GAO 

United States Government Accountability Office

Report to the Ranking Member, 

Committee on Finance, U.S. Senate 

NEW DRUG 

APPROVAL 

FDA Needs to 

Enhance Its Oversight 

of Drugs Approved on 

the Basis of Surrogate 

Endpoints 

September 2009 

GAO-09-866 
What GAO Found

United States Government Accountability Office

Why GAO Did This Study

Highlights

Accountability Integrity Reliability

September 2009

NEW DRUG APPROVAL

FDA Needs to Enhance Its Oversight of Drugs

Approved on the Basis of Surrogate Endpoints

Highlights of GAO-09-866, a report to the 

Ranking Member, Committee on Finance, 

U.S. Senate 

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 Recommends

GAO recommends that FDA clarify 

the conditions under which it 

would utilize its authority to 

expedite the withdrawal of drugs 

under its accelerated approval 

process. FDA disagreed with the 

need to develop such clarifying 

guidance. GAO believes doing so 

would enhance FDA’s oversight. 

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 lifethreatening 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 that would prompt it 

to do so. It has never exercised its authority, even when such study 

requirements have gone unfulfilled for nearly 13 years. 

View GAO-09-866 or key components.

For more information, contact Marcia Crosse 

at (202) 512-7114 or crossem@gao.gov. 
Page i GAO-09-866 FDA’s Use of Surrogate Endpoints 

Contents 

Letter 1

Background 8 

FDA Has Approved Many Applications Based on Surrogate 

Endpoints through Its Accelerated Approval Process and about 

Two-Thirds of Postmarketing Studies Have Been Closed 14 

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 24 

FDA’s Oversight of Postmarketing Studies Is Hindered by 

Weaknesses in Its Monitoring and Enforcement 29 

Conclusions 35 

Recommendations 36 

Agency Comments and Our Evaluation 37 

Appendix I Applications for Drugs Approved under FDA’s 

Accelerated Approval Process Using Surrogate 

Endpoints 42 

Appendix II Applications for Drugs Approved under FDA’s 

Traditional Process Using Surrogate Endpoints 49 

Appendix III Applications Selected and Questions Regarding 

FDA’s Oversight of Required Postmarketing 

Studies 54 

Appendix IV Sales for Selected Drugs Approved Based on 

Surrogate Endpoints under the Accelerated 

Approval Process 57 

Appendix V Comments from the Department of Health and 

Human Services 58 
Appendix VI GAO Contact and Staff Acknowledgments 65 

Tables 

Table 1: Summary of Surrogate Endpoints for Accelerated 

Application Approvals, from June 19, 1992–November 20, 

2008 17 

Table 2: Status of Postmarketing Studies Requested under the 

Accelerated Approval Process, June 19, 1992– 

November 20, 2008 23 

Table 3: Summary of Surrogate Endpoints for NME Drug 

Application Approvals, from January 1, 1998–June 30, 2008 26 

Table 4: Status of Postmarketing Studies Requested under the 

Traditional Approval Process, January 1, 1998–June 30, 

2008 28 

Table 5: NDAs and BLAs Approved Based on Surrogate Endpoints 

under the Accelerated Approval Process, from June 19, 

1992–November 20, 2008 42 

Table 6: NDAs Approved Based on Surrogate Endpoints under the 

Traditional Approval Process, from January 1, 1998– 

June 30, 2008 49 

Table 7: List of 15 Accelerated Approval Applications Selected for 

Review 54 

Table 8: Total U.S. Sales for Selected Drugs Approved under the 

Accelerated Process 57 

Figures 

Figure 1: Applications Approved Using Surrogate Endpoints under 

FDA’s Accelerated Approval Process, June 19, 1992–

November 20, 2008 15 

Figure 2: Percentage of Approved Applications Granted 

Accelerated Approval for Cancer and HIV/AIDS Drugs, 

June 19, 1992–November 20, 2008 16 

Figure 3: Status of Postmarketing Studies FDA Required under Its 

Accelerated Approval Process, June 19, 1992– 

November 20, 2008 19 

Figure 4: Elapsed Time from Drug Approval to Fulfillment for 

Postmarketing Studies Required under the Accelerated 

Approval Process, June 19, 1992–November 20, 2008 20 

Page ii GAO-09-866 FDA’s Use of Surrogate Endpoints 
Figure 5: Percentage of Postmarketing Studies Requested under 

the Accelerated Approval Process by Disease, June 19, 

1992–November 20, 2008 22 

Figure 6: Percentage of Applications for NME Drugs Approved 

Using Surrogate Endpoints under FDA’s Traditional 

Approval Process, January 1, 1998–June 30, 2008 25 

Figure 7: Percentage of Postmarketing Studies Requested under 

the Traditional Process, by Disease, January 1, 1998– 

June 30, 2008 27 

Abbreviations 

ASR annual status report 

BLA Biologic License Application 

DARRTS Document Archiving, Reporting and Regulatory Tracking 

 System 

FDA Food and Drug Administration 

FDAAA Food and Drug Administration Amendments Act 

FDAMA Food and Drug Administration Modernization Act of 1997 

HHS Department of Health and Human Services 

NDA new drug application 

NME new molecular entity 

OIG Office of Inspector General 

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Page iii GAO-09-866 FDA’s Use of Surrogate Endpoints 
Page 1 GAO-09-866 FDA’s Use of Surrogate Endpoints 

 

United States Government Accountability Office

Washington, DC 20548 

 

September 23, 2009 

The Honorable Charles E. Grassley 

Ranking Member 

Committee on Finance 

United States Senate 

Dear Senator Grassley: 

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.1

 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.2

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.3

 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 

1

Biological products are products derived from living sources—such as humans, animals, 

and microorganisms—that are intended for preventing, treating, or curing diseases or 

conditions. They include vaccines, blood products, and proteins. See 42 U.S.C. § 262(i), 

21 C.F.R. § 600.3(h)(2008). For the remainder of this report we use the term “drug” to refer 

to both therapeutic biological products and chemically synthesized drugs. 

2

Drug sponsors typically are the applicants who submit new drug applications (NDAs) and 

biological license applications (BLAs) to FDA for review. A drug sponsor may assume 

responsibility for the marketing of a new drug, including responsibility for complying with 

applicable laws and regulations. 

3

FDA’s approval of an NDA or BLA means a sponsor can market the new drug. Throughout 

the remainder of this report we refer to FDA’s approval of NDAs and BLAs as approval of 

“drugs”. 
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.4

 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 

 

4

21 C.F.R. pt. 314 subpt. H (2008), 21 C.F.R. pt. 601 subpt. E (2008). 

Page 2 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.5

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.6

 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.7

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 

 

5

Throughout this report we refer to those postmarketing studies which FDA requested and 

sponsors committed, in writing, to conduct as “requested” postmarketing studies. 

6

See Pub. L. No. 105-115, § 130, 111 Stat. 2296, 2331-2 (codified at 21 U.S.C. § 356b). 

7

21 C.F.R. §§ 314.81(b)(2)(vii), 601.70(a), (b)(2008). The regulations also explain that status 

reports of postmarketing studies are required for studies that address (1) clinical safety, 

(2) clinical efficacy, (3) clinical pharmacology, and (4) nonclinical toxicology. Drug 

sponsors, but not those producing biologics, must also submit annual reports on 

postmarketing studies that they have agreed to conduct, or that are conducted on their 

behalf that concern chemistry, manufacturing, controls, or product stability. 21 C.F.R. 

§ 314.81(b)(2)(viii)(2008). 

Page 3 GAO-09-866 FDA’s Use of Surrogate Endpoints 
endpoints used for approval, as well as the status of any associated 

postmarketing studies; 

2. 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 19928

 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;9

 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 

 

8

FDA issued final regulations for the accelerated approval process on December 11, 1992, 

but approved one application under this process, prior to issuing the final regulations. We 

have included this application in the scope of our review. 

9

For example, if a drug can be taken either as a pill or via injection, FDA may approve a 

separate application for each route of administration. 

Page 4 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.10 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 

 

10The scope of applications included in this review was limited to NDAs for NMEs. This 

review does not include any new BLAs. 

Page 5 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.11 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.12 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 

 

11FDA approved 15 NMEs for drugs used to aid in diagnosing diseases or in aiding the 

absorption of other drugs. Because these 15 were not used to actually treat a disease, we 

excluded them from our analyses. 

12We obtained this material from FDA’s Web site, 

www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/. 

