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. FDA’s oversight of postmarketing studies may be aided by enforcement tools, including administrative action letters and expedited withdrawal procedures of a drug from the market, in certain cases. If a sponsor fails to submit or is late in submitting an ASR, or if FDA determines a sponsor is not making adequate progress in completing a required or requested study, FDA may issue an administrative action letter—commonly referred to by FDA as “Dunner” letters. FDA uses these letters to remind sponsors about their need to meet federal requirements related to either submission of ASRs or completing a required or requested study. Also, under the accelerated approval regulations, FDA may initiate procedures to withdraw a drug from the market through an expedited process if required postmarketing studies to confirm and verify a drug’s clinical benefit are not performed with due diligence. In contrast, FDA does not require that drug sponsors complete requested postmarketing studies, regardless of whether a drug has been approved under the accelerated or traditional process. Such studies are typically related to safety, effectiveness, pharmacology, toxicology, or manufacturing controls. FDA has approved 90 applications based on surrogate endpoints under its accelerated approval process since the process was established in 1992. During this period, FDA required or requested sponsors to conduct over 450 postmarketing studies associated with the approval of applications for these drugs, and the majority of these studies have been classified by FDA as closed—meaning that drug sponsors had met FDA’s requirements for these studies or FDA determined the studies were no longer needed or feasible. However, several have been classified by FDA as open for an extended period of time. From June 19, 1992, through November 20, 2008, FDA approved a total of 90 applications based on surrogate endpoints, or an average of 5 per year. FDA approved these applications for a total of 64 different drugs. Over this period, there was variability in the number of applications FDA approved annually based on surrogate endpoints. For example, in 1992 and 1994, FDA approved 1 application based on surrogate endpoints under the accelerated approval process, while in 2004 it approved 10 applications applications (see fig. 1). (see fig. 1). Almost all—79 of the 90 applications—were for drugs to treat three diseases. Specifically, 38 of the applications were for drugs to treat cancer, 30 were for drugs to treat HIV/AIDS, and 11 were for drugs to treat inhalation anthrax. The remaining 11 applications were for drugs to treat a variety of other diseases (app. I contains a list of individual drugs, application numbers, and specific surrogate endpoints used for approval through the accelerated approval process). Since FDA began using the accelerated process in 1992, there has been a general shift in approvals based on surrogate endpoints from applications for HIV/AIDS drugs to applications for cancer drugs. In the first 9 years of the accelerated approval process, from 1992 through 2000, applications for drugs to treat HIV/AIDS made up 48 percent of the approvals, while applications for drugs to treat cancer made up 26 percent of these applications. Conversely, from 2001 through 2008, applications for drugs to treat cancer made up over half—59 percent—of the applications approved, while drugs to treat HIV/AIDS accounted for only 18 percent of approved applications (see fig. 2). Consistent with the types of applications approved under the accelerated process, the specific surrogate endpoints most frequently used to obtain approval were those used to demonstrate the effectiveness of cancer and HIV/AIDS drugs. Specifically, FDA approved, 38 applications for cancer drugs based on how the drugs impacted tumors, as measured by various tumor assessment surrogate endpoints such as response rate (e.g., tumor shrinkage), length of time until the cancer spread, or length of time until the drug no longer worked; 30 applications for HIV/AIDS drugs based on the drugs’ ability to lower the viral load of HIV in the blood stream, as measured by the drugs’ impact on the surrogate endpoint HIV-RNA; and the remaining 22 applications for drugs to treat other diseases—including inhalation anthrax and various bacterial infections—based on a variety of surrogate endpoints (see table 1). From June 1992 through November 20, 2008, FDA required drug sponsors to conduct 144 postmarketing confirmatory studies associated with drugs approved based on surrogate endpoints under the accelerated approval process. Consistent with the types of drugs FDA approved under the process, FDA required the majority of these studies—119 or 79 percent— for drugs approved to treat cancer or HIV/AIDS. Specifically, FDA required 82 studies for drugs to treat cancer, and another 37 studies for drugs to treat HIV/AIDS. The remaining studies were for drugs to treat a variety of other diseases. At the time of our review, we found FDA had classified 92, or 64 percent, of the 144 required studies as closed—meaning that drug sponsors had met FDA’s requirements for these studies or FDA determined the studies were no longer needed or feasible. In contrast, FDA had classified 52 of the 144 studies, or 36 percent, as open, and that sponsors had made varying levels of progress in completing them (see fig. 3). Of the 92 closed studies, sponsors had fulfilled requirements for 73 of them. This means that sponsors had completed these studies and submitted them to FDA, and upon review, FDA determined sponsors had fulfilled their study requirements. There were an additional 19 studies which FDA classified as released, meaning it had released the sponsors from the study requirements because it determined the studies were either no longer feasible or would no longer provide useful information. Based on our analyses of the 71 fulfilled studies, we found that in general, sponsors were able to fulfill about two-thirds of their study requirements in less than 5 years, with time frames ranging from 7 months to more than 12 years. In contrast, nearly one-third, or 23, of these studies took over 5 years to fulfill (see fig. 4). The amount of time needed to fulfill study requirements was generally longer for those studies involving drugs to treat cancer. Specifically, 61 percent of the postmarketing studies that took over 5 years (14 of 23) were studies for drugs to treat cancer. Conversely, only 9 percent of studies which took over 5 years (2 of 23), were studies for drugs to treat HIV/AIDS. According to FDA officials, the greater length of time needed to fulfill required confirmatory studies for drugs to treat cancer has resulted from the approach generally