New Drug Demagoguery

New Drugs Hit the Market, but Promised Trials Go Undone” and “FDA: Drug Companies Drop Ball on Studies,” the headlines blared. Are Americans getting untested drugs? Are drug developers taking short-cuts, or worse? Are regulators incompetent, or impotent? None of the above—although it's hard to tell that from the press coverage.As a condition of marketing approval of a new drug, the FDA often requires the manufacturer to perform additional studies to confirm efficacy or to look for previously undetected side effects. But according to a recent FDA report, which spurred the headlines, as of the end of last September, of the 1,231 “open post-marketing commitments” to perform clinical studies, only 14 percent had been duly reported to FDA, 65 percent were “pending” (that is, had not yet started), 19 percent were considered “ongoing,” and two percent were “delayed.”However, the government's evaluation and approval of new drugs is an exceedingly complex and arcane business, and these statistics can easily be misunderstood or misrepresented.American pharmaceuticals are the most intensively tested products in history. Moving a drug through laboratory studies and then animal and human testing requires on average 12-15 years and more than $800 million in direct and indirect costs. By the time a drug company applies to the FDA for marketing approval of a new product, on average it has performed more than 70 clinical studies on at least 4,000 patients.Even after exhaustive clinical testing, questions may remain, particularly if efficacy has been judged by improvement in a “surrogate” endpoint, such as high blood pressure as a marker for heart disease, or shrinkage of a tumor as a stand-in for actual prolonged survival. These kinds of criteria for measuring efficacy are both common-sensical and based on a scientific rationale—and most often they do correlate with more definitive measures of benefit. Sometimes they're essential to efficient drug testing. I'm reminded of a cartoon in which two pharmaceutical scientists are contemplating a beaker that contains a new medicine. One says to the other, “It looks as though this drug will confer immortality. The trouble is, it will take forever to test it.”The FDA can require manufacturers to perform certain post-marketing follow-up studies, and according to the regulations, “once a post-marketing study commitment has been made, an applicant must report on the progress of the commitment . . . until the post-marketing study commitment is completed or terminated, and FDA determines that the post-marketing study commitment has been fulfilled or that the post-marketing study commitment is either no longer feasible or would no longer provide useful information.” That seems straightforward enough, but in practice widespread prescribing and use of a drug following FDA approval often make the mandated post-marketing studies moot. In other words, the availability of large amounts of data obtained from usage under real-world conditions—sometimes from hundreds of thousands of patients within months of approval—makes additional data from small clinical trials superfluous. In spite of that, the FDA seldom follows through to determine “that the post-marketing study commitment is either no longer feasible or would no longer provide useful information.” Hence, the preponderance of post-marketing studies that are “delayed” or “pending.”Another related factor is that in recent years FDA regulators have tended to over-use the requirement for post-marketing studies—mandating them not because they're essential, but merely as a way to inoculate themselves against criticism for too-rapid approvals. The nuances of this phenomenon have eluded some who should know better. Congressman Maurice D. Hinchey (D-New York) claims mistakenly that the FDA's demands for demonstrations of safety “continue to be blatantly ignored by the pharmaceutical industry,” so he and Senators Charles Grassley (R-Iowa) and Christopher Dodd (D-Conn.) have introduced legislation that would give the FDA added authority to require drug companies to carry out post-marketing studies. Wrong diagnosis, wrong remedy.Instead of bean-counting and indulging in demagoguery, we should be trying to ascertain what fraction of mandated post-approval studies is really necessary, and FDA should clean up its backlog of superfluous post-marketing studies.<?xml:namespace prefix = o ns = “urn:schemas-microsoft-com:office:office” />