Page 6 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.13 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 

 

13For example, under the standards for internal control, information should be recorded 

and communicated to management and others within an entity who need it and within a 

time frame that enables them to carry out their internal control and other responsibilities. 

See GAO, Standards for Internal Control in the Federal Government, GAO/AIMD-00-21.3.1 

(Washington, D.C.: Nov. 1999) and its supplemental guide, Internal Control Management 

and Evaluation Tool, GAO-01-1008G (Washington, D.C.: Aug. 2001). 

Page 7 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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. 

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.14 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. 

Background 

The Benefits and Risks of 

Surrogate Endpoints in 

Drug Approval 

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 

 

14FDA will not approve an application if, for example, the methods used in, and the 

facilities and controls used for, the manufacture, processing, and packing of such drug are 

inadequate to preserve its identity, strength, quality, and purity. 21 U.S.C. § 355(d)(3). 

Page 8 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.15

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.16 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, longterm 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.17

FDA Role in the Drug 

Development and 

Application Review 

Process 

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. 

 

15FDA, Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New 

Medical Products (March 2004). 

16R. Temple, Are Surrogate Markers Adequate to Assess Cardiovascular Disease Drugs? 

The Journal of the American Medical Association, August 25, 1999; 282(8):790-795. 

17For example, see D.S. Echt, P.R. Liebson, L.B. Mitchell, et al, Mortality and Morbidity in 

Patients Receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia 

Suppression Trial, New England Journal of Medicine, 1991; 324:781-788. 

Page 9 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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 caseby-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.18 As a condition of approval under its 

 

18According to FDA officials, prior to 2001, they did not always establish time frames for 

completing postmarketing studies. 

Page 10 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.19 In addition, FDA may request 

sponsors to conduct postmarketing studies when it determines that 

additional information, while not essential for approval, is important in 

improving the prescribing, use, and quality of a drug or consistency in drug 

manufacturing. For example, FDA may request sponsors, and sponsors 

may agree, to continue to evaluate a drug’s safety, effectiveness, 

pharmacology, toxicology, or manufacturing controls. FDA may request 

these studies under both the accelerated and traditional review processes. 

FDA’s Oversight of 

Postmarketing Studies 

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.20 Federal regulations also require ASRs to contain, in 

 

19In addition to confirmatory studies, sponsors may be required to conduct postmarketing 

studies in other instances. For example, under the Pediatric Research Equity Act of 2003 

sponsors may be required to study products in children. When a sponsor is required under 

the act to study its product in pediatric populations, FDA can defer the required studies 

until after the product is approved in adults. Pub. L. No. 108-55, § 2(a), 117 Stat. 1936 

(codified at 21 U.S.C. § 355c(a)(3)(A)(i)(I)). Further, if FDA approves a drug based solely 

on animal studies, when human efficacy studies are not ethical or feasible, it requires the 

sponsor to subsequently conduct studies to verify and describe the drug’s efficacy and to 

assess its safety in humans when such studies become feasible and ethical. C.F.R. pts. 

314 subpt. I; 601 subpt. H (2008). Finally, the Food and Drug Administration Amendments 

Act of 2007 (FDAAA) provided FDA with additional authority to require postmarket safety 

studies in certain instances. Pub. L. No. 110-85, § 901(a), 121 Stat. 823, 922 (codified at 

21 U.S.C. § 355(o)). 

2021 C.F.R. §§ 314.81(b)(2), (b)(2)(vii), 601.70(a)-(c)(2008). The current reporting 

requirements became effective on April 30, 2001. In 2001, drug sponsors were required to 

submit their first progress report by October 30 for those postmarketing studies that 

addressed clinical efficacy, clinical safety, clinical pharmacology, or nonclinical toxicology. 

Page 11 GAO-09-866 FDA’s Use of Surrogate Endpoints 
part, information on the description of the required and requested 

postmarketing studies, along with the schedule for their completion.21

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.

22

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:23

• 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. 

 

2121 C.F.R. §§ 314.81(b)(2)(vii)(a)(6), (7); 601.70(b)(6), (7)(2008). 

2221 U.S.C. 356b(c),(d). 

23See 21 C.F.R. §§ 314.81(b)(2)(vii)(a)(8); 601.70(b)(8)(2008). 

Page 12 GAO-09-866 FDA’s Use of Surrogate Endpoints 
• 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.24

 

24According to FDA, conversion from accelerated to full approval means the sponsor has 

demonstrated, through clinical testing, that the drug is clinically effective in treating a 

specific disease or medical condition. 

Page 13 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.25 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.26 In contrast, FDA does not require that 

drug sponsors complete requested postmarketing studies, regardless of 

whether a drug has been approved under the accelerated or traditional 

process. Such studies are typically related to safety, effectiveness, 

pharmacology, toxicology, or manufacturing controls. 

FDA has approved 90 applications based on surrogate endpoints under its 

accelerated approval process since the process was established in 1992. 

During this period, FDA required or requested sponsors to conduct over 

450 postmarketing studies associated with the approval of applications for 

these drugs, and the majority of these studies have been classified by FDA 

as closed—meaning that drug sponsors had met FDA’s requirements for 

these studies or FDA determined the studies were no longer needed or 

feasible. However, several have been classified by FDA as open for an 

extended period of time. 

FDA Has Approved 

Many Applications 

Based on Surrogate 

Endpoints through Its 

Accelerated Approval 

Process and about 

Two-Thirds of 

Postmarketing 

Studies Have Been 

Closed 

 

25In 2007, FDAAA provided FDA with authority to assess civil monetary penalties against 

those who have not conducted required postmarketing studies under the accelerated 

approval process. Pub. L. No. 110-85, §§ 901(a), 902(b) (codified at 21 U.S.C. §§ 333(f)(4), 

355(p)). As of July 2009, FDA officials indicated they have never used this new authority. 

2621 C.F.R §§ 314.530(a)(2), 601.43(a)(2)(2008). 

Page 14 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.27 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 

(see fig. 1). 

 applications 

FDA Approved 90 

Applications Based on 

Surrogate Endpoints under 

the Accelerated Approval 

Process, the Majority for 

Drugs to Treat Cancer and 

HIV/AIDS 

Figure 1: Applications Approved Using Surrogate Endpoints under FDA’s Accelerated Approval Process, June 19, 1992–

November 20, 2008 

Number of applications

Source: GAO analysis of FDA data.

Year

0

2

4

6

8

10

12

14

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

0

2

4

6

8

10

12

14

FDA approved an average 

of 5 applications per year

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, 

 

27In several instances FDA approved multiple applications for the same drug through the 

accelerated approval process. Thus FDA approved a smaller number of drugs than 

applications. For example, in some cases a drug had several routes of administration 

(e.g., tablet, intravenous solution, oral suspension), and FDA approved a separate 

application for each. 

Page 15 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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). 

Figure 2: Percentage of Approved Applications Granted Accelerated Approval for 

Cancer and HIV/AIDS Drugs, June 19, 1992–November 20, 2008 

Percentage of applications

Year

Source: GAO analysis of FDA data.

Cancer

HIV/AIDS

0

10

20

30

40

50

60

70

80

90

100

1992-1996 1997-2000 2001-2004 2005-2008

Page 16 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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). 

Table 1: Summary of Surrogate Endpoints for Accelerated Application Approvals, 

from June 19, 1992–November 20, 2008 

Disease Surrogate endpoint(s) used for approval 

Number of 

applications

Cancer • Tumor assessment 

• Response rate 

• Disease-free survival 

• Progression-free survival 

• Time to treatment failure 

• Cytogenic and/or hemotologic response 

as measured in marrow or blood 

• Other 

38

HIV/AIDS • Viral load (HIV-RNA) 

• CD4 count 

• p24 antigen existence 

• Other 

30

Inhalation anthrax • Drug exposure in monkeys compared to 

human plasma concentrations 

• Serum CIPRO concentrations 

• Other 

11

Other diseases • Various 11

Total 90

Source: GAO analysis of FDA data. 

Page 17 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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. 

FDA Required 144 

Confirmatory 

Postmarketing Studies 

under the Accelerated 

Process, and About TwoThirds Have Been Closed 

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).28

 

28Two of these open studies are for the drug Levaquin, which was approved to treat the 

effects of inhalation anthrax. According to FDA officials, these studies will remain in the 

pending status indefinitely, because the sponsor cannot, for ethical reasons, test the 

medication on humans unless there is an anthrax attack or other widespread exposure. 

