Originally Published MDDI August 2004

Regulatory Affairs

The Medical Device Amendments of 1976 changed the landscape of FDA regulation of medical devices. With these changes came new policies and procedures that have transformed the industry.

Jonathan S. Kahan

Jonathan S. Kahan is a partner at Hogan & Hartson LLP and a member of the MD&DI editorial advisory board.

The editors of MD&DI have asked me to provide some thoughts regarding FDA regulation of medical devices over the last 28 years. Much has happened in terms of device regulation over this almost three-decade period. Since the passage of the Medical Device Amendments of 1976, not only has FDA's regulation of the medical device industry drastically changed—the industry itself has been transformed.

When I started working with the medical device industry in 1974, sales of medical devices by U.S. companies totaled $5 billion. By 1995, sales had grown to $52 billion. Today, sales by U.S. medical technology companies are close to $94 billion, and growing at an annual rate of 6%.

The advances in medical technology have been equally impressive. The industry began as one that manufactured commodity products such as surgical gloves and basic in vitro diagnostics (IVDs). By contrast, today's industry produces drug-eluting stents, artificial hearts, automatic implantable cardioverter-defibrillators, advanced magnetic resonance imaging machines, DNA-based IVDs, and even clinical laboratories on a chip. 

The Changing Regulatory Environment

My role, and the role of my colleagues who are regulatory counsel to the medical device industry, has changed almost as much as the industry and its technology. In 1976, it was not uncommon to file a 510(k) premarket notification with FDA that would be a mere five pages long. It would simply describe the “substantial equivalence” of the device to one that was on the market earlier that year (i.e., before May 28, 1976). Today, we rarely work on a submission that is not supported by significant amounts of data. Biocompatibility data, electromagnetic compatibility data, detailed information on the device software, and clinical data are often included. Premarket approval (PMA) applications for “not substantially equivalent” Class III devices have also become much more challenging. It is not unusual for our work on a premarket approval project to span several years.

Not only has the medical device premarket clearance and approval process changed significantly over the years, but the FDA enforcement laws, policies, and procedures have also evolved. Today's enforcement environment and FDA's tools for enforcement are somewhat different than those the industry faced even 10 years ago.

The Evolution of the Premarket Clearance and Approval Process

Before 1976, the federal government did not require the premarket clearance or approval of medical devices. In 1970, a government panel called the Cooper Committee was asked to analyze whether the premarket clearance of medical devices was appropriate and necessary. That committee reviewed the literature and reports on medical technology and determined that medical devices had caused thousands of injuries over the preceding decade. Hundreds of injuries, and some deaths, were linked to such devices as defective heart valves, faulty pacemakers, and substandard intrauterine devices.

Congress, under the leadership of Congressman Paul Rogers, determined that the imposition of FDA device premarket clearance was necessary to protect the public health. It was also designed to provide for a regulated environment in which the industry and its technologies could grow and prosper. While the resulting processes have certainly not been perfect, the underlying wisdom of the Medical Device Amendments of 1976 and their regulatory structure have withstood the test of time.

On November 28, 1990, President George H. W. Bush signed new legislation titled the Safe Medical Devices Act of 1990 (SMDA). SMDA constituted the first major change to the Medical Device Amendments of 1976. However, the new law essentially maintained the premarket clearance and approval structure of the original law. Many in Congress at the time felt that granting premarket clearance based on substantial equivalence to devices on the market prior to May 28, 1976, was a flawed paradigm. Regardless, Congress adopted FDA's existing substantial equivalence policies in the new law.

Specifically, for the purpose of determining substantial equivalence, SMDA stated that FDA must determine that the new device has the same intended use as the predicate device. FDA, by order, must find that the device has either the same technological characteristics or has different technological characteristics. If the characteristics are different, the information submitted must demonstrate that the device is substantially equivalent to the predicate device. This information can include clinical data that demonstrate that it is as safe and effective as the legally marketed device and does not raise different questions about safety and efficacy. This is the same paradigm that FDA operates under today; this approach was not changed by the FDA Modernization Act of 1997 (FDAMA). 

