Within FDA, CDER oversees the switch of drugs from prescription to OTC. Generally, prescription drugs are drugs that are safe for use only under the supervision of a health care practitioner. Approved prescription drugs that no longer require such supervision may be marketed OTC. In applying this standard, FDA will authorize a prescription-to-OTC switch only after it is determined that the drug in question has met the following FDA criteria: (1) it has an acceptable safety profile based on prescription use and experience; (2) it has a low potential to be abused; (3) it has an appropriate safety and therapeutic index; (4) it has a positive benefit–risk assessment; and (5) it is needed for a condition or illness that is self- recognizable, self-limiting, and requires minimal intervention by a health care practitioner for treatment. FDA tries to determine if the OTC availability of a prescription drug will prevent or delay someone from seeking needed medical attention. One class of OTC drugs switched from prescription status, the nicotine products (such as Nicorette gum), has restricted access based on age— they are available OTC only to persons 18 years of age or older. Generally, drugs considered for a prescription-to-OTC switch involving the same indication, strength, dose, duration of use, dosage form, patient population, and route of administration as the prescription drug require fewer new studies regarding safety and efficacy because such studies have already been submitted as part of the original new drug application (NDA). FDA also requires sponsors to address concerns related to consumers’ ability to self-diagnose and self-treat the condition. Thus, sponsors generally submit additional studies, such as an actual use study, which examines consumers’ ability to self-diagnose, and a label comprehension study, which examines how consumers interpret the drug’s proposed label. In addition to these actual use and label comprehension studies, FDA requires sponsors to submit updated safety information on adverse events reported for the prescription form of the drug. Figure 1 shows the flow of an OTC switch application of a first-in-a-class drug through the decision process within CDER. To begin the process for a prescription-to-OTC switch, the sponsor submits an efficacy supplement to an approved NDA. This sNDA is sent to the FDA Office of Drug Evaluation that oversaw the original NDA and usually is the office with relevant expertise. This Office of Drug Evaluation is generally responsible for reviews of the primary effectiveness data and safety results. After an application has been determined to be complete, a reviewer from this office assesses the design, general effectiveness, and safety of the product. If the application is determined to be incomplete, this office will issue a “refusal to file” letter to the sponsor, detailing the omissions or inadequacies that led to this decision. When an Office of Drug Evaluation with relevant expertise receives a fileable sNDA for an OTC drug switch, it notifies the Office of Drug Evaluation V and its Division of Over-the-Counter Drug Products, which has relevant expertise in OTC drug products. Generally, the Office of Drug Evaluation V oversees the review of (1) the suitability of the product for OTC use and (2) safety experiences during the marketing of the prescription product. A reviewer from this office assesses studies related to OTC marketing, including the actual use and label comprehension studies. CDER’s Office of Drug Safety conducts additional reviews of the label comprehension studies, reviews postmarketing safety data of the prescription drug, and provides reports to reviewing staff in other offices upon request. FDA can convene advisory committee meetings for prescription-to-OTC switch applications. Advisory committees include outside experts, such as medical professionals and researchers, who provide FDA with independent advice and recommendations. Members review data submitted by the sponsor or presented by FDA review staff, address questions, and vote, either supporting or opposing a switch from prescription-to-OTC status. Advisory committees conduct open meetings and offer members of the public the opportunity to express their views. FDA considers the advisory committees’ recommendations in its deliberations. However, the agency decides whether to adopt these recommendations on a case-by-case basis and is not required to follow the committees’ recommendations. FDA review staff from the appropriate offices of drug evaluation review the data presented, interpret the findings, and make recommendations to the respective office directors on whether the proposed OTC switch should be approved. Once these reviews are completed, they are sent to the directors of both the office of drug evaluation with relevant expertise and the Office of Drug Evaluation V. If both directors agree with each others’ review recommendation, the directors of the relevant offices of drug evaluation prepare an action package and an appropriate action letter for review, concurrence, and their final signatures. If the office directors do not concur on the decision, the application is reviewed by the Office of New Drugs. The Director of CDER is not directly involved in the approval of all drugs, but may overrule the decisions of subordinate officials. The authority to approve an OTC switch application ultimately rests with the Secretary of Health and Human Services. This approval authority is delegated to the Commissioner of FDA, then to other high-level management officials, and eventually to other FDA officials within lower levels of the agency. This delegated authority allows decisions to be made at lower levels within the agency but assumes that management agrees with these decisions. The FDA Commissioner and other officials within the Office of the Commissioner usually do not have a role in OTC switch decisions, but have the authority to overrule the decisions of other FDA officials. There are several types of contraceptive drugs and devices, including barrier methods, intrauterine devices, spermicides, and hormonal methods. Several types of hormonal methods of contraception are available, including birth control pills, injectable hormones, hormonal implants, and ECPs. FDA has approved two ECPs, Preven and Plan B, for use by prescription, and Plan B is the first drug in its class to go through the review process by FDA to determine whether it should be allowed to be sold OTC. ECPs are high dose birth control pills and have been available by prescription since 1998, when FDA approved Preven, a dedicated combined ECP containing the hormones estrogen and progestin. Prior to 1998, many physicians instructed patients to take higher doses of oral contraceptive pills for emergency contraception, an “off-label” use. Plan B is a dedicated ECP containing only levonorgestrel, a type of progestin. The Plan B regimen is a two-pill dose of levonorgestrel (0.75 mg each) that is most effective when the first pill is taken as soon as possible, but no later than 72 hours, after contraceptive failure or unprotected intercourse. The second pill is taken 12 hours after the first pill. Research suggests that a levonorgestrel-only hormone regimen, such as Plan B, can reduce the risk of pregnancy by 89 percent if taken within the 72-hour window. The time constraint for maximum effectiveness associated with Plan B has led many in the medical community and some reproductive health advocates to support switching Plan B to OTC, making it more readily available when needed. In addition, levonorgestrel-only regimens, such as Plan B, have fewer side effects than the combined ECP, reducing the incidence of two common side effects, nausea and vomiting, by 50 percent and 70 percent, respectively. Research has shown that levonorgestrel-only hormonal emergency contraception, such as Plan B, interferes with prefertilization events. It reduces the number of sperm cells in the uterine cavity, immobilizes sperm, and impedes further passage of sperm cells into the uterine cavity. In addition, levonorgestrel has the capacity to delay or prevent ovulation from occurring. ECPs have not been shown to cause a postfertilization event—a change in the uterus that could interfere with implantation of a fertilized egg. Some researchers argue that an interference with the implantation of a fertilized egg is unlikely to happen because progestins, whether natural or synthetic, help to sustain pregnancy. In addition, there is no evidence that one burst of levonorgestrel without estrogen can prevent implantation. However, researchers have concluded that the possibility of a postfertilization event cannot be ruled out, noting that it would be unethical and logistically difficult to conduct the necessary research. ECPs, including Plan B, do not interfere with an established pregnancy. On May 6, 2004, the Acting Director of CDER rejected the recommendations of a joint advisory committee and FDA review officials and signed the not-approvable letter for the Plan B OTC switch application. 