Page 18 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Figure 3: Status of Postmarketing Studies FDA Required under Its Accelerated Approval Process, June 19, 1992– 

November 20, 2008 

Source: GAO analysis of FDA data.

Closed (92) Open (52)

Closed postmarketing studies

21%

Fulfilled (73) 79%

Released (19)

All required postmarketing studies (total=144)

Open postmarketing studies

Submitted (16)

Ongoing (17)

Pending (7)

4%

Terminated (2)

Delayed (10)

64% 36%

33%

13%

19%

31%

Note: Status as of December 19, 2008. 

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 

Page 19 GAO-09-866 FDA’s Use of Surrogate Endpoints 
12 years. In contrast, nearly one-third, or 23, of these studies took over 

5 years to fulfill (see fig. 4).29

Figure 4: Elapsed Time from Drug Approval to Fulfillment for Postmarketing 

Studies Required under the Accelerated Approval Process, June 19, 1992–

November 20, 2008 

Note: Status as of December 19, 2008. 

Number of studies

Source: GAO analysis of FDA data.

0

5

10

15

20

25

30

Over 5 years

Between 4

and 5 years

Between 3

and 4 years

Between 2

and 3 years

Between 1

and 2 years

Less than

1 year

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 

 

29We determined the time to fulfill a study by measuring the amount of time that elapsed 

from the date the study was required in the approval letter to the date FDA determined the 

study was fulfilled. FDA was unable to provide the fulfillment dates for 2 of the 73 fulfilled 

studies; therefore the total number of studies used in fig. 4 is 71. 

Page 20 GAO-09-866 FDA’s Use of Surrogate Endpoints 
accelerated process. In particular, most of the cancer drugs gained 

accelerated approval based on single arm clinical trials,30 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.31 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 

 

30In a single arm trial there is one treatment group of patients who all take the drug being 

studied; there is not a separate group of patients taking another drug or a placebo for 

comparison. According to FDA, single arm trials can provide an accurate assessment of 

tumor response in patients with highly resistant tumors. 

31A randomized control trial is a study in which participants are randomly assigned to a 

group taking the drug under study, a placebo, or a comparison drug. FDA considers a 

randomized control trial as the most reliable type of trial. 

Page 21 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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. 

FDA Requested over 300 

Postmarketing Studies 

under the Accelerated 

Process, and About TwoThirds Have been Closed 

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). 

Figure 5: Percentage of Postmarketing Studies Requested under the Accelerated 

Approval Process by Disease, June 19, 1992–November 20, 2008 

10%

29%

61%

Source: GAO analysis of FDA data.

Other (32)

Cancer (91)

HIV/AIDS (194)

Page 22 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.32

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. 

Table 2: Status of Postmarketing Studies Requested under the Accelerated 

Approval Process, June 19, 1992–November 20, 2008 

Status of open studies 

Number of studies 

(% of Total)

Pending 57 (18%)

Ongoing 21 (7%)

Delayed 6 (2%)

Terminated 0 (0%)

Submitted 30 (9%)

Total open 114 (36%)

Status of closed studies 

Fulfilled 166 (52%)

Released 37 (12%)

Total closed 203 (64%)

Total 317 (100%)

Source: GAO analysis of FDA data. 

Note: Status as of January 6, 2009. 

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.33 We could not calculate the amount of time it 

 

32Status information on requested postmarketing studies under the accelerated approval 

process was provided by FDA as of January 6, 2009. 

33We determined the amount of time studies had been open by measuring the amount of 

time which elapsed from the date the study was requested to January 6, 2009. 

Page 23 GAO-09-866 FDA’s Use of Surrogate Endpoints 
took sponsors to close a requested study, because, according to FDA, the 

dates studies were fulfilled or released were not readily available. 

From January 1, 1998, through June 30, 2008, FDA approved about onethird 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. 

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 

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.34 Of these 204 applications, FDA approved 69, or about 

34 percent, on the basis of surrogate endpoints.35 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). 

 

34In addition to these 204 NMEs, FDA approved an additional 15 NMEs for drugs used to aid 

in diagnosing diseases or in aiding the absorption of other drugs. Because these 15 were 

not used to treat a disease, we excluded them from our analyses. 

35These 69 applications include one for a drug that was approved for many indications 

(diseases). This drug was approved for some of these indications primarily based on a 

surrogate endpoint and some were approved based on a clinical endpoint. Therefore, we 

included this drug in our scope. 

Page 24 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Figure 6: Percentage of Applications for NME Drugs Approved Using Surrogate 

Endpoints under FDA’s Traditional Approval Process, January 1, 1998–June 30, 

2008 

0

10

20

30

40

50

60

70

80

90

100

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Percentage

Source: GAO analysis of FDA data.

Year

Note: 2008 data include NME drug approvals only through June 30, 2008. 

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). 

Page 25 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Table 3: Summary of Surrogate Endpoints for NME Drug Application Approvals, 

from January 1, 1998–June 30, 2008 

Disease Surrogate endpoint(s) used for approval 

Number of 

applications

Cancer • Tumor assessment 

• Time to progression 

• Response rate 

• Progression-free survival 

• Other (e.g., serum testosterone levels) 

13

Cardiovascular 

conditions 

• Blood pressure 

• Lipid levels (cholesterol and 

triglycerides) 

11

Diabetes mellitus • Blood sugar 

• Fasting plasma glucose levels 

• HbA1c levels 

10

Other diseases • Various 35

Total 69

Source: GAO analysis of FDA data. 

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.36

 

36FDA and others have suggested that the identification of validated surrogate endpoints 

already used in drug approvals, as well as criteria for accepting new potential surrogate 

endpoints, may encourage more efficient drug development. See GAO, New Drug 

Development: Science, Business, Regulatory and Intellectual Property Issues Cited as 

Hampering Drug Development Efforts, GAO-07-49 (Washington, D.C.: Nov. 17, 2006). FDA 

planned to develop a comprehensive inventory of all surrogate endpoints used to approve 

new drugs, including those under the traditional process. FDA officials told us that they 

were able to compile a partial list of such endpoints, but due to other competing priorities, 

this inventory was never completed. 

Page 26 GAO-09-866 FDA’s Use of Surrogate Endpoints 
FDA Requested 175 

Postmarketing Studies 

under Its Traditional 

Process, and About OneHalf Have Been Closed 

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). 

Figure 7: Percentage of Postmarketing Studies Requested under the Traditional 

Process, by Disease, January 1, 1998–June 30, 2008 

25%

18%

14%

Source: GAO analysis of FDA data.

14%

6%

13%

11%

Other (25)

Cancer (43)

Hepatitis B (31)

Renal disease (25)

Diabetes (19)

HIV/AIDS (22)

Cardiovascular disease (10)

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). 

Page 27 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Table 4: Status of Postmarketing Studies Requested under the Traditional Approval 

Process, January 1, 1998–June 30, 2008 

Status of open studies 

Number of studies

(% of Total)

Pending 33 (19%)

Ongoing 21 (12%)

Delayed 7 (4%)

Terminated 4 (2%)

Submitted 16 (9%)

Total open 81 (46%)

Status of closed studies 

Fulfilled 87 (50%)

Released 7 (4%)

Total closed 94 (54%)

Total 175 (100%)

Source: GAO analysis of FDA data. 

Note: Status as of February 13, 2009. 

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.37 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. 

 

37We determined the amount of time studies had been open by measuring the amount of 

time which elapsed from the date the study was requested to February 13, 2009. 

Page 28 GAO-09-866 FDA’s Use of Surrogate Endpoints 
FDA has not been routinely monitoring the status of postmarketing 

studies, primarily because oversight of these studies is not considered a 

priority. Regarding its enforcement of postmarketing study requirements, 

we found FDA has not fully utilized its available enforcement tools, even 

when sponsors have failed to complete required studies. 

FDA’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, although 

Initiatives to Improve Its 

Monitoring Are Underway 

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 

200638 as well as FDA’s contractor, Booz Allen Hamilton, in 2008.39 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 

 

38For more information, see HHS’ Office of Inspector General’s report entitled FDA’s 

Monitoring of Postmarketing Study Commitments (June 2006). 

39FDA retained Booz Allen Hamilton in 2006 to conduct an independent analysis of the 

agency’s postmarket processes and procedures. In Postmarketing Commitments Study 

Final Report, issued in January 2008, the contractor highlighted further problems, and 

made recommendations designed to improve FDA’s monitoring and oversight of 

postmarketing studies. 

