TCS Daily

Dr. McClellan's Weak Medicine

By Henry I. Miller - January 15, 2004 12:00 AM

"Just when we thought sanity was emerging at the Food and Drug Administration, the scaremongers win again," begins the Wall Street Journal's January 13th editorial, "Breast Beating at the FDA." The piece laments the FDA's decision to continue a twelve-year ban on silicone breast implants -- a ban that was unjustified from the outset.

Notwithstanding the Journal's long-standing bullishness on FDA Commissioner Mark McClellan, this kind of policy should come as no surprise: Although Dr. McClellan has talked regulatory reform at every opportunity, the FDA's record on major policy decisions tells a very different story.

Drug Problem

The development of prescription drugs is in dire straits. In spite of increasingly more powerful and precise technologies for drug discovery, purification and production, development costs are soaring. According to the Tufts Center for the Study of Drug Development, between 1970 and 2003 companies' average expenditures to develop a single new drug increased from $138 million to more than $800 million. And while between 1970 and 2000 research-based companies' R&D outlays soared from about $2 billion to $30 billion, but you would never know it from the number of new drug approvals. In connection with the release of a study just this month, Kenneth I. Kaitin, the director of the Tufts group, observed, "Business as usual is no longer an option when it comes to developing new prescription drugs . . . Pharmaceutical and biopharmaceutical companies are spending more on R&D than ever before, yet the number of new drug approvals has declined steadily."

An important reason is that the highly risk-averse FDA keeps raising the bar for approval, especially for innovative, high-tech products. Human gene therapy and other treatments tailored to individual patients have been hit especially hard. Americans are literally dying for reform.

Dr. McClellan seems to recognize that the FDA's primary goal must no longer be to meet arbitrary, internal performance milestones, but actually to reduce the time and costs of clinical testing and the barriers to approval. He has put an end to a trick that FDA reviewing divisions played to "game" their performance numbers: Often they would stop the time clock for reviewing New Drug Applications (which are submitted by companies to obtain marketing approval), by asking for additional information at the eleventh hour of the time allotted for FDA review. This helped to create a paradox: FDA officials were meeting their quantitative performance goals, but few new drugs were being approved, and the costs and overall (calendar) time required for drug development were steadily increasing.

Dr. McClellan has expanded the use of therapeutic "surrogate endpoints" -- laboratory tests or physical signs that are expected to predict a drug's efficacy -- in lieu of more clinically definitive criteria such as prolonged survival. For example, Millennium Pharmaceuticals' Velcade® was approved for the treatment of multiple myeloma, a blood cancer, on the basis of improvement in laboratory tests in a relatively early stage clinical study. Traditionally, FDA has required evidence of actual increased survival, a policy which gave rise to a wonderfully evocative cartoon: Two scientists are in the laboratory, going over their results. One of them holds up a test tube and says to the other, "It looks as though this drug will confer immortality, but it will take forever to test it."

Culture War

Unfortunately, Commissioner McClellan has done little to reform the culture of risk-aversion and the fear of innovation that is pervasive at the FDA -- reform that is essential in order to effect meaningful change. The hidden agenda of regulatory agencies -- not just the FDA -- is that career bureaucrats generally care more about staying out of trouble than about public health. That biases them against innovation.

A regulator can commit an error by permitting something bad to happen (approving a harmful product), or by preventing something good from becoming available (delaying or denying approval of 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 highly visible, and causes regulators to be attacked by the media and patient groups and investigated by politicians. But the second kind of error -- which keeps a potentially important product out of consumers' hands -- is usually invisible. Many senior FDA officials, therefore, make decisions defensively, avoiding the first kind of error at all costs, even at the expense of committing egregious errors of the second kind.

Complicating efforts at significant reform, the FDA commissioner is relatively far removed from routine product review and approval, most of which occurs largely autonomously within the agency's product-specific "centers," which focus, respectively, on drugs, medical devices, and so on. Those that regulate food, veterinary drugs, and biologicals (blood products, vaccines and gene therapy), in particular, are plagued with senior officials who have shown themselves to be overly timid, risk-averse, or simply incompetent. Yet, no senior career bureaucrat has been removed.

On Dr. McClellan's watch, the FDA continues to throw rigid, one-size-fits-all solutions at non-problems. An example is the agency's recent decision to deny any drug company the ability to obtain multiple trademarks for the same drug -- for example, Sarafem®/Prozac®® and Propecia®/Proscar® -- even if they are different formulations for different ailments. Another is the agency's support of legislation, passed last year and signed by President George Bush, that requires drug companies to test drugs in children, even if they don't wish the label to recommend use in pediatric patients.

