New Drug Approval: FDA Needs to Enhance Its Oversight of Drugs Approved on the Basis of Surrogate Endpoints
Published: 2009-09-23T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: 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.
section_title: What GAO Found
paragraphs: 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.

section_title: Letter
paragraphs: The Food and Drug Administration (FDA), an agency within the  Department of Health and Human Services (HHS), is the federal agency  responsible for ensuring the safety and effectiveness of medical products,  including drugs and biological products. Before a new drug can be  marketed in the United States, a drug sponsor must demonstrate that it is  safe and effective for its intended use, and obtain approval from FDA.   Sponsors can demonstrate safety and effectiveness by conducting studies,  known as clinical trials, on human volunteers and then submitting the  results, as part of an application, to FDA for review. As part of its  approval process, FDA reviews the data in the application, including the  results of the clinical trials. If FDA determines that the drug’s benefits  outweigh its risks, it may approve the sponsor’s application to market a  new drug.
FDA generally prefers that when conducting clinical trials, sponsors  demonstrate the effectiveness of a new drug by showing its impact on a  clinical endpoint—a direct measure of how a patient feels, functions, or  survives. Demonstrating the effectiveness of a new drug, however, can  require a sponsor to study the drug on thousands of patients over several  years, potentially costing hundreds of millions of dollars. As an alternative  to demonstrating a drug’s effectiveness by its impact on a clinical  endpoint, sponsors may submit, and FDA may approve applications based  on clinical trials that demonstrate a new drug’s impact on a surrogate  endpoint—a laboratory measure or physical sign used as a substitute for a  clinical endpoint—that reasonably predicts a clinical benefit. For example,  demonstrating that a drug can lower blood pressure may be used as a  surrogate endpoint to predict whether the drug is effective in preventing  strokes. Through the use of surrogate endpoints, a drug sponsor can  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  effectiveness on a clinical endpoint. Unlike establishing clinical  effectiveness, however, demonstrating the effect of a new drug on a  surrogate endpoint does not always directly prove any benefit to a patient.  Thus, reliance on a surrogate endpoint can create uncertainty because a  drug’s effect on a clinical outcome may not be known until after the drug  is approved and further studied in patients.
FDA allows the use of surrogate endpoints in both the accelerated and  traditional approval processes. In 1992 FDA established an accelerated  approval process to expedite the approval of applications for certain new  drugs that are designed to treat serious or life-threatening illnesses and  which are expected to provide a meaningful therapeutic benefit over  existing therapy. Due to the need to expedite approval of such drugs,  under this process, FDA may accept, as a basis for approval, evidence that  demonstrates the drug’s impact on surrogate endpoints which are  reasonably likely to predict clinical benefit, and have not yet been  demonstrated to be valid substitutes for clinical endpoints. Because FDA’s  approval of a drug based on these surrogate endpoints rarely establishes  the drug’s clinical benefits in relation to a clinical endpoint, FDA has  developed additional regulatory requirements when sponsors use  surrogate endpoints under the accelerated process. Specifically, when  FDA approves a drug based on a surrogate endpoint under the accelerated  approval process, FDA requires a sponsor, as a condition of approval, to  conduct postmarketing confirmatory studies to validate that a drug’s  impact on a surrogate endpoint also leads to clinical benefits for patients.
In contrast, under the traditional process—by which FDA reviews most  drugs—FDA recognizes the surrogate endpoints as valid substitutes for  clinical endpoints, and thus there are no such postmarketing study  requirements. In addition, under both the accelerated and traditional  approval processes, FDA may request—and sponsors may agree—to  conduct additional postmarketing studies to address other matters that  FDA has determined are worthy of further examination.
Regardless of whether a postmarketing study has been required or  requested by FDA, sponsors conducting such studies must comply with  provisions in the Food and Drug Administration Modernization Act of 1997  (FDAMA) and implementing regulations to report annually to FDA on the  status of postmarketing studies. According to FDA’s regulations, sponsors  must continue to submit these reports each year until FDA notifies the  sponsor, in writing, that it has determined that the study has been fulfilled  or that the study is either no longer feasible or would no longer provide  useful information.
While FDA has long accepted surrogate endpoints to support drug  approval, the use of such endpoints can be controversial. Although the use  of surrogate endpoints can expedite drug approvals, it can also add  uncertainty when the relationship between a surrogate endpoint and  clinical benefit or endpoint has not been fully established. Recently,  concerns have surfaced about some drugs which FDA approved based on  surrogate endpoints. For example, in 2008 FDA approved the drug Avastin  to treat breast cancer based on its ability to limit tumor growth; however,  studies used to support approval also showed that the drug did not  improve overall survival. You asked us to examine FDA’s oversight of  drugs approved based on surrogate endpoints. In this report we:  1. identify applications FDA has approved based on surrogate endpoints  through its accelerated approval process, including the surrogate  2. endpoints used for approval, as well as the status of any associated  postmarketing studies;  identify applications FDA has approved for selected new drugs based  on surrogate endpoints in its traditional approval process, including  the surrogate endpoints used for approval, as well as the status of any  associated postmarketing studies; and 3.  evaluate FDA’s oversight of postmarketing studies.
