices approved first in Europe (including

CE-marked devices not yet approved in the US) was 27% (62 of 232) versus 14% (11 of 77) for

devices approved first in the US (risk ratio [RR], 2.1; 95% CI, 1.0-3.4; P=0.04). In univariable

analyses, the risk of safety alerts and recalls was also significantly higher for devices approved

via the PMA and PMA supplement pathways (RR, 2.1; 95% CI, 1.4-3.2; P<0.001) and

neurologic devices (RR, 2.0; 95% CI, 1.2-3.2; P=0.006). There were more safety events among

devices categorized as major innovations versus those that were not (29% [22/75] vs. 22%

[51/234]), but this difference was not statistically significant (RR, 1.3; 95% CI, 0.9-2.1; P=0.17).

In multivariable Cox regression modeling, devices approved first in Europe were associated with

a 2.9-fold greater rate of safety alerts and recalls (hazard ratio [HR], 2.9; 95% CI, 1.4-6.2;

P=0.005) and a 4.6-fold greater rate of recalls (HR, 4.6; 95% CI, 1.5-14.0; P=0.006) than

devices approved first in the US (Figure 3, Table 2). Similar results were obtained in sensitivity

analyses using a continuous time variable and adjustment for both therapeutic area and sub-

category (Appendix Tables 3 and 4). For example, a drug-eluting stent was CE-marked in

2006. However, a year later, the stent was recalled after results of a US pivotal trial showed that

the device was associated with significantly increased rates of major adverse cardiac events,

including myocardial infarction and target vessel revascularization.29

Peer-Reviewed Publication of Primary Trials of Device Safety and Effectiveness

Among the 75 novel devices categorized as major innovations, the pivotal trial results were

published for 37 (49%). The median time to publication from first regulatory approval either in

the US or EU was approximately 3 years (37 months; range, 0-118 months). Overall, the rates

of publication 1-, 2-, and 5-years following regulatory approval were 7%, 17%, and 37%. In

multivariable Cox regression modeling, devices approved in the US through the PMA pathway

were significantly more likely than non-PMA approved devices to achieve publication (HR, 8.6;

95% CI, 2.8-26.9; P<0.001).

DISCUSSION

We found that among high-profile cardiovascular, neurologic, and orthopedic devices authorized

for approval in Europe between 2005 and 2010, including those categorized as major

innovations, most were approved first in Europe and subsequently approved in the US. Overall,

a quarter of the devices in our study were associated with safety issues after they reached the

market, ranging from communications about expanded safety warnings to recalls. However,

devices approved first in Europe were also associated with a nearly three-fold greater rate of

safety alerts and recalls.

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nlyComparison with Other Studies

To our knowledge, this study is the first to compare rates of safety issues and recalls between

devices approved in Europe and those approved in the US. In a study of FDA-approved

prescription drugs, Carpenter and colleagues found that drugs approved quickly were more

likely than other drugs to have serious safety issues, including safety-based market withdrawal

and black-box warnings.30 In a review of urgent device recalls (those with reasonable chance of

causing serious injury or death) issued by the FDA, Zuckerman and colleagues found that these

recalls related to 35 cardiovascular devices between 2005 and 2009, including 12 devices

approved through the PMA pathway.24 During this period, the FDA approved 45 new

cardiovascular devices through the PMA pathway,31 implying a rate of safety issues (12 of 45,

27%) comparable to our estimate. Evaluating safety problems associated with devices in the US

and Europe has previously occurred mostly through anecdotal reports and uncontrolled

analyses. A case-series report by the FDA warned “the limited testing required in the EU can fail

to predict dangerous risks and lack of effectiveness in actual use” and documented twelve high-

risk devices approved only in Europe that were “ultimately withdrawn from the market, but only

after thousands of patients were harmed.”8 One industry-sponsored analysis found that there

was no difference in the absolute number of serious device recalls in the US and Europe, but

the relative rate of all safety issues was not determined.32

The median delay of three years between CE mark and US approval for PMA pathway devices–

which are usually the highest-risk implantable devices–in our study is consistent with prior

industry estimates during a comparable time period.33 The majority of medical devices (67%) in

our study were approved in both the US and Europe, similar to the proportion of new

prescription drugs approved in both geographies (66%).34

Roughly half (51%) of the primary trials assessing the safety and effectiveness of devices

judged to be major innovations remained unpublished or not conducted over five years after first

approval, comparable to the rate reported in a study22 of high-risk cardiovascular devices

approved in the US between 2000 and 2010 (46 of 106, 43%). Similarly, Kynaston-Pearson and

colleagues found that nearly half of recently introduced hip replacement prostheses had no

published evidence of clinical effectiveness.35 By contrast, previous studies36 37 have found that

the pivotal trial results of 76-78% of pivotal trials for new drugs are eventually published.