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. 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. This action concluded a review process that began on April 16, 2003, when WCC submitted a standard sNDA requesting that Plan B be made available without a prescription. In the OTC switch application, the proposed OTC dose and administration schedule were identical to that for Plan B’s prescription use. The application also included an actual use study and a label comprehension study to assess potential users’ understanding of how to administer the product. Following FDA’s procedures for a review of an OTC switch application, the sNDA was submitted to the Office of Drug Evaluation III—which includes the Division of Reproductive and Urologic Drug Products, whose staff also reviewed the prescription Plan B application. Table 1 includes a brief timeline of events involving Plan B and the initial OTC switch application. (See app. III for a more detailed timeline.) On June 9, 2003, review staff within the Office of Drug Evaluation III determined the Plan B sNDA to be fileable and accepted it for review. The sNDA was then submitted to the Office of Drug Evaluation V—which includes the Division of Over-the-Counter Drug Products, whose staff have expertise with OTC drugs—for concurrent review, also in accordance with FDA’s review procedures. FDA also convened a joint public meeting of two of its advisory committees—the NDAC and the ACRHD—during which the committees’ members reviewed documentation and voted on answers to specific questions asked by FDA review staff from both offices, including whether Plan B should be granted OTC marketing status. On December 16, 2003, the members of the joint advisory committee voted 23 to 4 to recommend approving a switch in Plan B’s marketing status from prescription to OTC. Members of the joint advisory committee also voted on other aspects of the Plan B application. For example, members voted 27 to 1 that Plan B could be appropriately used as recommended by the label and that the actual use data were generalizable to the overall population, including adolescents. A meeting was held on January 15, 2004, between officials within the office of the CDER Director and review staff within the Offices of Drug Evaluation III and V about the Office of the Commissioner’s position on the acceptability of the Plan B OTC switch application. FDA’s minutes from this meeting stated that the Acting Director of CDER informed review staff that a not-approvable letter was “recommended” based on the need for more data to clearly establish appropriate use in younger adolescents. Meeting minutes also stated that the Acting Director of CDER raised multiple issues, including the “very limited data” on younger adolescents in the actual use and label comprehension studies and concerns about younger adolescents’ ability to appropriately use Plan B without a learned intermediary, such as a physician. The minutes also noted that the Acting Director of CDER raised possible options to address these concerns, including asking the sponsor to collect more data to show appropriate use by those 18 years of age and under or by limiting the availability of the product by, for example, restricting distribution to minors or restricting pharmacy access to a behind-the-counter option. According to review staff within the Offices of Drug Evaluation III and V who we spoke with and as documented in their respective reviews, at this January 2004 meeting the Acting Director of CDER also told them that the decision on the Plan B OTC switch application would be made at a “level higher than them .” At this January 2004, meeting, review staff said they also told the Acting Director of CDER that they had not yet completed their reviews and that additional data existed on the use of ECPs in younger adolescents of which high-level management might not be aware. According to meeting minutes, it was agreed that review staff would complete their reviews as well as obtain these data and present them to the Commissioner, who had expressed a willingness to meet with review staff to further discuss the data and these concerns. Review staff told us they then requested additional data from the sponsor and contacted academic researchers in the United States as well as international researchers about ongoing studies examining younger adolescents and behavioral changes associated with increased access to ECPs. Review staff identified five additional studies in which ECPs were provided in advance to study participants. Review staff also reevaluated data previously submitted with the Plan B OTC switch application. On February 18, 2004, review staff within the Offices of Drug Evaluation III and V presented their findings to high-level management, including the Commissioner and the Acting Director of CDER. 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. According to the minutes, the meeting ended with the conclusion that CDER staff would continue working with the sponsor on a “marketing plan to limit availability of the product over the counter and to consider the most appropriate age groups to be restricted from access to the product.” In addition, according to meeting minutes, the Commissioner requested a “rapid action” on the Plan B OTC switch application. Aspects of FDA’s review of the Plan B OTC switch application were unusual compared to the agency’s regular review process. 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. Second, the review process for the Plan B OTC switch application was marked by a level of involvement by FDA high-level management that has not been typical for OTC switch applications. Third, conflicting accounts exist regarding when the decision to deny the application was made. Finally, the Acting Director of CDER’s rationale for denying the application was novel for an OTC switch decision. By early April 2004, the reviews from the Offices of Drug Evaluation III and V were completed. The directors of these offices agreed with the recommendations of the joint advisory committee and review staff that Plan B should be made available without a prescription. Nonetheless, the office directors told us that they were asked by high-level management to draft a not-approvable letter. Both office directors also told us they did not agree with a not-approvable action and did not sign the not-approvable letter. The issue was then raised to the Office of New Drugs. The Director of the Office of New Drugs reviewed the staff’s analysis of the application and concurred with the recommendations of both office directors. He also did not sign the not-approvable letter. The Director of the Office of New Drugs told us that it was “very, very rare” that his office would become involved in the signing of an action letter. According to FDA manuals of policies and procedures and The CDER Handbook, the Office of New Drugs would review decisions from the offices of drug evaluation only if there was disagreement between these two reviewing offices. In the case of Plan B, there was no disagreement between the two reviewing offices of drug evaluation on the approvability of the application. The Acting Director of CDER signed the not-approvable letter, which was issued