When is a point of view a conflict of interest?

A brief history of FDA recusals

The FDA has been long under fire for excluding certain advisory committee members from participating or voting in hearings on new drugs or products because of what it claims are “intellectual conflicts of interest.”

On 20 February 2009, Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, acknowledged that a “mistake was made” during a highly publicized incident in which an expert was recused for an alleged “intellectual conflict.” Eli Lilly, manufacturer of prasugrel, had called the FDA four days before an advisory panel was to review the drug. The company suggested that committee member Sanjay Kaul had an “intellectual bias” and objected to his presence on the panel.4 5 6 Kaul, a cardiologist, had independently studied the drug and found important safety problems. Two days before the hearing, the FDA “disinvited” Kaul because of an alleged intellectual conflict. The advisory committee approved prasugrel.⁴

Public Citizen, a watchdog organization based in Washington, DC, protested, saying that “the last-minute removal of Dr Sanjay Kaul, a regular voting member of the cardiovascular and renal drugs advisory committee with substantial knowledge about prasugrel, significantly limited critical discussion of the safety of this drug.”4

When the “disinvitation” came to light, Woodcock defended the agency’s action at a news conference, telling journalists that the call from Eli Lilly had nothing to do with Kaul’s exclusion.4 5 6 She said a mistake was made when the agency screened him for financial conflicts but “did not focus on the fact that there might have been an intellectual bias.” She said, “As soon as we realized what had happened…we put in place procedures along every step of the way that [everyone] is aware of now…. So I can pretty confidently say that this is not going to happen again.”7

But disinvitations and exclusions of critics have happened repeatedly—both before and after the 2009 episode.

In November 2004, the FDA barred advisor Curt Furberg from serving on the panel considering the safety of cyclo-oxygenase-2 (COX 2) inhibitors. He had been quoted in the New York Times saying that a study by him and his colleagues “showed that Bextra [valdecoxib] is no different than Vioxx [rofecoxib], and Pfizer is trying to suppress that information.”8 Valdecoxib was eventually withdrawn from the market because of excess cardiovascular harms. Controversy erupted following news reports that panelists with financial conflicts (on the committee from which Furberg was barred) were more likely than other panelists to vote that rofecoxib was safe. Rofecoxib was also withdrawn after it was associated with around 60 000 excess deaths.8

In December 2008, the FDA cleared Menaflex, a synthetic knee device, after FDA’s medical officers rejected approval or clearance of the device three times.9 10 The manufacturer, ReGen, demanded a new hearing, and further insisted that FDA’s medical officers be barred from the new panel as “biased.” FDA responded by excluding its medical officers from the newly constituted panel and appointing to the panel Gerald E Bisbee Jr, who was ReGen’s president and chief executive at the time.9 11

In 2011, Sidney Wolfe, a physician researcher with Public Citizen’s health research group was originally excluded from acting as a consumer advocate on an FDA panel considering the combined oral contraceptive Yaz (drospirenone/ethinyl estradiol).12 The FDA later allowed him to participate but not vote because of an alleged “intellectual conflict”; Wolfe had previously reviewed safety data for the drug and found a disturbingly high rate of stroke and thromboembolism and recommended against its use.13 Although Wolfe was excluded from voting, the FDA allowed five reviewers to remain on the panel despite current or pending ties to the manufacturer. In a 15-to-11 vote, the committee decided the benefits of the drug exceeded its harms. Had panelists with financial conflicts been excluded, the vote would have been reversed.12

This year, Kim Witczak, the consumer representative on a panel set to consider removing a “black box” warning on varenicline was recused at the last minute because of an unrelated lawsuit she filed over a decade earlier against Pfizer, the manufacturer. Witczak notes that the disclosure form regarding conflicts of interest did not ask panelists whether they recommended or prescribed varenicline to patients. The panel voted to remove the black box warning.

The FDA told The BMJ that the new guidance on “appearance issues” will provide additional guidance to its 2008 requirements regarding financial conflicts, which will remain in effect. The 2008 guidelines, which the agency states are “more stringent” than earlier guidelines, suggest that members “generally” would be disqualified if they have financial conflicts of $50 000 or more; however, a waiver can allow their participation if the agency believes the need for the services of the member outweighs the financial conflict.1

Critics of FDA’s practice of excluding experts on the basis of intellectual conflicts say the recusals are “asymmetric” and hamper objective reviews. They ask how the agency can distinguish a scientifically derived viewpoint from an intellectual conflict and question whether such a distinction is necessary.

