While FDA followed its general procedures for considering the application, four aspects of FDA’s review process were unusual. First, the directors of the offices that reviewed the application, who would normally have been responsible for signing the Plan B action letter, disagreed with the decision and did not sign the not-approvable letter for Plan B. The Director of the Office of New Drugs also disagreed and did not sign the letter. Second, FDA’s high-level management was more involved in the review of Plan B than in those of other OTC switch applications. Third, there are conflicting accounts of whether the decision to not approve the application was made before the reviews were completed. Fourth, the rationale for the Acting Director’s decision was novel and did not follow FDA’s traditional practices. The Acting Director stated that he was concerned about the potential behavioral implications for younger adolescents of marketing Plan B OTC because of their level of cognitive development and that it was invalid to extrapolate data from older to younger adolescents. FDA review officials noted that the agency has not considered behavioral implications due to differences in cognitive development in prior OTC switch decisions and that the agency previously has considered it scientifically appropriate to extrapolate data from older to younger adolescents.

Among their findings, GAO found that the Commissioner and Acting Director of CDER, Steven Galson, disputed the scientific findings of the drugmaker even after the company conducted additional studies at the request of the agency:

According to interviews with officials from the Office of New Drugs and review staff within the Offices of Drug Evaluation III and V, and as documented in their respective reviews of the Plan B application, they said these data provided sufficient evidence that there was neither an increase in risky behaviors nor any difference in appropriate use between younger adolescents and older populations. According to FDA’s minutes of this meeting, the Commissioner expressed multiple points, including the potential for changes in future contraceptive behaviors after adolescents took Plan B and that counseling by a learned intermediary might be beneficial, particularly for adolescents. He also noted that he was not convinced that the additional studies used as evidence had "enough power" to determine if behavioral differences existed between adults and adolescents.

GAO also found that though the Galson claimed the decision to not approve Plan B for over-the-counter use was made right before he signed the level of non-approval, Office of New Drug staff claim they were told the application would not be approved months before they had even completed their review of the application:

FDA officials gave conflicting accounts of when the not-approvable decision for the Plan B OTC switch application was made. FDA officials, including the Director and Deputy Director of the Office of New Drugs and the Directors of the Offices of Drug Evaluation III and V, told us that they were told by high-level management that the Plan B OTC switch application would be denied months before staff had completed their reviews of the application. The Director and Deputy Director of the Office of New Drugs told us that they were told by the Acting Deputy Commissioner for Operations and the Acting Director of CDER, after the Plan B public meeting in December 2003, that the decision on the Plan B application would be not-approvable. They informed us that they were also told that the direction for this decision came from the Office of the Commissioner. The Acting Deputy Commissioner for Operations and the Acting Director of CDER denied that they had said that the application would not be approved. In addition, although minutes of the January 15, 2004, meeting stated that the Acting Director told review staff that a not-approvable decision was "recommended," review staff documented that they were told at this meeting that the decision would be not-approvable. Both office reviews were not completed until April 2004.

Galson's rationale for rejecting the application was also highly unusual:

The rationale for the Acting Director of CDER’s decision was novel and did not follow FDA’s traditional practices. The Acting Director was concerned about the potential impact that the OTC marketing of Plan B would have on the propensity for younger adolescents to engage in unsafe sexual behaviors because of their lack of cognitive maturity. The Acting Director further concluded that because these differences in cognitive development made it inappropriate to extrapolate data from older to younger adolescents in this case, there was insufficient data on the use of Plan B among younger adolescents. FDA review officials disagreed with the Acting Director’s rationale and noted that the agency had not considered behavioral implications resulting from differences in cognitive development in prior OTC switch decisions

GAO report seems to prove incontrovertibly that the Plan B was not based on sound science and was likely politically motivated. The decision has been under scrutiny ever since it was made in May 2004. It remains to be seen whether this new evidence will force the agency to re-review the OTC application. For more on Plan B see FDA Ignores Experts, Reject Plan B for Over-the-Counter Use (5/17/2004), Details Emerge in Data Rejected in Morning-After Pill Decision (6/28/2004), Plan B Decision Delayed by FDA (8/29/2005).

Posted by Genevieve Smith, 12:10:01 PM

Thursday, November 10, 2005

Wednesday, November 02, 2005