on May 6, 2004. According to FDA, the Acting Director of CDER did not ask the Directors of the Offices of Drug Evaluation III and V or the Director of the Office of New Drugs to sign the not-approvable letter, nor was the letter presented to them for their signature, because it was known that they did not agree with the not-approvable action. High-level FDA management became more involved than usual in the review process for the Plan B OTC switch application. According to review staff within the Offices of Drug Evaluation III and V that we spoke with and as documented in their respective reviews, at a meeting held on January 15, 2004, the Acting Director of CDER informed them that the decision for the Plan B OTC switch application would be made by high- level management. This action removed decision-making authority from the directors of the reviewing offices who would normally make the decision. According to minutes from a subsequent meeting between review officials and the sponsor on January 23, 2004, the Director of the Office of New Drugs informed the sponsor that such a high-level decision was not typical of CDER’s procedures for drug approvals. The Acting Director of CDER told us that management needed to be comfortable with review staff’s final decision because of the high visibility and sensitivity of the Plan B OTC switch application. He and other senior FDA officials told us that involvement by high-level management stemmed from the agency’s practice of delegated authority. In addition to highly visible and sensitive cases, they said that the Commissioner and the Director of CDER would also generally become involved in cases that would potentially have a far-reaching impact or in cases in which management had a different view or disagreed with review staff. Although such cases are rare, FDA officials cited other examples when high-level management was more involved in the review process for a drug application than normal—the approval of thalidomide for the treatment of leprosy in 1998 and the approval of mifepristone for the termination of early pregnancy in 2000. Unlike Plan B, the examples FDA officials provided us did not involve OTC switch applications. 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. However, the Acting Director of CDER told us that he made the decision to not approve the Plan B OTC switch application shortly before signing the action letter. He also informed us that his decision was made in consultation with other high-level management officials, including the Commissioner and the Acting Deputy Commissioner for Operations, but that he was not directed to reach a particular decision. The Acting Director also told us that these high-level management officials agreed with his decision. When we asked the Acting Director about his meeting with officials from the Office of New Drugs in December 2003, he told us that he might have indicated to the Director and Deputy Director that the agency was “tending” or “thinking of going” in the direction of a not- approvable decision, but that this was not the final decision. Furthermore, although he told us that he was “90 percent sure” as early as January 2004, that the decision would be not-approvable, the Acting Director told us he made his final decision only in the last few weeks prior to issuing the action letter, after he had reviewed all of the documentation associated with the application. The Acting Director of CDER told us that the rationale for his decision was not fully developed until a few days before the action letter was issued on May 6, 2004. According to internal FDA e-mails we reviewed, the Acting Director of CDER contacted the Director of the Office of Pediatric Therapeutics on May 2, 2004, requesting assistance on language regarding cognitive development during early adolescence to support his decision. According to these e-mails, the Director of the Office of Pediatric Therapeutics responded that she would consult with another official with a background in developmental pediatrics and would follow up with “behavioral science information as to why one cannot extrapolate decision making on safety issues” from older to younger adolescents. 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. The Acting Director’s Rationale Was Based on His Concerns about Risk-Taking in Younger Adolescents The Acting Director of CDER told us he signed the not-approvable letter because of his concerns about the lack of cognitive development and the potential for risky behaviors among younger adolescents resulting from increased access to Plan B. For example, he noted increased access to Plan B could potentially result in an increase in unsafe sexual activity, particularly among younger adolescents—an age group, he noted, that has a tendency to engage in risky behaviors because of their level of cognitive development. This change in behavior could be represented by changes in measurable indicators, such as a decrease in condom use or an increase in the transmission of sexually transmitted diseases (STD). “In making decisions about pediatric use, it is often possible to extrapolate data from one age group to another, based on knowledge of the similarity of the condition. However, in this case, adolescence is known to be a time of rapid and profound physical and emotional change. . . . Because of these large developmental differences, I believe that it is very difficult to extrapolate data on behavior from older ages to younger ages. I am uncomfortable with our current level of knowledge about the potential differential impact of OTC availability of Plan B on these age subsets.” Some other officials we spoke with supported the Acting Director’s concerns about extrapolating data from older to younger adolescents. For example, the Director of the Office of Pediatric Therapeutics told us and noted in e-mails to the Acting Director of CDER, which we reviewed, that the difference in cognitive development and maturity between older and younger adolescents and the potential impact this would have on behaviors warranted a separate analysis of this latter age group. In addition, one of the members of the joint advisory committee we spoke with said he was also concerned about extrapolating data from older to younger age groups because he perceived weaknesses in the actual use and label comprehension studies submitted by the sponsor. Because of these concerns, the Acting Director concluded that the Plan B OTC switch application needed more data specific to younger adolescents. In the not-approvable letter, the Acting Director stated there were too few younger adolescents in the sponsor’s actual use study to support the Plan B OTC switch application. Specifically, he highlighted that only 29 of 585 participants in the study were 14 years to 16 years of age and none were under 14 years of age. Although he acknowledged concerns about the difficulty of including younger adolescents in actual use studies, he told us that it was not impossible to enroll younger adolescents in studies, noting that studies for other products have been conducted involving younger participants, including those as young as infants. Some of the Acting Director’s concerns regarding the low number of younger adolescents were also raised by other review staff and members of the joint advisory committee. For example, one FDA reviewer who recommended an approvable action on the Plan B OTC switch application noted that despite a reanalysis of the actual use study data of subjects aged 14 years to 17 years, the sample size was too small and “significantly limit assessment of potential risky/unsafe sexual behavior associated with OTC accessibility of Plan B.” Although review staff within the Offices of Drug Evaluation III and V presented him with additional data on sexual behaviors of younger adolescents in association with increased access to ECPs, the Acting Director of CDER determined that these data were not adequate to support the approval of Plan B for OTC use. He provided his reasoning in his memorandum, stating that these studies were either “not conducted in the general population or they provide product education assistance beyond what adolescents would receive in an OTC situation, where no contact with a health care professional is expected.” The Acting Director of CDER’s rationale varied from FDA’s traditional practices by considering the potential implications OTC access of Plan B would have on the sexual behavior of younger adolescents based on their lack of cognitive maturity and by not accepting the validity of extrapolating data from older to younger adolescents. Although he acknowledged to us that considering adolescents’ cognitive development as a rationale for a not-approvable decision was unprecedented, the Acting Director also told us that FDA had recently increased its focus on pediatric issues. He noted that pediatric issues were currently being raised in prescription drug reviews and believed the same should occur in OTC drug reviews. 