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.