Bioequivalence and narrow therapeutic index drugs.

Every prescription written for a generic drug requires an act of faith by the prescriber that any one of the several available products will be therapeutically equivalent to the innovator (brand name) products. Concerns about this act of faith have been expressed for many years, particularly in the wake of the generic scandals that occurred in 1989-1990, and especially relative to the drugs with a narrow therapeutic range. We contend that these drugs are actually the least likely to pose problems in ensuring therapeutic equivalence, but that new criteria must be established for bioequivalence because the present system is wasteful and is stifling innovation in the industry. We propose four suggestions to the scientific and regulatory communities that we believe could assist in modifying the process such that innovation is encouraged and practitioners are reassured relative to the appropriateness of using generic drugs.

The "trials" of a long-term clinical trial: the Ticlopidine Aspirin Stroke Study and the Canadian-American Ticlopidine Study.

The Ticlopidine Aspirin Stroke Study (TASS) and the Canadian-American Ticlopidine Study (CATS) were established by the Syntex Corporation to evaluate the potential efficacy of the antiplatelet agent ticlopidine. TASS was designed to address the use of the drug in the prevention of stroke in patients who had been diagnosed as having had one or more transient ischemic attacks (TIAs), using aspirin as a positive control. CATS was designed as a placebo-controlled trial to evaluate the drug's usefulness in prevention of a second stroke in patients after an initial stroke. Both studies were established in a "triple-blind" fashion where the patients, investigators, and Syntex were unaware of the patient assignments as to ticlopidine or control. In order to monitor the studies for potential toxicity/efficacy, Syntex established a "Safety Committee." The presentation describes, from the viewpoint of the Safety Committee, some of the issues raised by the results as they developed, by the investigators, the company, and the regulatory authorities involved. The decisions reached are discussed along with the rationale for those decisions and the outcomes.

The knowledge merchants.

Since World War II, increased funding by government and industry has turned the 'education business' of American universities into 'knowledge business'. Interactions between universities and industry can take the form of consulting, affiliate programmes, contracts, extradepartmental research and development, exchanges of scientists, research agreements and the involvement of venture capital companies. The experiences of the School of Pharmacy, University of California at San Francisco, with these interaction models are described and evaluated.

Science: part of the problem, most of the answer.

The history of the drug approval process in the United States includes three phases. First, the Food and Drug Act of 1906 essentially required that the labeling of drugs be truthful. The 1938 Food, Drug, and Cosmetic Act added a requirement that drugs be proven safe, and the 1962 act added the requirement that drugs be efficacious. Each of these steps required more and more sophisticated science. Subsequent to the Kefauver-Harris Amendments of 1962, the number of innovative molecular entities each year has declined, the reasons for which have been subject to great debate. This decline has paralleled decreases in innovation across almost all American industry, leading to questions about the future of our country as an industrialized society. Both the Carter and Reagan administrations attempted to address this problem in a number of ways, including cutting back on those regulations that are perceived as unnecessary. Other innovative approaches have been used, such as the establishment of an Office of Small Manufacturers Assistance in the FDA Bureau of Medical Devices, mandated by the 1976 Medical Device Amendments. The latter came about in recognition of the fact that small businesses tend to be more creative and efficient than larger industries and more adversely affected by regulation. However, the problems raised in the regulation of technology transfer almost inevitably arise because of perceived scientific questions. Such questions, in turn, can only be answered by good science performed by the sponsor and understood by the regulator. Thus, it is essential that the FDA be staffed with knowledgeable scientists who can interact easily with their peers in academia and industry. Although science is often the cause of our troubles, it is also our only hope for minimizing the costs of new drugs and other technology. In turn, minimizing such costs will maximize the opportunities for innovation.