used to approve many cancer drugs under the accelerated process. In particular, most of the cancer drugs gained accelerated approval based on single arm clinical trials, which studied these drugs’ impacts in small numbers of patients with resistant tumors. According to FDA officials, this approach has been used to approve drugs targeting resistant tumors because these patients have no other effective therapy and it would be too difficult and time consuming for sponsors to conduct more in-depth randomized control studies. Because patients need access to these drugs as soon as possible, FDA deemed this approach sufficient for accelerated approval. However, in order to establish clinical benefits of the drugs through the required confirmatory postmarketing studies, the sponsors needed to conduct randomized control trials comparing the drugs to either a placebo or another drug(s). To do this, sponsors must design and conduct new randomly controlled clinical trials and recruit new patients, many of whom may be reluctant to sign up for a clinical trial when an approved drug is already on the market. In contrast, according to FDA officials, it is typically easier for a sponsor to complete a required confirmatory study for HIV/AIDS drugs because sponsors may simply continue the study which led to the original accelerated approval of the drug and do not have to design new studies to fulfill the postmarketing study requirements. For example, sponsors typically obtain accelerated approval for HIV/AIDS drugs based on a 24-week randomized clinical trial, and to meet the confirmatory study requirement they continue the same study for an additional 24 weeks, using the same patients and the same endpoints. The 52 studies FDA classified as open covered a variety of statuses, and thus were at varying levels of completion. Specifically, 7 were pending and had not yet begun, 10 were delayed and thus behind the sponsor’s original schedule, and 17 were ongoing, and thus on or ahead of schedule. Additionally, 2 were terminated, meaning the sponsor had stopped the study, but had not submitted results to FDA. The remaining 16 had been submitted by the sponsor to FDA, and were awaiting FDA’s review. Based on our analyses of these 52 open studies, we found the majority— approximately 65 percent—were for drugs approved to treat cancer. In contrast, only 6 percent of the open studies were for drugs approved to treat HIV/AIDS. Based on information provided to us by FDA, we determined that the average age of the 52 open studies was just over 4 years and the majority—37 of the 52 studies, or 71 percent—had been required since 2004. However, we found that 15 studies had been open for more than 5 years, including several open for more than 8 years. For example, on May 17, 2000, FDA approved an application for the drug Mylotarg to treat certain patients with acute myeloid leukemia based on its ability to control cancer in blood cells. As a condition of accelerated approval FDA required the drug sponsor to conduct one confirmatory study, and as of December 19, 2008, more than 8 years later, the study was ongoing, with an anticipated completion date of October 2014. In addition to the 144 confirmatory studies FDA required from June 1992 through November 20, 2008, FDA also requested—and sponsors agreed to conduct—317 other postmarketing studies associated with drugs approved through the accelerated process based on surrogate endpoints. FDA requested the majority of these studies—90 percent—for drugs approved to treat HIV/AIDS and cancer. Specifically, FDA requested 194 studies for drugs to treat HIV/AIDS, and another 91 studies for drugs to treat cancer. FDA requested the remaining studies for drugs to treat a variety of other diseases (see fig. 5). Based on the status FDA assigned each study at the time of our review, FDA had classified 203 of the 317 requested studies, or 64 percent, as closed, meaning that drug sponsors had satisfied FDA’s request for these studies or FDA determined the studies were no longer needed or feasible. Additionally, we found that FDA had classified 114, or 36 percent, as open, and sponsors had made varying levels of progress in completing them (see table 2). These percentages are similar to those for studies FDA required sponsors to complete. Based on information FDA provided, we found that the length of time studies have been open varies by status. Specifically, those studies classified as pending had been open, on average, for about 5.5 years, with more than 40 percent pending for over 8 years. In addition, studies classified as ongoing and delayed had been open, on average, for 5.3 and 4 years respectively, and those classified as submitted have been open on average about 5.6 years. We could not calculate the amount of time it took sponsors to close a requested study, because, according to FDA, the dates studies were fulfilled or released were not readily available. From January 1, 1998, through June 30, 2008, FDA approved about one- third of NME drug applications based on surrogate endpoints under its traditional process. Many of these applications were for drugs to treat cancer, heart disease, and diabetes. FDA requested 175 postmarketing studies associated with these NMEs, and about one-half have been classified by FDA as closed. From January 1, 1998, through June 30, 2008, FDA approved 204 applications for NMEs to treat diseases through the traditional approval process. Of these 204 applications, FDA approved 69, or about 34 percent, on the basis of surrogate endpoints. The percentage of NME approvals based on surrogate endpoints per year varied, ranging from 17 percent in 1999 to 54 percent in 2005. Additionally, in most years from January 1998 through June 2008, NME applications that were approved based on surrogate endpoints comprised less than half of all NME approvals in any given year (see fig. 6). The most frequently used surrogate endpoints in the traditional process were those to establish the effectiveness of drugs to treat cancer, cardiovascular disease, and diabetes. Specifically, 13 of the 69 applications—or 19 percent of applications approved—were for drugs to treat cancer, using various tumor assessments as surrogate endpoints, including response rates, similar to those used in the accelerated process. In addition, 11 of the 69 applications, or 16 percent, were approved for drugs to treat cardiovascular disease, based on their ability to decrease blood pressure or control cholesterol levels. Furthermore, 10 of the 69, or 14 percent were for diabetes drugs, based on their ability to lower blood sugar levels (see table 3). Drugs to treat a variety of other diseases— including renal disease and hepatitis B—accounted for the remaining 35 applications, and their approval