Friday, September 29, 2006
Sneaking in Ethics at the FDA

In response to my recent Forum item on the FDA and Plan B, a few people wrote to say that they did not think I had it all quite straight. I agreed that was certainly possible. One of those who wrote about the piece was Michael Yesley, who was executive director of the National Commission for the Protection of Human Subjects and is now an independent scholar and consultant. I put to him some questions about the FDA, and I found his response most informative.

– Daniel Callahan

Dan's questions sent me to the Food, Drug & Cosmetic Act and other materials on the FDA website for answers. Essentially Dan raised parallel questions about the scope of authority of the FDA commissioner and the scientific advisory panels. He asked whether the basis for the commissioner’s approval or the advisory panel’s advice regarding marketing of a drug is limited to the scientific issues of safety and efficacy, or whether the commissioner and advisory panels also have some extra-scientific (ethical?) authority.

Under the act, advisory panels are established “for the purpose of providing expert scientific advice and recommendations.” The panels consist of “members who are qualified by training and experience to evaluate the safety and effectiveness of the drugs to be referred to the panel and who, to the extent feasible, possess skill and experience in the development, manufacture, or utilization of such drugs.” The members are drawn from medicine and related professions plus a representative of consumer interests, a representative of the drug manufacturing industry, and two or more specialists in the relevant disease or condition. See sec. 505(n). I believe these are the relevant provisions of the act, and they limit the panels to a “purely neutral ethical vote.”

The act directs the commissioner to approve an application unless he finds any of the following: inadequate testing to demonstrate safety, testing results that show the drug is unsafe or do not show it’s safe, inadequate manufacturing methods, insufficient information to determine safety, lack of substantial evidence that the drug will have the desired effect, or lack of required patent information. See sec. 505(d). (I've paraphrased, but the overlap among these bases for disapproval is present in the original.) None of these bases for disapproval (except the last concerning intellectual property) seems extra-scientific in any way.

But the fact that determinations by the advisory panel and commissioner must be scientific does not necessarily control the outcome. For we are not talking about the verities of physics here, but soft science ponderables. Safety and efficacy are not physical properties but opinions or interpretations of physical properties, about which there may be disagreement and argument. Like, how safe is safe enough? Etc., etc. True, a determination nominally about safety may be a pretext for a political or ethical position, but how can one prove it's a pretext short of overwhelming physical evidence supporting a contrary conclusion?

In any event, the FDA’s stated basis for denying the application to market nonprescription, or over the counter (OTC), Plan B in 2004 was inadequate safety data. A second stated deficiency was insufficient information about the implementation of simultaneous prescription and OTC marketing of Plan B for women of different ages (letter from Galson to Carrado, May 6, 2004). A year later, Commissioner Crawford deferred action on the manufacturer's amended application, notwithstanding a determination by the FDA’s own Center for Drug Evaluation and Research that the scientific data supported the safe use of Plan B OTC for women 17 and older. Crawford’s stated reason for this “action” (recall that he had promised Congress that he would “act” on the application) was the existence of “unresolved regulatory and policy issues,” to wit: Can age be used as a criterion for OTC marketing? Can prescription and OTC versions of the same drug be marketed in a single package? And how can an age criterion be enforced as a practical matter? (See the FDA Statement of August 26, 2005.) Finally, last month the FDA concluded that BTC (nonprescription but Behind The Counter) Plan B would be safe and effective for women 18 years and older (letter from Galson to Carrado, August 24(?), 2006).

Neither the manufacturer nor the FDA made an ethical claim on the record that it was right or wrong for young women to have convenient access to morning-after contraception. For the record, everyone focused on the statutory criteria for approval: safety and efficacy. Those criteria framed the argument. But since they are interpretive rather than objective criteria, they provided a screen or pretext enabling those who believe contraception for young women is wrong (whether or not it’s safe and effective) to prevent its availability on statutory grounds.

The pretext works only when there is a gray area of interpretation, however. Accordingly, since the evidence of safety and efficacy was overwhelming, the FDA shifted from substantive scientific issues to procedural regulatory issues. By that time the writing was on the wall. It was necessary, however, to maintain political pressure in order for the FDA to accept the inevitable, but politically distasteful, conclusion. Still, ethical positions (that is, that young women should – or should not – have convenient access to morning-after contraception) may have motivated the disputants but were not admissible as a legal foundation for the FDA’s decisions.

– Michael Yesley

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