Page 29 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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 HHSOIG 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.40 The 

 

40FDA is required to report annually in the Federal Register and to congressional 

committees the status of postmarketing studies that are the subject of annual status reports 

submitted to FDA. 21 U.S.C. §§ 356b(c), 356b note. 

Page 30 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.41 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. 

 

41According to FDA officials, their contractor has already identified numerous instances 

where status information was incorrect, such as when studies listed as pending were, in 

fact, ongoing. Based on this information FDA will be updating its database with the correct 

information, and this will be reflected in its next annual report in the Federal Register. 

Page 31 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.42 DARRTS is a Web-based system, which 

according to FDA officials should allow FDA staff greater access to 

information and provide enhancements over the current database, such as 

creating management reports on specific drugs and their respective 

studies. 

FDA Has Not Fully Utilized 

Its Enforcement Tools 

Related to Required 

Postmarketing Studies 

FDA has not fully utilized its two enforcement tools—issuing 

administrative action letters and withdrawing a drug from the market in 

certain cases—to encourage and compel drug sponsors to complete 

required confirmatory postmarketing studies. FDA has the discretion to 

issue administrative action letters to drug sponsors if 1) sponsors are late 

or fail to submit ASRs, or 2) FDA determines that sponsors are not 

sufficiently progressing in completing their studies. 

The extent to which FDA has issued administrative action letters related 

to its oversight of postmarketing studies required under the accelerated 

approval process is unclear. According to FDA officials, they do not have a 

centralized database which tracks the letters they have issued to sponsors 

when sponsors were late or failed to submit ASRs, or when FDA 

determined that sponsors were not sufficiently progressing in completing 

their studies. Our review of FDA’s oversight of a sample of postmarketing 

studies required under the accelerated approval process suggests its use 

may be limited when sponsors do not submit their ASRs within required 

time frames. Specifically, we found that sponsors were late in submitting 

ASRs for 12 postmarketing studies in our sample. However, FDA issued an 

administrative action letter to the sponsor of only 1 of these 12 studies. 

In addition to sending administrative action letters for drugs approved 

under the accelerated approval process, FDA also may begin expedited 

proceedings to withdraw a drug’s approval in a number of situations 

including if it determines that: 1) sponsors are not completing required 

confirmatory postmarketing studies with due diligence, or 2) a study failed 

to confirm the drug’s clinical benefit. According to FDA officials, the 

 

42DARRTS became operational for NDAs in July 2009. FDA will continue to use its current 

system to oversee postmarketing studies related to BLAs. Data related to BLAs are 

scheduled to be integrated into DARRTS in 2010. 

Page 32 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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.43 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 

 

43According to FDA officials, the agency did not mail these letters directly to the five 

generic manufacturers, but contacted certain key industry officials regarding FDA’s posting 

of these letters. 

Page 33 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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 

Page 34 GAO-09-866 FDA’s Use of Surrogate Endpoints 
diligence for withdrawal that could be generally applied to the wide range 

of diseases treated by drugs approved under the accelerated approval 

process. Additionally, they questioned the need for such specific criteria, 

because other than the case of ProAmatine, they have rarely faced 

circumstances where drug sponsors were reluctant to work toward 

completing their postmarketing study. Regarding cases when a 

confirmatory study failed to demonstrate a drug’s clinical benefit, agency 

officials indicated they would be hesitant to withdraw a drug in such 

cases. For example, they said that despite the confirmatory study results, 

Iressa may still be effective for a number of patients. 

The use of surrogate endpoints has been accepted by FDA as a means of 

demonstrating the efficacy of drugs approved through both its traditional 

and accelerated approval processes. While the use of surrogate endpoints 

can expedite the approval of drugs, reliance on these endpoints also 

introduces uncertainty regarding the risks and benefits of a drug because 

the clinical effectiveness is not directly measured. Thus their use can lead 

to the adoption of useless or even harmful therapies if the effect on a 

surrogate endpoint does not accurately predict whether treatments 

provide benefits to patients, or if the drug has a smaller than expected 

benefit and a larger than expected adverse effect. 

Conclusions 

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 

Page 35 GAO-09-866 FDA’s Use of Surrogate Endpoints 
drug sponsors, and information the agency needs to ensure that sponsors 

are completing required confirmatory studies in a timely manner was not 

consistently entered into its tracking database. Therefore, the agency has 

lacked an effective management information system capable of generating 

data needed to effectively monitor the progress of such studies. FDA has 

recently implemented several initiatives to enhance its oversight of 

postmarketing studies, which may provide the agency with an opportunity 

to develop reliable data needed to adequately monitor the progress of 

studies and improve oversight. Additionally, FDA’s plans to designate 

personnel to serve as focal points for monitoring postmarketing studies 

may provide a greater emphasis on oversight of such studies. It is too early 

to tell if these initiatives will be successful. While FDA’s new system, 

DARRTS, may have features superior to the tracking database it is 

replacing, the root cause of many problems associated with the previous 

system was not the system itself, but the failure to enter information into 

it. The ultimate success of FDA’s new initiatives is largely dependent on 

the timely review and prompt entry of ASRs into DARRTS. 

While FDA has implemented measures to enhance its monitoring of 

postmarketing studies, the agency has taken a passive approach to 

enforcing confirmatory study requirements. It has never exercised its 

authority to withdraw a drug it approved based on surrogate endpoints 

under the accelerated approval process, even when such studies have 

been outstanding for nearly 13 years. Further, FDA has not attempted to 

clarify the circumstances under which it would exercise this authority and 

has never developed specific time frames for sponsors to complete their 

confirmatory studies. The combination of its ineffective monitoring and 

lack of criteria outlining when a drug should be withdrawn from the 

market make it difficult for FDA to utilize its enforcement authority. 

Consequently, drugs which have not proven to be clinically effective may 

remain on the market while their associated confirmatory studies remain 

incomplete. 

To clarify FDA’s enforcement authority under the accelerated approval 

process, we recommend that the Commissioner of FDA take the following 

action: 

Recommendations 

• 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. 

Page 36 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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. 

Agency Comments 

and Our Evaluation 

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. 

Page 37 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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. 

Page 38 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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. 

Page 39 GAO-09-866 FDA’s Use of Surrogate Endpoints 
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. 

Page 40 GAO-09-866 FDA’s Use of Surrogate Endpoints 
As agreed with your office, unless you publicly announce the contents of 

this report earlier, we plan no further distribution until 30 days from the 

report date. At that time, we will send copies to the Commissioner of FDA 

and appropriate congressional committees. The report also will be 

available at no charge on GAO’s Web site at http://www.gao.gov. 

If you or your staff have any questions about this report, please contact me 

at (202) 512-7114 or crossem@gao.gov. Contact points for our Offices of 

Congressional Relations and Public Affairs may be found on the last page 

of this report. GAO staff who made major contributions to this report are 

listed in appendix VI. 

Sincerely yours, 

Marcia Crosse 

Director, Health Care 

Page 41 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix I: Applications for Drugs Approved 

under FDA’s Accelerated Approval Process 

Using Surrogate Endpoints 

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. 

Table 5: NDAs and BLAs Approved Based on Surrogate Endpoints under the Accelerated Approval Process, from June 19, 

1992–November 20, 2008 

Drug name NDA/BLA number Approval date Approved indication 

Surrogate endpoint(s) used to 

approve application 

Hivid 20199 June 19, 1992 Monotherapy and combination therapy 

for treatment of Human 

Immunodeficiency Virus infection in 

specific patients 

CD4 count (infection fighting 

white blood cells) and p24 

existence (antigen which 

indicates HIV infection) 

Betaseron 103471aJuly 23, 1993 Treatment of relapsing-remitting multiple 

sclerosis 

MRI evaluations of brain lesionsb

Biaxin 50697 Dec. 23, 1993 Treatment of disseminated mycobacterial 

infections due to specific bacteria 

Clearance of bacteremiab 

50698 Dec. 23, 1993 Treatment of disseminated mycobacterial 

infections due to specific bacteria 

Clearance of bacteremiab 

Zerit 20412 June 24, 1994 Treatment of advanced Human 

Immunodeficiency Virus infection in 

specific adult patients 

CD4 count (infection fighting 

white blood cells) and p24 

existence (antigen which 

indicates HIV infection) 