To identify the applications for new drugs that FDA has approved on the  basis of surrogate endpoints under the accelerated approval process, we  obtained information from FDA, which included a list of all such  applications the agency approved from June 1992 through November 20,  2008 (app. I contains a list of individual drugs, application numbers, and  specific surrogate endpoints used for approval through the accelerated  approval process). We analyzed this information to determine the number  of approvals per year, the endpoints used for approval (e.g., measures of  viral load), and the diseases that drugs were approved to treat based on  surrogate endpoints.
To identify the number and status of postmarketing studies FDA has  required or requested for those drugs approved based on surrogate  endpoints under the accelerated approval process, we obtained a list of  such studies from FDA. Because FDA may approve multiple applications  for the same drug, the same study can be associated with multiple  applications; therefore, we utilized a unique numerical identifier assigned  by FDA to each study to ensure that we did not count the same study more  than once. For those postmarketing studies required under the accelerated  approval process, FDA also provided certain key dates related to the  progress of these studies, including the dates drug sponsors submitted  their final study reports to FDA, and the dates FDA notified sponsors it  had approved these reports. We then used this information, which was  current as of December 19, 2008, to determine, among other things, the  number and percentage of postmarketing studies by status and the average  time it took sponsors to fulfill their postmarketing study requirement. To  provide the most current information on the status of these studies, FDA  had to research electronic and paper files because the information was not  readily available in the database FDA uses to track the status of  postmarketing studies. To assess the reliability of the information FDA  provided, we compared the status and key dates for a sample of studies to  the source data contained in FDA’s files. We determined the data were  sufficiently reliable for the purpose of our review.
Similar to the postmarketing studies FDA required under its accelerated  approval process, FDA did not have readily available data on studies it  requested, such as certain key dates related to progress of the studies  including the dates FDA approved final study reports. Because FDA  officials indicated that it would be too time consuming to generate these  time line data, as they did for the required studies, they only provided us  with status information from their database used to track postmarketing  studies. They provided us with data as of January 6, 2009. For these  requested postmarketing studies, we also used a unique numerical  identifier assigned by FDA for each study to ensure that we did not count  the same study more than once. We then identified the number and  percentage of studies by status and by the length of time studies have  remained open. We could not determine how long it took sponsors to  fulfill studies, because the dates FDA determined the studies were fulfilled  were not readily available. We did not verify the accuracy of this  information. One limitation of using these data was that status information  may not be current if FDA had not updated it in a timely manner.  However, this represents the best information available and is what FDA  uses to track the progress of requested postmarketing studies.
To identify applications for selected new drugs that FDA approved on the  basis of surrogate endpoints under the traditional process, we limited our  scope to a subset of drugs. Because FDA could not readily identify the  extent to which it approves applications based on surrogate endpoints  through its traditional process, we reviewed only those applications FDA  approved for new molecular entities (NMEs)—potentially innovative drugs  containing active chemical substances that have never been approved for  marketing in the United States in any form. Although applications for  NME drugs represented only about 10 percent of all applications FDA  approved during this period, we limited our review to NME drugs because  they represent the newest and potentially most innovative drugs. As a  result, we believe our analyses would capture many of the key concerns  related to the use of surrogate endpoints for new drug approval. One  limitation of our analysis is that the percentage of NME drugs approved  based on surrogate endpoints cannot be projected to the other drugs FDA  approved through the traditional process during this period.
Specifically, we reviewed information on all 219 applications for NME  drugs that FDA approved from January 1, 1998, through June 30, 2008, and  determined the proportion of applications FDA approved that were based  on surrogate and clinical endpoints. This time period provided the most  recent 10-year approval window at the time of our review. Of the 219 NME  drugs, we excluded 15 because they were not approved to treat a specific  disease. For the remaining 204 NME drugs, we examined documents  summarizing the results of clinical trials for each of them. These  documents, accessed from FDA’s Web site, included the drugs’ original  labeling and FDA’s original medical reviews. We reviewed these  documents and determined whether or not the primary endpoint—the  principal measure used to determine whether the drug was effective—for  each of the 204 NME drugs was a surrogate or clinical endpoint. We then  submitted our analyses to FDA to confirm that we correctly identified the  endpoints as surrogate or clinical for each of the 204 applications we  reviewed (app. II contains a list of individual drugs, application numbers,  and specific surrogate endpoints used for approval through the traditional  approval process). After identifying the number of applications for NME  drugs in our sample approved on the basis of surrogate endpoints through  the traditional approval processes, we determined the number of  approvals per year, the specific endpoints used for approval, and the  diseases for which drugs were approved.
To identify the number and status of postmarketing studies FDA requested  for the approved NME drugs, we obtained a list of such studies from FDA,  including information on the status of each study at the time of our review.  FDA provided us with data on the status of studies as of February 13, 2009.  We then used the same approach for analyzing information on these  requested postmarketing studies as we used for those studies requested by  FDA under the accelerated approval process, subject to the same  limitations.