Information on devices approved in the EU, or pathways in the US that do not require pre-

market clinical testing, is even more limited.21 In a study of ten devices reimbursed in Austria,

Wild and colleagues found that evidence available at the time of CE marking are more often

case-series or small feasibility trials, compared to the controlled trials and large prospective

cohort studies used as the basis for FDA approval.38 In turn, low rates of publication and lack of

high-quality evidence may adversely impact patient outcomes. Nieuwenhuijse and colleagues

found that innovative and well-known hip and knee replacement prostheses were widely

implanted despite a lack of high-quality evidence supporting their use; several of these devices

were also associated with inferior survival and higher rates of revision.25

Study Limitations

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nlyOur study has a number of limitations. First, we identified devices approved in Europe based

primarily on company announcements, investor reports, and news articles on marketed

products. Since we focused on devices for which the regulatory approvals were publicly

announced, our findings may not be generalizable to devices that are authorized but not

marketed or that are introduced without formal notice to the public or shareholders, and this

study likely underestimates the total number of approvals during the study period. However, this

cannot be definitively determined.39 In a prior investigation by the BMJ, the UK Medicines and

Healthcare Products Regulatory Agency was unable to provide any data on how many high-risk

devices were currently in use,40 and similarly denied this information to researchers.26 41

Nonetheless, given the strong incentives for companies to market and sell their products as

widely as possible,42 we believe our studied devices represent those most likely to be used by

patients and clinicians. Indeed, a market research firm used by industry to track device sales

(MRG, London, UK) estimated that its database had information on roughly 100-200

cardiovascular devices actively marketed in the EU after 2005 and used in clinical practice

(personal communication), which compares favorably to our study cohort of over 300 devices.

Second, we focused on three disease areas, but these are characterized by medical devices

that are among the most frequently used implantable and high-risk devices in clinical practice43 44 45 and together represent approximately 70% of all high-risk devices approved in the US.19

Third, although we chose our study period to allow at least five years of follow-up (consistent

with the upper bound of prior estimates of the time differential between CE mark and FDA

approval33), with time, more of the devices currently approved only in Europe may be approved

in the US, and more trials may be published. Fourth, we focused on devices approved in the

EU; further research is needed to identify devices approved in the US but not CE marked. Fifth,

receiving CE mark does not guarantee that patients will immediately have access to new

products, and actual delays in access between the US and Europe may be smaller after

accounting for the time associated with reimbursement decisions by payers.46 Finally, we

focused on safety risks associated with devices; an additional number of devices may be

ineffective, and other reasons (such as commercial factors) may explain why certain devices

approved in Europe are not also submitted in the US. For example, in a large randomized

controlled trial, a novel CE-marked biodegradable drug-eluting stent did not improve clinical

outcomes compared to an older drug-eluting stent; the stent remains marketed only in Europe.47

Conclusions and Policy Implications

Despite these limitations, this study provides an important empirical measure of the trade-offs

associated with the US and EU frameworks for regulating medical devices. Although most

devices, including the vast majority of those identified as major innovations, are ultimately

approved in both the US and EU, patients in the US may not have access for up to three years

later than patients in Europe. Supporters of the current EU system argue these delays have

public health implications if some patient populations can benefit from earlier treatment,

although a device’s true benefits may only be known in retrospect after the trials needed for

FDA approval are conducted. In the US, regulators could improve the efficiency of regulatory

processes and minimize delays by fast-tracking approval of devices with the potential to

substantially improve patient health outcomes. To that end, in 2014, the FDA announced a pilot

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nlyprogram to expedite development and approval of certain high-risk medical devices for serious

or life-threatening conditions.48

However, the possible benefits of faster access must be carefully weighed against the risks

arising from devices, such as a number of drug-eluting stents initially hailed as breakthroughs,49

later found to be unsafe or ineffective.50 51 52 53 There has been growing consensus by patients,

physicians, payers, and policymakers that the current EU system could be revised to better

safeguard patient safety.54 55 56 57 58 59 60 61 62 63 64 65 Compared to the US, at the time of

approval, patients in Europe have significantly less and lower-quality information on potential

benefits and harms of new devices, which raises ethical concerns because CE marks may be

misinterpreted as signifying that devices are safe and clinically effective.38 The European

Society of Cardiology and others have called for a centralized system for evaluating high-risk

devices; stronger and more transparent clinical data requirements that incorporate expert

medical advice; and public education on the limitations of the CE mark.66

However, as of January 2016, the proposed revisions of the EU’s medical device directives did

not include a new device-focused regulatory body. At a minimum, policymakers should require

greater transparency, including access to a register of all CE marked devices and summaries of

their regulatory decisions (as is the case for drugs in Europe and both drugs and devices in the

US). Such information is important for patients and clinicians to make informed treatment

decisions as well as for researchers, who may not know that products have been studied in

unpublished trials. Beyond greater transparency, policymakers could consider compromise

solutions that would benefit both patients and device manufacturers, such as coupling more

rigorous standards for clinical evidence for the highest-risk devices with a streamlined pathway

for reimbursement across the EU, as well as conditional approval and funding of breakthrough

technologies.67 Indeed, one economic modeling study found that devices studied in clinical trials

are more likely to be commercially successful than those that are not, and European utilization

of new devices increases markedly after the results of clinical trials conducted for US approval

are released; the authors concluded that the EU could meaningfully improve patient welfare by

increasing the informational standard required for market access.68

Patients and clinicians need access to, and balanced presentation of, the available evidence of

the safety and effectiveness of novel devices – or the lack thereof. Our findings suggest that

products introduced earlier in their development cycle are also more likely to increase the risk of

harms, underscoring the urgent need for transparency to make truly informed decisions.