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. FDA review officials, including those from the Office of New Drugs, noted that traditionally FDA has not considered whether younger adolescents would use an OTC product differently than older adolescents, and the Director of the Office of New Drugs told us that it was “atypical” to raise the question of maturity during a drug review. These officials also noted that FDA does not attempt to determine how a patient arrived at the need for a drug. Rather, drug evaluations usually begin with the need for a potential treatment already existing. Review staff we spoke with acknowledged that certain behavioral concerns and unintended consequences are examined for an OTC switch application, such as whether making a drug OTC would delay a person from seeking medical treatment or if the drug would potentially be abused if it were more readily available. They told us that these issues are usually examined during a benefit–risk review, which is an analysis of potential medical outcomes. Review staff told us they examined benefit–risk issues for Plan B, and they concluded that concerns regarding the potential for unsafe sexual behaviors among adolescents could not be supported. In addition, the review of the label comprehension study from the Office of Drug Safety noted that potential users of the product would be able to appropriately use it if the sponsor made its suggested changes to the proposed labeling. Also, at the public meeting, members of the joint advisory committee voted 27 to 1 that the actual use study demonstrated that consumers could properly use Plan B as recommended by the label. The members of the joint advisory committee also voted 28 to 0 that the literature review of Plan B included in the actual use study did not show that Plan B would be used as a regular form of contraception. Furthermore, the review of the application from the Office of Drug Evaluation III, which included the benefit–risk assessment for Plan B, noted that having Plan B in an OTC setting would “pose little risk” to the potential user and that the risk of an adverse pregnancy outcome, such as lower birth weight babies and premature delivery, is much higher among younger adolescents. The review concluded that OTC access to Plan B in helping younger adolescents avoid unintended pregnancies would be “of particular value given the greater risk of an adverse pregnancy outcome in this high risk group.” This review also noted that even for a large dose of the hormone used in Plan B, the “margin of safety appear to be high.” In an attempt to further address the Commissioner’s and Acting Director’s concerns about the potential for increased risky behavior by younger adolescents resulting from increased access to Plan B, review staff requested additional data from the sponsor and reviewed ongoing studies examining these concerns. FDA’s reviewers concluded that increased access to ECPs did not result in (1) inappropriate use by adolescents as a substitute form of contraception, (2) an increase in the number of sexual partners or the frequency of unprotected intercourse, or (3) an increase in the frequency of STDs. To reach these conclusions, review staff examined the five studies that provided supplies of ECPs in advance to study participants to assess the behavioral impact of OTC access. In one study, which included 2,090 women aged 15 years to 24 years, there was a decrease in unprotected sex among all age groups and no increase in the incidence of STDs compared to the baseline. Another study of 160 adolescent mothers included participants aged 14 years to 20 years. Although there were limited data available, this study concluded that there was no increase in unprotected intercourse and no decrease in condom use among participants. A third study of 301 adolescent women, aged 15 years to 20 years, showed similar results, with no increase in unprotected intercourse or STDs and no decrease in condom use. FDA officials, including those from the Office of New Drugs, also disagreed with the Acting Director’s determination that extrapolating data from older populations to younger adolescents was inappropriate. In their reviews, officials noted that data they reviewed showed that younger adolescents had outcomes similar to those of older populations. For example, the actual use study found that 82 percent of participants 16 years of age or under correctly took the second dose 12 hours later, compared to 78 percent of those 17 years and older. Also, review staff said that overall the number of participants who were younger adolescents was adequate to draw conclusions about potential use among the adolescent population. Review staff told us they encouraged the sponsor to not limit enrollment or exclude adolescents from the actual use study and felt the study included a representative population of women that would potentially use Plan B. Some of the members of the joint advisory committee we spoke with also said they considered the number of younger adolescents in the actual use study as adequate. In addition, the Director of the Office of New Drugs told us that the agency has not requested age-specific data often and that FDA often extrapolates findings, including findings on behaviors, from adults to adolescents. He added that given the agency’s traditional processes and the data provided in the Plan B OTC switch application, there was no reason to consider the extrapolations done in the staff’s reviews as inappropriate. “In my opinion, these studies provide adequate evidence that women of childbearing potential can use Plan B safely, effectively, and appropriately for emergency contraception in the non-prescription setting. The data submitted by the sponsor in support of non- prescription use of Plan B are fully consistent with the Agency’s usual standards for meeting the criteria for determining that a product is appropriate for such use. . . . Such a conclusion is consistent with how the Agency has made determinations for other OTC products, including other forms of contraception available without a prescription. Further, I believe that greater access to this drug will have a significant positive impact on the public health by reducing the number of unplanned pregnancies and the number of abortions.” In his memorandum, the Director of the Office of New Drugs also noted that FDA has a “long history” of extrapolating findings from older populations to younger adolescents. He wrote that this type of extrapolation from older populations to younger adolescents had been done in clinical trials for both prescription and OTC drug approvals and that this practice was incorporated into the Pediatric Research Equity Act (PREA)—the law authorizing FDA to require pediatric studies in certain defined circumstances. According to PREA, if the disease and the effects of the drug are “sufficiently similar” between adult and pediatric populations, it can be concluded that the effectiveness can be extrapolated from “adequate and well-controlled studies in adults” usually in conjunction with supplemental studies in pediatric populations. In addition, PREA provides that studies may not be necessary for all pediatric age groups, if data from one age group can be extrapolated to another. Members of the joint advisory committee expressed similar conclusions to those of FDA review officials earlier at the public meeting in December 2003. During the public meeting, committee members voted 27 to 1 that the actual use study data were generalizable to the overall population of OTC users, including adolescents. 