To evaluate FDA’s oversight of postmarketing studies, we reviewed  relevant laws and regulations, and policy documents describing FDA’s  program oversight and enforcement authority. We also examined internal  control standards, which include the need to establish policies and  procedures to help ensure effective and efficient operations. We  interviewed FDA officials to identify the oversight activities it engages in  to monitor the postmarketing studies it has required or requested sponsors  to conduct. We also reviewed the enforcement tools FDA uses or can use  to ensure sponsors conduct these studies. To review specific instances of  FDA’s 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 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   (app. III identifies the 15 applications which we selected, and provides the  standard series of questions we provided to FDA for each of the 35  postmarketing studies). 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  time lines, current statuses, and ASR submissions. The medical reviewers  or other staff provided information related to any study completion  problems, underlying issues, and monitoring activities. To obtain a better  understanding of FDA’s oversight of postmarket studies, we reviewed  reports issued by HHS’s Office of Inspector General (HHS-OIG) and Booz  Allen Hamilton, a contractor retained by FDA in 2006 to conduct an  independent analysis of the agency’s postmarket oversight processes and  procedures. Finally, for certain drugs approved under the accelerated  approval process, we obtained annual U.S. sales data from the time the  applications for these drugs were approved through December 2008   (app. IV identifies the applications and drugs and the total U.S. sales since  approval). As of December 19, 2008, these applications had not been  converted to full approval, and more than 5 years had elapsed since they  were initially approved. We obtained the annual sales data from IMS  Health, a provider of market information to the pharmaceutical and health  care industries.
We conducted this performance audit from June 2008 through September  2009 in accordance with generally accepted government auditing  standards. Those standards require that we plan and perform the audit to  obtain sufficient, appropriate evidence to provide a reasonable basis for  our findings and conclusions based on our audit objectives. We believe  that the evidence obtained provides a reasonable basis for our findings  and conclusions based on our audit objectives.
subsections: section_title: Background
paragraphs: 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.
subsections: section_title: The Benefits and Risks of Surrogate Endpoints in Drug Approval
paragraphs: 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.
section_title: FDA Role in the Drug Development and Application Review Process
paragraphs: 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.
section_title: FDA’s Oversight of Postmarketing Studies
paragraphs: 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.
section_title: FDA Has Approved Many Applications Based on Surrogate Endpoints through Its Accelerated Approval Process and about Two-Thirds of Postmarketing Studies Have Been Closed
paragraphs: 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.
subsections: section_title: FDA Approved 90 Applications Based on Surrogate Endpoints under the Accelerated Approval Process, the Majority for Drugs to Treat Cancer and HIV/AIDS
paragraphs: 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).
section_title: FDA Required 144 Confirmatory Postmarketing Studies under the Accelerated Process, and About Two- Thirds Have Been Closed
paragraphs: 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.
section_title: FDA Requested over 300 Postmarketing Studies under the Accelerated Process, and About Two- Thirds Have been Closed
paragraphs: 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.
section_title: FDA Approved about One-Third of NME Drug Applications Based on Surrogate Endpoints through Its Traditional Process and about Half of the Postmarketing Studies Requested Have Been Closed
paragraphs: 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.
subsections: section_title: About One-Third of the Applications for NME Drugs Approved under the Traditional Process Were Based on Surrogate Endpoints, Many for Drugs to Treat Cancer, Cardiovascular Disease, and Diabetes
paragraphs: 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.
section_title: FDA Requested 175 Postmarketing Studies under Its Traditional Process, and About One- Half Have Been Closed
paragraphs: 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.
section_title: FDA’s Oversight of Postmarketing Studies Is Hindered by Weaknesses in Its Monitoring and Enforcement
paragraphs: 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.
subsections: section_title: FDA Has Not Been Routinely Monitoring the Status of Postmarketing Studies, although Initiatives to Improve Its Monitoring Are Underway
paragraphs: 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.
section_title: FDA Has Not Fully Utilized Its Enforcement Tools Related to Required Postmarketing Studies
paragraphs: 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.
section_title: Conclusions
paragraphs: 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.
section_title: Recommendations
paragraphs: 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.
section_title: Agency Comments and Our Evaluation
paragraphs: 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.
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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.
section_title: Appendix I: Applications for Drugs Approved under FDA’s Accelerated Approval Process Using Surrogate Endpoints
paragraphs: 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.
section_title: Appendix II: Applications for Drugs Approved under FDA’s Traditional Process Using Surrogate Endpoints
paragraphs: 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.
section_title: Appendix III: Applications Selected and Questions Regarding FDA’s Oversight of Required Postmarketing Studies
paragraphs: 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.
section_title: Appendix IV: Sales for Selected Drugs Approved Based on Surrogate Endpoints under the Accelerated Approval Process
paragraphs: 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.
section_title: Appendix V: Comments from the Department of Health and Human Services
section_title: Appendix VI: GAO Contact and Staff Acknowledgments
subsections: section_title: Acknowledgments
paragraphs: 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.