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nlySTATEMENTS

Funding: No specific financial support was received for this study.

Competing Interests: All authors have completed the Unified Competing Interest form at

http://www.icmje.org/coi_disclosure.pdf and declare that (within the past three years): TJH has

received funding from Harvard University and the Interfaculty Initiative in Health Policy, and was

employed by Blackstone and Bain Capital; ES has no relevant financial or non-financial

competing interests to declare; JMF has received funding from the Patient-Centered Outcomes

Research Institute (PCORI) and Merck, and has consulted for Aetion, Inc., a software company;

and ASK is a Greenwall Faculty Scholar and has received funding from the Harvard Program in

Therapeutic Science, the Laura and John Arnold Foundation, and the FDA Office of Generic

Drugs and Division of Health Communication.

Role of Sponsor: The authors’ employers and funders had no role in the design and conduct of

the study; collection, management, analysis, and interpretation of the data; preparation, review,

or approval of the manuscript; and decision to submit the manuscript for publication.

Contributors: All authors contributed to the conception and design of the study. TJH extracted

the data, and TJH and JMF did the statistical analyses. All authors contributed to interpretation

of the results. All authors read, wrote, and critically revised the manuscript for important

intellectual content. All the authors made a significant contribution to the research and

manuscript, and approved the final version for publication. TJH is the guarantor.

Transparency Statement: The authors affirm that the manuscript is an honest, accurate, and

transparent account of the study was reported; that no important aspects of the study have been

omitted; and that any discrepancies from the study as planned have been explained.

Copyright Statement: The Corresponding Author has the right to grant on behalf of all authors

and does grant on behalf of all authors, an exclusive licence on a worldwide basis to the BMJ

Publishing Group Ltd to permit this article (if accepted) to be published in BMJ editions and any

other BMJPGL products and sublicences such use and exploit all subsidiary rights.

Ethical Approval: Not required for this study.

Data Sharing: No additional data available.

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nlyReferences 1 Kramer DB, Xu S, Kesselheim AS. Regulation of medical devices in the United States and European

Union. N Engl J Med 2012;366(9):848-55. 2 Curfman GD, Redberg RF. Medical devices--balancing regulation and innovation. N Engl J Med

2011;365(11):975-7. 3 Hwang TJ, Carpenter D, Kesselheim AS. Assessment of US pathway for approving medical devices for

rare conditions. BMJ 2014;348:g217. 4 Sorenson C, Drummond M. Improving medical device regulation: the United States and Europe in

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6 Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic-valve

implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363(17):1597-607. 7 Reinöhl J, Kaier K, Reinecke H, Schmoor C, Frankenstein L, Vach W, et al. Effect of availability of

transcatheter aortic-valve replacement on clinical practice. N Engl J Med 2015;373(25):2438-47. 8 Food and Drug Administration. Unsafe and ineffective devices approved in the EU that were not

approved in the US. FDA, 2012. 9 Cohen D. How a fake hip showed up failings in European device regulation. BMJ 2012;345:e7090.

10 Heneghan C. The saga of Poly Implant Prosthese breast implants. BMJ 2012;344:e306.

11 Horton R. A serious regulatory failure, with urgent implications. Lancet 2012;379:1060.

12 Gartenberg AJ, Peleg A, Dhruva SS, Redberg RF. Presumed safe no more: lessons from the

Wingspan saga on regulation of devices. BMJ 2014;348:g93. 13

Maisel WH. Semper fidelis--consumer protection for patients with implanted medical devices. N Engl J Med 2008;358(10):985-7. 14

Institute of Medicine. Medical devices and the public’s health: the FDA 510(k) clearance process at 35 years. Washington, DC: National Academies Press, 2011. 15

Kramer DB, Xu S, Kesselheim AS. How does medical device regulation perform in the United States and the European union? A systematic review. PLoS Med 2012;9(7):e1001276. 16

Zuckerman D, Brown P, Das A. Lack of publicly available scientific evidence on the safety and effectiveness of implanted medical devices. JAMA Intern Med 2014;174(11):1781-7. 17

Dhruva SS, Bero LA, Redberg RF. Strength of study evidence examined by the FDA in premarket approval of cardiovascular devices. JAMA 2009;302(24):2679-85. 18

Rome BN, Kramer DB, Kesselheim AS. FDA approval of cardiac implantable electronic devices via original and supplement premarket approval pathways, 1979-2012. JAMA 2014;311(4):385-91. 19

Rathi VK, Krumholz HM, Masoudi FA, Ross JS. Characteristics of clinical studies conducted over the total product life cycle of high-risk therapeutic medical devices receiving FDA premarket approval in 2010 and 2011. JAMA 2015;314(6):604-12. 20

Kramer DB, Mallis E, Zuckerman BD, Zimmerman BA, Maisel WH. Premarket clinical evaluation of novel cardiovascular devices: quality analysis of premarket clinical studies submitted to the Food and Drug Administration 2000-2007. Am J Ther 2010;17(1):2-7. 21

Rising JP, Moscovitch B. Characteristics of pivotal trials and FDA review of innovative devices. PLoS One 2015;10(2):e0117235. 22