Casodex 20498 Oct. 4, 1995 Combination therapy for the treatment of 

advanced prostate cancer 

Time to treatment failureb

Epivir 20564 Nov. 17, 1995 Combination therapy for treatment of 

Human Immunodeficiency Virus infection 

in certain circumstances 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

20596 Nov. 17, 1995 Combination therapy for treatment of 

Human Immunodeficiency Virus infection 

in certain circumstances 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

Doxil 50718 Nov. 17, 1995 Treatment of Kaposi’s sarcoma in 

specific patients with Acquired 

Immunodeficiency Syndrome 

Response ratec

50718-SE1-006 June 28, 1999 Treatment of metastatic carcinoma of the 

ovary in specific patients 

Response ratec

Invirase 20628 Dec. 6, 1995 Combination therapy for treatment of 

advanced Human Immunodeficiency 

Virus infection in specific patients 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

Appendix I: Applications for Drugs Approved 

under FDA’s Accelerated Approval Process 

Using Surrogate Endpoints 

Page 42 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix I: Applications for Drugs Approved 

under FDA’s Accelerated Approval Process 

Using Surrogate Endpoints 

Drug name NDA/BLA number Approval date Approved indication 

Surrogate endpoint(s) used to 

approve application 

Norvir 20659 Mar. 1, 1996 Treatment of Human Immunodeficiency 

Virus infection 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

20680 Mar. 1, 1996 Treatment of Human Immunodeficiency 

Virus infection 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

Crixivan 20685 Mar. 13, 1996 Treatment of Human Immunodeficiency 

Virus infection when antiretroviral 

therapy is warranted 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

Ethyol 20221-SE1-002 Mar. 15, 1996 Treatment for the toxicities associated 

with intensive regimens of specific 

chemotherapy 

Creatinine clearance and 

response rate to assess tumor 

protection 

Taxotere 20449 May 14, 1996 Treatment of locally advanced or 

metastatic breast cancer in specific 

patients 

Response ratec

Camptosar 20571 June 14, 1996 Treatment of metastatis carcinoma of the 

colon or rectum in certain circumstances 

Response ratec

Viramune 20636 June 21, 1996 Combination antiretroviral treatment for 

Human Immunodeficiency Virus infection 

in specific patients 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

20636-SE1-009 Sept. 11, 1998 Combination antiretroviral treatment for 

Human Immunodeficiency Virus-1 

infection in pediatric patients 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

20933 Sept. 11, 1998 Combination antiretroviral treatment for 

Human Immunodeficiency Virus-1 

infection in pediatric patients 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

ProAmatine 19815 Sept. 6, 1996 Treatment of idiopathic orthostatic 

hypotension 

Increase in 1-minute standing 

systolic blood pressure 

Viracept 20778 Mar. 14, 1997 Treatment of Human Immunodeficiency 

Virus infection in children when 

antiretroviral therapy is indicated 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

20779 Mar. 14, 1997 Treatment of Human Immunodeficiency 

Virus infection when antiretroviral 

therapy is indicated 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

Rescriptor 20705 April 4, 1997 Treatment of Human Immunodeficiency 

Virus-1 infection 

CD4 count (infection fighting 

white blood cells) and viral load 

(HIV-RNA) 

Xeloda 20896 April 30, 1998 Treatment of a specific type of 

metastasis breast cancer in certain 

patients 

Response ratec 

Sulfamylon 19832 June 5, 1998 Treatment of bacterial infections in 

certain circumstances 

Necessity to change topical 

antimicrobial treatment during 

the first 5 days of application 

due to infection or colonization 

Page 43 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix I: Applications for Drugs Approved 

under FDA’s Accelerated Approval Process 

Using Surrogate Endpoints 

Drug name NDA/BLA number Approval date Approved indication 

Surrogate endpoint(s) used to 

approve application 

Priftin 21024 June 22, 1998 Treatment of pulmonary tuberculosis Negative sputum culture at 6 

month post-treatment (6 month 

relapse rate) 

Sustiva 20972 Sept. 17, 1998 Treatment of Human Immunodeficiency 

Virus infection 

Viral load (HIV-RNA) 

Ziagen 20977 Dec. 17, 1998 Combination antiretroviral treatment for 

Human Immunodeficiency Virus infection 

Viral load (HIV-RNA) 

20978 Dec. 17, 1998 Combination antiretroviral treatment for 

Human Immunodeficiency Virus infection 

Viral load (HIV-RNA) 

Ontak 103767aFeb. 5, 1999 Treatment of a specific type of persistent 

or recurrent Cutaneous T-cell Lymphoma 

Response ratec

DepoCyt 21041 April 1, 1999 Treatment of lymphmatous meningitis Response rate (complete 

cytologic response with absence 

of neurologic progression)c

Agenerase 21007 April 15, 1999 Combination antiretroviral treatment for 

Human Immunodeficiency Virus-1 

infection 

Viral load (HIV-RNA) 

21039 April 15, 1999 Treatment of Human Immunodeficiency 

Virus infection 

Viral load (HIV-RNA) 

Temodar 21029 Aug. 11, 1999 Treatment of refractory anaplastic 

astrocytoma in specific adult patients 

Progression free survival at 

6 months and objective 

response 

Synercid 50747 Sept. 21, 1999 Treatment of serious or life-threatening 

infections associated with vancomycinresistant enterococcus faecium 

bacteremia 

Clearance of vancomycinresistant Enterococcus faecium 

bacteremia 

Celebrex 21156 Dec. 23, 1999 To reduce the number of adenomatous 

colorectal polyps in familial adenomatous 

polyposis, and as an adjunct to usual 

care 

Mean reduction in colorectal 

polyp count 

Mylotarg 21174 May 17, 2000 Treatment of CD33+ acute myeloid 

leukemia in specific patients 

Complete responses (blasts, 

bone marrow, CBC, 

transfusions)c

Cipro 19537-SE1-038 Aug. 30, 2000 Treatment of inhalation anthrax 

(post-exposure) 

Serum CIPRO concentrations 

19847-SE1-024 Aug. 30, 2000 Treatment of inhalation anthrax 

(post-exposure) 

Serum CIPRO concentrations 

19857-SE1-027 Aug. 30, 2000 Treatment of inhalation anthrax 

(post-exposure) 

Serum CIPRO concentrations 

19858-SE1-021 Aug. 30, 2000 Treatment of inhalation anthrax 

(post-exposure) 

Serum CIPRO concentrations 

20780-SE1-008 Aug. 30, 2000 Treatment of inhalation anthrax 

(post-exposure) 

Serum concentrations 

(compared to effective animal 

concentrations) 

Page 44 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix I: Applications for Drugs Approved 

under FDA’s Accelerated Approval Process 

Using Surrogate Endpoints 

Drug name NDA/BLA number Approval date Approved indication 

Surrogate endpoint(s) used to 

approve application 

Kaletra 21226 Sept.15, 2000 Combination antiretroviral treatment for 

Human Immunodeficiency Virus-1 

infection in specific patients 

Viral load (HIV-RNA) 

21251 Sept. 15, 2000 Combination antiretroviral treatment for 

Human Immunodeficiency Virus-1 

infection in specific patients 

Viral load (HIV-RNA) 

Trizivir 21205 Nov. 14, 2000 Treatment of Human Immunodeficiency 

Virus infection 

Viral load (HIV-RNA) 

Campath 103948aMay 7, 2001 Treatment of B-cell chronic lymphocytic 

leukemia in specific patients 

Response ratec

Gleevec 21335 May 10, 2001 Treatment of chronic myeloid leukemia in 

certain circumstances 

Hematologic/cytogenic response

21335-SE1-001 Feb. 1, 2002 Treatment of Kit (CD117) positive 

unresectable and/or metastatic malignant 

gastrointestinal stromal tumors 

Response ratec

21335-SE1-004 Dec. 20, 2002 Treatment of Philadelphia chromosome 

positive chronic myeloid leukemia in 

specific patients 

Time to accelerated phase or 

blast crisis 

21588 April 18, 2003 Treatment of newly diagnosed adult 

patients with Philadelphia chromosome 

positive chronic myeloid leukemia in 

specific patients under certain 

circumstances 

Hematologic/cytogenic response 

(CML); response rate (GIST); 

time to accelerated phase or 

blast crisis (1st line CML)c

21335-SE5-003 May 20, 2003 Treatment of pediatric patients with Ph+ 

chronic phase chronic myeloid leukemia 

whose disease has recurred after stem 

cell transplant or who are resistant to 

interferon alpha therapy 

Cytogenic response 

21588-SE5-001 May 20, 2003 Treatment of pediatric patients with Ph+ 

chronic phase chronic myeloid leukemia 

whose disease has recurred after stem 

cell transplant or who are resistant to 

interferon alpha therapy 

Cytogenic response 

21588-SE1-016 Sept. 27, 2006 Treatment of newly diagnosed 

Philadelphia positive chronic myeloid 

leukemia in pediatric patients 

Major hematologic and complete 

cytogenic response 

Viread 21356 Oct. 26, 2001 Combination antiretroviral treatment of 

Human Immunodeficiency Virus-1 

infection in adults 

Viral load (HIV-RNA) 

