FDA Approval Process for Medical Devices
FDA Approval Process for Medical Devices
Medical devices, developed through physician and industry partnerships, have helped to revolutionize the treatment of disease spanning most medical disciplines. This includes such entities as deep brain stimulation implants for Parkinson's disease, knee replacements for osteoarthritis, coil embolization technologies for intracranial aneurysms and implantable cardiac defibrillators for life-threatening arrhythmias. These remarkable products have undeniably led to increased patient longevity and improved quality of life. Such marvels of modern medicine, however, do not come without cost, to either the consumer or the manufacturer. Recent estimates suggest that the annual expenditures on medical devices in the USA approximates $95–150 billion, which represents almost one-half to three-quarters of the $200 billion spent on such devices across the world and about 6% of our total national health expenditures. Development of new technologies requires considerable investment from companies in terms of research and development costs, manufacturing and marketing, as well as a rigorous approval process through the Food and Drug Administration (FDA). All-in-all, the price of innovation is monumental for those invested in advancing medicine through cutting edge technologies. Recently, there has been a push among lobbyists representing device manufacturers to streamline the lengthy FDA approval process, arguing that the USA will lose its ability to compete globally due to the excessive costs and delays in obtaining FDA approval.
However, in direct contrast to any effort to 'streamline' the approval process, the oversight of device innovation and the approval process has been criticized recently due to several notable device 'failures' that have been linked to patient harm. These devices were approved for use through FDA humanitarian device exemption (HDE) or 510(k) processes, which do not require randomized controlled trial evidence demonstrating safety and effectiveness prior to approval. Unfortunately, such failures are certainly not new. Between 2005 and 2009 nearly 700 voluntary recalls of devices occurred per year, and the vast majority of these were class II recalls, defined as technologies that could result in 'temporary or medically reversible adverse health consequences'. The failure of these processes to detect potentially harmful devices before their release onto the US market has led to a strong backlash, by both physicians and the public at large, against the current regulatory processes in place through which such technologies are approved for use.
The specialty of neurointerventional surgery (also known as interventional neuroradiology or endovascular neurosurgery) is heavily leveraged to medical device development. In this article we will review some recent devices that have generated controversy, review the current FDA approval processes, discuss current issues being debated regarding these processes for new devices and offer further insight into the effect of experience in outcomes for new devices. Finally, we will review possible alternative pathways towards improving the safety and effectiveness of new devices through regulation that both encourages innovation among clinicians and industry and closely monitors new devices after their release.
Adoption of new technologies is not without risk. While initial experience may demonstrate benefit, further experience or longitudinal measures may detect concept, design or manufacturing flaws that were not immediately evident. The most prominent of such devices is the ASR XL Acetabular System (DePuy, Johnson & Johnson, Warsaw, Indiana, USA), which was approved for use by the FDA through 510(k) clearance (described below) and introduced into the US market in 2005. This device has gained considerable negative media attentionwith numerous websites recruiting clients for plaintiff attorneys and over one million unique web pages produced after a Google search using the keywords 'Depuy ASR hip recall'. The ASR featured a metal-on-metal acetabular cup design that was borrowed from a second device, the ASR Hip Resurfacing System, and fitted onto a predicate hip implant. Depuy applied for 510(k) clearance and the new device was deemed substantially equivalent to the prior hip implant without rigorous safety and effectiveness testing. Between 2005 and 2010, approximately 100 000 ASR Acetabular systems were implanted. By 2008 the FDA had received about 300 complaints regarding the device, most arising from patients who had had to undergo early revision surgery. Recent studies have demonstrated an increased rate of implant dysfunction with need for revision surgery that far exceeds that of other hip replacement devices. In fact, results presented at the British Hip Society meeting in 2011 indicated a failure rate nearing 50% at 6 years, which is three times the rate of other devices (approximately 15% at 5 years). Furthermore, elevated levels of blood chromium and cobalt were identified as a side effect of dysfunctional joints. Based on these data, a voluntary recall of the ASR devices was enacted in August 2010 after an estimated 100 000 ASR devices had been implanted (one-third in the USA) and 6 months after the company warned physicians of a high early failure rate. Examination of the dysfunctional implants after removal identified flaws inherent to the design. It is possible that more rigorous safety testing prior to market release, or close post-market clinical follow-up, would have detected irregularities and prevented (or halted) the implantation of ASR devices.