As the 510(k) process was becoming more data driven, the PMA process also changed, becoming more extenuated and more difficult over the years. For example, in 1987, the average time for PMA reviews was approximately 337 days. In 1991, PMA times had risen to 633 days, and by 1994, times had grown to a staggering 840 days. Many in the device industry called the early 1990s the dark ages of FDA medical device regulation. Both the 510(k) and PMA processes were essentially paralyzed during the early days of the administration of Commissioner David Kessler, MD. Kessler's “zero risk” regulatory philosophy was quickly understood and adopted by many within CDRH. For example, Kessler believed that there were many devices on the market whose risks outweighed their benefits. This philosophy had a significant effect on the market clearance of new devices and led to the withdrawal of some devices, including silicone gel breast implants.

Kessler's concerns also led to the creation of the infamous Committee for Clinical Review. Leading the committee was Robert J. Temple, MD, a drug evaluation official from FDA's Center for Drug Evaluation and Research (CDER). The Temple Committee reviewed device clearances and approvals by CDRH and concluded that there were significant deficiencies in the policies and procedures for clinical trials. The committee recommended that CDRH require, whenever possible, randomized controlled trials (RCTs) for all Class III device approvals. The RCT, at the time, was the controlling CDER paradigm for all drug studies.

The resulting CDRH preference for RCTs and the clinical trial requirements adopted in the early 1990s are still the controlling policy today. The imposition of the RCT requirement has led to much consternation in the device industry. One reason for such consternation is that an RCT is often unethical or impractical for many medical device clinical studies. The industry continues to struggle with questions of appropriate clinical trial design for novel new medical technologies. While the agency has been directed to impose only the “least burdensome” requirements for device approval, that direction has barely dented the continuing CDRH preference for RCTs.

Medical Device Reengineering and FDAMA

Reengineering. Following the dark ages of the early 1990s, CDRH management recognized that many of its regulatory procedures needed improvement. Industry had made its dissatisfaction known to both FDA and Congress. It became clear that if CDRH did not reform itself, Congress might reform the center through legislation. This well-justified fear of congressionally mandated change led FDA to examine many of its processes. Among those examined was the 510(k) process, to determine whether there were more-efficient methods for clearing substantially equivalent devices to market. To this end, CDRH drafted what became known as the 510(k) Paradigm, which put in place the new special 510(k) submission as well as the abbreviated 510(k) option. 

The special 510(k) submission essentially allowed limited data to be submitted to the agency. It covered new devices that, though modified in a way that could significantly affect safety and efficacy, changed neither the intended use nor basic technology of the predicate device. CDRH determined that a summary of the company's design control activities related to such changes, plus a comparison with the cleared predicate device, might be adequate for clearance. With this process, device sponsors are not required to include the typical submission of detailed supporting data. The special 510(k) submission has become a significant factor in medical device clearance over the last few years. Indeed, the majority of special 510(k) submissions are cleared in less than 30 days, as opposed to the more-extended clearances of traditional 510(k)s. This idea not only made sense on paper, but when put into practice, it became a successful program for expediting clearances.

The same cannot be said for the abbreviated 510(k). Under this process, a declaration of conformity to individual consensus standards could theoretically be the primary basis for a device's clearance. The abbreviated 510(k) process, unlike the special 510(k) process, has not been a successful program. But it has not entirely been a failure, either. To this day, FDA continues to evaluate how to utilize the abbreviated 510(k) process more effectively.

FDA's reengineering efforts in the mid-1990s also led to a reevaluation of the product development protocol (PDP) process, originally a part of the Medical Device Amendments of 1976. Without going into the mind-numbing details of the PDP law, CDRH's reengineering teams believed that device sponsors could use the PDP process to get their Class III devices approved more quickly. The agency consequently reissued and updated its PDP guidance, hoping that the process would become another important route for approval of novel new devices. 

Once again, FDA's hopes for the PDP process were dashed. The industry does utilize the PDP path for a few products to a limited extent. However, the PDP has never become a significant alternative route to market for innovative technologies. 

Finally, the reengineering teams within CDRH also looked at ways to streamline the PMA supplement process. They initiated new procedures for Real-Time PMA Supplements and 120-day PMA supplement reviews for certain devices. These changes were a primary focus of FDAMA.