Zevalin 125019aFeb. 19, 2002 Treatment of relapsed or refractory lowgrade, follicular or transformed B-cell 

non-Hodgkin’s lymphoma in specific 

patients 

Response ratec

Eloxatin 21492 Aug. 9, 2002 Treatment of metastatic carcinoma of the 

colon or rectum in specific patients 

Response ratec

Page 45 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix I: Applications for Drugs Approved 

under FDA’s Accelerated Approval Process 

Using Surrogate Endpoints 

Drug name NDA/BLA number Approval date Approved indication 

Surrogate endpoint(s) used to 

approve application 

Armidex 20541-SE1-010 Sept. 5, 2002 Adjuvant treatment of postmenopausal 

women with specific breast cancer 

Disease free survival 

Fuzeon 21481 Mar. 13, 2003 Combination antiretroviral treatment for 

Human Immunodeficiency Virus-1 

infection in specific patients 

Viral load (HIV-RNA) 

Fabrazyme 103979a April 24, 2003 Treatment of Fabry disease Intracellular substrate 

accumulation in the vascular 

endothelium 

Iressa 21399 May 5, 2003 Treatment of locally advanced or 

metastatic non-small cell lung cancer in 

specific patients under certain 

circumstances 

Response ratec

Velcade 21602 May 13, 2003 Treatment of multiple myeloma in 

specific patients under certain 

circumstances 

Response ratec

Erbitux 125084aFeb. 12, 2004 In combination with other drugs for the 

treatment of EGFR-expressing, 

metastatic colorectal carcinoma in 

specific patients 

Response ratec

Truvada 21752 Aug. 2, 2004 Combination antiretroviral treatment for 

Human Immunodeficiency Virus-1 

infection in adults 

Viral load (HIV-RNA) 

Alimta 21677 Aug. 19, 2004 Treatment of patients with locally 

advanced or metastatic non-small cell 

lung cancer after prior chemotherapy 

Response ratec

Luveris 21322 Oct. 8, 2004 Concomitantly use for stimulation of 

follicular development in infertile 

hypogonadotropic hypogonadal women 

with profound LH deficiency 

Follicular development 

Femara 20726-SE1-011 Oct. 29, 2004 Extended adjuvant treatment of early 

breast cancer in specific 

postmenopausal women 

Disease free survival 

20726-SE1-012 Dec. 28, 2005 Adjuvant treatment of postmenopausal 

women with hormone receptor positive 

early breast cancer 

Disease free survival 

Levaquin 20634-SE1-035 Nov. 24, 2004 Treatment of inhalation anthrax (postexposure) Drug exposure in surviving 

Rhesus monkeys compared to 

human plasma concentrations 

20635-SE1-035 Nov. 24, 2004 Treatment of inhalation anthrax (postexposure) Drug exposure in surviving 

Rhesus monkeys compared to 

human plasma concentrations 

21721-SE1-003 Nov. 24, 2004 Treatment of inhalational anthrax (postexposure) Plasma concentrations 

Page 46 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix I: Applications for Drugs Approved 

under FDA’s Accelerated Approval Process 

Using Surrogate Endpoints 

Drug name NDA/BLA number Approval date Approved indication 

Surrogate endpoint(s) used to 

approve application 

20634-SE5-047 May 5, 2008 Treatment of inhalational anthrax 

(post-exposure) in pediatric patients 

(over 6 months of age) in certain 

circumstances 

PK modeling in pediatric patients 

to extrapolate plasma 

concentration/exposure from 

adult data 

20635-SE5-051 May 5, 2008 Treatment of inhalational anthrax 

(post-exposure) in pediatric patients 

(over 6 months of age) in certain 

circumstances 

PK modeling in pediatric patients 

to extrapolate plasma 

concentration/exposure from 

adult data 

21721-SE5-015 May 5, 2008 Treatment of inhalational anthrax 

(post-exposure) in pediatric patients 

(over 6 months of age) in certain 

circumstances 

PK modeling in pediatric patients 

to extrapolate plasma 

concentration/exposure from 

adult data 

Bexxar 125011-24a Dec. 22, 2004 Treatment of relapsed or refractory, low 

grade, follicular or transformed CD20 

positive non-Hodgkin’s lymphoma in 

specific patients 

Response ratec

Clolar 21673 Dec. 28, 2004 Treatment of pediatric patients 1 to 

21 years old with relapsed or refractory 

acute lymphoblastic leukemia after at 

least two prior regimens 

Complete response rate and 

complete response without 

platelet recoveryc

Aptivus 21814 June 22, 2005 Treatment of Human Immunodeficiency 

Virus-1 infection in specific adult patients 

under certain circumstances 

Viral load (HIV-RNA) 

Arranon 21877 Oct. 28, 2005 Treatment of T-cell acute lymphoblastic 

leukemia and T-cell lymphoblastic 

lymphoma in specific patients 

Complete response ratec

Exjade 21882 Nov. 2, 2005 Treatment of chronic iron overload due to 

blood transfusions in patients 2 years of 

age and older 

Lowering of liver iron content 

Sutent 21968 Jan. 26, 2006 Treatment of advanced renal cell 

carcinoma 

Response ratec

Thalomid 21430 May 25, 2006 Treatment of newly diagnosed multiple 

myeloma 

Response rate (serum or urine 

paraprotein)c

Prezista 21976 June 23, 2006 Treatment of human immunodeficiency 

virus infection in specific patients 

Viral load (HIV-RNA) 

Sprycel 21986 June 28, 2006 Treatment of chronic myeloid leukemia 

with resistance or intolerance to prior 

therapy including imatinib in adults 

Major cytogenic response 

Vectibix 125147a Sept. 27, 2006 Treatment of specific metastatic 

colorectal carcinoma with disease 

progression on or following 

fluoropyrimidine oxaliplatin and 

irinotecan containing chemotherapy 

regimens 

Progression-free survival 

Selzentry 22128 Aug. 6, 2007 Treatment of CCR5-tropic Human 

Immunodeficiency Virus-1 

Viral load (HIV-RNA) 

Page 47 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix I: Applications for Drugs Approved 

under FDA’s Accelerated Approval Process 

Using Surrogate Endpoints 

Drug name NDA/BLA number Approval date Approved indication 

Surrogate endpoint(s) used to 

approve application 

Isentress 22145 Oct. 12, 2007 Treatment of Human Immunodeficiency 

Virus infection in specific patients 

Viral load (HIV-RNA) 

Tasigna 22068 Oct. 29, 2007 Treatment of chronic phase and 

accelerated phase Philadelphia 

chromosome positive chronic 

myelogenous leukemia in specific adult 

patients 

Major cytogenic response and 

hematologic response 

Intelence 22187 Jan. 18, 2008 Combination antiretroviral treatment for 

Human Immunodeficiency Virus-1 

infection in specific patients 

Viral load (HIV-RNA) 

Avastin 125085-91aFeb. 22, 2008 Treatment of breast cancer in specific 

patients 

Progression-free survival 

Promacta 22291 Nov. 20, 2008 Treatment of thrombocytopenia in 

specific patients 

An increase from the baseline 

platelet count to a count greater 

than or equal to 50,000/mcL 

Source: GAO analysis of FDA data. 

a

Applications for therapeutic BLAs. These therapeutic biologics were transferred from the Center for 

Biologics Evaluation and Research to the Center for Drug Evaluation and Research on June 30, 

2003. 

b

In addition to the surrogate endpoint used for approval, there was evidence of clinical benefit 

supporting the approval of this application. 

c

Response rate and complete response surrogate endpoints are tumor assessment endpoints which 

measure the proportion of patients with tumor size reduction of a predefined amount and for a 

minimum time period. 

Page 48 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix II: Applications for Drugs Approved 

under FDA’s Traditional Process Using 

Surrogate Endpoints 

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. 

