BMJ 2014;349:g5303 doi: 10.1136/bmj.g5303 (Published 9 September 2014)
Page 1 of 2
Editorials
EDITORIALS Regulating incremental innovation in medical devices Patients need active regulatory oversight, linked to compulsory post-marketing research Aaron S Kesselheim associate professor of medicine, Prashant V Rajan medical student 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 02120, USA
As therapeutic options, medical devices differ from prescription drugs in many ways, but one of the most important is their potential for rapid evolution in basic design or technology. In the context of prescription drugs, it would be completely unreasonable to take a basic chemical structure, add another methyl group to it, and presume the drug would work the same (or better) without subjecting the new molecule to additional clinical testing. Medical devices, by contrast, change often. In a study published earlier this year, we found that cardiac implantable electronic devices approved in the US had a median of 50 applications to the Food and Drug Administration (FDA) for big and small changes over their median 15 year regulatory lifespans.1 In a linked paper (doi:10.1136/bmj.g5133), Nieuwenhuijse and colleagues provide important insights into the evidence base supporting new versions of hip and knee replacement devices.2 After conducting a systematic review of the literature and registry data, they found no good evidence of improved clinical outcomes for five widely used and marketed “advances” in hip and knee replacement technology, but they did find concerns about the safety of some implants when compared with previously marketed versions. None of the new devices improved functional or patient reported outcomes or survival rates, while three of the five implants were associated with higher rates of revision than previous versions.
These data shine a light on the limited regulatory oversight of incremental device innovations that exists in Europe, US, and other countries. In the US, most total hip or knee replacements are classified as moderate risk, class II medical devices, for which incremental innovations are cleared through the FDA’s 510(k) pathway based on manufacturers demonstrating that their devices hold “substantial equivalence” to pre-existing products.3 European Union device approval is moderated through private Notified Bodies that issue a CE (Conformité Européenne) mark when a device performs safely and as intended.4 It is unclear whether there is a consistent approach among Notified Bodies to the data required to support incremental innovations since their decision making processes are far from transparent. Given that “times to market” for class II devices are consistent between the US and EU, it is unlikely that changes
to existing devices are subject to any heightened evidence gathering by Notified Bodies or the national Competent Authorities that oversee them.5
Regulating evolving technologies that introduce potentially beneficial changes is a practical and ethical challenge. Lack of testing puts patients at risk, since even incremental innovations can change how some devices function in the body. This occurred with metal-on-metal total hip replacements, for example, when the FDA cleared a hip implant under the 510(k) pathway that was later shown to possess a high risk of wear, corrosion, and metal release into the bloodstream.6 Some experts have argued that the threshold for incremental changes fostered by Notified Bodies and the FDA 510(k) process is set too low. As the US Institute of Medicine concluded in a widely cited and controversial report on the 510(k) pathway, the principle of substantial equivalence “does not require an independent demonstration that the new device provides a ‘reasonable assurance of safety.’”7
However, the Institute of Medicine’s recommendation to replace the 510(k) clearance process with a more rigorous pre-approval review system may not be the best solution. If regulators required testing of every potential change to a medical device, it might slow the uptake of important updates to the basic technology, to the detriment of patients. As an alternative, Nieuwenhuijse and colleagues recommend controlled introduction of new versions of medical devices so that they are not used widely until we know more about their comparative effectiveness and safety. Professional society guidelines may help impose such rigour on the marketplace but are unlikely to achieve this goal alone. Kynaston-Pearson and colleagues previously showed widespread use of new hip prostheses despite their being rated unfavourably by the National Joint Registry of England and Wales because of lack of supporting evidence.8 To complement this approach, we need to communicate better with patients so they understand the benefits and risks of new technologies and can make fully informed decisions about treatment. In the pharmaceutical market, investigators have tested plainly worded drug facts boxes that provide summaries of a product’s supporting evidence, and these communication tools have resulted in more rational choices between treatment
[email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;349:g5303 doi: 10.1136/bmj.g5303 (Published 9 September 2014)
Page 2 of 2
EDITORIALS
alternatives.9 An equivalent device facts box for hip and knee replacement devices could help correct the overestimation of benefits and underestimation of harms that many consumers would otherwise expect when learning of “new and improved” models.
Meanwhile, regulators could be more circumspect when manufacturers seek to introduce major new design changes before the previous alterations have been evaluated properly. In addition, incremental innovation should be tied to mandatory enrolment of patients in registries. The FDA is taking steps towards constructing a robust nationwide surveillance network for medical devices,10 and Europe should also continue to expand registry initiatives and promote EU-wide versions.
