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. 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. FDA Has Approved Many Applications Based on Surrogate Endpoints through Its Accelerated Approval Process and about Two-Thirds of Postmarketing Studies Have Been Closed

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. 2). 3). 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. The 52 studies FDA classified as open covered a variety of statuses, and  thus were at varying levels of completion. 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

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. 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

From January 1, 1998, through June 30, 2008, FDA approved 204  applications for NMEs to treat diseases through the traditional approval  process. FDA’s Oversight of Postmarketing Studies Is Hindered by Weaknesses in Its Monitoring and Enforcement

FDA has not been routinely monitoring the status of postmarketing  studies, primarily because oversight of these studies is not considered a  priority. In addition,  FDA does not know whether drug sponsors are submitting complete and  accurate ASRs in a timely manner. 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. Despite this, FDA did not  utilize its authority to withdraw the drug from the market. Despite these tools, weaknesses in FDA’s monitoring and enforcement  process hamper its ability to effectively oversee postmarketing studies. It is too early  to tell if these initiatives will be successful. 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. Recommendations

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. Of those 204, 69 NME drugs were approved using  surrogate endpoints. Appendix III: Applications Selected and Questions Regarding FDA’s Oversight of Required Postmarketing Studies

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.
Why GAO Did This Study

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.

What GAO Found

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.