On February 20, 2005 Gardiner Harris wrote in the New York Times about the Food and Drug Administration (FDA) deliberations that led to recent coverage about an advisory committee’s decision to support use of three drugs, Vioxx, Bextra and Celebrex. Gardiner’s article suggests that the FDA is moving toward a new culture of openness.

“Instead of certainty, the agency embraced doubt. Instead of presenting a united front, agency officials bickered openly. Instead of keeping secret its dealings with drug companies, the agency gave a public accounting of lengthy and contentious negotiations with the drug maker Merck… These changes were not voluntary. The FDA has been forced by a series of embarrassing scandals over the past year to transform its “Daddy knows best” culture… [Dr. Lester M. Crawford, head of the FDA said] “Our culture, which has received some criticism in recent months is not to alarm the public when we get a signal. That era is sort of past. What the public, we think, is demanding to know as soon as we know what’s going on. And they are fully prepared and adult enough to interpret whether or not this is a final decision.” To be sure, the changes so far have been relatively small. But the tentative steps made at this week’s meeting seemed to go well, and agency officials have promised more.”

Well, be careful what you wish for. Only 5 days later the New York Times reported,

“Ten of the 32 government drug advisers who last week endorsed continued marketing of the huge-selling pain pills Celebrex, Bextra and Vioxx have consulted in recent years for the drugs’ makers, according to disclosures in medical journals and other public records. If the 10 advisers had not cast their votes, the committee would have voted 12 to 8 that Bextra should be withdrawn and 14 to 8 that Vioxx should not return to the market. The 10 advisers with company ties voted 9 to 1 to keep Bextra on the market and 9 to 1 for Vioxx’s return.”

[Note: The information was gathered by the Center for Science in the Public Interest (CSPI) and can be found here.]

The findings of the CSPI are incredible. They show a profound difference in voting between those on the FDA advisory committee with financial ties to the companies producing the Cox-2 drugs and those on the advisory committees without such ties. The apparent solution to this situation – to simply bar those with such conflicts from participating in advisory committees – may not be the best course of action in all such situations. Conflicts of interest, financial or otherwise, are a difficult policy problem in the federal scientific advisory structure.

What is a “conflict of interest” anyway?

In 1993, Harvard’s Dennis Thompson provided a useful definition of conflict of interest in The New England Journal of Medicine:

“A conflict of interest is a set of conditions in which professional judgment concerning a primary interest (such as a patient’s welfare or the validity of research) tends to be unduly influenced by a secondary influence (such as financial gain)… The secondary interest is usually not illegitimate in itself, and indeed it may even be a necessary and desirable part of professional practice. Only its relative weight in professional decisions is problematic. The aim is not to eliminate or necessarily to reduce financial gain or other secondary interests (such as preference for family and friends or the desire for prestige and power). It is rather to prevent these secondary factors from dominating or appearing to dominate the relevant primary interest in the making of professional decisions.”

Reference: Thompson D. F., 1993. Understanding Financial Conflicts of Interest. The New England Journal of Medicine, 329:573-576.

It is safe, I think, to say that financial gain (personal or professional) is among those “secondary influences” that has great potential to influence the advice proffered by experts. But the Federal Advisory Committee Act (FACA), which is the legislation that describes the terms for advisory committees to provide advice to government, provides little guidance on what to do about such secondary interests. Here is how one government official described in congressional testimony the provisions of FACA with respect to conflicts of interest:

“The Act does not include provisions covering individual committee member conflicts of interest. The applicability of conflict of interest laws and various ethical requirements for members of advisory committees who serve as Special Government Employees (SGEs), are covered by other laws and regulations issued by the U.S. Office of Government Ethics. The Act, however, does include two important provisions designed to promote the objectivity of advisory committee deliberations. First, sections 5(b)(2) and (c) require that “the membership of the advisory committee be fairly balanced in terms of the points of view represented and the functions to be performed by the committee.” Second, sections 5(b)(3) and (c) require “provisions to assure that the advice and recommendations will not be inappropriately influenced by the appointing authority or by any special interest, but will instead be the result of the advisory committee’s independent judgment.” Thus, while the Act stresses the importance of assuring an advisory committee’s independent judgment, it also requires that the composition of advisory committees reflect the expertise and interests that are necessary to accomplish the committee’s mission. The Act does not define those factors that should be considered in achieving “balance.”"

[Note: based on this testimony, it would seem that the CSPI is simply wrong when it asserted that the composition of the FDA advisory panel violated the FACA. For background see this overview by Deborah Stein.]

The existence of possible financial conflicts of interest raises some difficult questions, such as:

At what level does a secondary influence become problematic? For a doctor making $250,000 per year, is $5,000 significant? $1,000?

Is a speaking fee (for a lecture) to be treated the same as consulting fees (for work done)?

How should industry-sponsored research funding be handled? It may be the case that the people with the most expertise on the effects of particular drugs are those who have overseen studies sponsored by the industries seeking approval of the drugs.

How should government-sponsored research be handled? Is government research properly considered a secondary interest?

And how far should we go with considerations of finances? Oklahoma Republican Senator James M. Inhofe has raised a few eyebrows by asking a group that has testified before congress on air quality issues to release its financial statements for the past few years. The approach taken by Senator Inhofe does seem pretty heavy handed, but substantively is it any more improper to want to see financial support for an NGO offering government advice than to want to see the same for an FDA advisory committee member?

And what about non-financial secondary interests, such as political, religious and other factors. Are these important? Presumably they are. (E.g., religion would seem to matter on advice on teaching of evolution and there have been many instances in recent years of complaints about the political views of members of federal advisory committees.)

Questions such as these (and there are more) suggest that once one moves beyond the instinctive reflex of suggesting that conflicts of interest should be settled on a case-by-case basis in line with one’s own values, it becomes more difficult to identify general policies and procedures to deal with values, interests and the — for lack of a better term – the quintessential humanness of participants in the political process proffering policy advice. This is a subject worth the attention of the science policy community.

But one point does seem exceedingly clear. Early disclosure of interests and values would seem to be a good thing. And in this regard the FDA is moving in the right direction, but the events of the past week show that it still has a way to go.