Chang L, Dhruva SS, Chu J, Bero LA, Redberg RF. Selective reporting in trials of high risk cardiovascular devices: cross sectional comparison between premarket approval summaries and published reports. BMJ 2015;350:h2613. 23

Hines JZ, Lurie P, Yu E, Wolfe S. Left to their own devices: breakdowns in United States medical device premarket review. PLoS Med 2010;7(7):e1000280. 24

Zuckerman D, Brown P, Nissen SE. Medical device recalls and the FDA approval process. Arch Intern Med 2011;171(11):1006-11. 25

Nieuwenhuijse MJ, Nelissen RG, Schoones JW, Sedrakyan A. Appraisal of evidence base for introduction of new implants in hip and knee replacement: a systematic review of five widely used device technologies. BMJ 2014;349:g5133. 26

Thompson M, Heneghan C, Billingsley M, Cohen D. Medical device recalls and transparency in the UK. BMJ 2011;342:d2973. 27

Rockoff JD. Boston Scientific issues big recall of its implantable defibrillators. Wall Street Journal, 2010.

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ConforMIS. Press release: ConforMIS Initiates voluntary recall of specific serial numbers of patient-specific instrumentation for the iUni, iDuo and iTotal Systems. ConforMIS, 2015. 29

Krucoff MW, Kereiakes DJ, Petersen JL, Mehran R, Hasselblad V, Lansky AJ. A novel bioresorbable polymer paclitaxel-eluting stent for the treatment of single and multivessel coronary disease: primary results of the COSTAR (Cobalt Chromium Stent With Antiproliferative for Restenosis) II study. J Am Coll Cardiol 2008;51(16):1543-52. 30

Carpenter D, Zucker EJ, Avorn J. Drug-review deadlines and safety problems. N Engl J Med 2008;358(13):1354-61. 31

Premarket approval (PMA) database. US Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm. Accessed February 10, 2016. 32

Davis S, Gilbertson E, Goodall S. EU medical device approval safety assessment: A comparative analysis of medical device recalls 2005-2009. BCG, 2011. 33

California Healthcare Institute. Taking the pulse of medical device regulation and innovation. CHI, 2014. 34

Downing NS, Aminawung JA, Shah ND, Braunstein JB, Krumholz HM, Ross JS. Regulatory review of novel therapeutics--comparison of three regulatory agencies. N Engl J Med 2012;366(24):2284-93. 35

Kynaston-Pearson F, Ashmore AM, Malak TT, Rombach I, Taylor A, Beard D, et al. Primary hip replacement prostheses and their evidence base: systematic review of literature. BMJ 2013;347:f6956. 36

Lee K, Bacchetti P, Sim I. Publication of clinical trials supporting successful new drug applications: a literature analysis. PLoS Med 2008;5(9):e191. 37

Rising K, Bacchetti P, Bero L. Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation. PLoS Med 2008;5(11):e217. 38

Wild C, Erdös J, Zechmeister I. Contrasting clinical evidence for market authorisation of cardio-vascular devices in Europe and the USA: a systematic analysis of 10 devices based on Austrian pre-reimbursement assessments. BMC Cardiovasc Disord 2014;14:154. 39

European Commission. Market surveillance and vigilance: EUDAMED. http://ec.europa.eu/growth/sectors/medical-devices/market-surveillance/index_en.htm. Accessed January 18, 2016 40

Cohen D, Billingsley M. Europeans are left to their own devices. BMJ 2012;342:d2748. 41

Heneghan C, Thompson M, Billingsley M, Cohen D. Medical-device recalls in the UK and the device-regulation process: retrospective review of safety notices and alerts. BMJ Open 2011;1(1):e000155. 42

Mitka M. Direct-to-consumer advertising of medical devices under scrutiny. JAMA 2008;300(17):1985-1986. 43

Zhan C, Baine WB, Sedrakyan A, Steiner C. Cardiac device implantation in the United States from 1997 through 2004: a population-based analysis. J Gen Intern Med 2008;23 Suppl 1:13-9. 44

Maisel WH, Moynahan M, Zuckerman BD, Gross TP, Tovar OH, Tillman DB, Schultz DB. Pacemaker and ICD generator malfunctions: analysis of Food and Drug Administration annual reports. JAMA 2006;295(16):1901-6. 45

Mond HG, Proclemer A. The 11th world survey of cardiac pacing and implantable cardioverter-defibrillators: calendar year 2009--a World Society of Arrhythmia's project. Pacing Clin Electrophysiol 2011;34(8):1013-27. 46

Basu S, Hassenplug JC. Patient access to medical devices--a comparison of U.S. and European review processes. N Engl J Med 2012;367(6):485-8. 47

Christiansen EH, Jensen LO, Thayssen P, Tilsted HH, Krusell LR, Hansen KN, et al. Biolimus-eluting biodegradable polymer-coated stent versus durable polymer-coated sirolimus-eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V): a randomised non-inferiority trial. Lancet 2013;381(9867):661-9. 48

Kesselheim AS, Hwang TJ. Breakthrough Medical Devices and the 21st Century Cures Act. Ann Intern Med 2016 Jan 19. doi: 10.7326/M15-1906. [Epub ahead of print] 49

Maisel WH. Unanswered questions--drug-eluting stents and the risk of late thrombosis. N Engl J Med 2007;356(10):981-4. 50

Wentholt IM, Hoekstra JB, Zwart A, DeVries JH. Pendra goes Dutch: lessons for the CE mark in Europe. Diabetologia 2005;48(6):1055-8. 51

Mercer NS. Dermal fillers are medical devices in the UK. BMJ 2009;339:b2923.

