Posted 12 November 2012
By Alexander Gaffney, RF News Editor
The consumer advocacy group Project on Government Oversight (POGO) is re-engaging the US Food and Drug Administration (FDA) on whether a panel of experts convened by the agency to review the safety of a class of oral contraceptives was sufficiently independent of conflicts of interest.
The entire incident is the result of a January 2012 investigation by the Wall Street Journal into an FDA advisory committee charged with reviewing birth control products containing drospirenone. Drugs under review by the panel included Yaz, Yasmin, Beyaz and Safyral-all manufactured by Bayer AG. The Journal's investigation found at least three of the committee's 26 members had direct ties to Bayer, having served as consultants, speakers or researchers to the company.
Those conflicts might well have swayed the committee's decision to affirm the products' positive risk-benefit profile, argued critics, as the committee only voted 15-11 in favor of that decision. A fourth advisory committee member was later found to have potential conflicts as well.
POGO Asks FDA to Act
Shortly after the Journal's investigation was made public, POGO went public with its criticism of FDA over its failure to disclose the conflicts, and asked for a full investigation of the conflicts of interest.
In addition, POGO asked FDA to make public all conflict information, which is currently treated as confidential and not subject to public review. "These cases may demonstrate the failure of the FDA to adequately determine potential conflicts of interest and questionable impartiality," POGO charged. "At a minimum, the financial disclosure forms of all members should be thoroughly reviewed by the FDA before each meeting to determine whether questions might arise about an advisory committee member's impartiality with regard to the subject(s) of the meeting. If such questions arise, the FDA must clearly document why that member is authorized or not to participate in the meeting and the documentation should be made publicly available online before the meeting occurs."
The controversy eventually led to Jill Hartzler, FDA's acting associate commissioner for special medical programs-in charge of overseeing FDA's advisory committees-to issue a public response to POGO and others.
"I want to specifically address recent reports related to the December 8, 2011 advisory committee meeting that discussed drospirenone-containing oral contraceptives," wrote Hartzler. "Based on our review of the members' reported financial interests, we did not identify any financial interests that would have precluded their participation." She noted that FDA only granted approximately 1% of all waivers requested by advisory committee participants in 2011-down from 15% in 2007-and that the agency needed to balance transparency with the ability to access the most knowledgeable experts.
"Given our interest in this area, we have been working closely with outside stakeholders and the Institute of Medicine (IOM) to explore whether a common financial disclosure form or website could be created, making it easier for individuals to report their financial interests," concluded Hartzler.
A Dormant Issue Returns
Since then, the issue has mostly been dormant, save for an April 2012 safety warning for drospirenone explaining that the product class may be associated with a higher risk for blood clots relative to other progesterone-based pills-something originally highlighted by some of those who dissented against the advisory committee's decision to affirm drospirenone's risk-benefit profile. In a statement at the time, FDA said some of the products would require revised labeling, but noted it had been unable to conclusively link the drugs with the increased blood clot risk.
Then, in September 2012, FDA issued a reply to POGO by way of a letter from Hartzler, who expressed her confidence in the advisory committee's December 2011 decision. "You request that FDA convene a new advisory committee to reevaluate the safety of dropirenone contraceptive products," wrote Hartzler. "This is not necessary."
She explained that while the advisory committee's advice was and remains important, the ultimate decision of whether or not to approve a product falls on FDA itself. The agency, she continued, had concluded that the risk-benefit profile of the drug remained positive, though it had also recommended a revised labeling scheme. "The agency will continue to closely monitor the safety of these drugs and take appropriate regulatory action as necessary," Hartzler added.
Hartzler's response also hit back at POGO's allegations that the agency had been too lax in its conflict of interest disclosures and may have broken federal law, saying the agency had acted properly and logically in both cases. "FDA's disclosures regarding financial interests and waivers are broader than those of many other Federal agencies," she noted.
Pogo Hits Back at FDA Response
In a 9 November 2012 letter, however, POGO hit back at FDA's response, arguing that it ignored much of their original letters' substance. "You discuss waivers at some length and note that the FDA makes publicly available certain financial information about committee members to whom it grants waivers," POGO wrote. "However, this point is one that we barely discussed and certainly did not contest in our January 11 letter to Dr. Hamburg. Instead, we argued that the public release of information about financial arrangements should apply to all advisory committee members, not just those with waivers."
POGO also testily took issue with FDA's assertion that no participating members had identified any "disqualifying interests."
"It's obvious that an advisory committee member could not have participated if the FDA had found, before the meeting, any disqualifying financial interests that would have precluded that member's participation," quipped POGO. The organization also wrote that it was concerned that FDA did not appear to investigate whether self-reported conflicts were accurate or complete, and remained perturbed that FDA officials "continue to believe that there were no financial interests that were disqualifying."
"Even if the financial interests of advisory committee members are not disqualifying (in the opinion of FDA officials), there is a strong case for disclosing those interests publicly in order to help reassure the public about the objectivity of committee members," POGO argued.
A Need for Voluntary Action?
The group also disagreed with FDA's contention that its guidance document on information disclosure and federal law prevented it from taking other actions.
POGO noted, for instance, that's FDA's March 2007 draft guidance on financial interest disclosures says that the agency "intend[s] to implement a policy of generally limiting participation when a member has a financial interest within the preceding twelve months that would be a disqualifying financial interest if it were currently held, even though full participation would be permitted under 18 U.S.C. 208."
The final version of that guidance document, dated August 2008, contained no such language, though the existence of it in the draft version would appear to validate POGO's concerns, it said.
Finally, POGO said FDA appeared to be hiding behind the letter of the law instead of seeking voluntary methods of compliance to meet its spirit.
"There may well be legal barriers to the public release of the form FDA 3410," noted POGO. But officials should always be encouraged to disclose such information voluntarily, it continued. Such encouragement would not be against the Ethics in Government Act or the federal Privacy Act.