- The Washington Times - Tuesday, March 21, 2006

“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 shortcuts, or worse? Are regulators incompetent, or impotent? None of the above — though it’s hard to tell that from the press coverage.

As a condition of marketing approval of a new drug, the FDA often requires additional manufacturer 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 postmarketing commitments” to perform clinical studies, only 14 percent had been duly reported to FDA, 65 percent were “pending” (had not yet started), 19 percent were considered “ongoing,”and 2 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 to 15 years and more than $800 million in direct and indirect costs. When 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 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 contemplate a beaker containing 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 postmarketing follow-up studies, and according to the regulations, “once a postmarketing study commitment has been made, an applicant must report on the progress of the commitment … until the postmarketing study commitment is completed or terminated, and FDA determines that the postmarketing study commitment has been fulfilled or that the postmarketing 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 postmarketing studies moot.

In other words, availability of large amounts of data obtained from use under real-world conditions — sometimes from hundreds of thousands of patients within months of approval — makes additional data from small clinical trials superfluous.

Despite that, FDA seldom follows up to determine “that the postmarketing study commitment is either no longer feasible or would no longer provide useful information.” Hence, the preponderance of “delayed” or “pending” postmarketing studies.

Another related factor is that in recent years FDA regulators have tended to overuse the requirement for postmarketing 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. Rep. Maurice D. Hinchey, New York Democrat, claims mistakenly that the FDA demands for demonstrations of safety “continue to be blatantly ignored by the pharmaceutical industry,” so he and Sens. Charles Grassley, Iowa Republican, and Christopher Dodd, Connecticut Democrat, have proposed authorizing FDA to require that drug companies do postmarketing studies.

Wrong diagnosis, wrong remedy.

Instead of bean-counting and indulging in demagoguery, we should try to ascertain what fraction of mandated postapproval studies are really necessary, and FDA should clean up its backlog of superfluous postmarketing studies.

Henry I. Miller, a physician and fellow at the Hoover Institution and Competitive Enterprise Institute, headed the FDA’s Office of Biotechnology, 1989-1994. His most recent book, “The Frankenfood Myth” was selected by Barron’s one of the 25 Best Books of 2004.

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