FDAMA. The foregoing CDRH reengineering efforts were not successful in heading off new legislation. On November 21, 1997, President Clinton signed the FDA Modernization Act of 1997 into law. Many of the reengineering efforts discussed above were codified in FDAMA. For example, Section 205 of the act included a provision for reducing the burden of PMA supplements. In addition, the 30-day/135-day PMA supplement paradigm now in place for certain modifications in manufacturing procedures or methods were enacted into law.

Similarly, Section 201 of FDAMA provided streamlined procedures for making certain changes to investigational devices. In addition, it made these devices more readily available when needed for humanitarian uses. Once again, Congress decided not to drastically change the substantial equivalence paradigm adopted for 510(k) clearances. The lawmakers did, however, add an important new provision allowing the “downclassification” of certain low-risk novel technologies for which no substantially equivalent product is available. 

Under what became known as the de novo downclassification process, a manufacturer can request de novo downclassification within 30 days of receiving a “not substantially equivalent” determination. In other words, the manufacturer can seek to have the device reclassified down to Class I or II. The potential benefits of this provision have not yet been entirely recognized, but the de novo process has become an important consideration for companies developing devices that otherwise would require PMA clearance.

Finally, Section 210 of FDAMA directed CDRH to consider the “least burdensome” means of evaluating device effectiveness or demonstrating substantial equivalence. Much ink has been spilled concerning this provision. In my experience, however, the congressional admonishment has had little or no effect on CDRH's practices in actually approving or clearing devices to market. The RCT, clearly not the least-burdensome method for evaluating a device in most cases, remains FDA's default clinical trial policy.

Medical Device User Fees

The Medical Device User Fee and Modernization Act of 2002 (MDUFMA) was enacted into law on October 26, 2002. For many years, FDA had argued that one way to clear up its review backlog was the institution of user fees. The medical device industry had resisted such fees for many years. Unlike the drug industry, which was made up of much larger firms and had been paying user fees for some time, the device industry consisted primarily of small companies. These companies could not afford significant payments to FDA to carry out governmental tasks that they already supported through the payment of taxes. Many said FDA did not need user fees and should instead internally streamline its processes for greater effect.

The “small company” segment of the medical device industry continued to resist the imposition of user fees up to the bitter end. These companies argued that the payments would have a disproportionate effect on innovation by smaller companies and even jeopardize their survival. Nevertheless, AdvaMed (Washington, DC) and many large device companies ultimately gave in to legislative and executive branch pressures to accept user fees. These companies hoped that the fees would speed new products to market, a valid but entirely elusive expectation.

I think it is safe to say that, generally, the user fee program has been a significant disappointment for the industry. FDA has held stakeholder meetings seeking to publicize the improvements resulting from user fees. For example, FDA has stated that during FY 2004, the agency hopes to spend user fees to add more than 100 staff members to CDRH. The agency has said that the fees will allow CDRH to meet the law's performance targets that become applicable in 2005. 

It remains to be seen whether either the performance targets or the increase in staff will truly materialize. To date, FDA has touted its hiring of 50 new scientific, medical, engineering, and other review staff, including 14 new statisticians, with user fee monies. However, Congress has concurrently underfunded CDRH. Most importantly, no drastic change in the times of clearances or approvals has been seen, to the dismay of industry. Has the device industry been bamboozled by congressional and FDA promises? This is a question that can only be answered by watching CDRH activities over the next few years.

FDA Medical Device Enforcement Policies and Procedures

The Federal Food, Drug, and Cosmetic Act (FD&C Act) has, for decades, allowed FDA to take action against adulterated and misbranded medical devices. Those actions have included medical device seizures, injunctive actions against companies, and criminal prosecutions of individuals and corporations.

FDA practices in the enforcement area, including the issuance of warning letters and litigation against device companies, have generally been appropriate and consistent. While there are some who would disagree with this assessment, it is clear that rarely does FDA bring a criminal prosecution or take draconian action against a medical device company without some clear evidence of wrongdoing. A review of a few of the most prominent FDA actions helps prove this point. On August 31, 1988, the government filed a 24-count information against Cordis Corp. charging it with violations of the FD&C Act. The charges related to the shipment of adulterated and misbranded pacemakers. In 1989, Cordis pled guilty to 25 criminal counts and agreed to pay close to $6 million in civil and criminal penalties. After a month-long trial, all individuals charged in the case were acquitted.

