Continuation of MDDI's January 1996 article, "Clinical Trials: An Introduction"

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Over the past few years, there has been much controversy and upheaval in the regulation of medical devices in the United States and, to a lesser extent, in Europe. The result has been a variety of emerging structural and directional changes in the clinical trial arena that bear not only watching, but active participation by the regulatory, clinical, patient, and industry communities.

Drug-Model Science. At FDA, the ethical and organizational controversy that arose over the agency's regulation of generic drugs raised concerns about the rigor of other FDA processes--including the product approval process at its Center for Devices and Radiological Health (CDRH). Shortly afterward, the breast implant controversy seemed to indicate, to some individuals, that the practice of science at CDRH was lacking the physician's perspective. These controversies, together with the appointment of Commissioner David Kessler and the press of congressional investigations, produced a sudden shift in the culture of FDA's device center. Traditionally a bastion of engineers and physical scientists where physicians acted primarily as scientific and medical reviewers, CDRH underwent a rapid change to a physician-managed structure resembling that of FDA's drug center.

In 1992, to investigate some of the perceived concerns regarding the quality of science in the device area, a Committee for Clinical Review was formed and placed under the direction of Robert Temple, director of the Office of Drug Evaluation I at FDA's Center for Drug Evaluation and Research (CDER). Temple had then, and still has, an outstanding record as a scientific conscience of the drug approval process.

The Temple committee reviewed 29 device applications and pointed out a number of deficiencies in their use of scientific evidence.⁶ Although many of these deficiencies were legitimate, members of the device industry complained that they were valid only when viewed from the perspective of the drug approval process. Industry argued that many of the findings of the Temple Report were not deficiencies at all, but were due to the basic differences between devices and drugs.

To be sure, there are significant differences between drugs and devices. The law and burden of proof for drugs differ from those for devices, and FDA's drug approval process is significantly longer and more elaborate than the approval process for devices. The device law was developed later and included lessons learned from the burdens of the drug process. For example, the medical device regulations define valid scientific evidence much more broadly than the equivalent regulations for drugs do, and thereby allow the device researcher much greater flexibility than is permissible under the drug law and approval process.

The nature of drug research also differs from that of device research. Studies of complex devices may involve equally complex procedures and other concomitant treatments that prevent researchers from using controls to the same extent that they would do in a drug trial. For instance, controls for orthopedic or cardiovascular implants must sometimes be based on historical experience. Equally daunting is the challenge of locating a patient population that can participate in a device trial. For some conditions, the available populations of patients are so small that it would take a very long time to make up a statistically significant sample for a trial.

Without acknowledging these differences, the Temple Report criticized the existing product approval practices at FDA's device center, and effectively established a frame of reference for the new philosophy at FDA. The only problem was that the new philosophy was clearly the drug approval philosophy. In the hands of highly experienced and discriminating scientists, the new direction might have been more manageable. In the hands of a reviewing organization that had been traumatized by seemingly unnecessary changes and brutal congressional second-guessing, it became an excuse to impose new and unnecessary burdens in the name of "good science." Among the many disastrous effects of these political and philosphical changes is the catatonia in the product approval process that has affected the device industry for the past few years.

The controversy over the validity of these different scientific philosophies continues to affect industry. One result has been that manufacturers are moving more of their device-related R&D--including clinical research--to sites outside the United States.⁷ Sadly, a political phenomenon--the 1994 takeover of Congress by the Republicans--has influenced action on this issue more than all the scientific debate that preceded it. Today, the pendulum at FDA seems to be swinging back to a more moderate approach.

Clinical Utility. Another issue that is influencing clinical research in the United States is that of clinical utility. At its most simplistic level, the issue is whether proof of efficacy relates only to the functional efficacy of the product or requires an outcome-based demonstration of clinical benefit or clinical utility. For example, is it enough to show that a cholesterol-lowering therapy can effectively reduce cholesterol, or does one have to show that such a reduction also provides a proven clinical benefit?