A more familiar neurointerventional device recently drawing considerable negative attention is the Wingspan Stent System (Stryker, Kalamazoo, Michigan, USA), a stent designed for use with the Gateway PTA Balloon Catheter in the treatment of intracranial atherosclerotic disease. The stent was approved under a FDA HDE in 2005, based on a safety study conducted in 45 patients at 12 sites in Asia and Europe, for the treatment of intracranial atherosclerotic disease refractory to medical therapy in intracranial vessels with stenosis of ≥50%. Early retrospective analyses of outcomes performed by independent centers indicated both safety and efficacy with the Wingspan, and many clinicians involved in stroke care were optimistic about how the system would fare in a randomized controlled trial of stroke prevention. The Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial (SAMMPRIS), the first randomized trial comparing best medical therapies to angioplasty and stenting, began enrolling its first patients in October 2008. However, enrollment for SAMMPRIS was halted prematurely in a report in September 2011 owing to a 30-day stroke rate of 14.7% in the angioplasty and stenting arm compared with 5.8% in the medical management arm.These results have led a consumer advocacy group to seek the repeal of the Wingspan HDE and to criticize the FDA for the original approval. However, these efforts are not without controversy as the patient population evaluated in SAMMPRIS was in some respects different from the population indicated on the patient HDE (who would only comprise a subset of the patients evaluated in SAMMPRIS), and the 1-year stroke rate of 20.2% was still perceived as a dramatic improvement over the 24.9% stroke rate demonstrated in the WASID study for the HDE-approved population. Thus, while portrayed as 'dangerous' by groups such as Public Citizen, outcomes with Wingspan in SAMMPRIS were no different from those observed in the same patient cohort treated with conventional medical therapy. The true advance in the SAMMPRIS trial was an observation that was independent of the actual device in that aggressive medical management resulted in a primary event rate that was half the rate (12.2% over 1 year) expected on the basis of the WASID study (24.9%). So while no one debates that aggressive medical management is superior to angioplasty and stenting in the SAMMPRIS study population, this unexpected finding in no way indicates a breakdown of the regulatory process but merely reflects a tremendous advance in the medical management of the disease process.
A final example of a neurointerventional device not performing as anticipated is the Cerecyte coil (Micrus Endovascular, San Jose, California, USA), a specific type of detachable bioactive coil designed for the endovascular embolization of intracranial aneurysms. The Cerecyte coil contains a polyglycolic acid element within the wind of the coil, in contrast to traditional coils which are composed of bare platinum. The Cerecyte coil was approved for use in the USA via the 510(k) process in 2004. Early non-randomized studies suggested better results than bare platinum coils, leading the device manufacturer to charge a premium for these coils as they were deemed superior to traditional coils. However, the Cerecyte Coil Trial, a company-sponsored randomized controlled trial comparing Cerecyte coils with bare platinum coils, demonstrated no benefit for Cerecyte over traditional coils. Although it is unlikely that patients were physically harmed due to the use of this technology, the amount of money spent on premiums for what was eventually determined to be an equivalent product is substantial. This problem is not isolated to the Cerecyte coil; other devices such as the Matrix coil (Stryker) were similarly charged at a premium for years, only to reveal no difference in primary outcomes in later definitive trials. This scenario represents an additional point of contention: unvalidated increases in financial expenditures following a market release without rigorous testing and post-market follow-up.
Introduction
Medical devices, developed through physician and industry partnerships, have helped to revolutionize the treatment of disease spanning most medical disciplines. This includes such entities as deep brain stimulation implants for Parkinson's disease, knee replacements for osteoarthritis, coil embolization technologies for intracranial aneurysms and implantable cardiac defibrillators for life-threatening arrhythmias. These remarkable products have undeniably led to increased patient longevity and improved quality of life. Such marvels of modern medicine, however, do not come without cost, to either the consumer or the manufacturer. Recent estimates suggest that the annual expenditures on medical devices in the USA approximates $95–150 billion, which represents almost one-half to three-quarters of the $200 billion spent on such devices across the world and about 6% of our total national health expenditures. Development of new technologies requires considerable investment from companies in terms of research and development costs, manufacturing and marketing, as well as a rigorous approval process through the Food and Drug Administration (FDA). All-in-all, the price of innovation is monumental for those invested in advancing medicine through cutting edge technologies. Recently, there has been a push among lobbyists representing device manufacturers to streamline the lengthy FDA approval process, arguing that the USA will lose its ability to compete globally due to the excessive costs and delays in obtaining FDA approval.
However, in direct contrast to any effort to 'streamline' the approval process, the oversight of device innovation and the approval process has been criticized recently due to several notable device 'failures' that have been linked to patient harm. These devices were approved for use through FDA humanitarian device exemption (HDE) or 510(k) processes, which do not require randomized controlled trial evidence demonstrating safety and effectiveness prior to approval. Unfortunately, such failures are certainly not new. Between 2005 and 2009 nearly 700 voluntary recalls of devices occurred per year, and the vast majority of these were class II recalls, defined as technologies that could result in 'temporary or medically reversible adverse health consequences'. The failure of these processes to detect potentially harmful devices before their release onto the US market has led to a strong backlash, by both physicians and the public at large, against the current regulatory processes in place through which such technologies are approved for use.
The specialty of neurointerventional surgery (also known as interventional neuroradiology or endovascular neurosurgery) is heavily leveraged to medical device development. In this article we will review some recent devices that have generated controversy, review the current FDA approval processes, discuss current issues being debated regarding these processes for new devices and offer further insight into the effect of experience in outcomes for new devices. Finally, we will review possible alternative pathways towards improving the safety and effectiveness of new devices through regulation that both encourages innovation among clinicians and industry and closely monitors new devices after their release.