The Cordis prosecution was followed by the prosecution of C. R. Bard Inc. On October 14, 1993, Bard pled guilty to a 391-count information, again related to the shipment of adulterated and misbranded devices. Individuals were also prosecuted in that case.
In 2003, Guidant Corp. pled guilty to nine felony counts related to its failure to submit medical device reports to the agency in connection with its implantable aortic aneurysm grafts. The company ultimately agreed to pay $92.5 million in civil and criminal penalties for the settlement of that case. No charges against individuals have yet been brought.

While there have been numerous other device company criminal prosecutions and enforcement actions over the years, I mention these three actions for a reason. They were brought against large medical device manufacturers, and they demonstrate how rarely FDA and the Department of Justice (DOJ) have had to bring major cases against the medical device industry. Under the present FDA and DOJ regimes, it appears that this selective and discrete enforcement will continue. There will always be overzealous prosecutors who will want to change this long-accepted balanced approach, but overall, the FDA and DOJ enforcement policies have largely been moderate and reasonable.

In addition to the agency's authority to criminally prosecute medical device companies, SMDA also gave the agency authority to seek civil penalties. Under this act, anyone who violates a requirement of the FD&C Act relating to devices is liable for a civil penalty of up to $15,000 per violation, with a maximum of $1 million for all violations. Again, FDA has used its civil penalty authority discretely, and few companies have been subject to civil penalties since 1990. Some have argued that FDA should have been much more aggressive in both its prosecution of device companies and the application of civil penalties. Overall, however, I think that the agency's enforcement policies in the medical device area have been balanced and, in most cases, fair.

The Future

It is always difficult to predict the future of medical device regulation or technologies. But it is perfectly clear that with new technologies, both industry and FDA will face challenges. One major challenge relates to the quickly advancing field of combination products. Under Section 204 of MDUFMA, Congress mandated the formation of an Office of Combination Products (OCP). That office, now under the leadership of Mark Kramer, a former CDRH official, has been extremely active. It is seeking to streamline FDA's review of the rapidly evolving field of combinations of drugs, devices, biologics, and human tissues. FDA must be extremely creative in regulating this area so as not to stifle new developments, such as drug-delivery devices. The agency has been holding public workshops and meetings to address how it might better regulate these new technologies and foster better cooperative efforts between its own centers.

Another area of rapid development has been IVDs. CDRH created the new Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) to provide one organizational unit for cradle-to-grave regulation of IVDs. The office's duties encompass the premarket review responsibilities of the Office of Device Evaluation, the enforcement responsibilities of the CDRH Office of Compliance, and the postmarket surveillance responsibilities of the CDRH Office of Surveillance and Biometrics. 

The rapid advancement of home-use tests, genetic testing, pharmacogenomics, and home-brewed tests by clinical laboratories raise many significant issues for the IVD industry and OIVD. Whether former CDRH director David Feigal's vision of device regulation based on the “total product life cycle” will be an advance in regulatory philosophy is questionable. Nevertheless, suffice it to say at this point that OIVD has been an interesting experiment, and device regulation based on the total product life cycle may in fact be the basis for future regulatory advances.

Finally, one cannot write about developments in the field of medical device regulation without addressing quality system regulation (QSR) issues. One yet-untested CDRH initiative involves using accredited persons to conduct factory inspections of U.S. and European Union device manufacturers. MDUFMA authorized FDA to accredit third parties to perform QSR inspections of eligible manufacturers of Class II and Class III devices. This voluntary program gives certain manufacturers the option of requesting inspection by an accredited person rather than by FDA. However, the jury is still out as to whether the accredited persons program will be a significant benefit to the industry. At this point, FDA has accredited 14 entities.

FDA also has a program allowing accredited third parties to review 510(k) premarket notifications for certain devices. It is clear that these third-party product review and inspection programs are part of a more robust global harmonization agenda. Third-party reviews and the involvement of accredited bodies to oversee the device industry has been a well-accepted structure in the European Union and elsewhere. Ultimately, in a perfect world, the regulatory schemes for devices would be harmonized worldwide, with consistent review and inspection practices across national lines. That is a future that would benefit the industry, patients, and regulatory authorities. Hopefully, such a rational consolidated regulatory scheme will be an important future part of what has become a global device industry. 

Copyright ©2004 Medical Device & Diagnostic Industry