FDA’s responsibilities for overseeing the safety and effectiveness of drugs begin before a product is brought to market and continue after a drug’s approval. Its premarket responsibilities include reviewing a drug sponsor’s proposal for conducting clinical trials, as well as reviewing applications. If FDA determines that a drug is safe and effective—that its clinical benefits outweigh its potential health risks—and that other requirements are met, it will approve the application. Once it approves a new drug, FDA is charged with monitoring the safety and effectiveness of the drug, which includes overseeing a sponsor’s progress in completing postmarketing studies. Reliance on surrogate endpoints to predict clinical benefit can bring treatment benefits to patients years before definitive information on a drug’s effect on clinical outcome is available, and at relatively low cost. This is because a drug sponsor may be able to demonstrate the effect of a new drug on a surrogate endpoint based on smaller and shorter trials than would be required to prove the drug’s effect on a clinical endpoint. In order to further enhance drug development, some have called for their expanded use as a basis for drug approval. For example, FDA’s 2004 report on the slowdown of innovative medical therapies calls for the acceptance of new surrogate endpoints to guide drug development. Based on this report, FDA cited the need to clarify the conditions for the use of new surrogate endpoints in the drug approval process. To facilitate this effort, FDA planned to develop an inventory of surrogate endpoints which had been used as the basis for approval of drugs through the traditional and accelerated approval processes. Despite the potential benefits of using surrogate endpoints, reliance on these endpoints may introduce uncertainty regarding the risks and benefits of a drug, and may lead to the adoption of useless or even harmful therapies. This can arise if the effect on a surrogate endpoint does not accurately predict whether treatments provide benefits to patients, or if the drug has a smaller than expected benefit and a larger than expected adverse effect, which might not be recognized without large-scale, long- term clinical trials. For example, several large trials assessing drugs based on surrogate endpoints found those drugs to be clinically ineffective, and in some cases, identified unexpected adverse effects such as increased rates of death. Once a drug sponsor identifies a promising chemical compound or biologic organism capable of curing or treating diseases, the sponsor may decide to test it on humans. Before doing so, a sponsor must submit the data that have been collected on the compound or organism in prior studies and outline its plans for clinical trials. The clinical trial stage gradually introduces experimental drugs to increasingly larger numbers of patients to determine the drug’s safety and efficacy. It is during this stage that a sponsor determines whether it will evaluate a drug’s effectiveness using a clinical or surrogate endpoint. Once a drug sponsor completes clinical trials, it may submit an application to FDA for review. The application contains scientific and clinical data intended to demonstrate that the drug is safe and effective for its proposed use. Depending on factors such as the types of disease the drug is designed to treat, whether other effective treatments are available, and whether the sponsor assessed the drug based on a surrogate or clinical endpoint, FDA will review the application under either the accelerated or traditional approval process. If the application is for a drug designed to treat serious or life-threatening illnesses and the drug is expected to provide meaningful therapeutic benefits compared to existing treatments, and the sponsor evaluated the drug’s impact on a surrogate endpoint that only reasonably suggested clinical benefit, FDA will review the application under its accelerated approval process. In general, if the sponsor assessed the drug’s impact on a clinical endpoint, or a surrogate endpoint that FDA considers to be a valid substitute, FDA will review the application under its traditional approval process. According to FDA officials, they do not have specific criteria for determining when they will accept a surrogate endpoint as a valid substitute for a clinical endpoint, and such decisions are made on a case- by-case basis. This determination is dependent on factors such as the type of drug being approved and the disease being treated. However, FDA generally considers surrogate endpoints as valid substitutes for clinical endpoints when these endpoints have been shown to accurately predict a clinical benefit over time through definitive studies. For example, FDA considers lowering blood pressure as a valid surrogate endpoint to establish a drug’s clinical effectiveness in reducing the risk of stroke. Regardless of which process FDA uses, the application will be reviewed by one of FDA’s medical review divisions, depending on the disease being treated by the drug. The medical review division evaluates data contained in the application to determine whether the drug should be approved. If the medical review division determines the sponsor has demonstrated the drug is safe and effective for its intended use, and has met other applicable requirements, FDA will issue an approval letter. The approval letter outlines any postmarketing studies that FDA has required or requested the sponsor to conduct while the drug is being marketed for sale in the United States—including any associated