Generally, prescription drugs are drugs that are safe for use only under the  supervision of a health care practitioner. FDA considers the advisory committees’ recommendations in its  deliberations. Four aspects of FDA’s review process were unusual: officials  who would normally have been responsible for signing an action letter  disagreed with the decision and did not sign the not-approvable letter for  Plan B; high-level management was more involved than for other OTC  switch applications; conflicting accounts exist of whether the decision to  not approve the application was made before the reviews were completed;  and the rationale for the not-approvable decision was novel and did not  follow FDA’s traditional practices. The Acting Director of CDER Rejected the Recommendations of a Joint Advisory Committee and FDA’s Review Officials

On May 6, 2004, the Acting Director of CDER rejected the  recommendations of a joint advisory committee and FDA review officials  by signing the not-approvable letter for the Plan B OTC switch application. First, the FDA  officials who would normally sign an action letter for an OTC switch  application disagreed with the decision and did not sign the Plan B not- approvable letter; as a result, the Acting Director of CDER did so. High-Level FDA Management Was More Involved Than Usual in the Review Process for the Plan B Prescription-to-OTC Switch Application

High-level FDA management became more involved than usual in the  review process for the Plan B OTC switch application. FDA Officials Gave Conflicting Accounts of When the Decision to Not Approve Plan B Was Made

FDA officials gave conflicting accounts of when the not-approvable  decision for the Plan B OTC switch application was made. 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. FDA Review Officials Disagreed with the Acting Director’s  Rationale for the Not-Approvable Decision  FDA review staff, the Directors of the Offices of Drug Evaluation III and V,  and the Director of the Office of New Drugs disagreed with the Acting  Director of CDER’s rationale for not approving the Plan B OTC switch  application. Plan B Decision Was Not Typical of Other Proposed Prescription-to-OTC Switch Decisions

The decision to not approve the Plan B OTC switch application was not  typical of the other 67 proposed prescription-to-OTC switch decisions  made from 1994 through 2004. Plan B Was the Only Prescription-to-OTC Switch Decision from 1994 through 2004 in Which the Action Letter Was Signed by the Director of CDER

From 1994 through 2004, 94 action letters were issued during the review  processes for the 68 prescription-to-OTC switch applications, and only 1  action letter—the not-approvable letter for Plan B—was signed by the  Director, in this case the Acting Director, of CDER. Plan B was the only contraceptive  or emergency contraceptive proposed for an OTC switch during this  period. There Are No Age- Related Restrictions for Safety Reasons for Any FDA-Approved Contraceptives

According to the Deputy Director of the Office of New Drugs, there are no  age-related marketing restrictions for any FDA-approved contraceptives,  and FDA has not required any pediatric studies. Also, it was unusual  for the Acting Director of CDER to inform FDA’s review staff that it had  been determined that the Plan B decision would be made by high-level  management. Third, FDA disagreed with our finding that the Acting Director’s rationale  for denying the application was novel and did not follow FDA’s traditional  practices. In his May 6, 2004,  memorandum, the Acting Director stated that “Because of these large  developmental differences, I believe that it is very difficult to extrapolate  data on behavior from older to younger ages.” The Acting Director  acknowledged that considering adolescents’ cognitive development as a  rationale for a not-approvable decision was unprecedented for an OTC  switch application. Appendix I: Scope and Methodology

To examine how the decision was made to not approve the switch of Plan  B from prescription to over-the-counter (OTC), we reviewed documents,  such as the Plan B OTC switch action package related to the May 6, 2004,  decision from the Food and Drug Administration (FDA).
Why GAO Did This Study

In April 2003, Women's Capital Corporation submitted an application to the Food and Drug Administration (FDA) requesting the marketing status of its emergency contraceptive pill(ECP), Plan B, be switched from prescription to over-the-counter (OTC). ECPs can be used to prevent an unintended pregnancy when contraception fails or after unprotected intercourse, including cases of sexual assault. In May 2004, the Acting Director for the Center for Drug Evaluation and Research (CDER) issued a "not-approvable" letter for the switch application, citing safety concerns about the use of Plan B in women under 16 years of age without the supervision of a health care practitioner. Because the not-approvable decision for the Plan B OTC switch application was contrary to the recommendations of FDA's joint advisory committee and FDA review staff, questions were raised about FDA's process for arriving at this decision. GAO was asked to examine (1) how the decision was made to not approve the switch of Plan B from prescription to OTC, (2) how the Plan B decision compares to the decisions for other proposed prescription-to-OTC switches from 1994 through 2004, and (3) whether there are age-related marketing restrictions for prescription Plan B and other prescription and OTC contraceptives. To conduct this review, GAO examined FDA's actions prior to the May 6, 2004, not-approvable letter for the initial application.

What GAO Found

On May 6, 2004, the Acting Director of CDER rejected the recommendations of FDA's joint advisory committee and FDA review officials by signing the not-approvable letter for the Plan B switch application. 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. The Plan B decision was not typical of the other 67 proposed prescription-to-OTC switch decisions made by FDA from 1994 through 2004. The Plan B OTC switch application was the only one during this period that was not approved after the advisory committees recommended approval. The Plan B action letter was the only one signed by someone other than the officials who would normally sign the letter. Further, there are no age-related marketing restrictions for any prescription or OTC contraceptives that FDA has approved, and FDA has not required pediatric studies for them. FDA identified no issues that would require age-related restrictions in the review of the original prescription Plan B new drug application. In its comments on a draft of this report, FDA disagreed with GAO's finding that high-level management was more involved with the Plan B OTC switch application than usual, with GAO's discussion about when the not-approvable decision was made, and with GAO's finding that the Acting Director of CDER's rationale for denying the application was novel. However, GAO found that high-level management's involvement for the Plan B decision was unusual for an OTC switch application and FDA officials gave GAO conflicting accounts about when they believed the decision was made. The Acting Director acknowledged to GAO that considering adolescents' cognitive development as a rationale for a not-approvable decision was unprecedented for an OTC application, and other FDA officials told GAO that the rationale differed from FDA's traditional practices.