Table 6: NDAs Approved Based on Surrogate Endpoints under the Traditional Approval Process, from January 1, 1998– 

June 30, 2008 

Drug name NDA number Approval date Approved indication 

Surrogate endpoint(s) used 

to approve application 

Refludan 20807 Mar. 6, 1998 Anticoagulation treatment in patients 

with heparin-induced thrombocytopenia 

and thromboembolic disease 

Time courses of platelets and 

activated partial thromboplastin 

time for regimen A1, A2, and B, 

and on the time course of 

Ecarin clotting time (ECT) for 

regimen C 

Lotemax 20583 Mar. 9, 1998 Treatment of post-operative 

inflammation and uveitisa

Measurements of cell and flare 

and resolution of anterior 

chamber cell 

Actonel 20835 Mar. 27, 1998 Treatment of Paget’s disease of bone in 

specific patients 

Serum alkaline phosphatase 

levels 

Azopt 20816 April 1, 1998 Treatment of elevated intraocular 

pressure in specific patients 

Intraocular pressure levels 

Zemplar injection 20819 April 17, 1998 Prevention and treatment of secondary 

hyperparathyroidism associated with 

chronic renal failure 

Intact parathyroid hormone 

levels 

Atacand 20838 June 4, 1998 Treatment of hypertension Systolic and diastolic pressure 

levels 

Vitravene 20961 Aug. 26, 1998 Treatment of cytomegalovirus retinitis in 

specific patients with Acquired 

Immunodeficiency Syndrome 

Median time to cytomegalovirus 

retinitis progression 

Valstar 20892 Sept. 25, 1998 Treatment of BCG -refractory carcinoma 

in situ of the urinary bladder in specific 

patients 

Time to recurrence of disease 

after treatment compared to 

recurrence after previous 

courses of intravesical therapy 

Renagel 20926 Oct. 30, 1998 Treatment of end-stage renal disease Serum phosphorous levels 

Micardis 20850 Nov. 10, 1998 Treatment of hypertension Blood pressure levels 

Ferrlecit 20955 Feb. 18, 1999 Treatment for iron deficiency in specific 

patients undergoing chronic 

hemodialysis 

Hemoglobin levels 

Avandia 21071 May 25, 1999 Treatment of type 2 diabetes mellitus Blood sugar (fasting plasma 

glucose and HBA1c levels) 

Hectorol 20862 June 9, 1999 Treatment of secondary 

hyperparathyroidism in specific patients 

Intact parathyroid hormone 

levels 

Appendix II: Applications for Drugs 

Approved under FDA’s Traditional Process 

Using Surrogate Endpoints 

Page 49 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix II: Applications for Drugs Approved 

under FDA’s Traditional Process Using 

Surrogate Endpoints 

Drug name NDA number Approval date Approved indication 

Surrogate endpoint(s) used 

to approve application 

Actos 21073 July 15, 1999 Treatment of type 2 diabetes mellitus Blood sugar (fasting plasma 

glucose and HBA1c levels) 

Aromasin 20753 Oct. 21, 1999 Treatment of advanced breast cancer in 

postmenopausal women 

Objective response rate (partial 

and complete)b

Protonix 20987 Feb. 2, 2000 Treatment of erosive esophagitis 

associated with gastroesophageal reflux 

disease 

Healing of lesions to grade 1 or 

0 in the Hetzel-Dent scale 

Lantus 21081 April 20, 2000 Treatment of type 1 diabetes mellitus in 

adults or pediatric patients or type 2 

diabetes mellitus in specific adult 

patients 

Blood sugar (glycated 

hemoglobin levels) 

Welchol 21176 May 26, 2000 Treatment of elevated LDL cholesterol in 

specific patients 

LDL cholesterol levels 

NovoLog 20986 June 7, 2000 Treatment of diabetes mellitus in adult 

patients 

Glycemic control, the rates of 

hypoglycemia, and the 

incidence of ketosis 

Trelstar Depot 20715 June 15, 2000 Treatment of advanced prostate cancer Achievement of castration by 

Day 29 and maintenance of 

castration levels of serum 

testosterone from Day 57 

through Day 253 

Rescula 21214 Aug. 3, 2000 Treatment of open-angle glaucoma or 

ocular hypertension 

Intraocular pressure levels 

Cetrotide 21197 Aug. 11, 2000 Treatment of premature luteinizing 

hormone surges in women undergoing 

controlled ovarian stimulation 

Luteinizing hormone surge 

Trisenox 21248 Sept. 25, 2000 Treatment of acute promyelocytic 

leukemia 

Cytogenic conversion to no 

detection of the acute 

promyelocytic leukemia 

chromosome rearrangement 

Starlix 21204 Dec. 22, 2000 Treatment of type 2 diabetes mellitus Blood sugar (fasting plasma 

glucose and HBA1c levels) 

Foradil Aerolizer 20831 Feb. 16, 2001 Treatment of asthma and prevention of 

bronchospasm 

Forced expiratory volume in 

one second 

Lumigan 21275 Mar. 16, 2001 Treatment of elevated intraocular 

pressure in certain populations 

Intraocular pressure levels 

Travatan 21257 Mar. 16, 2001 Treatment of intraocular pressure in 

certain populations 

Intraocular pressure levels 

Natrecor 20920 Aug. 10, 2001 Treatment of acute decompensated 

congestive heart failure in specific 

populations 

Pulmonary capillary wedge 

pressure levels 

Zometa 21223 Aug. 20, 2001 Treatment of hypercalcimia of 

malignancy 

Complete response (lowering 

of the corrected serum 

calcium)b

Page 50 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix II: Applications for Drugs Approved 

under FDA’s Traditional Process Using 

Surrogate Endpoints 

Drug name NDA number Approval date Approved indication 

Surrogate endpoint(s) used 

to approve application 

Benicar 21286 April 25, 2002 Treatment of hypertension Peak and trough blood 

pressure levels 

Faslodex 21344 April 25, 2002 Treatment of metastatic breast cancer Response rate and time to 

progressionb

Hepsera 21449 Sept. 20, 2002 Treatment of chronic hepatitis B Knodell Necroinflammatory 

Score (i.e. liver biopsy) 

Inspra 21437 Sept. 27, 2002 Treatment of hypertension Sitting diastolic and systolic 

blood pressure at trough 

Zetia 21445 Oct. 25, 2002 Treatment of elevated total cholesterol 

levels and LDL-C 

Cholesterol levels 

Extraneal 21321 Dec. 20, 2002 Single daily exchange for the long dwell 

during continuous ambulatory peritoneal 

dialysis or automated peritoneal dialysis 

for the treatment of chronic renal failure 

Ultrafiltration rate 

Somavert 21106 Mar. 25, 2003 Treatment of acromegaly in specific 

patients 

Serum IGF-I levels 

Reyataz 21567 June 20, 2003 Treatment of Human Immunodeficiency 

Virus-1 infection 

CD4 count (infection fighting 

white blood cell) and viral load 

(HIV-RNA) 

Emtriva 21500 July 2, 2003 Treatment of Human Immunodeficiency 

Virus-1 infection in adults 

CD4 count (infection fighting 

white blood cell) and viral load 

(HIV-RNA) 

Zavesca 21348 July 31, 2003 Treatment of mild to moderate type 1 

Gaucher disease 

Liver and spleen volume after 

12 months of treatment 

Crestor 21366 Aug. 12, 2003 Treatment of cholesterol levels Cholesterol levels 

Radiogardase 21626 Oct. 2, 2003 Treatment of internal contamination with 

radioactive cesium and/or radioactive 

thallium 

Whole body effective half life of 

cesium or thallium 

Plenaxis 21320 Nov. 25, 2003 Palliative treatment for men with 

advanced symptomatic prostate cancer 

for specific reasons 

Avoid orchiectomy and lower 

serum testosterone levels 

Spiriva Handihaler 21395 Jan. 30, 2004 Treatment of bronchospasm associated 

with chronic obstructive pulmonary 

disease 

Forced expiratory volume in 

one second, with peak effect 

occurring within 3 hours 

following the first dose 

Sensipar 21688 Mar. 8, 2004 Treatment of secondary 

hyperparathyroidism in patients with 

chronic kidney disease on dialysis 

Intact parathyroid hormone 

levels 

Apidra 21629 April 16, 2004 Treatment of diabetes mellitus in adult 

patients 

Blood sugar (glycated 

hemoglobin and HbA1c 

equivalents) 