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. The decision of the Plan B application stands out from these other OTC switch applications for two reasons: it was the only decision that was not approved after the members of the joint advisory committee voted to recommend approval of the application, and the action letter was signed by the Acting Director of CDER instead of the directors of the offices where the application was reviewed. From 1994 through 2004, Plan B was the only prescription-to-OTC switch decision that was not approved after the joint advisory committee voted to recommend approval of the application. FDA advisory committees considered 23 OTC switch applications during this period; the Plan B OTC switch application was the only 1 of those 23 that was not approved after the joint advisory committee voted to recommend approval of the application. In addition, there has been only 1 other decision for an OTC switch application that did not follow the recommendations of the joint advisory committee. This other OTC switch application, for the drug Aleve, was approved for OTC status by FDA in 1994, although the joint advisory committee opposed the switch. The NDAC met jointly with the Arthritis Drugs Advisory Committee to discuss the OTC switch application for Aleve in June 1993 and recommended that the application not be approved. Following this meeting, the sponsor made changes to address the joint advisory committee’s concerns, and as a result of these changes, FDA decided to approve the application. 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. Given that Plan B was a first-in-a-class drug, the Directors of the Offices of Drug Evaluation III and V would normally jointly sign the action letter. The Plan B application was 1 of 68 proposed OTC switch applications decided by FDA from 1994 through 2004, and 14 of those 68 applications, including the Plan B application, were issued not-approvable letters. Eight of those 14 applications were eventually approved. Plan B was the only contraceptive or emergency contraceptive proposed for an OTC switch during this period. Thirty-eight OTC switch applications, including Plan B, were for the same dose, population, and indication, and all but 3 applications were eventually approved. 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. Condoms and spermicides are available to anyone OTC, while intrauterine devices; diaphragms; cervical caps; and hormonal methods of contraception, including ECPs, are available to anyone with a prescription. For hormonal contraceptives, FDA has assumed that suppression of ovulation is the same in all postmenarcheal females, regardless of age. The Deputy Director of the Office of New Drugs told us that all birth control pills, including ECPs, contain the following class labeling: “Safety and effectiveness of [trade name] have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.” FDA officials from the Office of New Drugs explained that for an OTC switch, the safety and effectiveness issues have already been addressed during the initial approval process for the drug to become a prescription drug. For an OTC switch application, the review process is primarily focused on whether the drug meets the OTC switch criteria, specifically whether it is safe and effective for use in self-medicating. There were no safety issues that would require age-related restrictions that were identified with the original NDA for prescription Plan B. FDA approved this application upon determining that Plan B met the statutory standards of safety and effectiveness, manufacturing and controls, and labeling. The original NDA for Plan B for use as an emergency contraceptive contained an extensive safety database that included controlled trials and literature on over 15,000 women. The label for prescription Plan B makes no age distinctions about the pharmacological processes of the drug, and prescription Plan B is available to anyone with a prescription. FDA reviewed a draft of this report and provided comments, which are reprinted in appendix VI. FDA also provided technical comments, which we incorporated as appropriate. In its comments, FDA disagreed with our finding that three aspects of its decision process for the May 2004, Plan B OTC switch application were unusual. First, FDA said that the involvement of high-level management in the Plan B decision was not as unusual as the draft report found. FDA commented that the Director of CDER is ultimately responsible for all decisions made within CDER, and that the Director of CDER is regularly involved in regulatory decisions that are not routine, including those that involve controversial issues. FDA also commented that the Director of CDER typically discusses high-profile and controversial regulatory decisions with officials within the Office of the Commissioner. While we agree with FDA that the Director of CDER and other high-level officials generally are more likely to become directly involved in high- profile regulatory decisions and noted that in the draft of the report, we found that this level of involvement is unusual for OTC switch applications. The other examples of high-level management involvement given to us by FDA officials during the course of our work involved decisions about the marketing of prescription drugs. 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. The Acting Director did so on January 15, 2004, before the review staff had completed their reviews of the application. Second, FDA took issue with what it characterized as the tone of our discussion about when the decision was made to deny the Plan B OTC switch application. FDA commented that discussions about alternative regulatory actions ordinarily occur in the course of decision making within CDER and that it is inaccurate to conclude that a decision to deny the application was made several months before the not-approvable letter was issued. However, the draft report did not assert that a decision was actually made several months before the letter was issued. Rather, it accurately noted that FDA officials gave us conflicting accounts of when the not-approvable decision was made. The Director and Deputy Director of the Office of New Drugs and other officials told us that they were informed during December 2003 and January 2004 that the application would not be approved. The Acting Director of CDER denied this, and we reported that his rationale for the not-approvable decision was not fully developed until early May 2004. 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. FDA commented that the Acting Director’s focus on the potential implications to the sexual behavior of adolescent women of approving the Plan B OTC switch application was appropriate and consistent with FDA’s treatment of other OTC switch applications. In response to this comment, we have revised the report to more clearly describe the reasons for our finding. We found that the Acting Director’s rationale was novel because it explicitly considered the differing levels of cognitive maturity of adolescents of different ages, and that because of the Acting Director’s views about these cognitive maturity differences, he concluded that it was inappropriate to extrapolate data related to risky sexual behavior from older to younger adolescents. 