How attempts to adjudicate “impartiality” undermine scientific process

Shannon Brownlee, senior vice president of the Lown Institute, a think tank focused on appropriate use of healthcare resources, told The BMJ that the claim that someone “lacks impartiality” has been used to favor industry interests historically, thereby undermining the scientific process. She said, “The degree to which the FDA is willing to convene advisory panels that are biased in favor of industry is simply jaw-dropping. Just because a person has a strong point of view should not be grounds for exclusion.” Brownlee said the history of medicine is littered with people who today might seem to lack impartiality but whose observations, rooted in sound science, led them to buck received wisdom, ultimately resulting in a better outcome for the public. She cites the example of Ignaz Semmelweis, who insisted that doctors were causing childbed fever because they didn’t wash their hands after autopsies.

Each of these instances of alleged intellectual conflict led to a decision by the FDA that favored the interests of industry. Furthermore, most FDA panels include people with financial ties to industry—often with a majority influence.14 15 16

The BMJ asked the FDA to give an example of an expert being barred from participating on a panel because he or she supported a drug or device. The FDA responded that the agency “reviews all reported conflicts of interests based on appropriate laws and regulations” and that “federal law” prohibits them from disclosing the names of people recused for intellectual conflicts because it is “confidential information.” When asked whether any such instance has ever occurred (without naming names) the FDA did not respond.

Howard Brody, professor of family practice and philosophy in the Center for Ethics and Humanities in the Life Sciences at Michigan State University, says that attempts to eliminate intellectual conflicts of interest “amounts to excluding anyone who has previously thought carefully about an issue, which seems to be overkill on a scientific matter.”17

Roy Poses, president of the Foundation for Integrity and Responsibility in Medicine in Rhode Island, says he hasn’t seen an adequate definition of an intellectual conflict. He told The BMJ, “People accused of an intellectual conflict usually seem to be those who strongly disagree with their accusers.” He said the charge can be made to divert attention from financial conflicts of interest.18 19 20 21

Poses says that genuine scientific disagreement, or conflicts among experts should not be confused with conflicts of interest, financial or “intellectual.” He said disagreement and conflict “is the very way science moves forward,” and that experts with strong viewpoints may provide the most important insights. He told The BMJ, “We need open discussion and even open disagreement; as in court, you want a vigorous presentation of both sides. It makes no more sense to ban scientists who zealously advocate a point of view as lacking impartiality than to ban trial lawyers essentially for being their clients’ best advocates.”

Healthy debate

Thomas J Moore, senior scientist with the Institute for Safe Medication Practices in Horsham, Pennsylvania, told The BMJ that he was concerned that the advisory panel meeting on the varenicline black box warning was conducted in a manner that strongly favored industry and handicapped those with critical views. Moore, who is an expert on varenicline safety,22 said he had requested 15 minutes to discuss peer reviewed studies showing serious safety problems with varenicline; however, while the company was given two hours to present its case for removing the warning, he was allotted only three and a half minutes.

Furberg, emeritus professor of public health sciences at the Wake Forest University School of Medicine, told The BMJ: “It appears that the FDA simply wants its advisory panels as a rubber stamp.”

Wolfe fears that the FDA’s industry friendly posture is only going to get worse; he told The BMJ that the proposed 2017 budget for FDA’s Center for Drug Evaluation and Research is “$1.41bn, of which $917m or 66% is industry funded.” Under the center’s current leadership, he said, “industry seems to be getting its money’s worth.”

Michael Carome, director of Public Citizen’s Health Research Group, told The BMJ, that FDA’s use of intellectual conflicts to exclude advisors is “entirely asymmetric.” He said that as a member of the Pharmacy Compounding Advisory Committee, he has been allowed to participate on panels but has been barred from voting several times. Carome said that he is required by FDA to announce the conflict barring him from voting at the beginning of the meeting, but he said he always follows that statement with his own statement about Public Citizen’s strong opposition to the FDA determination that he has an intellectual conflict.

The FDA was given an opportunity to review each of the criticisms and events as described in this article and a spokesperson for the agency told The BMJ that it had “no additional comment.”

Protecting the body of science

Brownlee says the notion that “intellectual conflicts” are as important, or even more important than financial conflicts has become increasingly common but she says financial conflicts, which almost invariably support a pro-industry position, pose unique problems that demand attention.

She is also critical of FDA’s inclusion of financially conflicted experts under the pretense that industry independent experts can’t be found.23

Critics like Poses and Brownlee say that to protect the scientific process, it’s necessary to stop the highly subjective process of vetting the mental processes and “impartiality” of experts and instead ensure balanced constituencies on advisory and guideline panels that reflect all sides of the scientific debate.

The FDA has extended the comment period on its draft guidance on the “appearance” of conflicts until 26 Nov 2016 at 11:59 pm eastern time.20