Page 51 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix II: Applications for Drugs Approved 

under FDA’s Traditional Process Using 

Surrogate Endpoints 

Drug name NDA number Approval date Approved indication 

Surrogate endpoint(s) used 

to approve application 

Vidaza 50794 May 19, 2004 Treatment of myelodysplastic syndrome 

subtypes: refractory anemia or refractory 

anemia with ringed sideroblasts, 

refractory anemia with excess blasts, 

refractory anemia with excess blasts in 

transformation, and chronic 

myelomonocytic leukemia 

Response rateb

Pentetate Calcium 

Trisodium 

21749 Aug. 11, 2004 Treatment of known or suspected 

internal contamination with plutonium, 

americium, or curium to increase rates of 

elimination 

Ratio of urine radioactivity 

before treatment to the 

maximum urine radioactivity 

after treatment (excretion 

enhancement factor) 

Pentetate Zinc 

Trisodium 

21751 Aug.11, 2004 Treatment of known or suspected 

internal contamination with plutonium, 

americium, or curium to increase rates of 

elimination 

Ratio of urine radioactivity 

before treatment to the 

maximum urine radioactivity 

after treatment (excretion 

enhancement factor) 

Fosrenol 21468 Oct. 26, 2004 Treatment of end stage renal disease Serum phosphate levels 

Omacorc21654 Nov. 10, 2004 Treatment of very high triglyceride levels 

in adults 

Triglyceride levels 

Symlin 21332 Mar. 16, 2005 Treatment of type 1 or type 2 diabetes 

mellitus 

Blood sugar (HbA1c levels) 

Mycamine 21506 Mar. 16, 2005 Treatment of esophageal candidiasis or 

prophalaxis against fungal infection 

Endoscopic appearance of the 

esopageal mucosa 

Baraclude 21797 Mar. 29, 2005 Treatment of chronic hepatitis B in adults Knodell Necroinflammatory 

Score (i.e. liver biopsy) 

Byetta 21773 April 28, 2005 Treatment of type 2 diabetes mellitus Blood sugar (HbA1c levels) 

Levemir 21536 June 16, 2005 Treatment of diabetes mellitus in adults 

who require basal insulin for control of 

hyperglycemia 

Blood sugar (fasting blood 

glucose and HBA1c levels) 

Nexavar 21923 Dec. 20, 2005 Treatment of advanced renal cell 

carcinoma 

Progression free survival 

Vaprisol 21697 Dec. 29, 2005 Treatment of euyolemic hyponatremia in 

hospitalized patients 

Serum sodium concentration 

levels 

Sutent 21938 Jan. 26, 2006 Treatment of gastrointestinal stromal 

tumor and advanced renal cell 

carcinoma 

Time to progression 

Pylera 50786 Sept. 28, 2006 Treatment of helicobacter pylori infection 

and duodenal ulcer disease 

C-urea breath tests 

Januvia 21995 Oct. 16, 2006 Treatment of type 2 diabetes mellitus Blood sugar (fasting blood 

glucose, HBA1c levels and post 

prandial glucose) 

Tyzeka 22011 Oct. 25, 2006 Treatment of chronic hepatitis B in 

specific populations of adults 

Composite serologic endpoint 

requiring suppression of HBV 

DNA to a specific amount in 

conjunction with another serum 

Page 52 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix II: Applications for Drugs Approved 

under FDA’s Traditional Process Using 

Surrogate Endpoints 

Drug name NDA number Approval date Approved indication 

Surrogate endpoint(s) used 

to approve application 

Tekturna 21985 Mar. 5, 2007 Treatment of hypertension Seated trough cuff blood 

pressure 

Tykerb 22059 Mar. 13, 2007 Treatment of advanced metastatic breast 

cancer 

Time to progression 

Somatuline Depot 22074 Aug. 30, 2007 Treatment of acromegalic patients who 

have inadequate response to surgery 

and/or radiotherapy 

Growth hormone and insulin 

growth factor levels 

Ixempra 22065 Oct. 16, 2007 Treatment of metastatic or locally 

advanced breast cancer 

Progression free survival 

Kuvan 22181 Dec. 13, 2007 Treatment of hyperphenylalaninemia Blood phenylalanine levels 

Bystolic 21742 Dec. 17, 2007 Treatment of hypertension Trough sitting systolic/diastolic 

blood pressure 

Treanda 22249 Mar. 20, 2008 Treatment of chronic lymphocytic 

leukemia 

Objective response and 

progression-free survivalb

Durezol 22212 June 23, 2008 Treatment of inflammation and pain in 

the eye associated with ocular surgery 

Complete clearing (count = 0) 

Source: GAO analysis of FDA data. 

a

Also approved for treatment of giant papillary conjunctivitis and seasonal allergic conjunctivitis. 

However, these indications were approved based on clinical endpoints and are not included in the 

table. 

b

Response rate is a measure of the proportion of patients with tumor size reduction of a predefined 

amount and for a minimum time period. 

c

In July 2007, the name of this drug was changed from Omacor to Lovaza. 

Page 53 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix III: Applications Selected and 

Questions Regarding FDA’s Oversight of Appendix III: Applications Selected and Required Postmarketing Studies 

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. 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. 

Table 7: List of 15 Accelerated Approval Applications Selected for Review 

Drug name NDA/BLA number Approval date 

ProAmatine 19815 Sept. 6, 1996 

Xeloda 20896 April 30, 1998 

Sulfamylon 19832 June 5, 1998 

Priftin 21024 June 22, 1998 

Remicade 103772 Aug. 24, 1998 

Viramune 20933 Sept. 11, 1998 

Sustiva 20972 Sept. 17, 1998 

Ziagen 20977 Dec. 17, 1998 

Celebrex 21156 Dec. 23, 1999 

Gleevec 21588 April 18, 2003 

Zevalin 125019 Feb. 19, 2002 

Fuzeon 21481 Mar. 13, 2003 

Fabrazyme 103979 April 24, 2003 

Iressa 21399 May 5, 2003 

Velcade 21602 May 13, 2003 

Source: GAO analysis of FDA data. 

Page 54 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix III: Applications Selected and 

ions Regarding FDA’s Oversight of 

ostmarketing Studies 

Quest

Required P

Page 55 GAO-09-866 FDA’s Use of Surrogate Endpoints 

Appendix III: Applications Selected and 

Questions Regarding FDA’s Oversight of 

Required Postmarketing Studies 
Appendix III: Applications Selected and 

Questions Regarding FDA’s Oversight of 

Required Postmarketing Studies 

Page 56 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix IV: Sales for Selected Drugs 

Approved Based on Surrogate Endpoints Appendix IV: Sales for Selected Drugs under the Accelerated Approval Process 

Approved Based on Surrogate Endpoints 

under the Accelerated Approval Process 

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. 

Table 8: Total U.S. Sales for Selected Drugs Approved under the Accelerated 

Process 

Application 

type 

Application 

number Drug name Approval date 

Total U.S. sales 

since approvala 

NDA 19815 ProAmatine Sept. 6, 1996 $257,574,554

NDA 19832 Sulfamylon June 5, 1998 $72,963,020b

NDA 21024c Priftin June 22, 1998 $177,502

NDA 50747 Synercid Sept. 21, 1999 $206,741,816

NDA 21174 Mylotarg May 17, 2000 $206,982,392

NDA 21399 Iressa May 5, 2003 $416,699,000

BLA 103979 Fabrazyme April 24, 2003 $56,308,877

Source: GAO analysis of FDA data and National Sales Perspectives (TM) IMS Health, Inc. 

a

Sales data through December 2008. 

b

Annual sales since 1998 for Sulfamylon include sales for this approval and an earlier approval, which 

occurred prior to the implementation of the accelerated approval process. 

c

The Food and Drug Administration converted the application for Priftin to full approval on June 1, 

2009. 

Page 57 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix V: Comments from the Department of Appendix V: Comments from the Department Health and Human Services 

of Health and Human Services 

Page 58 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix V: Comments from the Department of 

Health and Human Services 

Page 59 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix V: Comments from the Department of 

Health and Human Services 

Page 60 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix V: Comments from the Department of 

Health and Human Services 

Page 61 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix V: Comments from the Department of 

Health and Human Services 

Page 62 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix V: Comments from the Department of 

Health and Human Services 

Page 63 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix V: Comments from the Department of 

Health and Human Services 

Page 64 GAO-09-866 FDA’s Use of Surrogate Endpoints 
Appendix VI: 

A

GAO Contact and Staff 

cknowledgments 

Page 65 GAO-09-866 FDA’s Use of Surrogate Endpoints 

Appendix VI: GAO Contact and Staff 

Acknowledgments 

Marcia Crosse, (202) 512-7114 or crossem@gao.gov 

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. 

GAO Contact 

Acknowledgments 

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