Attorney Marc J. Scheineson, former FDA Associate Commissioner for Legislative Affairs, argues that the agency's policy towards multiple trademarks is possibly illegal under several theories, including the absence of required formal notice-and-comment rule-making, interference with constitutionally protected commercial speech, impermissible "taking" of corporate "property," and arbitrary and capricious action.

In addition, Dr. McClellan has failed to modernize the FDA's bureaucratic, risk-averse approach to regulating old drugs that have been on the market for decades without specific FDA approvals -- but that do not pose significant concerns about safety or efficacy. The FDA has said that if the manufacturer of one of these drugs expends the effort and expense to obtain an approval, all of its competitors will be forced off the market until they also obtain approvals. This recently occurred with extended-release guaifenesin, a well known cough suppressant. FDA justified forcing competitors off the market as necessary to "protect the integrity of the drug approval process," but the outcome has been exactly the opposite: With no incremental protection of public health, the approved product now sells for 700 percent of the price of comparable products prior to FDA's action.

Although this article is primarily concerned with the regulation of drugs, two other instances of dubious FDA policies adopted during Dr. McClellan's tenure are illustrative.

Biotech and Breast Implants

The first is the FDA's recent, deplorable approach to the regulation of biotech foods. At the same time that U.S. Trade Representative Robert Zoellick and other senior officials in the Bush Administration were working for more science-based and logical treatment of biotech foods (that is, those produced from gene-spliced, or GM, organisms) internationally, they were outflanked by European and American -- yes, American -- bureaucrats at the deliberations of the Codex Alimentarius Commission, the food standards program of the United Nations. Codex's task force on gene-spliced foods last year completed work on preposterously unscientific regulations that will hugely inflate the costs of using the most precise and predictable techniques for genetic improvement of plants used for food, and also provide cover for those who wish to regulate agricultural biotechnology into oblivion.

During three years of negotiations by the task force, the Europeans and NGOs (which were permitted full participation) led the assault on technological innovation and free trade. The participants -- including the U.S. delegation, headed by senior FDA food regulator Robert Lake, who apparently sees excessive, unscientific international regulation as a possible (desirable) stimulus to excessive, unscientific domestic regulation -- willfully ignored scientific principles and the basic axiom that the degree of regulatory scrutiny should be proportionate to risk. They chose to disregard the scientific consensus that gene-splicing is an extension, or refinement, of older, traditional techniques of genetic modification, and that it does not warrant discriminatory over-regulation. Likewise, they chose to overlook the fact that during a decade of widespread use, the performance of gene-spliced crops has been spectacular, with farmers enjoying increased yields, decreased costs of agricultural chemicals, and lower occupational exposures to pesticides. The environmental benefits likewise have been stunning, with less chemical runoff into waterways and greater availability of no-till farming techniques that reduce soil erosion.

Dr. McClellan was apprized repeatedly of the collusion between his own minions and the anti-science, anti-biotech Europeans and NGOs, and he could easily have adopted an enlightened, scientific course -- which would not have exacted a significant political price -- but he chose not to rein in his bureaucrats-running-amok.

The second is the decision that so exercised the Wall Street Journal -- the FDA's unexpected rejection, contrary to the advice of an advisory committee, of an application by Inamed Corporation to return silicone breast implants to widespread cosmetic use. This decision leaves in place severe restrictions imposed more than a decade ago because of safety concerns -- concerns that although unfounded, virtually destroyed an industry, and needlessly terrified tens of thousands of American women.

These are not the actions of an FDA head who believes in science as the basis for public policy, data as the basis for regulatory decisions, and patients' and physicians' right to assume a modicum of responsibility for the risk of medical interventions.

Returning to the main issue -- the oversight of drug development -- Dr. McClellan's best efforts at reform ultimately may be frustrated by history. The FDA's long-standing excesses have caused the number of drug companies' submissions for marketing approval to decline steadily for the past eight years, so there is now relatively little in the pipeline. Even the most highly motivated regulator cannot approve a submission he doesn't have.

Therefore, even if Dr. McClellan is able to fulfill his promise to increase the FDA's efficiency, it is unlikely that in the near future we'll see a marked increase in the number of drugs approved. His most valuable legacy could be to begin the lengthy process of making changes in infrastructure, performance plans and personnel that will alter the culture of the FDA. But it won't be easy, and it won't please the bureaucrats -- the same bureaucrats whom Dr. McClellan seems increasingly loathe to offend.

Henry I. Miller, a physician, is a fellow at the Hoover Institution. From 1979-1994, he was an official at the FDA.


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