was based on a variety of surrogate endpoints (app. II contains a list of individual drugs, application numbers, and specific surrogate endpoints used for approval of NME drugs through the traditional approval process). Our analysis of NME drug applications represents only a small subset of all applications which FDA may have approved based on surrogate endpoints under the traditional approval process during this time period. From January 1, 1998, through June 30, 2008, FDA approved about 2,000 other applications; however, it does not track whether they approved these applications based on surrogate endpoints. Thus the extent to which FDA used these and other surrogate endpoints as a basis for approval is unclear. From January 1, 1998, through June 30, 2008, FDA requested 175 postmarketing studies for NMEs approved based on surrogate endpoints under the traditional process. During this time frame, FDA requested studies for drugs to treat a variety of diseases. Of the 175 studies, FDA requested 43, or 25 percent, for drugs to treat cancer. In addition, FDA requested 31 studies, or 18 percent, for drugs to treat hepatitis B. The remaining studies were for drugs to treat a variety of other diseases, including renal disease, diabetes, HIV/AIDS, and cardiovascular disease (see fig. 7). Hepatitis B (31) Renal disease (25) Diabetes (19) HIV/AIDS (22) Based on the status FDA assigned each study at the time of our review, FDA had classified 94 of the 175 requested studies, or 54 percent, as closed, meaning that drug sponsors had satisfied FDA’s request for these studies or FDA determined the studies were no longer needed or feasible. Additionally, we found that FDA had classified 81, or 46 percent, as open, and sponsors had made varying levels of progress in completing them (see table 4). Based on information FDA provided, we found that the length of time studies have been open varies by status. Specifically, those studies classified as pending had been open, on average, for 3.8 years, ranging from less than 1 year to 10.9 years. In addition, studies classified as ongoing and delayed had been open, on average, for 2.9 and 5.8 years respectively, and those classified as submitted have been open on average 4.2 years. We could not calculate the amount of time it took sponsors to close a requested study, because, according to FDA, the dates studies were fulfilled or released were not readily available. FDA has not been routinely monitoring the status of postmarketing studies, primarily because oversight of these studies is not considered a priority. Regarding its enforcement of postmarketing study requirements, we found FDA has not fully utilized its available enforcement tools, even when sponsors have failed to complete required studies. FDA has not been routinely reviewing ASRs to confirm the accuracy of information and verify the status of studies within its goal of 90 days. Our review of information provided by FDA for 35 specific required postmarketing studies showed that just over half of the ASRs provided for 19 of these studies had never been reviewed by FDA medical reviewers, and that for those that had been reviewed, about half were not done in a timely manner (see app. III for a copy of the information request we submitted to FDA for these postmarketing studies). FDA medical reviewers indicated that they were not able to complete scheduled reviews of ASRs, and according to FDA officials, this task was a lower priority compared to their other responsibilities, such as review of applications for new drugs. This finding is consistent with the results reported by the HHS-OIG in 2006 as well as FDA’s contractor, Booz Allen Hamilton, in 2008. Both found that FDA was not completing reviews of ASRs in a timely manner and had not made such reviews a priority. For example, the HHS-OIG 2006 study, which examined FDA’s review of ASRs submitted during fiscal year 2004, found that FDA did not meet its goal of reviewing ASRs in 90 days 55 percent of the time. For 26 percent of these ASRs, it took FDA more than 180 days to complete its review. Similarly, the contractor’s study, which examined FDA’s review of ASRs for requested studies, found that FDA reviewers were missing the agency’s goal of reviewing ASRs in 90 days 47 percent of the time. Both HHS-OIG and the contractor reported that the monitoring of postmarketing studies is not a top priority of the agency. Specifically, the HHS-OIG reported that FDA officials indicated that other tasks, including reviewing drug applications and documenting FDA/industry meetings, are higher priorities than reviewing postmarketing studies and ASRs. In addition, the contractor similarly reported that a reason for missing review deadlines was heavy reviewer workload and that postmarketing study review-related tasks, including review of ASRs, were often given a lower priority as compared to application reviews. Without routine monitoring, FDA’s database does not contain complete and reliable information, including key dates and study information needed to track the progression of postmarketing studies. When we requested information on time frames associated with the progression of postmarketing studies, FDA could not provide it to us from its database. This is because FDA had not entered into the database the key dates such as when studies started, are scheduled for completion, and their current status. To provide us with the information we requested, FDA had to comb through multiple data systems and paper files to recreate milestones and status outcome by study. This problem is not new. The HHS-OIG reported in 2006 that FDA was not entering into the database the information from ASRs, noting, for example, that for primarily requested studies, the study start dates were present for only 6 percent and original projected completed dates were present for only 21 percent. As a result, the HHS- OIG recommended that FDA improve its database for monitoring postmarketing studies so that it provides timely, accurate, and useful information and ensure that studies are being monitored. Given that FDA’s medical reviewers are not routinely reviewing ASRs and do not have reliable information readily available to track the status of postmarketing studies, the agency cannot effectively monitor these studies. FDA does not know the current status of many postmarketing studies or whether they are progressing towards completion. In addition, FDA does not know whether drug sponsors are submitting complete and accurate ASRs in a timely manner. As a result, FDA lacks current, reliable, and easily accessible information on the status of open postmarketing studies, and meeting federal reporting requirements is difficult. The information available regarding postmarketing studies can only be