Finally, regulators should encourage manufacturers to conduct comparative effectiveness trials of their products against pre-existing versions, but may require greater authority from legislators to mandate timely follow-up clinical trials for device updates.11 Reforms that provide more robust post-market oversight of incremental innovations in medical devices and generate evidence of effectiveness and safety quickly and efficiently will be key in helping to promote more rational use of these products. Funding: ASK’s work is supported by the Greenwall Foundation as a faculty scholar and the Harvard Program in Therapeutic Science.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Competing interests: We have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare. Provenance and peer review: Commissioned; not peer reviewed 1 2 3 4 5 6 7 8 9 10 11
Rome BN, Kramer DB, Kesselheim AS. FDA approval of cardiac implantable electronic devices via original and supplement premarket approval pathways, 1979-2012. JAMA 2014;311:385-91. Nieuwenhuijse MJ, Nelissen RGHH, Schoones JW, Marinac-Dabic D, 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. Food and Drug Administration. Medical devices: premarket notification (510k). 2014. www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/ PremarketSubmissions/PremarketNotification510k/default.htm. Kramer DB, Xu S, Kesselheim AS. Regulation of medical devices in the United States and European Union. N Engl J Med 2012;366:848-55. Cohen D, Billingsley M. Europeans are left to their own devices. BMJ 2011;342:d2748. Ardaugh BM, Graves SE, Redberg RF. The 510(k) ancestry of a metal-on-metal hip implant. N Engl J Med 2013;368:97-100. Institute of Medicine. Medical devices and the public’s health: the FDA 510(k) clearance process at 35 years . National Academies Press; 2011. 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. Schwartz LM, Woloshin S, Welch HG. Using a drug facts box to communicate drug benefits and harms: two randomized trials. Ann Intern Med 2009;150:516-27. Food and Drug Administration. Strengthening our national system for medical device postmarket surveillance: update and next steps . Center for Devices and Radiological Health, 2013. Sorenson C, Drummond M. Improving medical device regulation: the United States and Europe in perspective. Milbank Q 2014;92:114-50.
Cite this as: BMJ 2014;349:g5303 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
Page 1 of 2
Editorials
EDITORIALS Regulating incremental innovation in medical devices Patients need active regulatory oversight, linked to compulsory post-marketing research Aaron S Kesselheim associate professor of medicine, Prashant V Rajan medical student 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 02120, USA
As therapeutic options, medical devices differ from prescription drugs in many ways, but one of the most important is their potential for rapid evolution in basic design or technology. In the context of prescription drugs, it would be completely unreasonable to take a basic chemical structure, add another methyl group to it, and presume the drug would work the same (or better) without subjecting the new molecule to additional clinical testing. Medical devices, by contrast, change often. In a study published earlier this year, we found that cardiac implantable electronic devices approved in the US had a median of 50 applications to the Food and Drug Administration (FDA) for big and small changes over their median 15 year regulatory lifespans.1 In a linked paper (doi:10.1136/bmj.g5133), Nieuwenhuijse and colleagues provide important insights into the evidence base supporting new versions of hip and knee replacement devices.2 After conducting a systematic review of the literature and registry data, they found no good evidence of improved clinical outcomes for five widely used and marketed “advances” in hip and knee replacement technology, but they did find concerns about the safety of some implants when compared with previously marketed versions. None of the new devices improved functional or patient reported outcomes or survival rates, while three of the five implants were associated with higher rates of revision than previous versions.