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nly 52

Ross S, Robert M, Harvey MA, Farrell S, Schulz J, Wilkie D, et al. Ethical issues associated with the introduction of new surgical devices: or just because we can doesn't mean we should. J Obstet Gynaecol Can 2008;30(6):508-513. 53

Lieberman JR, Wenger N. New technology and the orthopaedic surgeon: are you protecting your patients? Clin Orthop Relat Res 2004;(429):338-41. 54

Eikermann M, Gluud C, Perleth M, Wild C, Sauerland S, Gutierrez-Ibarluzea I, et al. Commentary: Europe needs a central, transparent, and evidence based regulation process for devices. BMJ 2013;346:f2771. 55

Fraser AG, Krucoff MW, Brindis RG, Komajda M, Smith SC Jr. Commentary: International collaboration needed on device clinical standards. BMJ 2011;342:d2952. 56

Cohen D. Patients are let down by poor device regulation, warn surgeons. BMJ 2012;345:e7221. 57

Williams N. The scandal of device regulation in the UK. Lancet 2012;379:1789-90. 58

Cohen D. Patient groups accuse European parliament of putting economic interests ahead of safety on medical devices. BMJ 2013;347:f6446. 59

McCulloch P. The EU's system for regulating medical devices. BMJ 2012;345:e7126. 60

Storz-Pfennig P, Schmedders M, Dettloff M. Trials are needed before new devices are used in routine practice in Europe. BMJ 2013;346:f1646. 61

Hulstaert F, Neyt M, Vinck I, Stordeur S, Huić M, Sauerland S, et al. Pre-market clinical evaluations of innovative high-risk medical devices in Europe. Int J Technol Assess Health Care 2012;28(3):278-84. 62

Boulton AJ. Registration and regulation of medical devices used in diabetes in Europe: need for radical reform. Lancet Diabetes Endocrinol 2013;1(4):270-2. 63

Stordeur S, Vinck I, Neyt M, Van Brabandt H, Hulstaert F. Mise sur le marché européen des dispositifs médicaux innovants à haut risque : l’efficacité clinique et la sécurité sont-elles garanties ? Rev Epidemiol Sante Publique 2013;61(2):105-10. 64

Freemantle N. Commentary: Evaluating and regulating device therapy. BMJ 2011;342:d2839. 65

Campillo-Artero C. A full-fledged overhaul is needed for a risk and value-based regulation of medical devices in Europe. Health Policy 2013;113(1-2):38-44. 66

Fraser AG, Daubert JC, Van de Werf F, Estes NA 3rd, Smith SC Jr, Krucoff MW, et al. Clinical evaluation of cardiovascular devices: principles, problems, and proposals for European regulatory reform. Report of a policy conference of the European Society of Cardiology. Eur Heart J 2011;32(13):1673-86. 67

Pinto F, Fraser AG, Kautzner J, Kreutzer K, Piat S, Siebert M, et al. Barriers to cardiovascular device innovation in Europe. Eur Heart J 2016;37(2):140-4. 68

Grennan M, Town RJ. Regulating innovation with uncertain quality: information, risk, and access in medical devices. Working Paper, Wharton School of Business at the University of Pennsylvania, 2015.

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nlyBox 1. Overview of Medical Device Regulation in the EU and US

Europe

In Europe, moderate- and high-risk devices can be marketed after gaining a

Conformité Européenne (CE) mark from any one of over 60 Notified Bodies, which are

independent, private-sector companies located across the EU that evaluate the

performance, reliability, and risk-benefit balance of all consumer products, including

medical devices. Notified Bodies do not have uniform, mandatory standards for the

evidence they require.

United States

In the US, medical devices are regulated by the FDA according to their level of risk,

and moderate- and high-risk devices (which represent virtually all therapeutic and

prescribed devices) must receive approval before they can be marketed.

• High-risk devices, defined as those that support life or that may present an

unreasonable risk of illness or injury (such as deep brain stimulators), are

approved through the premarket approval (PMA) pathway. PMA devices must

provide valid scientific evidence collected from human clinical trials showing

“reasonable assurance” that the device is safe and effective for its intended use.

• Subsequent changes to high-risk devices, including design changes, are approved

through the PMA supplement process, which may not require additional testing.

• Certain high-risk devices that are intended to treat rare diseases (fewer than 4,000

patients in the US annually) may receive a Humanitarian Device Exemption and be

approved on the basis of “probable” benefits.

• Moderate-risk devices (such as intravascular embolic protection devices) and

some high-risk devices can be marketed after gaining “clearance” through the

510(k) pathway, ordinarily without needing additional clinical data.