postmarketing study time frames a sponsor may need to meet. As a condition of approval under its accelerated approval process, FDA requires that sponsors conduct postmarketing studies known as confirmatory studies. FDA requires sponsors to conduct these postmarketing studies to verify and describe the drug’s clinical benefits and thereby resolve any remaining uncertainty regarding the drug’s clinical benefit. In addition, FDA may request sponsors to conduct postmarketing studies when it determines that additional information, while not essential for approval, is important in improving the prescribing, use, and quality of a drug or consistency in drug manufacturing. For example, FDA may request sponsors, and sponsors may agree, to continue to evaluate a drug’s safety, effectiveness, pharmacology, toxicology, or manufacturing controls. FDA may request these studies under both the accelerated and traditional review processes. FDA’s oversight of postmarketing studies consists of a variety of monitoring and enforcement activities. After it outlines required and requested studies in the approval letter, FDA is responsible for monitoring sponsors’ progress in completing the studies, and taking actions to help ensure studies are completed. A key component of FDA’s oversight is the requirement that sponsors of all approved drugs report annually on their progress or status towards completing postmarketing studies. According to the implementing regulations, drug sponsors must report on the status of required and requested postmarketing studies in annual status reports (ASR), which are due within 60 days of the drug application’s approval anniversary date. Federal regulations also require ASRs to contain, in part, information on the description of the required and requested postmarketing studies, along with the schedule for their completion. FDA has established a goal of reviewing ASRs within 90 days of receipt to confirm the accuracy of the information provided. FDA may use information obtained from the ASRs to update a database that includes information on postmarketing studies. The database, which was designed to allow FDA to track and monitor the status of required and requested postmarketing studies, and identify those studies which are falling behind established time frames, includes information on dates the studies were required or requested in the approval letter, a description of the study, and its status. FDA also makes certain information from this database regarding the status of postmarketing studies available to the public, and is required to report certain information annually in the Federal Register. Based on its review of an ASR, FDA designates a status of either “open” or “closed” for each required and requested postmarketing study every year. FDA further classifies open studies into one of the following five categories: Pending – Those required and requested studies that have not been initiated, but are not yet delayed. Generally, the first patient has not been enrolled in the study. Ongoing – Those required and requested studies that are proceeding according to or ahead of any original schedule. Delayed – Those required and requested studies that are proceeding, but are behind their original schedule. Terminated – Those required and requested studies that were ended before their actual completion, but the sponsor has not yet submitted a final report to FDA. A postmarketing study may be terminated because the study would no longer provide useful information or the study is no longer feasible. In some instances, there may be another postmarketing study that the drug sponsor must conduct in lieu of the terminated study. Submitted – Those required and requested studies that have been completed—that is, the last patient has finished the protocol—or terminated and a final study report has been submitted to FDA, but FDA has not yet notified the drug sponsor that the study has been fulfilled or released. Drug sponsors are required to continue to annually submit an ASR on the status of its study until FDA provides written confirmation that the obligations have been met. FDA further classifies “closed” studies into one of the following two categories: Fulfilled – Those required and requested studies that have been completed and a final study report has been submitted and reviewed by FDA. When FDA completes its review of a study and finds that the postmarketing study has satisfied FDA’s request or requirement, the agency will issue a written confirmation to the drug sponsor that it considers the study requested or required in the approval letter to have been fulfilled. Released – Those required and requested studies that have not been completed and have been found to be no longer needed or feasible. For example, FDA may release a sponsor from the need to compete a study because a new drug has been developed which renders the drug being studied obsolete, thus eliminating the need to conduct the original study. Once a drug sponsor has completed a postmarketing study, it submits a final study report to FDA for review. FDA’s goal is to review the final study report within 12 months of receipt and notify the sponsor whether FDA considers the study closed. If the postmarketing study is a confirmatory study required under the accelerated approval process, the final study report should provide information confirming the drug’s clinical benefit. If it provides confirming information, and FDA agrees that the report satisfies the confirmatory study requirements, then FDA converts the drug from accelerated to full approval.