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. In addition, other FDA officials told us that the agency had not previously considered whether younger adolescents would use a product differently than older adolescents. For example, the Director of the Office of New Drugs told us that it was “atypical” to raise the question of maturity during a drug review and that FDA has traditionally extrapolated findings from older to younger adolescents. Furthermore, in his April 22, 2004, memorandum, the Director of the Office of New Drugs said that “the Agency has a long history of extrapolating findings from clinical trials in older patients to adolescents in both prescription and non- prescription approvals.” In addition, FDA disagreed with our statement in the draft report that the Directors of the Offices of Drug Evaluation III and V and the Director of the Office of New Drugs refused to sign the not-approvable letter. We used the term “refused” in the draft report because, in our interviews with them, all three of the directors told us that they did not agree with the not- approvable decision and did not sign the action letter, and one of the directors told us that she had been given an opportunity to sign the letter and refused to do so. However, in its comments, FDA said that the directors were not asked to sign the action letter because it was known that they disagreed with the Acting Director’s decision. We have revised the report to reflect this. In its technical comments, FDA asked us to emphasize that safety concerns regarding OTC use of drug would not be raised for prescription products because of the involvement of health practitioners. The draft report noted that prescription drugs are drugs that are safe for use only under supervision of a health care practitioner and that approved prescription drugs that no longer require such supervision may be marketed OTC. We are sending copies of this report to the Acting Commissioner of the Food and Drug Administration and other interested parties. We will also provide copies to others upon request. In addition, the report will be available at no charge on GAO’s Web site at http://www.gao.gov. If you or your staffs have any questions about this report, please contact me at (202) 512-7119 or crossem@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made major contributions to this report are listed in appendix VII. 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). We examined documents produced by FDA, including official meeting minutes and the reviews of the Plan B OTC switch application from the Offices of Drug Evaluation III and V and the Office of New Drugs, related to the review of the Plan B OTC switch application. FDA officials told us that documentation was not available concerning some communications within FDA. It was not possible to determine whether such communications may have concerned the Plan B OTC switch application. However, we acquired sufficient information from other FDA documents and our interviews with FDA officials to fully address our objectives. We interviewed FDA officials involved in the Plan B OTC switch application review, including officials from the Office of Drug Evaluation III, Office of Drug Evaluation V, Office of New Drugs, and Office of Drug Safety. We also interviewed the Acting Director of the Center for Drug Evaluation and Research (CDER), the Acting Deputy Commissioner for Operations, and the Director of the Office of Women’s Health. We interviewed members of FDA’s advisory committees that met jointly to discuss the Plan B OTC switch application—the Nonprescription Drugs Advisory Committee (NDAC) and the Advisory Committee for Reproductive Health Drugs (ACRHD)—and reviewed the transcripts of the meeting. In addition, we interviewed officials from Barr Pharmaceuticals, Inc., the company currently sponsoring the Plan B application for the prescription-to-OTC switch, and Women’s Capital Corporation (WCC), the original sponsor of the Plan B OTC switch application. To examine how the Plan B decision compares to the decisions for other proposed prescription-to-OTC switches made from 1994 through 2004, we examined the recommendations of the joint advisory committee and if they were followed for Plan B and the proposed OTC switch drugs that were decided from 1994 through 2004. We reviewed action letters and interviewed FDA officials and review staff as well as other outside experts involved with the Plan B OTC switch application. We also interviewed officials from the Consumer Healthcare Products Association (the association representing OTC drug manufacturers) about the prescription- to-OTC switch process. To determine if there were age-related marketing restrictions for prescription Plan B and other prescription and OTC contraceptives, we reviewed FDA documents and interviewed FDA officials and review staff regarding safety concerns for prescription Plan B and the safety concerns for other prescription and OTC contraceptives. We also interviewed representatives from the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, Concerned Women for America, and the Planned Parenthood Federation of America, Inc., regarding safety concerns for Plan B and other contraceptives. When the source of evidence we cited is from an interview, we identified the respondent’s title and FDA office. Whenever possible, we reviewed documents to verify testimonial evidence from FDA officials. When this was not possible, we attempted to corroborate testimonial evidence by interviewing multiple people about the information we obtained. In situations where there was no concurrence among the interviewees, we presented all the information provided. Minutes of the internal FDA meetings discussed in this report were written either by a staff member within the Office of Drug Evaluation III or by the Executive Secretariat within the Office of the Commissioner. For meeting minutes written by the office staff member, attendees either reviewed or concurred with the minutes and documented this by including their names at the end of the minutes. For summaries written by the Executive Secretariat, there was no documentation of a review or of concurrence by attendees included with these summaries. FDA officials told us that summaries from meetings within the Office of the Commissioner were not reviewed or concurred with by attendees. To verify data we received from FDA regarding proposed prescription-to- OTC switch decisions made from 1994 through 2004 and the outcomes of advisory committee meetings for these drugs, we compared FDA’s data with prescription-to-OTC switch data obtained from the Consumer Healthcare Products Association on OTC drug switches. Our work examined only events and communications within FDA and between FDA and the Plan B sponsors; we did not consider any communications that may have occurred between FDA officials and other executive agencies. Our work examined only FDA’s actions prior to the May 6, 2004, not-approvable letter, and we did not examine any aspects of FDA’s subsequent deliberations about Plan B. We conducted our work from September 2004 through November 2005 in accordance with generally accepted government auditing standards. A notice in the Federal Register stated that the FDA Commissioner had concluded that certain combined oral contraceptives are safe and effective for use as emergency contraception and requested submission of a new drug application (NDA) for this use. FDA approved Plan B as a prescription form of emergency contraception. A citizens’ petition for direct over-the-counter (OTC) access to Plan B was filed, requesting that FDA grant Plan B OTC status. FDA review staff within the Office of Drug Evaluation III sent Women’s Capital Corporation (WCC) a letter, denying its proposal that FDA request that it conduct pediatric studies on the use of prescription Plan B as an emergency contraceptive in exchange for extending the drug’s marketing exclusivity for 6 months, as permitted under the Federal Food, Drug, and Cosmetic Act. According to the letter to WCC and a memorandum by review staff within the Office of Drug Evaluation III, the proposed studies would have included a pharmacokinetic study and a safety study and would have used Plan B as an emergency contraceptive in subjects as young as 12 years of age. According to review staff within the Office of Drug Evaluation III, once a young female reached menarche, she was considered an adult for contraceptives and the condition for using an emergency contraceptive is not unique to the pediatric population. The letter concluded that trials could be conducted in the adult population and then extrapolated to the pediatric population. A Center Director Informational