Recent Device Failures
Adoption of new technologies is not without risk. While initial experience may demonstrate benefit, further experience or longitudinal measures may detect concept, design or manufacturing flaws that were not immediately evident. The most prominent of such devices is the ASR XL Acetabular System (DePuy, Johnson & Johnson, Warsaw, Indiana, USA), which was approved for use by the FDA through 510(k) clearance (described below) and introduced into the US market in 2005. This device has gained considerable negative media attentionwith numerous websites recruiting clients for plaintiff attorneys and over one million unique web pages produced after a Google search using the keywords 'Depuy ASR hip recall'. The ASR featured a metal-on-metal acetabular cup design that was borrowed from a second device, the ASR Hip Resurfacing System, and fitted onto a predicate hip implant. Depuy applied for 510(k) clearance and the new device was deemed substantially equivalent to the prior hip implant without rigorous safety and effectiveness testing. Between 2005 and 2010, approximately 100 000 ASR Acetabular systems were implanted. By 2008 the FDA had received about 300 complaints regarding the device, most arising from patients who had had to undergo early revision surgery. Recent studies have demonstrated an increased rate of implant dysfunction with need for revision surgery that far exceeds that of other hip replacement devices. In fact, results presented at the British Hip Society meeting in 2011 indicated a failure rate nearing 50% at 6 years, which is three times the rate of other devices (approximately 15% at 5 years). Furthermore, elevated levels of blood chromium and cobalt were identified as a side effect of dysfunctional joints. Based on these data, a voluntary recall of the ASR devices was enacted in August 2010 after an estimated 100 000 ASR devices had been implanted (one-third in the USA) and 6 months after the company warned physicians of a high early failure rate. Examination of the dysfunctional implants after removal identified flaws inherent to the design. It is possible that more rigorous safety testing prior to market release, or close post-market clinical follow-up, would have detected irregularities and prevented (or halted) the implantation of ASR devices.
A more familiar neurointerventional device recently drawing considerable negative attention is the Wingspan Stent System (Stryker, Kalamazoo, Michigan, USA), a stent designed for use with the Gateway PTA Balloon Catheter in the treatment of intracranial atherosclerotic disease. The stent was approved under a FDA HDE in 2005, based on a safety study conducted in 45 patients at 12 sites in Asia and Europe, for the treatment of intracranial atherosclerotic disease refractory to medical therapy in intracranial vessels with stenosis of ≥50%. Early retrospective analyses of outcomes performed by independent centers indicated both safety and efficacy with the Wingspan, and many clinicians involved in stroke care were optimistic about how the system would fare in a randomized controlled trial of stroke prevention. The Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial (SAMMPRIS), the first randomized trial comparing best medical therapies to angioplasty and stenting, began enrolling its first patients in October 2008. However, enrollment for SAMMPRIS was halted prematurely in a report in September 2011 owing to a 30-day stroke rate of 14.7% in the angioplasty and stenting arm compared with 5.8% in the medical management arm.These results have led a consumer advocacy group to seek the repeal of the Wingspan HDE and to criticize the FDA for the original approval. However, these efforts are not without controversy as the patient population evaluated in SAMMPRIS was in some respects different from the population indicated on the patient HDE (who would only comprise a subset of the patients evaluated in SAMMPRIS), and the 1-year stroke rate of 20.2% was still perceived as a dramatic improvement over the 24.9% stroke rate demonstrated in the WASID study for the HDE-approved population. Thus, while portrayed as 'dangerous' by groups such as Public Citizen, outcomes with Wingspan in SAMMPRIS were no different from those observed in the same patient cohort treated with conventional medical therapy. The true advance in the SAMMPRIS trial was an observation that was independent of the actual device in that aggressive medical management resulted in a primary event rate that was half the rate (12.2% over 1 year) expected on the basis of the WASID study (24.9%). So while no one debates that aggressive medical management is superior to angioplasty and stenting in the SAMMPRIS study population, this unexpected finding in no way indicates a breakdown of the regulatory process but merely reflects a tremendous advance in the medical management of the disease process.
A final example of a neurointerventional device not performing as anticipated is the Cerecyte coil (Micrus Endovascular, San Jose, California, USA), a specific type of detachable bioactive coil designed for the endovascular embolization of intracranial aneurysms. The Cerecyte coil contains a polyglycolic acid element within the wind of the coil, in contrast to traditional coils which are composed of bare platinum. The Cerecyte coil was approved for use in the USA via the 510(k) process in 2004. Early non-randomized studies suggested better results than bare platinum coils, leading the device manufacturer to charge a premium for these coils as they were deemed superior to traditional coils. However, the Cerecyte Coil Trial, a company-sponsored randomized controlled trial comparing Cerecyte coils with bare platinum coils, demonstrated no benefit for Cerecyte over traditional coils. Although it is unlikely that patients were physically harmed due to the use of this technology, the amount of money spent on premiums for what was eventually determined to be an equivalent product is substantial. This problem is not isolated to the Cerecyte coil; other devices such as the Matrix coil (Stryker) were similarly charged at a premium for years, only to reveal no difference in primary outcomes in later definitive trials. This scenario represents an additional point of contention: unvalidated increases in financial expenditures following a market release without rigorous testing and post-market follow-up.
Source...