Sunday, February 27, 2005

FDA Advisory Panels: Elephants in the Room


The New York Times recently reported that "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..." (10 Voters on Panel Backing Pain Pills Had Industry Ties, NYT, 2/25/2005).

If these 10 panelists were taken out of the voting, which would be expected if FDA policies on conflict of interest were adhered to (they weren't -- more on that below), then the committee would have voted to take both Bextra and Vioxx off the market (12 to 8 against Bextra and 14 to 8 against Vioxx).

Ninety-three percent (93%) of the time these 10 panelists voted in favor of the drugs, whereas the 22 other panelists favored the drugs in their votes only 56% of the time.
"Of the 30 votes cast by the 10 panel members on whether Celebrex, Bextra and Vioxx should continue to be marketed, 28 favored the drugs. Among the 66 votes cast by the remaining 22 members of the panel, just 37 favored the drugs." -- NYT
It should be noted that the voting preferences of these 10 panelists did not influence the decision to keep Celebrex, marketed by Pfizer, on the market. That is, the vote would have been in favor of Celebrex even if these panelists were excluded from voting.

Financial ties to industry of FDA advisory committee members is not a new issue. A USA TODAY analysis of financial conflicts at 159 FDA advisory committee meetings from Jan. 1, 1998, through June 30, 2000 found:
  • At 92% of the meetings, at least one member had a financial conflict of interest.

  • At 55% of meetings, half or more of the FDA advisers had conflicts of interest.

  • Conflicts were most frequent at the 57 meetings when broader issues were discussed: 92% of members had conflicts.

  • At the 102 meetings dealing with the fate of a specific drug, 33% of the experts had a financial conflict.

Elephants in the Room
If you have ever attended one of these Advisory Committee meetings, you would find that the majority of attendees are representatives of drug companies with perhaps a smattering of public interest groups and a large contingent of press people.

So you can expect that every vote by each panelist is noted and reported back to drug companies with an interest in the matter. This has got to put a lot of pressure on the panel members, many of whom have accepted money from the industry in the past or perhaps would like to accept money from them in the future!

This goes with the territory of open, public meetings. It certainly would not be in the public interest to have secret ballots. So there's not much we can do about that.

But, can't the FDA find panelists without any ties to the pharmaceutical industry? Apparently not. A Washington lawyer "who was until last year the agency's general counsel, said that finding knowledgeable experts without financial conflicts was difficult." (NYT)

The reason is that the industry creates these "knowledgeable experts," which has as much to say about physician education in this country as it does about pharma industry influence over physicians. In short, physicians absolutely depend upon the industry to learn about new products and even the conditions they treat. At least a couple of the "gang of 10" advisors stated as much:
Dr. Steven Abramson, a rheumatologist at New York University School of Medicine who was on the panel, has consulted for Pfizer and Novartis. "The F.D.A. is looking for people who understand the science behind these medicines," and such an understanding often results from working with drug makers, he said.

Dr. John Farrar, a neurologist at the University of Pennsylvania who has received research support from Pfizer and is a panel member, agreed. "I think F.D.A. would have a hard time finding people who are good at what they do who never spoke to a pharmaceutical company," he said.
Pharma companies "educate" physicians directly and indirectly in many ways:
  • Sales Representatives -- these "detail" men (and women) are supposed to provide physicians with much needed details about products, but more often than not sales reps are merely there for the hard sell and to drop off samples (see, for example,"A Crisis in Professional Detailing")

  • Support of Continuing Medical Education -- pharma companies often support accredited continuing medical education for physicians, which means that physicians need not spend their own money to obtain CME credits that are required to maintain their licenses to practice medicine. There is some debate on how unbiased industry-supported CME is and there have been abuses (e.g., paying for junkets for physicians to attend "educational" activities at resorts along with their spouses). See, for example,"Provider/Pharmaceutical Partnerships - Are They Possible Without Conflict of Interest?" and "When Is Commercial Support Appropriate for CME Activities?"

  • Key Opinion Leaders -- Key Opinion Leaders are physicians who influence their peers' medical practice, including but not limited to prescribing behavior. Pharmaceutical companies generally engage key opinion leaders early in the drug development process to provide advocacy activity and key marketing feedback. See "Developing Win-Win Key Opinion Leader Relationships" for insights on how pharma companies leverage key opinion leaders. It is probably from this pool of physicians that most FDA advisory boards solicit members.
Anyway, physicians are beholding to the industry for much of their education, a point that was well-documented by Marcia Angell in her book "The Truth About Drug Companies. How They Deceive Us and What to Do About It" (see "The Truth About the Drug Companies: What To Do About It" for a review). As long as that is the case, it will be impossible to find a group of experts without some past ties to the pharmaceutical industry to serve on advisory committees.

Is this necessarily bad? I mean, can advisory committees still make credible decisions given these conflicts?

The FDA, in 2003, did a study of "public attitudes and opinions" regarding conflicts of interest and FDA advisory committee meetings (see "Conflicts of Interest and FDA Advisory Committee Meetings"). They surveyed a sampling of people who attended FDA advisory committee meetings in the spring of 2003 and advisory committee members who participated in those meetings. The study's intent was to examine the perceived fairness and credibility of FDA advisory committee meetings related to FDA's management of real or potential conflicts of interest among advisory committee members.

An overwhelming majority of respondents (67%) disagreed with the statement "When committee members have conflicts of interest, they will always decide in favor of their interest." Maybe they don't "always" do so, but the COX-2 gang of 10 did so 93% of the time (see above). Eighty-seven percent of respondents disagreed with the statement "You cannot trust an advisory committee's decision if any of its members have conflicts of interest." What about if 10 out of 32 have conflicts?

This study was really a survey of the "elephants" in the room -- i.e., representatives of pharma companies. 82% of respondents were "paid by an employer or organization to attend the meeting." Guess what organizations pay employees to attend such meetings?

FDA "Openness" Is At Issue Here
The law requires that FDA advisory committee members disclose financial interests in the subject of the meeting. Financial interest is defined in FDA regulations "as the potential for gain or loss as a result of government action on a particular matter."

But the FDA chose not to reveal the financial ties to the pharma industry of the COX-2 committee members. As reported in the NYT:
Before each of three meetings of the advisory board last week, an agency secretary read a statement absolving panel members of conflicts of interest because the committee's agenda involved "issues of broad applicability and there are no products being approved."

The secretary also said, "The Food and Drug Administration acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussions before the committee, these potential conflicts are mitigated."
On February 15, HHS Secretary Leavitt said "The public has spoken and they want more oversight and openness" (see "Reforms Will Improve Oversight and Openness at FDA" FDA Press Release)
. Unfortunately, during the COX-2 meetings the FDA chose not to take this path, chose to ignore the public and was far from "open" and transparent.

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