Briefing was held in response to the citizens’ petition, filed on February 14, 2001. Meeting attendees included the Center for Drug Evaluation and Research (CDER) Director and Deputy Director, the Director of Office of New Drugs, and review staff from the Offices of Drug Evaluation III and V. A briefing for the Office of the Commissioner was held to discuss the expected application to switch Plan B to OTC. Attendees included the Deputy Commissioner, the agency’s Chief Counsel, the then Director of CDER, the Director of the Office of New Drugs, and review staff from the Offices of Drug Evaluation III and V. According to the executive summary of the briefing, issues discussed included (1) the political sensitivity of the application, (2) consumer understanding of the proposed nonprescription product label, (3) the results of actual use studies to adequately address safety issues, (4) the review status of the supplemental new drug application (sNDA) upon submission, and (5) regulatory issues. The Director of CDER provided the Deputy Commissioner and FDA’s Chief Counsel with materials on the safety of emergency contraception and its mechanism of action, which were requested at the June 5, 2002, briefing. FDA officials within the Office of New Drugs and the Offices of Drug Evaluation III and V and the sponsor held a meeting in which FDA provided guidance on the Plan B OTC switch application, which was to be submitted. According to meeting minutes, agency officials and the sponsor discussed behavioral issues in adolescents and the possibility of a behind-the-counter option or a possible age restriction. WCC submitted an sNDA to FDA to allow Plan B to be sold OTC. FDA review staff from the Office of Drug Evaluation III determined that the sNDA was fileable and accepted it for review. FDA set a Prescription Drug User Fee Act (PDUFA) goal date of February 22, 2004, to reach a decision on the application. A teleconference was held between review staff within Offices of Drug Evaluation III and V and the sponsor. According to minutes of this teleconference, review staff began working with the sponsor to prepare for the meeting of the joint advisory committee in December. Minutes also noted that FDA review staff suggested that the sponsor plan to address issues of age, literacy, or label comprehension regarding the administration of Plan B. Review within the Office of Drug Evaluation V requested additional information on the label comprehension study results from WCC. According to the official request, review staff asked for information including results for each question asked in the label comprehension study based on literacy levels; details on what criteria were used to determine if a communication objective was met; and other specific points of clarification on how responses were scored. A teleconference was held in which review staff within the Offices of Drug Evaluation III and V discussed the upcoming December 16, 2003, public meeting of its two advisory committees with WCC. According to teleconference minutes, review staff requested additional information on the labels used for the label comprehension and the actual use studies and on the label proposed for approval in the sNDA. Minutes also noted that WCC informed FDA that on September 23, 2003, a majority of its board voted to sell the marketing rights of Plan B to Barr Pharmaceuticals, Inc. Barr Pharmaceuticals, Inc., was finalizing the purchase of the marketing rights for Plan B from WCC and began to act as the agent for WCC for Plan B. At the request of Barr Pharmaceuticals, Inc., a teleconference was held to discuss the upcoming joint public meeting of FDA’s advisory committees. Meeting participants from FDA included review staff within the Offices of Drug Evaluation III and V. According to teleconference minutes, review staff asked Barr Pharmaceuticals, Inc., about possible age restrictions for use of Plan B. Minutes also noted that Barr Pharmaceuticals, Inc., said that it intended to offer its product to women as young as 15 years of age. Also, Barr Pharmaceuticals, Inc., agreed to explore and report back to FDA on behind-the-counter marketing and the implementation of age limitations on the sale of Plan B. A reviewer within the Office of Drug Safety completed her review of the Plan B label comprehension study, which was initially submitted to review staff within the Office of Drug Evaluation III. According to the official memorandum on the review of the label comprehension study, the reviewer concluded that making the proposed changes to the Plan B label would likely result in acceptable levels of comprehension. Review staff within the Office of Drug Evaluation V told GAO they concurred with the reviewer’s findings. A meeting was held between FDA officials within the Office of New Drugs and the Offices of Drug Evaluation III and V and the sponsor. According to meeting minutes, FDA officials informed Barr Pharmaceuticals, Inc., that the agency may not be able to present a clear regulatory path for alternate OTC distribution mechanisms for Plan B in time for the December 16, 2003, public meeting. A briefing for the Office of the Commissioner was held to discuss the upcoming public meeting of the Nonprescription Drugs Advisory Committee (NDAC) and Advisory Committee for Reproductive Health Drugs (ACRHD). FDA participants included the Commissioner, the Acting Director of CDER, the Director and Deputy Director of the Office of New Drugs, and review staff within the Office of Drug Safety and the Offices of Drug Evaluation III and V. According to the executive summary of the briefing, issues discussed included the sponsor’s marketing and distribution plan and the effect making Plan B available OTC might have on consumers’ behavior. At a joint meeting of the NDAC and the ACRHD, members voted 23 to 4 to recommend approving the switch of Plan B from prescription to OTC. The Director and the Deputy Director of the Office of New Drugs told GAO they were told by the Acting Deputy Commissioner for Operations and the Acting Director of CDER that the Plan B application could not be approved. These officials said they were told that this direction came from the Office of the Commissioner. The Acting Deputy Commissioner for Operations and the Acting Director of CDER told GAO they did not say this. A meeting was held between officials within the Office of the CDER Director and review staff within the Offices of Drug Evaluation III and V about the Office of the Commissioner’s position on the acceptability of the Plan B OTC switch application. According to meeting minutes, the Acting Director of CDER said that a not-approvable decision was recommended by the Office of the Commissioner based on the need for more data to more clearly establish appropriate use in younger adolescents, the need to develop a restricted distribution plan, or both. Meeting minutes also indicated that review staff also informed the Acting Director that their reviews were not yet completed and that there were additional data regarding adolescent use of Plan B. It was then agreed that review staff would complete their reviews and collect the additional data and present them to the Commissioner and the Acting Director of CDER some time in February. Review staff within both Offices of Drug Evaluation III and V later noted in their completed reviews of the Plan B OTC switch application that they were told at this meeting that the decision on the Plan B application would be made at a level higher than the offices of drug evaluation. A teleconference was held between review staff from the Office of Drug Evaluation V and the sponsor. According to meeting minutes, review staff informed the sponsor that a meeting was held with CDER management, including the Acting Director of CDER and the Director and Deputy Director of the Office of New Drugs, in which “some issues” were raised that would require review staff to “provide additional information and have additional discussions with CDER upper management.” Minutes also noted that review staff told the sponsor they would not be discussing labeling revisions at that time and that they had been instructed by