The regulation of medical devices in the US has grown increasingly complex, with multiple pathways to gain marketplace entry and a shift toward collecting evidence in the postmarket setting.
The findings come from a sweeping study of more than 40 years of medical device regulation by the US Food and Drug Administration (FDA), beginning with the Medical Device Amendments of 1976, which first provided the agency with premarket review authority for devices. The analysis was conducted by researchers at the Program on Regulation, Therapeutics, and Law (PORTAL) at Brigham and Women’s Hospital and Harvard Medical School, Boston, and was published as a Special Communication in JAMA.
With the enactment of the Medical Device Amendments of 1976, FDA began a risk-based approach to device regulation that required premarket approval of high-risk class III devices, with lower-risk devices following good manufacturing practices and adhering to performance standards. The Amendments of 1976 also introduced the 510(k) pathway for devices that are “substantially equivalent” to a previously marketed device. Over the years, the 510(k) pathway has evolved, with both an abbreviated pathway and a special pathway being established in 1998 to lower the evidence burden on manufacturers. FDA has also exempted many Class I and II devices from the 510(k) notification process over time. In 2012, Congress further streamlined the process for low risk de novo devices, allowing manufacturers to bypass the 510(k) process.
The agency has also introduced multiple pathways for compassionate use of devices; these include the Humanitarian Device Exemption enacted in 1990, which exempts devices intended to benefit those with rare diseases from the usual requirements for showing effectiveness. Similarly, the Expanded Access Program begun in 1997 gives the patients with serious or immediately life-threatening conditions access to unapproved devices.
The 21st Century Cures Act gave the agency the authority to create a Breakthrough Devices Program. In 2016, the agency established a pathway for devices that address life-threatening or irreversibly debilitating conditions to receive expedited testing and priority review.
“Regulatory professionals should be aware of the growing array of special pathways that may be available to their clients and the benefits and drawback of each,” PORTAL’s Jonathan J. Darrow told Focus. “The Breakthrough Devices designation, created in 2016, may be particularly valuable simply because of the halo its name confers, even before considering the actual features of the program,” said Darrow, the lead author of the analysis.
The other significant shift in device regulation came in 2002 with enactment of the Medical Device User Fee and Modernization Act (MDUFA), allowing FDA to collect user fees from device manufacturers. As of 2019, user fees made up 43% of the agency’s device review budget, according to the JAMA analysis.
Approval speed, evidence base varies across pathways
The analysis also tracked how these regulatory changes impacted the number of approvals and clearances of medical devices, as well as their speed in getting to the marketplace. Since 1976, the agency has approved or cleared more than 155,000 new devices and about 99% have used the 510(k) pathway. However, most 510(k) devices have not used the special or abbreviated pathways. Use of the Breakthrough Device pathway has increased steadily since it began, with just 11 designations in 2016 and 138 in 2019.
The speed of approvals varies greatly, with the average time from premarket approval application submission to approval ranging from 300 to 1,000 days. For 510(k) clearance, that timeline is on average less than 200 days, according to the analysis.
Evidence for approvals and clearances is also varied. For instance, an evaluation of 78 premarket approval applications for cardiovascular devices showed that decisions were based on 123 studies, fewer than a third of which were randomized trials. The researchers also reported that FDA requests clinical information in fewer than 10% of the 510(k) submissions.
Evidence collection moves to postmarket phase
The impact of efforts to streamline review processes is “unclear,” the researchers wrote, but there has been a clear trend toward shifting evidence collection from the premarketing period to the postmarketing period. For instance, the Safe Medical Devices Act of 1990 allowed the use of post-approval surveillance or patient registries in place of performance standards.
“For patients and prescribing physicians, one of the most important aspects of the evolving device regulation landscape is that evidence collection has increasingly shifted to the postmarket period,” Darrow explained. “Whenever possible, it may be best to use a device that has been on the market for several years, to allow time for real-world data to collected and analyzed.”
Despite the decades of experience with FDA’s risk-based regulatory system, better data are needed to understand what benefits approved or cleared medical devices have provided to patients, Darrow said. “In the case of 510(k) submissions, the underlying (‘predicate’) device might never have been evaluated for safety or efficacy, making it difficult to know how safe or effective its successor devices are,” he said. “Once these data are generated, principles of bioethics require that patients be educated about expected benefits and risks, so that their consent to treatment is truly informed. Currently the healthcare system gives lip service to the concept of informed consent, but in practice patients are rarely told in quantitative terms what the outcome of their treatment is likely to be.”