These data shine a light on the limited regulatory oversight of incremental device innovations that exists in Europe, US, and other countries. In the US, most total hip or knee replacements are classified as moderate risk, class II medical devices, for which incremental innovations are cleared through the FDA’s 510(k) pathway based on manufacturers demonstrating that their devices hold “substantial equivalence” to pre-existing products.3 European Union device approval is moderated through private Notified Bodies that issue a CE (Conformité Européenne) mark when a device performs safely and as intended.4 It is unclear whether there is a consistent approach among Notified Bodies to the data required to support incremental innovations since their decision making processes are far from transparent. Given that “times to market” for class II devices are consistent between the US and EU, it is unlikely that changes
to existing devices are subject to any heightened evidence gathering by Notified Bodies or the national Competent Authorities that oversee them.5
Regulating evolving technologies that introduce potentially beneficial changes is a practical and ethical challenge. Lack of testing puts patients at risk, since even incremental innovations can change how some devices function in the body. This occurred with metal-on-metal total hip replacements, for example, when the FDA cleared a hip implant under the 510(k) pathway that was later shown to possess a high risk of wear, corrosion, and metal release into the bloodstream.6 Some experts have argued that the threshold for incremental changes fostered by Notified Bodies and the FDA 510(k) process is set too low. As the US Institute of Medicine concluded in a widely cited and controversial report on the 510(k) pathway, the principle of substantial equivalence “does not require an independent demonstration that the new device provides a ‘reasonable assurance of safety.’”7
However, the Institute of Medicine’s recommendation to replace the 510(k) clearance process with a more rigorous pre-approval review system may not be the best solution. If regulators required testing of every potential change to a medical device, it might slow the uptake of important updates to the basic technology, to the detriment of patients. As an alternative, Nieuwenhuijse and colleagues recommend controlled introduction of new versions of medical devices so that they are not used widely until we know more about their comparative effectiveness and safety. Professional society guidelines may help impose such rigour on the marketplace but are unlikely to achieve this goal alone. Kynaston-Pearson and colleagues previously showed widespread use of new hip prostheses despite their being rated unfavourably by the National Joint Registry of England and Wales because of lack of supporting evidence.8 To complement this approach, we need to communicate better with patients so they understand the benefits and risks of new technologies and can make fully informed decisions about treatment. In the pharmaceutical market, investigators have tested plainly worded drug facts boxes that provide summaries of a product’s supporting evidence, and these communication tools have resulted in more rational choices between treatment
[email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;349:g5303 doi: 10.1136/bmj.g5303 (Published 9 September 2014)
Page 2 of 2
EDITORIALS
alternatives.9 An equivalent device facts box for hip and knee replacement devices could help correct the overestimation of benefits and underestimation of harms that many consumers would otherwise expect when learning of “new and improved” models.
Meanwhile, regulators could be more circumspect when manufacturers seek to introduce major new design changes before the previous alterations have been evaluated properly. In addition, incremental innovation should be tied to mandatory enrolment of patients in registries. The FDA is taking steps towards constructing a robust nationwide surveillance network for medical devices,10 and Europe should also continue to expand registry initiatives and promote EU-wide versions.
Finally, regulators should encourage manufacturers to conduct comparative effectiveness trials of their products against pre-existing versions, but may require greater authority from legislators to mandate timely follow-up clinical trials for device updates.11 Reforms that provide more robust post-market oversight of incremental innovations in medical devices and generate evidence of effectiveness and safety quickly and efficiently will be key in helping to promote more rational use of these products. Funding: ASK’s work is supported by the Greenwall Foundation as a faculty scholar and the Harvard Program in Therapeutic Science.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Competing interests: We have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare. Provenance and peer review: Commissioned; not peer reviewed 1 2 3 4 5 6 7 8 9 10 11
Rome BN, Kramer DB, Kesselheim AS. FDA approval of cardiac implantable electronic devices via original and supplement premarket approval pathways, 1979-2012. JAMA 2014;311:385-91. Nieuwenhuijse MJ, Nelissen RGHH, Schoones JW, Marinac-Dabic D, 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. Food and Drug Administration. Medical devices: premarket notification (510k). 2014. www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/ PremarketSubmissions/PremarketNotification510k/default.htm. Kramer DB, Xu S, Kesselheim AS. Regulation of medical devices in the United States and European Union. N Engl J Med 2012;366:848-55. Cohen D, Billingsley M. Europeans are left to their own devices. BMJ 2011;342:d2748. Ardaugh BM, Graves SE, Redberg RF. The 510(k) ancestry of a metal-on-metal hip implant. N Engl J Med 2013;368:97-100. Institute of Medicine. Medical devices and the public’s health: the FDA 510(k) clearance process at 35 years . National Academies Press; 2011. 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. Schwartz LM, Woloshin S, Welch HG. Using a drug facts box to communicate drug benefits and harms: two randomized trials. Ann Intern Med 2009;150:516-27. Food and Drug Administration. Strengthening our national system for medical device postmarket surveillance: update and next steps . Center for Devices and Radiological Health, 2013. Sorenson C, Drummond M. Improving medical device regulation: the United States and Europe in perspective. Milbank Q 2014;92:114-50.
Cite this as: BMJ 2014;349:g5303 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