Although FDA has historically allowed some drug and device indications that were clearly based on functional efficacy, in the past few years it has shown a preference for a more rigorous showing of clinical utility. In doing so, the agency has drawn criticism that it is venturing into the regulation of the practice of medicine. This inflammatory argument continues, but answers may yet be found in moderate approaches to the issues. One resolution might be for FDA to consider acceptable surrogate end points that demonstrate functional efficacy, so long as current medical opinion (rather than rigorous proof) considers them to be clinically significant. Such a solution would be particularly applicable to diagnostic products.

Relative Efficacy. If a recent statement published by FDA in the Federal Register is any indication, the question of relative efficacy is another emerging issue that may affect device studies.⁸ While seemingly innocuous, the statement suggests that FDA intends to broaden its requirements for proof of a device's safety and effectiveness to include a determination of relative efficacy. If this interpretation were to be accepted, labels that now must include adequate instructions for use might also be required to include information comparing the efficacy of the product to that of alternative therapies. In turn, such a requirement would compel manufacturers to conduct multiarm trials in order to compare their new devices with all other competing drug or alternative therapies. Even if that is not the explicit requirement at present, FDA's statement appears to indicate an alarming policy trend.

Leanings in this direction are especially worrisome in light of recent political efforts to influence federal health-care reimbursement policies by involving FDA in the evaluation of outcomes research. So far, the agency has resisted this pressure, but one can envision an integrated system in which outcomes research would become part of the regulatory requirements for product approval. Such a system would require a host of new regulatory metrics for such areas as quality of life, cost comparison, and cost-effectiveness. Efforts to include the fledgling science of outcomes research into a legally mandated criminal code such as the Federal Food, Drug, and Cosmetic Act could well become the next big nightmare of the medical device industry.

Economic Challenges. The economics of clinical trials present real challenges for medical device manufacturers and for society at large. By its very nature, clinical research is expensive to conduct. If new requirements for clinical data are imposed upon the device industry, there is some concern about whether the small companies that make up most of the industry will be able to afford the costs of conducting clinical research. Similarly, since budget pressures on the federal government show no signs of abating, there is concern about what will become of the funding for large-scale clinical work now being carried out by the National Institutes of Health, by other government agencies, and by university researchers supported through government grants.

It is not clear that society at large is willing and able to support ever more sophisticated and costly testing for medical interventions. The growing use of quality-of-life measurements as part of clinical test responses and the relatively recent inclusion of pharmacoeconomic end points in clinical trials are attempts to come to grips with this important question. Given these challenges, the need for efficiency in the conduct of clinical studies will become greater with time.

Although clinical trials are among the most useful methods for determining the safety and effectiveness of medical devices, there are dangers inherent in their use. If misunderstood or misused, the methods of clinical research can become a vehicle for callous disregard of the rights of the individual. Overreliance on clinical trials can also create unnecessary barriers to the advancement of medical science.

The dangers inherent in clinical research can be minimized. Manufacturers can ensure the protection of human subjects of clinical trials by observing the three principles of respect for persons, beneficence, and justice. Thoughtful and rational consideration of the concepts of clinical utility and relative efficacy can be used to determine a practical level of proof for showing safety and effectiveness. And statistical rigor in the design and expectations of clinical trials need not be a burden if it is applied in a way that accounts for the complexity of today's medical devices and their use.

Increasingly, new drugs and devices are being developed for world markets rather than for individual countries or regions. Groups such as the International Conference on Harmonization are developing consensus standards that will eventually be accepted by regulatory authorities in multiple countries. In time, such standards will lead to less duplication of clinical research efforts across international boundaries and, hence, more efficient clinical development of products for worldwide markets.

At the same time, increasing use is being made of modeling activities and small-scale pilot or feasibility studies. This practice promises to enable manufacturers to more rapidly identify medical interventions that have clinical efficacy and weed out less-promising therapies before large-scale clinical trials are performed.

As with any scientific tool, if used appropriately, clinical trials can aid the scientific process and the rapid introduction of safe and effective products. If not used correctly, however, their scientific requirements can become regulatory barriers.

Kshitij Mohan is a former director of FDA's Office of Device Evaluation; he is now corporate vice president for research and technical services at Baxter Healthcare Corp. (Round Lake, IL), and a member of the MD&DI editorial advisory board. Harold E. Sargent is director of applied statistics in the corporate research and technical services office of Baxter Healthcare Corp.