A progressive brain disease that destroys an individual's memory and other mental and physical functions, Alzheimer's disease (AD) may at first present only mild symptoms, such as slight confusion and difficulty forming new memories. Eventually, though, the afflicted person's brain cells degenerate and die, causing a steady decline in general functioning and, eventually, death. Solutions to the public health scourge of AD have been elusive, primarily because its pathophysiology is so complex—but also because government pharmaceutical regulation has created many obstacles.
AD is about to become an epidemic. The most common cause of dementia, it is already extremely prevalent, with approximately 2.6 million to 5.1 million Americans 65 years and older suffering from it, and with annual costs exceeding $100 billion. Because age is the biggest risk factor, Alzheimer's prevalence might triple by 2050 in the United States, due to the nation's graying demographics. Recent prospects for winning the fight against AD in the near term have been dimmed by late-stage clinical-trial failures of several drugs. Pharmaceutical giant Pfizer has decided simply to give up, shuttering its neuroscience research into AD and Parkinson's disease.
Progress has been stymied by several problems, including the FDA's past insistence that both cognitive and functional deterioration be indicated for final clinical testing of promising treatments; in other words, subjects must demonstrate mental and physical impairment together. But researchers now believe that successful intervention must start much earlier in the course of the disease, before the appearance of either form of impairment. In February, the FDA loosened its requirements somewhat, allowing approvals to be based on either cognitive outcomes or biomarkers (biological evidence of disease)—acknowledging that early-stage AD is not necessarily accompanied by functional impairment.
This is a promising start, but for now, anyway, it seems unlikely that the FDA will approve AD drugs based on biomarkers alone, since these signs have not been shown to predict unfailingly the development or progression of AD. Further, the FDA seems committed to the remote possibility that AD will be treated successfully with a single "miracle drug," though the much safer bet is that a cocktail of drugs will be required to tackle this complex disease. The FDA is poorly equipped to handle this eventuality.
One of us (Joseph V. Gulfo) has proposed a market-based solution to the AD epidemic that would allow the speedier approval of drugs. If drugs are demonstrated to be safe—to a level commensurate with the urgent need for treatment—and effective, using more flexible criteria than those imposed currently by regulators, they should be approved for use. Following approval, physicians at leading research centers would then be able to administer the new drugs to patients whose cases resemble those treated in late-stage testing; and the doctors could combine drugs, in formal and informal clinical trials, to identify tandems that have the greatest impact. Physicians currently manage hypertension in a similar fashion.
Currently, however, combination trials with more than one new drug are seldom feasible as the basis for FDA approval. The FDA typically demands that drug companies demonstrate the safety and effectiveness of each of the discrete components of a combination separately; then, in addition to being safe, the combination must be shown to have additive, positive effects over the discrete components. These trials are large, expensive, and time-consuming. Moreover, they flout fundamental concepts of complex biological processes, such as the notion of potentiation—the principle that certain drugs administered together have an effect greater than the sum of their parts. And unless a drugmaker has a number of drugs that might work, the trials are not likely to be performed preapproval, for commercial and practical reasons.
Small companies, which often develop the most novel solutions, cannot afford to develop drugs that attack several different pathways. Though they might possess a critical component of what becomes the winning cocktail, that won't be known, because the drug would not be tested in combination with other drugs in development. For all these reasons, we believe that combinations—of new and older drugs—in the post-approval setting are the most feasible solution to many of our most vexing diseases, including obesity, heart failure, and Alzheimer's. To make that possible, we need a true paradigm shift from the FDA.
Joseph V. Gulfo, M.D., M.B.A., of Altium Capital, is the author of Innovation Breakdown: How the FDA and Wall Street Cripple Medical Advances. Henry I. Miller, M.D., is the Robert Wesson Fellow in Scientific Philosophy & Public Policy at Stanford University's Hoover Institution. He was the founding director of the FDA's Office of Biotechnology.