New surgical devices and ethical challenges

An FDA perspective on device regulation

By Daniel Schultz, MD

As a surgeon, I know that not making a decision actually amounts to a decision in itself. In my current work with the Center for Devices and Radiological Health (CDRH) at the US Food and Drug Administration (FDA), there are times when we may not have all the information that we feel we need to make a decision but we are obligated to make one anyway. We try to apply a risk-based approach that makes the most sense for patients and for public health. Surgeons probably appreciate this method better than most people do, as they do risk-benefit analyses many times a day and do so almost subconsciously. In the government we have to do so in a more transparent and explainable way.

FDA MISSION ADDRESSES THE FULL PRODUCT LIFE CYCLE

The CDRH mission encompasses the entire life cycle of a device, from encouraging product development, to ensuring postmarket safety, to enabling access to innovation. Our mission is threefold, as outlined below:

• To get safe and effective devices to market as quickly as possible. This is a balancing act. On one hand, some people feel that “as quickly as possible” is not fast enough, yet safety and efficacy obviously need to be established. On the other hand, if we wait to be absolutely certain that a new device is safe and effective, large numbers of patients may miss out on potentially benefiting from it in the interim. We try to analyze risks and benefits, and also to bring some common sense to the analysis. Our review process draws on whatever mix of expertise is necessary for evaluating a given product, so we consult with statisticians, engineers, physicians, and other experts as needed. In addition, the CDRH has a medical device fellowship program that brings in experts from academic settings—including physicians, biomedical engineers, computer scientists, statisticians, and law and policy experts—to contribute expertise in the evaluation of cutting-edge technologies.¹

The CDRH attempts to work with companies prior to submission to understand their technology, what they intend to do, and the population for which they intend their product. We aim for clarification rather than overregulation: our goal is to make the pathway as clear as possible to increase the likelihood that we will get the information we need to make a decision, to give companies a good sense of what to expect, and to promote mutual understanding.

• To ensure that devices currently on the market remain safe and effective. We are all well aware of cases in which questions are raised about safety or efficacy after a product has gone to market. From the FDA’s perspective, interpreting and dealing with postmarket data can be very complex.
• To provide the public with accurate, science-based information about devices. Communicating postmarket data to the public adds another level of complexity. For example, not long ago questions arose about serious adverse events related to implantable cardioverter-defibrillators (ICDs). Because of publicity about these questions, many people who needed an ICD did not get one and many others had their ICDs replaced with a different model. Subsequently, a study in Canada showed that the risk of ICD replacement far outweighed any risk that was inherent in the product.

We can all agree that transparency and timely sharing of information are important, but exactly how to carry these things out is a challenge. When the FDA, as a government agency, makes a statement, it carries additional weight, so we try to be very careful about sending the right message to physicians and to patients.

Finally, we use the information that we gain in the postmarketing period to guide our regulation of the next generation of products, which contributes to all three broad aspects of our mission.

AS DEVICES GET MORE COMPLEX, NEW REGULATORY QUESTIONS ABOUND

It used to be that when people thought of medical devices, they pictured mechanical tools. Now, however, we deal with a huge variety of different types of technology, including computer-related technology, molecular medicine, robotics, minimally invasive techniques, microelectromechanical systems, nanotechnology, organ replacement, and wireless systems.

Not only is the technology new, but the way in which it is used is increasingly novel: devices are being used more and more in nontraditional settings, such as home care, and by nonclinicians who do not normally use medical devices. Can decisions about regulating a medical device that is safe and effective when used by a physician in the hospital be applied to its use by a relative caring for a 90-year-old patient in the home?

In addition, we now see combination products that increasingly blur the distinctions between medical devices and drugs. Genetic biomarkers have implications for the development of new drugs and for the refined use of existing drugs. One example is a test—already in existence—to assess individual patients’ sensitivity to the anticoagulant warfarin. There are also drug–diagnostic combinations in which a drug is developed along with a companion diagnostic test.

We are probably seeing just the beginning of these combined diagnostic and therapeutic systems as we move toward the concept of personalized medicine. When we consider the current challenges in designing appropriate clinical trials for specific populations and for off-label uses, it begs the question of how much more difficult trial design will be as technology moves closer and closer to individualized therapies for each patient.

FDA’S APPROACH TO MEDICAL DEVICE REGULATION

Our approach to medical device regulation is based on a number of objectives and principles:

• Basing the degree of control or oversight on the amount of risk with a given device
• Weighing risks and benefits to determine safety and effectiveness
• Using valid scientific evidence, which involves looking at clinical outcomes while recognizing that our mandate is not to regulate the practice of medicine
• Considering the “least burdensome means”—ie, being open to any of several acceptable approaches that answer the pertinent regulatory questions (not, however, giving license to cut corners in submissions)
• Providing “reasonable assurance,” recognizing that “reasonable” is in the eye of the beholder and that the agency and applicants may not always agree on its meaning.

Other key elements: Intended use, adequate labeling

Beyond these principles, the FDA’s approach to regulating device safety and effectiveness gives priority to at least two other key elements: specifying a well-defined intended use and ensuring adequate labeling. Sometimes applicants who are proposing a new device are very excited about their new technology but are not very specific about exactly how it will be applied to patients, so we need to focus them on clearly defining the intended population and the expected impact on patients. Similarly, device labeling must be developed to contain as much information as possible to help physicians make good choices without overpromoting the product or going beyond the submitted data.