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nlyTable 1. Characteristics of New Devices Granted CE Marks Between 2005 and 2010

Novel Medical Devices (N = 309) No. (%)

Therapeutic area

Cardiovascular 245 (79.3%)

Neurologic 28 (9.1%)

Orthopedic 36 (11.6%)

CE Mark year

2005 29 (9.4%)

2006 37 (12.0%)

2007 36 (11.6%)

2008 57 (18.4%)

2009 79 (25.6%)

2010 71 (23.0%)

Firm type

Small (<US$1B) 134 (43.7%)

Large (≥US$1B) 174 (56.3%)

FDA approval

Yes 206 (66.7%)

No 103 (33.3%)

Major innovation

Yes 75 (24.3%)

No 234 (75.7%)

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nlyFigure 1. Study Flowchart

Press releases and

other reports screened

(n=3,586)

Full text records

assessed (n=374)

Records excluded for

relevance (n=3,212)

Included from review

of FDA data (n=18)

Final study device

cohort (n=309)

Excluded (n=130)

• Ineligible or missing

date (n=98)

• Duplicates (n=28)

• Not devices (n=4)

Date identified after

manual review (n=47)

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nlyFigure 2. Median Time Differential between CE Mark and FDA Approval

Notes: Values plotted in the figure are medians. Approval refers to CE marking in Europe and clearance or approval by the FDA in the United States. IQR = interquartile range. PMA = premarket approval.

Approval Pathway

PMA (n=44)

PMA Supplement (n=76)

Humanitarian (n=4)

510(k) (n=82)

Therapeutic Area

Cardiovascular (n=165)

Neurologic (n=22)

Orthopedic (n=19)

Novelty

Major Innovation (n=54)

Other Change (n=152)

Firm size

Small (n=67)

Large (n=139)

Median (IQR)

36.3 (20.9, 58.2)

11.1 (-0.4, 30.3)

12.3 (-2.2, 32.5)

-0.8 (-7.2, 9.0)

12.1 (-0.9, 37.2)

0.0 (-12.7, 15.4)

-2.8 (-9.6, 3.4)

25.1 (-0.2, 38.5)

3.3 (-1.9, 29.8)

5.9 (-3.2, 31.5)

9.8 (-1.2, 35.5)

-40 -30 -20 -10 0 10 20 30 40 50 60

Median Time Differential from EU (CE Mark) to US (FDA) Approval (months)

US faster EU faster

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nlyFigure 3. Cumulative Incidence Curves of First Safety Alert or Recall a

b

Notes: Panel (a) plots cumulative incidence rates of safety alerts and recalls. Panel (b) plots cumulative incidence rates of recalls only. Approval refers to CE marking in Europe and clearance or approval by the FDA. Devices approved first in the US are represented by the blue curve; devices approved first in Europe are represented by the green curve.

-

0.2

0.4

0.6

0.8

1.0

0 20 40 60 80

Cumulative Incidence Rate of Safety Alerts or Recalls

Months since First Approval

Log-rank P = 0.02

US First

EU First

-

0.2

0.4

0.6

0.8

1.0

0 20 40 60 80

Cumulative Incidence Rate of Recalls

Months since First Approval

Log-rank P = 0.004

US First

EU First

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nlyTable 2. Results from Multivariable Cox Regression Models of Safety Alerts and Recalls

Characteristic HR (95% CI) Alert or Recall

P value

HR (95% CI) Recall Only

P value

First approval year

2005a 1 [Reference] 1 [Reference]

2006 0.80 (0.29-2.17) 0.66 0.67 (0.16-2.81) 0.58

2007 0.98 (0.42-2.30) 0.97 1.56 (0.52-4.64) 0.43

2008 0.96 (0.43-2.13) 0.91 1.28 (0.44-3.67) 0.65

2009 0.80 (0.36-1.77) 0.58 1.58 (0.58-4.34) 0.38

2010 0.57 (0.23-1.39) 0.22 0.71 (0.21-2.33) 0.57

Therapeutic category

Cardiac assist devices 1 [Reference] 1 [Reference]

Cardiac prosthetic devices 1.25 (0.39-4.02) 0.70 1.42 (0.38-5.37) 0.60

Cardiac rhythm management 1.32 (0.39-4.40) 0.66 0.95 (0.23-3.83) 0.94

Interventional cardiology 0.43 (0.13-1.42) 0.17 0.40 (0.10-1.57) 0.19

Electrophysiology 0.70 (0.15-3.31) 0.66 0.62 (0.10-3.97) 0.61

Cardiac surgery and other 0.53 (0.13-2.24) 0.39 0.79 (0.16-3.76) 0.76

Neuromodulation devices 2.45 (0.66-9.08) 0.18 2.43 (0.51-11.5) 0.26

Neurology therapeutic devices 1.40 (0.28-7.04) 0.68 –b –

b

Other neurologic devices 2.49 (0.24-26.1) 0.45 5.95 (0.46-77.8) 0.17

Joint reconstruction 0.98 (0.17-5.56) 0.99 1.13 (0.18-7.00) 0.90

Spinal and other orthopedic 0.50 (0.11-2.33) 0.38 0.20 (0.02-2.02) 0.17

First approved in EU

Yes 2.95 (1.40-6.22) 0.005 4.64 (1.54-14.0) 0.006

No 1 [Reference] 1 [Reference]

Major innovation

Yes 0.99 (0.57-1.70) 0.96 0.76 (0.38-1.52) 0.44

No 1 [Reference] 1 [Reference]

Regulatory pathway

Not FDA approved 1 [Reference] 1 [Reference]