as accurate and complete as the data contained in FDA’s postmarketing database. FDA has three initiatives in place to address the agency’s oversight weaknesses. First, to ensure FDA has current information on the status of open postmarketing studies and facilitate the timely review of ASRs, FDA retained the contractor in 2008 to review ASRs for all postmarketing studies classified as open. As part of this effort, the contractor will support the work performed in FDA’s medical review divisions and conduct an initial review of all newly submitted ASRs. This initial review is intended to help ensure that ASRs are reviewed within FDA’s 90-day review goal. Based on its review, the contractor will determine whether the status of the postmarketing studies that sponsors listed in the ASR is correct, and meet biweekly with FDA staff to discuss ongoing issues. FDA staff will use this information to determine the appropriate status of open studies and update its tracking database. This year FDA renewed its contract with Booz Allen Hamilton, which is now scheduled to expire in 2014, to continue review of outstanding and new ASRs associated with postmarketing studies. The second initiative is the creation of a new tracking coordinator position within each medical review division with responsibility for a variety of tasks related to the tracking of postmarketing studies. First, the tracking coordinators will ensure that reviewers are kept informed of key postmarketing schedule dates. They will also verify the accuracy of postmarketing study information and monitor whether expected activities are conducted within specified time lines. Further, the coordinator will serve as a key point of contact to interface with the contractor and ensure that status information provided by the contractor is entered into the postmarketing database. Currently, tracking coordinator responsibilities are shared between other existing positions within the divisions. FDA officials indicated that they were not sure whether the tracking coordinator position would be filled by one person in each medical review division or if the duties would be divided among many individuals in each division. To the extent that the ASR reviews and tracking coordinator initiatives are successful, FDA’s third initiative—the Document Archiving, Reporting and Regulatory Tracking System (DARRTS)—could facilitate the monitoring of postmarketing studies for NDAs. DARRTS is a Web-based system, which according to FDA officials should allow FDA staff greater access to information and provide enhancements over the current database, such as creating management reports on specific drugs and their respective studies. FDA has not fully utilized its two enforcement tools—issuing administrative action letters and withdrawing a drug from the market in certain cases—to encourage and compel drug sponsors to complete required confirmatory postmarketing studies. FDA has the discretion to issue administrative action letters to drug sponsors if 1) sponsors are late or fail to submit ASRs, or 2) FDA determines that sponsors are not sufficiently progressing in completing their studies. The extent to which FDA has issued administrative action letters related to its oversight of postmarketing studies required under the accelerated approval process is unclear. According to FDA officials, they do not have a centralized database which tracks the letters they have issued to sponsors when sponsors were late or failed to submit ASRs, or when FDA determined that sponsors were not sufficiently progressing in completing their studies. Our review of FDA’s oversight of a sample of postmarketing studies required under the accelerated approval process suggests its use may be limited when sponsors do not submit their ASRs within required time frames. Specifically, we found that sponsors were late in submitting ASRs for 12 postmarketing studies in our sample. However, FDA issued an administrative action letter to the sponsor of only 1 of these 12 studies. In addition to sending administrative action letters for drugs approved under the accelerated approval process, FDA also may begin expedited proceedings to withdraw a drug’s approval in a number of situations including if it determines that: 1) sponsors are not completing required confirmatory postmarketing studies with due diligence, or 2) a study failed to confirm the drug’s clinical benefit. According to FDA officials, the agency has never withdrawn from the market a drug approved through the accelerated process due to either of these issues. Our review of the 90 applications approved based on a surrogate endpoint under the accelerated approval process revealed several circumstances that appeared to meet the regulatory conditions for withdrawal, but FDA was hesitant to use its enforcement authority. Specifically, we found that for 36 of the 90 applications, drug sponsors had not fulfilled their confirmatory study requirements by establishing the clinical effectiveness of those drugs. This includes several applications for drugs that FDA had approved more than 10 years ago and for which sponsors had not yet completed all of their required studies, and others where the studies failed to confirm the drug’s clinical effectiveness. An example of sponsors not completing confirmatory studies includes the case of ProAmatine: FDA approved ProAmatine in 1996 to treat individuals with low blood pressure based on the surrogate endpoint of raising 1-minute standing systolic blood pressure. As a condition of approval, it required the sponsor, Shire Pharmaceuticals, to conduct a confirmatory study to validate long-term clinical benefits. However, the sponsor was not able to design and conduct a sufficiently adequate clinical study, and the clinical benefit of the drug has never been established. Despite this, the sponsor benefited from market exclusivity between 1996 and 2003, and sales of this drug generated millions of dollars for the company (see app. IV for total U.S. sales since approval for ProAmatine and six other drugs for which applications had not converted to full approval as of December 19, 2008). Furthermore, once ProAmatine’s market exclusivity ended in 2003, FDA approved five generic versions of the drug, although the clinical benefit of the drug was never confirmed. Recognizing that the study requirement related to ProAmatine was still outstanding; in August 2007 FDA posted a letter on its Web site inquiring about certain legal and regulatory issues related to the generic manufacturers’ potential completion of the confirmatory study. In August 2008, according to officials, FDA posted another letter in which it threatened to withdraw approval of ProAmatine and the generic drugs based on its accelerated approval authority if no