CDER management to complete their written reviews regarding the OTC switch application. A memorandum from the Director of Office of Drug Evaluation V indicated that she was in agreement with the favorable assessment of review staff and the majority votes by members of the joint advisory committee. Her memorandum concluded that adequate data had been submitted to approve Plan B for OTC marketing with certain product-labeling modifications—such as strengthening the message that Plan B is not for regular contraceptive use—included to address concerns raised at the public meeting and in the agency’s reviews. A meeting was held between FDA officials within the Office of New Drugs and the Offices of Drug Evaluation III and V and Barr Pharmaceuticals, Inc./WCC. According to meeting minutes, FDA officials told the sponsor that the decision on the application would be made at a level higher than the Offices of Drug Evaluation. The Director of the Office of New Drugs told the sponsor that such a high-level decision was not typical of CDER’s procedures for drug approvals. The minutes also noted that review staff within the Offices of Drug Evaluation were in the process of completing their reviews and would forward them with their final recommendations to high-level management. Meeting minutes also indicated that FDA officials told the sponsor that they would need to request a meeting directly with the Office of the Center Director or the Office of New Drugs to understand high-level management’s concerns. In addition, meeting minutes noted that FDA officials told the sponsor that the Office of the Commissioner and the Acting Director of CDER had raised concerns as to whether there were adequate data to establish that minors (i.e., those under 18 years of age) would use Plan B appropriately in the absence of a learned intermediary. Potential options that were suggested from FDA and CDER management included the possible need to (1) collect additional data, perhaps from another actual use study targeted to minors, or (2) to impose an age restriction on the OTC sale of the product. Review staff within the Office of Drug Evaluation III requested that the sponsor reanalyze the adolescent data of the Plan B actual use study. According to the official request, staff asked for a “ummary presentation of the Actual Use data from the participants in the less than 18 years of age subset, including comparisons to the older subset within the study.” FDA confirmed that it had extended the PDUFA goal date for a decision on the Plan B OTC switch application for 90 days due to the submission of the requested adolescent data from the actual use study by the sponsor. The extended PDUFA goal date was May 21, 2004. A briefing was held during which review staff within Offices of Drug Evaluation III and V presented their analysis of additional summary data to the Commissioner on the use and behavior of adolescents in association with increased access to emergency contraceptive pills. Other attendees included the Acting Deputy Commissioner for Operations and the Acting Director of CDER. According to meeting minutes, included in the presentation were the review staff’s recommendations that Plan B have an OTC marketing status without restriction. The meeting minutes also noted that the Commissioner raised concerns regarding adolescents, including the potential for changes in future contraceptive behaviors and the potential benefits of counseling from a learned intermediary for younger adolescents. In addition, the meeting minutes noted that CDER was directed by the Commissioner to work with the sponsor on a marketing plan to limit the availability of Plan B in an OTC setting and to consider the most appropriate ages that should have OTC access restricted. The Commissioner requested a “rapid action” on the application. Review staff within the Offices of Drug Evaluation III and V met with the Acting Deputy Commissioner for Operations, the Acting Director of CDER, and the Director and the Deputy Director of the Office of New Drugs. According to a reviewer’s memorandum, in part, during this meeting, the Acting Deputy Commissioner for Operations expressed her and the Commissioner’s concerns regarding adolescents and the potential for adverse behaviors resulting from increased access to Plan B. The Acting Director of CDER concurred with these concerns. This was the original PDUFA goal date for the initial Plan B OTC switch application. Barr Pharmaceuticals, Inc., completed acquisition of the marketing rights for Plan B from WCC. Barr Pharmaceuticals, Inc., submitted an amendment to its sNDA, proposing a dual-marketing strategy, making Plan B OTC for women 16 years of age and older and prescription only for women under 16 years of age. The Deputy Director of the Office of Drug Evaluation III completed her review of the Plan B OTC switch application and recommended that Plan B be approved for use as an emergency contraceptive in the OTC setting without age restriction. The review concluded there were sufficient data on the safety and effectiveness of Plan B to approve its use in the OTC setting. The Director of the Office of New Drugs issued his review of the Plan B application and concurred with the recommendations of the offices of drug evaluation that the sponsor had provided adequate data to demonstrate that Plan B could be safely, effectively, and appropriately used by women of childbearing potential for the indication of emergency contraception without a prescription. He recommended that this application be approved to permit availability of Plan B without a prescription and without age restriction. The Acting Director of CDER contacted the Director of the Office of Pediatric Therapeutics, within the Office of the Commissioner, via e-mail requesting assistance on language regarding cognitive development among adolescents. According to internal FDA e-mails, the Director of the Office of Pediatric Therapeutics responded that she would consult with another official with a background in developmental pediatrics and would follow up with “behavioral science information as to why one cannot extrapolate decision making on safety issues” from older populations to younger adolescents. According to internal FDA e-mails, the Director of the Office of Pediatric Therapeutics provided the Acting Director of CDER with information on brain development and the maturation of higher-order thinking among adolescents 10 years to 21 years of age. In her e-mail to the Acting Director, the Director of the Office of Pediatric Therapeutics included the statement that “uring early adolescence (10-13) there is an emergence of impulsive behavior without the cognitive ability to understand the etiology of their behavior.” According to teleconference minutes, the Acting Director of CDER called Barr Pharmaceuticals, Inc., officials to inform them of the not-approvable action and asked permission to release the not- approvable letter. According to FDA regulations, without consent of the sponsor, the agency cannot publicly release data or information contained in an application before an approval letter is issued. Minutes noted that the Acting Director told sponsor officials that (with their permission) he would conduct a press interview to discuss the not-approvable action and the staff’s disagreement with the not-approvable action would be acknowledged publicly. FDA issued a not-approvable letter, denying Plan B OTC marketing status, citing a lack of adequate data regarding safe use among younger adolescents. The letter also stated that FDA was not able to conduct a complete review of the dual-marketing strategy in the amendment to the sNDA because of the absence of the draft product labeling describing how Barr Pharmaceuticals, Inc., would comply with both the prescription and OTC labeling requirements in a single package. In addition to the contact named above, Martin T. Gahart, Assistant Director; Cathleen Hamann; Julian Klazkin; Gay Hee Lee; and Deborah J. Miller made key contributions to this report.

Summary: 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. 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.