510(k) clearance 1.28 (0.56-2.90) 0.56 0.92 (0.33-2.58) 0.88

PMAc 1.71 (0.78-3.75) 0.18 1.28 (0.48-3.41) 0.63

PMA supplement 1.82 (0.86-3.88) 0.12 1.86 (0.81-4.30) 0.15

Firm type

Large (≥US$1B) 0.93 (0.54-1.62) 0.81 0.75 (0.39-1.47) 0.40

Small (<US$1B) 1 [Reference] 1 [Reference]

Notes: Hazard ratios (HR) and confidence intervals (CI) are from multivariable Cox regression models for safety alerts and recalls or recalls only. First approval year refers to the earlier of the year of device approval in Europe (CE mark) or in the US (premarket approval, premarket supplement, 510(k) clearance, or humanitarian device exemption [HDE]). a Includes six devices that were first approved in the US before 2005 (2003-2004). b Omitted due to collinearity. c Includes 4 HDE devices.

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nlySupplemental Appendix Appendix Table 1. Sub-Categorization of Medical Devices Included in Study Sample

Novel Medical Devices (N = 309) Examples

Cardiovascular

Cardiac assist devices Embolization device

Cardiac prosthetic devices Transcatheter heart valve

Cardiac rhythm management Implantable cardioverter defibrillators

Interventional cardiology Drug-eluting coronary stent

Electrophysiology Cardiac ablation catheter

Cardiac surgery and other Vascular closure device

Neurologic

Neuromodulation Deep brain stimulation device

Neurology therapeutic devices Intracranial aneurysm flow diverter

Other neurology Neurodiagnostic electrodes

Orthopedic

Joint reconstruction Knee replacement

Spinal and other orthopedic Intervertebral fusion device

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nlyAppendix Table 2. Results from Multivariable Linear Regression Model of Time Differentials between CE Mark and FDA Approval

Characteristic Coefficient (months)

95% confidence interval (CI)

P value

CE mark year

2005 1 [Reference]

2006 -4.69 (-17.5-8.10) 0.47

2007 0.04 (-10.3-10.4) 0.99

2008 -0.75 (-12.2-10.7) 0.90

2009 -3.13 (-13.6-7.4) 0.56

2010 -6.45 (-16.8-3.9) 0.22

Therapeutic sub-category

Cardiac assist devices 1 [Reference]

Cardiac prosthetic devices 0.25 (-10.9-11.4) 0.97

Cardiac rhythm management -12.8 (-23.4--2.06) 0.02

Interventional cardiology -2.04 (-11.1-7.0) 0.66

Electrophysiology -2.14 (-14.5-10.2) 0.73

Cardiac surgery and other -3.98 (-15.7-7.70) 0.50

Neuromodulation devices -13.7 (-31.8-4.39) 0.14

Neurology therapeutic devices -16.0 (-32.0-0.02) 0.05

Other neurologic devices -15.6 (-26.5--4.66) 0.01

Joint reconstruction -4.32 (-26.7-18.0) 0.70

Spinal and other orthopedic -5.95 (-16.0-4.04) 0.24

Major innovation

Yes 0.93 (-5.14-6.99) 0.76

No 1 [Reference]

Regulatory pathway

Not FDA approved 1 [Reference]

510(k) clearance 5.89 (-0.23-12.0) 0.06

PMAa 38.0 (29.9-46.1) <0.001

PMA supplement 20.5 (12.5-28.5) <0.001

Firm type

Large (≥US$1B) -2.05 (-7.80-3.71) 0.49

Small (<US$1B) 1 [Reference]

Notes: Estimated time differentials and confidence intervals (CI) are from multivariable linear regression models. Regulatory

pathway refers to approval route in the US (premarket approval, premarket supplement, 510(k) clearance, or humanitarian device

exemption) or not yet FDA approved. a Includes 4 HDE devices

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nlyAppendix Table 3. Results from Multivariable Cox Regression Model in Sensitivity Analysis with Continuous Time Variable



P value

First approval year 0.92 (0.79 – 1.07) 0.29

Therapeutic category


Cardiac prosthetic devices 1.54 (0.33 – 7.07) 0.58

Cardiac rhythm management 1.65 (0.35 – 7.80) 0.53

Interventional cardiology 0.42 (0.09 – 2.06) 0.29

Electrophysiology 0.76 (0.12 – 4.73) 0.77

Cardiac surgery and other 0.72 (0.12 – 4.16) 0.71

Neuromodulation devices 3.28 (0.65 – 16.5) 0.15

Neurology therapeutic devices 1.10 (0.09 – 13.9) 0.94

Other neurologic devices 5.65 (0.43 – 74.0) 0.19

Joint reconstruction 1.34 (0.18 – 9.87) 0.77

Spinal and other orthopedic 0.24 (0.02 – 2.82) 0.26


Yes 2.55 (1.14 – 5.71) 0.02

No 1 [Reference]

Major innovation

Yes 1.06 (0.59 – 1.92) 0.84

No 1 [Reference]

Regulatory pathway


510(k) clearance 0.45 (0.15 – 1.31) 0.14

PMAa 1.25 (0.56 – 2.79) 0.59

PMA supplement 1.20 (0.56 – 2.56) 0.65

Firm type

Large (≥US$1B) 0.84 (0.47 – 1.48) 0.54


Notes: Hazard ratios (HR) and confidence intervals (CI) are from multivariable Cox regression model of safety alert or recall. First approval year refers to the earlier of the year of device approval in Europe (CE mark) or in the US (premarket approval, premarket supplement, 510(k) clearance, or humanitarian device exemption). a Includes 4 HDE devices.