company completed the required studies. At the same time it indicated that 3 years of market exclusivity would be available if a company completes the study and it confirms clinical benefit. As of June 2009, nearly 13 years after it approved ProAmatine, FDA had not initiated the withdrawal of ProAmatine or the generic versions, but FDA officials indicated that it planned to issue a final administrative action letter to the sponsor and generic manufacturers in a final effort to obtain completion of the required study. An example of sponsors completing confirmatory studies which failed to confirm the drug’s clinical effectiveness includes the case of Iressa: FDA approved Iressa in May 2003 to treat patients with non-small cell lung cancer based on the surrogate endpoint that showed that it causes significant shrinkage in tumors in about 10 percent of patients. As a condition of approval, FDA required the sponsor to conduct a postmarketing study to verify the expected clinical benefit. In December 2004, FDA announced that the results of the clinical trial in 1,700 patients indicated that the drug did not prolong survival. Despite this, FDA did not utilize its authority to withdraw the drug from the market. However, it did take the step of restricting Iressa’s use to a subset of patients who had already taken the medicine and whose doctor believed it was helping them. FDA directed new patients wanting to take Iressa to two other available therapies shown in studies to improve survival in patients whose cancer has progressed while on previous therapies. According to FDA officials, they have not developed guidance to specify the conditions under which they would exercise their authority to withdraw approval of a drug that the agency approved based on surrogate endpoints under the accelerated approval process. Under the regulations, FDA can initiate expedited withdrawal procedures for drugs approved based on surrogate endpoints when sponsors fail to perform required confirmatory postmarketing studies with due diligence, or a study failed to confirm the drug’s clinical effectiveness. Although the regulations outline conditions under which FDA could utilize expedited withdrawal authority for drugs approved under the accelerated approval process based on surrogate endpoints, withdrawal is not required and the agency has latitude in determining when to exercise this authority. The officials recognized that they have not specified criteria for defining how they would implement the due diligence requirement of the regulations, such as determining how long it should take a sponsor to complete a study or when a sponsor is taking too long, which could result in a drug’s withdrawal from the market. Without such guidance, officials indicated that it is not clear as to when or how to enforce the due diligence criteria for withdrawal, but acknowledged that ProAmatine may have been a case where they could have fully utilized their withdrawal authority. Officials further stated that it would be difficult to develop specific criteria for due diligence for withdrawal that could be generally applied to the wide range of diseases treated by drugs approved under the accelerated approval process. Additionally, they questioned the need for such specific criteria, because other than the case of ProAmatine, they have rarely faced circumstances where drug sponsors were reluctant to work toward completing their postmarketing study. Regarding cases when a confirmatory study failed to demonstrate a drug’s clinical benefit, agency officials indicated they would be hesitant to withdraw a drug in such cases. For example, they said that despite the confirmatory study results, Iressa may still be effective for a number of patients. The use of surrogate endpoints has been accepted by FDA as a means of demonstrating the efficacy of drugs approved through both its traditional and accelerated approval processes. While the use of surrogate endpoints can expedite the approval of drugs, reliance on these endpoints also introduces uncertainty regarding the risks and benefits of a drug because the clinical effectiveness is not directly measured. Thus their use can lead to the adoption of useless or even harmful therapies 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. With the creation of the accelerated approval process in 1992, FDA expanded the use of surrogate endpoints, thus expediting the approval of certain drugs for serious or life-threatening diseases. While the availability of these drugs provided new treatment options to patients, it also introduced new elements of uncertainty, as FDA allowed the use of surrogate endpoints which had not yet been shown to be valid predictors of a drug’s clinical effectiveness. Thus, patients could potentially find themselves taking drugs approved under the accelerated process that may not be clinically effective in treating their illness. Recognizing the need to mitigate this uncertainty and risk, FDA required that drug sponsors conduct postmarketing studies with due diligence to confirm that such drugs actually have clinical benefits. It also implemented a process for monitoring the progression and completion of these studies, including establishing a database to track the progression of the studies, and instituting expedited withdrawal procedures for drugs when studies are not completed or if they failed to confirm clinical benefits. Despite these tools, weaknesses in FDA’s monitoring and enforcement process hamper its ability to effectively oversee postmarketing studies. FDA has not routinely and consistently reviewed the ASRs submitted by drug sponsors, and information the agency needs to ensure that sponsors are completing required confirmatory studies in a timely manner was not consistently entered into its tracking database. Therefore, the agency has lacked an effective management information system capable of generating data needed to effectively monitor the progress of such studies. FDA has recently implemented several initiatives to enhance its oversight of postmarketing studies, which may provide the agency with an opportunity to develop reliable data needed to adequately monitor the progress of studies and improve oversight. Additionally, FDA’s plans to designate personnel to serve as focal points for monitoring postmarketing studies may provide a greater emphasis on oversight of such studies. It is too early to tell if these initiatives will be successful. While FDA’s new system, DARRTS, may have features superior to the tracking database it is replacing, the root cause of many problems associated with the previous system was not the system itself, but the failure to enter information into it. The ultimate success of FDA’s new initiatives is largely dependent on the