- The Washington Times - Friday, September 28, 2007

The pendulum swings back and forth about what ails the regulation of drug development. Thirty years ago, the concerns were primarily about “drug lag” — indolent reviews and approvals by the Food and Drug Administration that put Americans at disadvantage to consumers in other countries.

In recent years, however, there have been repeated accusations about what might be called “drug leap” — a supposedly “too cozy” relationship between regulators and industry, along with too little attention to drug safety, possibly as the result of regulators’ pressing to meet arbitrary deadlines.

The reality is that over the last decade or so the FDA has become more progressively risk-averse and defensive in its decision-making. Regulators have been encouraged on “drug safety” but no longer are called to account for the unnecessary suffering and deaths of patients who don’t get the new drugs they need in a timely way.

This asymmetry will be further worsened by the tragically misnamed FDA Revitalization Act, passed by Congress last week and expected to be signed by the president. The bill focuses on providing regulators with more sticks with which to flog drug developers, while what is needed are more ways to get regulators to be more efficient, effective and smart. Drug development, already in dire straits, will become even more difficult, slow and expensive.

Despite increasingly more powerful and precise technologies for drug discovery, purification and production during the last 20 years, development costs have skyrocketed. On average it takes 12 to 15 years and costs more than a billion dollars to bring a drug to market. Of that amount, capitalized out-of-pocket preclinical costs and clinical testing each account for about half.

Why the huge costs and lengthy development times, which exceed even those for conventional drugs? Regulatory excesses, for the most part. Regulators are inflexible and inconsistent and keep raising the bar for approval, especially for innovative, high-tech products. Another factor is user fees (nothing more than a discriminatory tax) paid to FDA by drug companies — raised to almost $400 million in the new bill.

Several highly publicized events have heightened public and congressional concern about drug safety in the last few years: inadequate warnings on the labels of anti-depressants and the discovery of previously unknown side effects from nonsteroidal anti-inflammatory drugs (NSAIDS) and from the multiple sclerosis drug Tysabri.

However, contrary to perceptions that regulatory oversight might have become lax, drug regulation in the United States in recent years has actually become progressively more risk-averse, as the FDA has steadily made it more difficult to initiate and perform the clinical testing of new drugs.

Recent criticism from Congress, the media and others regarding drug safety has caused an already risk-averse agency to become even more conservative and defensive in its decision-making. The FDA has been requiring ever larger numbers of patients in clinical trials; its demands for post-marketing clinical trials have proliferated wildly; and “risk management” plans for newly approved drugs have been inconsistently applied, punitive and often more appropriate for weapons-grade plutonium than prescription drugs.

Regulators moving the goalposts in the middle of the game is particularly vexing for drug developers. In September 2006, Genentech announced that approval of its colon cancer drug Avastin for breast cancer would be delayed at least a year because of requests from the FDA for more data. The company said regulators appeared to be increasing the stringency of requirements for certain types of clinical trials and had arbitrarily demanded that its trials be “audited and summarized” in a way different from that earlier agreed upon with regulators.

Another recent and particularly problematic example involves Somaxon Pharmaceuticals’ testing of an already-approved drug, doxepin, for a new indication. The drug, approved for treating depression since 1969, is being tested in very low doses for use as a sleeping pill. The FDA initially assured the company it could begin human clinical trials without first doing animal tests because of doxepin’s long history of use in people and because Somaxon was using a dose less than one-tenth that used to treat depression. However, in May 2006, after having completed several clinical trials, while the company was meeting with the FDA to discuss the submission of a New Drug Application, regulators unexpectedly asked for a full battery of testing in animals.

Animal testing is usually considered to be “preclinical,” so it is difficult to understand the logic of animal testing for an almost 40-year-old drug that is undergoing trials for a new indication, and at a far lower dose than it is normally used.

In addition, a number of drugs previously granted marketing approval in Europe have received “approvable,” instead of approval, letters from the FDA, meaning additional data is required before the drug can be marketed. These include Sanofi-Aventis’ Acomplia for weight loss and cessation of smoking, NPS Pharmaceuticals’ Preos for osteoporosis and Encysive Pharmaceuticals’ Thelin for pulmonary hypertension.

Many new targeted therapies are difficult to assess with traditional clinical trial designs or endpoints. For example, a drug intended to arrest or eliminate cancer by boosting the patient’s immune system might be most efficacious in early stage cancers when the tumor load is low and the patient is not debilitated.

Thus, were the company to adopt a clinical design that called for recruiting and treating only patients with advanced cancers, one would expect suboptimal efficacy. This kind of situation, in which there is a high level of novelty and uncertainty, argues for greater flexibility both in clinical trial design and in agreeing on what constitutes “efficacy.” Instead, the FDA has been risk-averse and defensive, sometimes intransigent. In the review of cancer drugs in particular, FDA reviewers and managers often are characterized as inadequately prepared for meetings with industry scientists and insensitive to the needs of dying patients.

Times are tough for drug development and are getting worse. Beleaguered regulators are hunkered down and in go-slow mode. Congress has once again shirked its responsibility to appropriate sufficient funds for the FDA or to perform the kind of informed, intelligent oversight that promotes innovation and ingenuity in drug development. The absence of outrage means that the worst has become the norm.

Henry I. Miller, a physician and fellow at Stanford University’s Hoover Institution, headed the Food and Drug Administration’s Office of Biotechnology from 1989 to 1993. He is the author, most recently, of “The Frankenfood Myth.”

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