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nlyAppendix Table 4. Results from Multivariable Cox Regression Model in Sensitivity Analysis



P value

First approval year

2005a 1 [Reference]

2006 0.32 (0.08 – 1.23) 0.10

2007 0.96 (0.39 – 2.37) 0.94

2008 0.92 (0.40 – 2.11) 0.84

2009 0.79 (0.34 – 1.84) 0.59

2010 0.39 (0.15 – 1.01) 0.05

Therapeutic area

Cardiovascular 1 [Reference]

Neurologic 4.11 (0.79 – 21.2) 0.09

Orthopedic 0.27 (0.02 – 3.09) 0.29

Therapeutic sub-category


Cardiac prosthetic devices 1.97 (0.42 – 9.21) 0.39

Cardiac rhythm management 2.14 (0.45 – 10.2) 0.34

Interventional cardiology 0.47 (0.10 – 2.31) 0.35

Electrophysiology 0.95 (0.15 – 6.14) 0.96

Cardiac surgery and other 0.94 (0.16 – 5.66) 0.95

Neuromodulation devices –b –

b –

b

Neurology therapeutic devices 0.25 (0.03 – 2.36) 0.23

Other neurologic devices 1.26 (0.12 – 12.8) 0.85

Joint reconstruction 4.48 (0.40 – 50.5) 0.23

Spinal and other orthopedic –b –

b –

b


Yes 2.58 (1.14 – 5.83) 0.02

No 1 [Reference]

Major innovation

Yes 1.09 (0.60 – 1.96) 0.78

No 1 [Reference]

Regulatory pathway


510(k) clearance 0.42 (0.14 – 1.26) 0.12

PMAc 1.25 (0.54 – 2.90) 0.60

PMA supplement 0.94 (0.42 – 2.08) 0.88

Firm type

Large (≥US$1B) 0.79 (0.43 – 1.44) 0.44


Notes: Hazard ratios (HR) and confidence intervals (CI) are from multivariable Cox regression model of safety alert or recall. First approval year refers to the earlier of the year of device approval in Europe (CE mark) or in the US (premarket approval, premarket supplement, 510(k) clearance, or humanitarian device exemption). a Includes six devices that were first approved in the US before 2005 (2003-2004). b Omitted due to collinearity. c Includes 4 HDE devices

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nlyAppendix Protocol:

Determination of ‘Major Innovation’ Status for Studied Devices

Criteria for Major Innovation Example and Commentary

1. The device is the first in an entirely new class of

products in the US (by FDA, any pathway) and Europe (CE mark).

• e.g., Melody Transcatheter Pulmonary Valve – first transcatheter pulmonary valve that received regulatory approval in US and Europe (CE marked in 2006)

• Most such new devices are subject to FDA premarket approval (see 21 CFR 814.1)

2. The device involves new technology (and may

incorporate components of already marketed devices) and makes new claims w/r/t the safety and/or effectiveness of the device.

• e.g., Epiducer Lead Delivery System – first-of-its-kind system intended to introduce neurostimulation perc-paddle leads, typically as an alternative to laminotomy (As seen from this example, some 510(k)-cleared devices were classified as ‘major innovations,’ reflecting the fact that the choice of regulatory pathway is not a perfect predictor of device risk or novelty.)

3. The device involves new technology (and may

incorporate components of already marketed devices) and is intended to be used in a new or expanded patient population.

• e.g., Resolute Integrity Zotarolimus-Eluting Coronary Stent – uses the same stent design, drug, and base material as existing stents but uses a new polymer in the drug-polymer stent coating, uses a different delivery system, and is indicated for a target population that now includes those with diabetes mellitus with symptomatic ischemic heart disease

• We propose to use some discretion to define an “expanded” patient population. For example, we would not consider as a ‘major innovation’ a minor difference in indication for a stent for patients with stenotic lesions length ≤ 27mm with reference vessel diameter of 2.75-5.0mm versus a stent for patients with lesions of length ≤ 28mm with reference vessel diameters of 2.5-5.0mm.

“Other Change” Devices

• We propose to exclude already marketed devices that are

approved for an entirely new patient population, or approved with new or expanded claims on its safety and/or effectiveness, than that for its already approved indication(s). This is consistent with the FDA’s definitions for new molecular entities (see 21 CFR 314.108)

• We propose to exclude devices that are substantially equivalent (or that may differ due to minor technical changes) to existing devices on the market and do not make new safety and/or effectiveness claims or are not intended to be used in a new or expanded patient population. We referred to the definition used by FDA for “substantial equivalence” (see section 513(i) of the Food, Drug, and Cosmetic Act)

• We propose to exclude devices that differ from existing products due to minor technical, mechanical, procedural, system / process, or manufacturing changes

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Documents

Confidential: For Review Only - BMJ · 2016. 6. 29. · Confidential: For Review Only Safety, trial outcomes reporting, and regulatory approval of medical devices in Europe and the