timely review and prompt entry of ASRs into DARRTS. While FDA has implemented measures to enhance its monitoring of postmarketing studies, the agency has taken a passive approach to enforcing confirmatory study requirements. It has never exercised its authority to withdraw a drug it approved based on surrogate endpoints under the accelerated approval process, even when such studies have been outstanding for nearly 13 years. Further, FDA has not attempted to clarify the circumstances under which it would exercise this authority and has never developed specific time frames for sponsors to complete their confirmatory studies. The combination of its ineffective monitoring and lack of criteria outlining when a drug should be withdrawn from the market make it difficult for FDA to utilize its enforcement authority. Consequently, drugs which have not proven to be clinically effective may remain on the market while their associated confirmatory studies remain incomplete. To clarify FDA’s enforcement authority under the accelerated approval process, we recommend that the Commissioner of FDA take the following action: Clarify the conditions under which the agency would utilize its authority to expedite the withdrawal of drugs approved based on surrogate endpoints under the accelerated approval process if sponsors either fail to complete required confirmatory studies with due diligence, or if studies are completed, but fail to demonstrate the clinical effectiveness of the drugs. We provided a draft of this report to HHS for review. HHS provided written comments from FDA, which are reprinted in appendix V. In its comments, FDA disagreed with our recommendation to clarify the conditions under which it would utilize its authority to expedite the withdrawal of drugs approved based on surrogate endpoints under the accelerated approval process. FDA also said that it thought we minimized the success of the accelerated approval program. The agency stressed that this program has provided millions of patients access to new treatments sooner than would have been possible under the traditional approval process. In addition, FDA described its efforts to improve monitoring of the completion of required and requested postmarketing studies. FDA also provided technical comments, which we incorporated as appropriate. Regarding our recommendation, FDA indicated that it would be difficult, if not impossible, to provide further clarification as to when it might utilize its authority to expedite withdrawal of a drug approved on the basis of surrogate endpoints. FDA acknowledged that there have been cases where confirmation of the clinical benefit of drugs approved under the accelerated approval program did not occur in a timely manner. However, FDA stressed that, unless there are clear safety concerns emanating from the confirmatory trial, it must carefully assess each case and consider the underlying reasons and consequences of all regulatory options, including their potential impact on patients. In expressing its disagreement and the need for case-by-case assessments, FDA cited the examples of two drugs mentioned in our report—ProAmatine and Iressa. In the case of ProAmatine, for which adequate clinical trials have never been completed to establish the drug’s benefit, FDA stated that it would not be appropriate to initiate expedited withdrawal, as ProAmatine is the only approved therapy for the condition that it treats. FDA stated that rather than providing an example of the agency failing to exercise its authority to withdraw approval, ProAmatine provides a good example of the complex issues it must consider when a clinical benefit has not been confirmed and the drug approved remains the only FDA-approved treatment for a serious or life-threatening condition. Regarding Iressa, FDA noted that, despite the fact that the clinical trials failed to confirm the drug’s clinical benefit, they nonetheless suggested there were some positive outcomes for certain patients. Therefore, rather than withdraw approval of Iressa, FDA indicated that it took an appropriate and balanced approach by restricting access to those patients who were already receiving treatment and whose physicians felt they were benefiting from Iressa and to other patients based on physician assessments. We recognize that FDA faces challenges in determining whether it should initiate the expedited withdrawal of a drug approved under the accelerated approval process. Acknowledging that the clinical benefit of these drugs is uncertain at the time of their approval, FDA’s 1992 regulations provided that expedited withdrawal of drugs may be appropriate when confirmatory studies fail to show clinical benefits. Indeed, FDA’s ability to require sponsors to complete clinical trials with due diligence and its authority to undertake the expedited withdrawal of a drug if a clinical benefit is not confirmed are specifically cited by FDA in its comments as two important safeguards intended to minimize the risks inherent in the accelerated approval process. Although nearly 17 years have elapsed since FDA issued the accelerated approval regulations, the agency has not attempted to define the circumstances under which the authority that this important safeguard provides would be used. While FDA commented that it would consider exercising its withdrawal authority if a clear safety concern emerged from a confirmatory trial, which would certainly be appropriate, the regulations governing the use of surrogate endpoints and the purpose of the required studies are focused on establishing the clinical benefit of a drug, not its safety. We agree that it may be challenging for FDA to develop guidance to clarify the conditions under which it would utilize its expedited withdrawal authority. However, we do not agree that it is impossible—or even too difficult—to do so, nor do we believe that such guidance would have to be so prescriptive as to prevent FDA from considering the unique circumstances of individual cases. As the scientific experts charged with overseeing the use of drugs it approves, FDA should be in a position to implement this recommendation. In our view, this would serve two purposes. First, this would clarify within FDA when this option should be considered in order to mitigate risks to patients taking drugs which FDA has approved. Second, it would serve to clarify, for drug sponsors, FDA’s expectations regarding performance requirements related to completing required confirmatory studies, and the consequences of not meeting requirements. This would put drug sponsors on notice that, although FDA has not utilized this authority to date, it remains a viable option, and would enhance the agency’s ability to effectively carry out its oversight responsibilities. Without specific