The Heartbreak of Pharmaceutical Failure

Human Trials: Scientists, Investors and Patients in the Quest for a Cure By Susan Quinn Cambridge, MA: Perseus Publishing (2001). 295 pp. $26.00This book transports the reader into the universe of currently incurable diseases, there to appreciate the lengthy, expensive, and often heart breakingly unsuccessful search for new remedies able to provide desperately needed major clinical improvement.The leading figure in Quinn's scenario is Harvard neurologist Howard Weiner, whose talents and personality are well described in the book's early chapters. He fights a daily battle against his patients' multiple sclerosis (MS), a disease of clinical “ups and downs” occurring mysteriously over time, but with a course that is essentially downhill, with each remission ending not with a return to the former baseline, but to a less normal status. Quinn points out early on that the same unpredictability that makes MS hard to treat makes it difficult to study.While there is some genetic predisposition to MS, genetics seems to be a minor player here. The disease occurs most commonly in northern latitudes, is common in Scandinavia and almost nonexistent among African blacks.Weiner's domain is the Boston Center for Neurological Diseases, established in 1985. It has a staff of 140 employees from 33 different countries.In the battle against MS, a rodent disease has been used as a model. It is referred to as EAE, which is shorthand for experimental autoimmune encephalomyelitis. Unfortunately, while EAE is curable by a number of chemicals, MS is not.Weiner believed that success might be achievable by taking advantage of what is called “oral tolerance.” This term applies to a phenomenon known to exist for a long time. It consists of systemic hyporesponsiveness to an agent fed prior to immunization. Legend has it that Mithradates, a first century Mediterranean king, drank the blood of ducks that had been fed a poisonous weed to protect himself against poisoning by his enemies. Today, a potion made from poison oak is available at homeopathic pharmacies to protect against the risk of poison oak.Encouraged by some early results in animals, Weiner decided to pursue the cure of not only MS but also rheumatoid arthritis, giving by mouth the brain substance myelin to MS patients and collagen-rich cartilage from calf noses to the arthritis patients. As optimism and excitement increased, the search became one capable of attracting venture capital and biotech firms. Quinn's book captures this anticipating atmosphere in a highly readable form, taking in not only Wall Street but the media and academe as well.The early positive screening results were, sad to say, not substantiated in the chronic clinical trials. Improvement was seen in some patients, but the results did not show a significant advantage of active treatment over placebo. The conclusion was heart breaking and the reader gets caught up in the anticipation as the bad news is reported for each trial.The process of drug development is slow, expensive, and risky. This book was published before the latest report from the Tufts Center for the Study of Drug Development, a report whose expensive figures were $800,000,000 to bring a new chemical entity to market if we count the “dry holes” as well as the “gushers” and both the out-of-pocket expenses and the “cost of money,” i.e., what you could have earned with the money spent if it were invested so as to generate a 11% return. Quinn's book accurately describes the many years spent from discovery to new drug approval, and the fact that even when a developer reaches phase I with a drug, i.e., the first human exposure, only 1 in 4 or 1 in 5 such drugs ever make it to market. Only 30% or so of approved drugs ever earn back the money invested in their development.An especially fascinating part of the Weiner story is the high rate of improvement after placebo. (Fifty six percent was reported in one trial). Placebo benefit is partially explicable on the basis of optimistic anticipation and partially by spontaneous improvement. One can only guess at the explanation in the trials summarized in this book, but MS patients clearly have good reason for hoping that a new medication that showed promise would help them. (Ditto for the research physicians.)