FDA medical officers have been pressured to withhold opinions or data from advisory committee presentations at least 14 times in the last three years, a report by Public Citizen's Health Research Group maintains.

In a survey of 172 Center for Drug Evaluation and Research medical officers, eight of 53 responders said they were instructed not to present data or opinions that could have influenced an FDA advisory committee against recommending approval, HRG reported.

"The company is always going to say the drug is safe and effective whether or not they believe it or if they have the data," HRG Director Sidney Wolfe, MD, declared during a Dec. 2 press conference in Washington, D.C. "Depending on how careful and thorough the medical officer's presentation is, it may make a difference as to what the advisory committee recommends."

"If medical officers are saying 'we were told not to present information that might have jeopardized approval,' this distorts the whole public advisory committee process," he maintained.

During the press conference, he also suggested FDA should make it easier for outsiders to engage in informed discussion of the issues before committees. "We believe that participation by anyone, and that includes ourselves or drug companies other than the one that is affected, would be better if more information was available," Wolfe said.

For example, HRG requested "several weeks ago" that it be given a copy of the advisory committee briefing book for the review of Searle/Pfizer's Celebrex. "We did not get it," he said. Wolfe made a presentation during the Celebrex review arguing against treating the product differently than approved NSAIDs (see preceding story).

Wolfe is an ad hoc advisor to the Center for Biologics Evaluation and Research and is a former member of the Transmissible Spongiform Encephalopathies Advisory Committee.

HRG solicited comments from 172 CDER medical officers through a seven-page survey mailed in September and October and received 53 responses. The group identified a total of 216 CDER medical officers, but eliminated 41 from participation in the survey who are directors or deputy directors of either an office or division, and officers from the Office of Scientific Investigation who do not review NDAs.

The FDAers were asked to comment on pressure to approve drugs more rapidly, whether the accelerated approval program is being used inappropriately, approvals based on commitments for post-marketing studies, whether standard for safety and efficacy have been lowered over the past three years and whether drugs they had reviewed had been either approved or disapproved contrary to their opinion.

According to HRG, 19 medical officers identified a total of 27 drugs approved in the past three years that they felt should not have been approved. Twelve responders identified 25 drugs that they felt were approved too quickly. As a matter of confidentiality, reviewers were asked not to specify drug names so that the responses could not be linked to a reviewer.

Some of the responses were linked to a specific division. Of the 27 highlighted drugs, 15 could be attached to a specific division. Of those, seven came from the Endocrine & Metabolic Drug Products Division.

One reviewer in the E&M division has already gone public with his concerns. Medical officer Robert Misbin, MD, published a letter in The Washington Post in August claiming that pressure for productivity under the Prescription Drug User Fee Act was hurting FDA's ethical standards ("The Pink Sheet" Aug. 31, p. 9).

Misbin had previously expressed concern over pivotal trial data presented to the Endocrine & Metabolic Drugs Advisory Committee for Lilly's Humalog, Novo Nordisk's Prandin and Parke-Davis' Rezulin. HRG also opposed approval of Rezulin (troglitazone), and has petitioned to have the anti-diabetic drug removed from the market.

Misbin's concern over the Rezulin approval stemmed largely from the use of placebo-controlled trials. In testimony before the House Government Reform & Oversight Committee April 22, HRG suggested that active controlled trials be required by law ("The Pink Sheet" April 27, p. 8).

HRG included a section on placebo-controlled trials in the survey, but the results were not analyzed. According to the group, after reading several of the responses, the survey authors felt that the question, "How do you feel about the use of placebos in clinical trials designed to lead to FDA approval which are for serious conditions for which effective treatment exists?" was not phrased correctly.

Misbin's letter to The Washington Post also raised issues of morale within FDA. The reviewer had not discussed the letter with anyone at the agency prior to its publication, and the letter provoked an angry exchange between Misbin and a supervisor.

According to HRG, the survey results show that the morale issue is not limited to one or two reviewers, but is widespread across the agency.

"In the 27 years since I started this group with [Ralph] Nader, things are as bad as they have ever been at FDA in terms of the morale of employees as evidenced by these surveys, and in terms of the trust of the American public," Wolfe declared. "The study shows that many medical officers are being pressured to lower the standards for drug approval and to approve drugs that they believe should not be approved."

Wolfe and Nader participated in the 1974-75 Kennedy hearings which included testimony from FDA reviewers appearing under subpoena about pressure to approve more drugs.

While many of the themes of the report are a reprise of HRG's position 24 years ago, the political environment has changed. With the Republicans in control of Congress, HRG is unlikely to be able to generate Congressional interest in the topic.

Indeed, HRG is now targeting Congress as a source of "inappropriate pressure" on medical officers.

"Inappropriate pressure from Congress, the drug companies and senior FDA employees creates an atmosphere in which the likelihood of drug approval is maximized," the report asserts.

"The pressure takes the form of inappropriate phone calls, pressure to withhold data or personal opinions unfavorable to a drug from FDA advisory committees and pressure from supervisors to change their opinion in the direction of approving the drug."

According to the report, nine medical officers reported a total of 23 inappropriate phone calls in the past three years. Thirteen officers reported being asked to change their opinion on a drug to match that of a supervisor.

None of the responders indicated that inappropriate phone calls were received directly from members of congress or their staff, but comments cited Congressional pressure during the review of Cephalon's Myotrophin and rumors of one reviewer who resigned due to pressure from Capitol Hill.

One reviewer cited a Wyeth-Ayerst application as an example of implicit political pressure: "my office director told me that he was going to overrule me because the sponsor (Wyeth-Ayerst) would just go over our heads to Capitol Hill."

The office director "felt it was best to approve the drug for an indication not studied and have the sponsors do a Phase IV post-marketing trial in support of the indication," the reviewer maintained. "I reminded him that this sponsor had failed to honor other Phase IVs. He went ahead and approved the drug." Wyeth has withdrawn two recently approved products, the anti-obesity agent Redux and the analgesic Duract.

Many of the comments submitted to HRG reflected a more balanced discussion between reviewers and directors: "My interactions with supervisors have been marked by disagreements about different issues that we discuss and even argue about but I have not felt that they were pressuring me one way or another," one medical officer wrote.

"Half the time I was right, half the time I was wrong. The free discussion of the issues led us most of the time to make the right decisions or decisions that if wrong, didn't have a major public health impact."

HRG is preparing another report specifically focusing on the approval of Zeneca's Nolvadex (tamoxifen) for reduction in the risk of breast cancer, Wolfe announced.

HRG feels the tamoxifen approval was "based on very questionable data, and itself reflects some of the downsides of deadlines where the agency is faced with a deadline for making a decision but the sponsor hands in data very late," he said.

While only nine of the 53 responders identified drugs that they felt were approved inappropriately, HRG believes that there are more medical officers who feel the same way, but who did not respond. "For these questions, the limited number of responses more likely leads to an undercount of an already serious number of events," the report asserts.

FDA Reviewers Pressured To Omit Data From Cmte. Meetings, HRG Asserts

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