parameters governing the use of this authority, such as definitive time frames or other requirements for when sponsors need to complete confirmatory studies, there appears to be little likelihood that FDA would ever utilize its authority, thus potentially diminishing the value of what FDA considers an important safeguard. Regarding the examples of ProAmatine and Iressa, we recognize that FDA faced numerous scientific and ethical issues in overseeing the use of these drugs, and that it ultimately needed to balance such factors when determining the best approach to take in overseeing the completion of required confirmatory studies. However, we chose to discuss these drugs because the very circumstances surrounding them illustrated specific oversight issues which FDA considered when it developed the 1992 accelerated approval regulations. The circumstances involving these drugs also highlighted the challenges that FDA faces in determining how to conduct its oversight responsibilities. As delineated in the regulations, the purpose of these confirmatory studies is to verify and describe the clinical benefits of these drugs. When sponsors fulfill these requirements, they establish the clinical evidence similar to what would ordinarily have been required were the drugs reviewed under the traditional approval process. In neither of these two instances has this level of evidence been established—no adequate study has ever been completed to confirm the clinical benefits of ProAmatine and, while the studies for Iressa were conducted, they failed to confirm any clinical benefit. Specifically, in the case of ProAmatine, as we noted in our report, FDA officials acknowledged that this matter may have gone on too long without being resolved. Although FDA’s comments indicate that it believes the sponsor conducted trials with due diligence, 13 years have elapsed, and although the drug is also available generically, sufficient confirmatory trials have not been completed. As FDA indicates in its comments, obtaining the completion of the trials has become a complex matter and it is still seeking ways to encourage one or more of the generic manufacturers to conduct the confirmatory clinical trials. Thus, we believe that this example raises questions about whether the sponsor had displayed due diligence in meeting the confirmatory study requirements as well as what circumstances would lead the agency to exercise its withdrawal authority. We provided the example of Iressa to illustrate the challenges that FDA faces in overseeing the accelerated approval process. In developing the 1992 regulations, FDA specifically anticipated a situation similar to that posed by Iressa—the completion of a confirmatory study that failed to demonstrate a drug’s clinical benefit. Although 17 years have passed, FDA has not established guidance clarifying how it would exercise its expedited withdrawal authority in such circumstances. While FDA’s actions in these two cases may have been appropriate, they nonetheless serve to illustrate the need to clarify use of the expedited withdrawal authority, consistent with our recommendation. Regarding FDA’s statement that the accelerated approval process has been very successful, and has resulted in the early approval of many significant therapeutic advances for patients, we believe that this conclusion is a matter of scientific judgment, and beyond the scope of our review. However, our report clearly identified both the purpose of the accelerated approval process, and the specific drugs that FDA has approved using this process. Thus, we believe we provide an accurate factual description of the drugs approved on the basis of surrogate endpoints through this process since it was instituted in 1992. Further, we do not believe that our emphasis on examples of FDA’s decisions regarding specific drugs and the results of their associated confirmatory studies, in any way minimizes the benefits provided by the accelerated process. Instead they are meant to illustrate challenges associated with FDA’s oversight of such an important program. Finally, regarding FDA’s ongoing efforts to improve its oversight of postmarketing studies in both the accelerated and traditional approval processes, FDA acknowledged that its oversight of postmarketing studies in general has been inadequate, and agreed that improvements are needed. The agency indicated that because of inadequate staffing and information technology resources and competing priorities, its past tracking of postmarketing studies has not been timely. FDA stated that it has begun to implement a number of improvements to ensure appropriate oversight, more efficient tracking, and expeditious review of postmarketing submissions from sponsors, but stated that these efforts were not fully reflected in our report. We believe our report’s discussion of FDA’s efforts to improve the monitoring of postmarketing studies sufficiently addresses FDA’s ongoing initiatives. Specifically, we discuss its contract with Booz Allen Hamilton, the establishment of new tracking coordinator positions which are outlined in its revised Manual of Policies and Procedures, and planned improvements in data reporting capabilities through the DARRTS system. In particular, FDA highlighted the results of efforts from its contractor, Booz Allen Hamilton, which FDA said resulted in extensive updating of the data in the agency’s tracking database. However, the results of these updates to the database by FDA’s contractor became available subsequent to our work, and thus could not be reflected in the data we presented in this report. The fact that extensive updates needed to be made, however, confirms our assessment that FDA’s monitoring and oversight has been ineffective. We are encouraged that FDA is taking steps to facilitate timely oversight of postmarketing studies through improved tracking provided by its contractor and a new database. As agreed with your office, unless you publicly announce the contents of this report earlier, we plan no further distribution until 30 days from the report date. At that time, we will send copies to the Commissioner of FDA and appropriate congressional committees. The report also will be available at no charge on GAO’s Web site at http://www.gao.gov. If you or your staff have any questions about this report, please contact me at (202) 512-7114 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 VI. Since the Food and Drug Administration (FDA) began approving drugs under the accelerated approval process in 1992, it has approved 90 applications based on surrogate endpoints. In several cases, FDA approved multiple applications for the same drug; as a result, as of November 20, 2008, FDA had approved 64 drugs associated with these applications under