The findings come from a sweeping study of more than 40 years of medical device regulation by the US Food and Drug Administration (FDA), beginning with the Medical Device Amendments of 1976, which first provided the agency with premarket review authority for devices. The analysis was conducted by researchers at the Program on Regulation, Therapeutics, and Law (PORTAL) at Brigham and Women’s Hospital and Harvard Medical School, Boston, and was published as a Special Communication in JAMA.
With the enactment of the Medical Device Amendments of 1976, FDA began a risk-based approach to device regulation that required premarket approval of high-risk class III devices, with lower-risk devices following good manufacturing practices and adhering to performance standards. The Amendments of 1976 also introduced the 510(k) pathway for devices that are “substantially equivalent” to a previously marketed device. Over the years, the 510(k) pathway has evolved, with both an abbreviated pathway and a special pathway being established in 1998 to lower the evidence burden on manufacturers. FDA has also exempted many Class I and II devices from the 510(k) notification process over time. In 2012, Congress further streamlined the process for low risk de novo devices, allowing manufacturers to bypass the 510(k) process.
The agency has also introduced multiple pathways for compassionate use of devices; these include the Humanitarian Device Exemption enacted in 1990, which exempts devices intended to benefit those with rare diseases from the usual requirements for showing effectiveness. Similarly, the Expanded Access Program begun in 1997 gives the patients with serious or immediately life-threatening conditions access to unapproved devices.
The 21st Century Cures Act gave the agency the authority to create a Breakthrough Devices Program. In 2016, the agency established a pathway for devices that address life-threatening or irreversibly debilitating conditions to receive expedited testing and priority review.
“Regulatory professionals should be aware of the growing array of special pathways that may be available to their clients and the benefits and drawback of each,” PORTAL’s Jonathan J. Darrow told Focus. “The Breakthrough Devices designation, created in 2016, may be particularly valuable simply because of the halo its name confers, even before considering the actual features of the program,” said Darrow, the lead author of the analysis.
The other significant shift in device regulation came in 2002 with enactment of the Medical Device User Fee and Modernization Act (MDUFA), allowing FDA to collect user fees from device manufacturers. As of 2019, user fees made up 43% of the agency’s device review budget, according to the JAMA analysis.
Approval speed, evidence base varies across pathways
The analysis also tracked how these regulatory changes impacted the number of approvals and clearances of medical devices, as well as their speed in getting to the marketplace. Since 1976, the agency has approved or cleared more than 155,000 new devices and about 99% have used the 510(k) pathway. However, most 510(k) devices have not used the special or abbreviated pathways. Use of the Breakthrough Device pathway has increased steadily since it began, with just 11 designations in 2016 and 138 in 2019.
The speed of approvals varies greatly, with the average time from premarket approval application submission to approval ranging from 300 to 1,000 days. For 510(k) clearance, that timeline is on average less than 200 days, according to the analysis.
Evidence for approvals and clearances is also varied. For instance, an evaluation of 78 premarket approval applications for cardiovascular devices showed that decisions were based on 123 studies, fewer than a third of which were randomized trials. The researchers also reported that FDA requests clinical information in fewer than 10% of the 510(k) submissions.
Evidence collection moves to postmarket phase
The impact of efforts to streamline review processes is “unclear,” the researchers wrote, but there has been a clear trend toward shifting evidence collection from the premarketing period to the postmarketing period. For instance, the Safe Medical Devices Act of 1990 allowed the use of post-approval surveillance or patient registries in place of performance standards.
“For patients and prescribing physicians, one of the most important aspects of the evolving device regulation landscape is that evidence collection has increasingly shifted to the postmarket period,” Darrow explained. “Whenever possible, it may be best to use a device that has been on the market for several years, to allow time for real-world data to collected and analyzed.”
Despite the decades of experience with FDA’s risk-based regulatory system, better data are needed to understand what benefits approved or cleared medical devices have provided to patients, Darrow said. “In the case of 510(k) submissions, the underlying (‘predicate’) device might never have been evaluated for safety or efficacy, making it difficult to know how safe or effective its successor devices are,” he said. “Once these data are generated, principles of bioethics require that patients be educated about expected benefits and risks, so that their consent to treatment is truly informed. Currently the healthcare system gives lip service to the concept of informed consent, but in practice patients are rarely told in quantitative terms what the outcome of their treatment is likely to be.”
JAMA: FDA Regulation and Approval of Medical Devices: 1976-2020
© 2021 Regulatory Affairs Professionals Society.
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