- The Washington Times - Monday, September 5, 2005

“The fault, dear Brutus, is not in our stars, but in ourselves,” wrote Shakespeare. It’s the sort of frank self-assessment not popular with bureaucrats.

The latest example is a just-published joint report by the Food and Drug Administration and the Association of American Medical Colleges (AAMC) seeking remedies for the following: “Support for basic science in the United States has been demonstrated by the recent 5-year doubling of the NIH budget. The biopharmaceutical industry continues to increase funding for the science of drug and medical product discovery and for commercialization. In spite of this considerable investment, the number of innovative drugs and biologicals (so-called New Molecular Entities) approved by the FDA, which rose steadily during the early 1990s, appears to have peaked in 1996 and has since declined.”

That’s only part of a most alarming story. Drug research-and-development costs have skyrocketed, with direct and indirect expenses now exceeding $800 million to bring an average drug to market. Fewer than 1 in 3 drugs approved for marketing recoup their development costs.

Why do we find ourselves — and more important, patients who need innovative new drugs — in this situation? Well, the FDA constantly raises the bar for initiation and progress of new drug clinical testing. For example, in just the last few years FDA officials have arbitrarily and unexpectedly directed clinical investigators to begin trials at inappropriately low dosages; limited approval of Phase 1 studies to single-dose, instead of dose-ranging, studies; demanded unnecessary, invasive procedures on patients; and even required completion of foreign trials and results submitted before the U.S. trials begin.

The FDA’s constant raising of the bar for approval, tendency to overreact and anxiety about new technologies has made the U.S. drug development process the world’s longest, and it has grown longer over time. According to the Tufts University Center for the Study of Drug Development, since the 1960s total time required for drug development — from lab synthesis or discovery to delivery to the patient — has nearly doubled, from 8.1 to 15.2 years. Clinical testing, the part of development the FDA most intensely scrutinizes, averages eight years in the U.S., or about a third longer than in Europe.

But FDA — and its partner in producing the recent report, AAMC (whose senior vice president, David Korn, is one of the two authors and happens to be married to a former FDA deputy commissioner) — are blind to all this, somehow managing not to see the 800-pound gorilla at the dining room table.

Instead, they offer suggestions that, while not bad, certainly will not address FDA’s manifest shortcomings. Their proposals include: Develop mechanisms to learn from failures at various drug development stages, including clinical trials and drug targeting; industry-FDA collaborations to share toxicology data; construct models for biomarker validation; propose new congressionally enacted regulatory incentive policies for small-market drugs; develop ways to share information now restricted as intellectual property or proprietary, to increase shared knowledge; and stimulate industry-government collaborative research and development.

We need changes that will fix the current system’s fundamental and systematic flaws. Aggressive reform must redress the asymmetry of outcomes from the two types of mistakes regulators can make. A regulator can err by permitting something bad to happen (approving a harmful product) or by preventing something good (not approving a beneficial product). Both outcomes are bad for the public, but the consequences for the regulator are very different.

The first kind of error is very visible, bringing attacks on the regulators from the media and patient groups and congressional investigations. (All this has happened in recent months.) But the second kind of error — keeping a potentially important product out of consumers’ hands — usually is a nonevent, eliciting little attention, let alone outrage.

Former FDA Commissioner Alexander Schmidt summarized the conundrum: “In all our FDA history, we are unable to find a single instance where a congressional committee investigated the failure of FDA to approve a new drug. But the times when hearings have been held to criticize our approval of a new drug have been so frequent that we have not been able to count them. The message to FDA staff could not be clearer.”

As a result, regulators make decisions defensively — to avoid approvals of harmful products at any cost. So they tend to delay or reject all sorts of new products, from fat substitutes to vaccines and painkillers. That’s bad for public health and for consumers’ freedom to choose.

We need sweeping FDA reform. First, we need to insulate policymaking and individual product decisions from politics as far as possible. Second, we need to make regulators’ decisions more scientific and evidence-based. Third, we need to improve pharmacovigilance — the monitoring of the safety of already marketed drugs — by enhancing regulators’ access to more and better data. Finally, and most important, we need to redress the culture of excessive risk-aversion and defensiveness that pervades FDA.

Henry I. Miller, a fellow at the Hoover Institution, was a Food and Drug Administration official, 1979-1994. His most recent book, “The Frankenfood Myth,” was selected by Barron’s as one of the 25 Best Books of 2004.



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