the accelerated approval process. Table 5 provides a description of each of these 64 drugs, their new drug application (NDA) or biologic license application (BLA) numbers, and the surrogate endpoints used for approval. Between January 1998 and June 2008, the Food and Drug Administration (FDA) approved 204 New Molecular Entity (NME) drugs under its traditional process. Of those 204, 69 NME drugs were approved using surrogate endpoints. Table 6 provides a description of each of the 69 NME drugs, their new drug application (NDA) numbers, and the surrogate endpoints used for approval. To review specific instances of the Food and Drug Administration’s (FDA) monitoring and enforcement activities, we selected a judgmental sample of 15 applications approved based on surrogate endpoints under the accelerated program and the 35 postmarketing studies that FDA required drug sponsors to complete for these drugs. These applications were selected to generate a sample that included a variety of drugs and a range of studies at various stages of completion. We then provided FDA with a standard series of questions for each of the 35 studies, and requested that FDA’s medical reviewers, who are responsible for monitoring these 35 studies, provide specific information on them, including a description of the studies, FDA’s efforts to monitor these studies, and applicable enforcement actions taken, if any, to prompt sponsors’ compliance. FDA officials indicated that several individuals were involved in completing the questions provided for each of the 15 applications. FDA staff completed the first half of the questions related to description of the studies. The medical reviewers or other review staff provided information on the agency’s monitoring efforts and enforcement actions. The applications we selected and the information request are provided below. Listed in table 8 are seven applications for drugs approved based on surrogate endpoints under the accelerated approval process, and total U.S. sales, since approval, associated with those drugs. This listing includes applications, which as of December 19, 2008, had not been converted to full approval, and more than 5 years had elapsed since they were initially approved. In addition to the contact named above, Geri Redican-Bigott, Assistant Director; Shaunessye Curry; Krister Friday; Mollie Hertel; Julian Klazkin; David Lichtenfeld; Rich Lipinski; and Thanh Lu made key contributions to this report.

Summary: Before approving a drug, the Food and Drug Administration (FDA) assesses a drug's effectiveness. This assessment may be based on evidence showing that a drug has a positive impact on a surrogate endpoint--a laboratory measure, such as blood pressure--instead of more direct clinical evidence, like preventing strokes. After approval, FDA often requires or requests a drug sponsor to further study the drug. Concerns have been raised about FDA's reliance on surrogate endpoints and its oversight of postmarketing studies. This report provides information on (1) all drug applications approved based on surrogate endpoints in FDA's accelerated approval process, (2) a subset of applications for potentially innovative drugs approved based on surrogate endpoints under FDA's traditional process, and (3) FDA's oversight of postmarketing studies. GAO identified drugs approved based on surrogate endpoints, obtained the status of related postmarketing studies, and reviewed FDA's oversight of a sample of 35 studies it required under its accelerated approval process, selected to include studies which were at varying levels of completion. FDA approved 90 applications for drugs based on surrogate endpoints through its accelerated approval process from the creation of the process in 1992 through November 20, 2008, and about two-thirds of postmarketing studies have been closed. FDA created the accelerated approval process to expedite the approval of drugs which are designed to treat serious or life-threatening illnesses and are expected to provide meaningful therapeutic benefits compared to existing treatments. Under this process, 79 of the 90 applications were approved for drugs to treat cancer, HIV/AIDS, and inhalation anthrax. Because of the need to expedite approval, FDA approves drugs under this process based on surrogate endpoints which are not yet proven substitutes for clinical endpoints, but does require that drug sponsors complete postmarketing studies to confirm the drug's clinical benefit. FDA had required drug sponsors to conduct 144 postmarketing confirmatory studies associated with these 90 applications, and as of December 19, 2008, classified 64 percent as closed--meaning that drug sponsors had met FDA's requirements for these studies or FDA determined the studies were no longer needed or feasible. However, several of the remaining studies have been classified by FDA as open for an extended period. FDA approved 69 applications on the basis of surrogate endpoints for new molecular entities (NME)--potentially innovative drugs containing active chemical substances that have never been approved for marketing in the United States in any form--through its traditional approval process from January 1998 through June 30, 2008. These 69 NME drugs accounted for about one-third of the 204 applications for NME drugs which FDA approved through its traditional process during this period, many for drugs to treat cancer, heart disease, and diabetes. Unlike surrogate endpoints used in the accelerated process, FDA considers those used in the traditional process as valid substitutes for demonstrating the clinical benefit of drugs, and thus does not require sponsors to complete postmarketing confirmatory studies. However, FDA requested that sponsors complete 175 postmarketing studies to obtain other information on many of these NME drugs, and as of February 13, 2009, FDA classified about one-half as closed. Weaknesses in FDA's monitoring and enforcement process hamper its ability to effectively oversee postmarketing studies. FDA has not routinely been reviewing sponsors' annual submissions on the status of studies in a timely manner. It has little in the way of readily accessible, comprehensive data to monitor studies' progression and does not consider such oversight a priority. FDA is implementing initiatives to improve its oversight, but it is too early to tell if they will be effective. Although FDA has authority to expedite the withdrawal of a drug from the market if a sponsor does not complete a required confirmatory study with due diligence, or if a study fails to confirm a drug's clinical benefit, it has not specified the conditions thatwould prompt it to do so. It has never exercised its authority, even when such study requirements have gone unfulfilled for nearly 13 years.