Classifying devices

To ensure that appropriate oversight is applied to different types of medical devices, the CDRH uses a product classification system that differs from that used for drugs and biologics. It breaks down as follows:

• Class I devices, which are very simple (eg, gloves) and most of which are exempt from premarket submission
• Class II devices, which are subject to some special controls and require premarket notification (510[k] submissions)
• Class III devices, which are the highest risk and tend to be the most cutting edge. They require premarket application and approval.

There are two additional classifications:

• De novo devices, which have never been marketed in the United States but have a safety profile and technology that are reasonably well understood. Prior to the creation of this classification, a cutting-edge technology would have automatically been deemed Class III and required to go through the premarket approval process. Now a novel product may be recognized as lower risk and can be placed into its appropriate classification immediately.
• Humanitarian device exemption, for devices that address orphan diseases (conditions that affect fewer than 4,000 patients per year in the United States and thus may not offer an economic incentive for technology development). The motivation here is to help facilitate getting products to market for underserved niche patient populations with the understanding that some regulatory controls may be added.

Postmarket surveillance

The CDRH is working to make postmarket surveillance a stronger part of our program. In the past, people questioned whether the required postapproval studies for devices were actually getting done. Over the last few years, epidemiology staff from our premarket approval area helped design better post-market studies, and we then transferred tracking and follow-up to the postmarket staff. In 2006, we issued a final guidance to manufacturers about how to submit follow-up reports and we developed a public Web site containing the postmarket studies that are required, including start dates, when reports are due, and whether studies are on schedule.² This helps us to have a transparent process and also prompts companies to follow through with agreements.

RISK/BENEFIT ASSESSMENT: REAL-WORLD EXAMPLES

The risk/benefit assessments undertaken by the FDA range from straightforward to highly complex. Devices that are life-sustaining have much potential for significant benefit, which makes most people willing to accept more risk. On the other hand, it can be difficult to quantify the benefit of cosmetic procedures (many of which we regulate), and people are less willing to tolerate risk for these procedures. Consider the handful of examples below.

Drug-eluting stents

When the CDRH first evaluated drug-eluting coronary stents, the data showed a greater than 50% reduction in the need for repeat interventions compared with bare metal stents, as well as low rates of complications. People asked us, “Why is it taking the FDA so long to approve them?” Soon after their approval, drug-eluting stents became the standard of care for about 60% of patients undergoing percutaneous coronary intervention.

Five years later, studies started showing some long-term complications, although the absolute risks and benefits are still not known with certainty. If we had spent another 5 to 10 years studying these devices, a lot of these questions might have been answered, but at what cost to those patients who actually benefited from this technology in the interim?

Cardiac occluder

Although studies showed that the muscular ventricular septal defect occluder had a high procedural success rate (81%), the adverse event rate was also very high: 44%. But because this device is for patients who have no treatment alternatives other than open-heart surgery but are considered to be at high risk from surgery, the risk/benefit assessment favored approval in this case.

Total artificial heart

The total artificial heart went through the humanitarian device exemption process. It is intended for patients with severe biventricular end-stage heart disease who are not candidates for transplant or a left ventricular assist device and are thus essentially at the end of life with no other treatment options.

Although studies showed that the device helped extend life, whether quality of life improved enough to support approval was in question. The device is clearly not benign: out of 12 patients studied, support was withdrawn secondary to cerebrovascular accident in 6 of the patients. Four patients died of multiorgan failure or sepsis, and all patients had bleeding complications. However, 10 of the patients were able to interact with family members and 4 patients were able to have out-of-hospital activities.

How does one balance this ability to extend life for perhaps a few months—allowing patients to have additional time with their family, maybe to see a grandchild’s birthday or attend a wedding—against all of these attendant adverse events?

Breast implants

Saline-filled and silicone gel-filled breast implants are designed for breast augmentation and breast reconstruction. Two saline-filled implants were approved in 2000 and two silicone-filled implants were approved in 2006, but only after complicated regulatory histories. Breast implants were first marketed in the early 1960s and were later “grandfathered” into the FDA’s regulatory scheme upon passage of the Medical Device Amendment of 1976. They were classified as Class III devices in 1988, and the FDA called for submission of a premarket approval application in 1991 after the emergence of many reports (but scant solid clinical data) of adverse events related to these devices.

Over this period, breast implants became a considerable regulatory, scientific, and political controversy, for good reason: they are not life-saving devices, yet they involve a lifetime commitment. How much clinical data and how much follow-up should be required? What should be the end points for studies? The FDA cannot determine the value that a woman puts on breast reconstruction or augmentation. What is clear is that adequate informed consent is critical, including a thorough explanation to patients of the benefits, the risks, and the nature of their commitment.

DILEMMAS MOVING FORWARD

Several dilemmas arise out of the FDA’s mandates. Although our mission is to ensure product safety and effectiveness, what about patient autonomy? What about the rights of patients to be able to choose the therapies they want? While we are required to protect the public health, what if that conflicts with making products available?

Advertisements are another big challenge. We recently held a panel meeting on the LASIK eye procedure that included some very heart-wrenching stories told by patients who have had bad experiences. Part of the problem is how such procedures are advertised, without a balanced message about potential risks and benefits. People end up with the impression that the procedure is almost like getting their hair cut. Advertisements in newspapers and on Web sites tout a special price “for this month only,” exhorting patients to get the procedure done immediately. The surgeons who place such ads are at least as responsible for the problem as industry is, if not more so.