Department of Health and Human Services


OFFICE OF 

INSPECTOR GENERAL 

FDA’S MONITORING OF 


POSTMARKETING STUDY 


COMMITMENTS


Daniel R. Levinson


Inspector General 


June 2006 


OEI-01-04-00390

Office of Inspector General 
 http://oig.hhs.gov 

The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, 

as amended, is to protect the integrity of the Department of Health and Human Services 

(HHS) programs, as well as the health and welfare of beneficiaries served by those 

programs. This statutory mission is carried out through a nationwide network of audits, 

investigations, and inspections conducted by the following operating components: 

Office of Audit Services 

The Office of Audit Services (OAS) provides all auditing services for HHS, either by 

conducting audits with its own audit resources or by overseeing audit work done by others. 

Audits examine the performance of HHS programs and/or its grantees and contractors 

in carrying out their respective responsibilities and are intended to provide independent 

assessments of HHS programs and operations. These assessments help reduce waste, 

abuse, and mismanagement and promote economy and efficiency throughout HHS. 

Office of Evaluation and Inspections 

The Office of Evaluation and Inspections (OEI) conducts national evaluations to provide 

HHS, Congress, and the public with timely, useful, and reliable information on 

significant issues. Specifically, these evaluations focus on preventing fraud, waste, or 

abuse and promoting economy, efficiency, and effectiveness in departmental programs. 

To promote impact, the reports also present practical recommendations for improving 

program operations. 

Office of Investigations 

The Office of Investigations (OI) conducts criminal, civil, and administrative 

investigations of allegations of wrongdoing in HHS programs or to HHS beneficiaries 

and of unjust enrichment by providers. The investigative efforts of OI lead to criminal 

convictions, administrative sanctions, or civil monetary penalties. 

Office of Counsel to the Inspector General 

The Office of Counsel to the Inspector General (OCIG) provides general legal services to 

OIG, rendering advice and opinions on HHS programs and operations and providing all 

legal support in OIG's internal operations. OCIG imposes program exclusions and civil 

monetary penalties on health care providers and litigates those actions within HHS. 

OCIG also represents OIG in the global settlement of cases arising under the Civil False 

Claims Act, develops and monitors corporate integrity agreements, develops compliance 

program guidances, renders advisory opinions on OIG sanctions to the health care 

community, and issues fraud alerts and other industry guidance. 
ΔINTROD UCT ION

 EXECUTIVE SUMMAR Y 

OBJECTIVES 

1. To determine the extent to which new drug applications involve 

postmarketing study commitments with the Food and Drug 

Administration (FDA). 

2. To determine how and the extent to which FDA monitors open 

postmarketing study commitments for new drug applications. 

BACKGROUND 

FDA requires all new drugs to undergo clinical testing to demonstrate 

their safety and efficacy prior to approval for sale in the United States. 

However, these premarket clinical trials involve relatively small 

numbers of individuals compared to the actual numbers who will 

eventually use the drugs. Therefore, it is possible that additional 

information regarding the safe and effective use of any drug may not be 

fully known until the drug is approved and prescribed to larger numbers 

of individuals in the general population. To learn more about the risks, 

benefits, and optimal use of an approved drug, drug applicants may 

conduct postmarketing studies, which are studies conducted while drugs 

are already on the market. These studies have become increasingly 

common in recent years. Meanwhile, members of Congress, FDA, and 

others have raised concerns that drug applicants are not completing 

these studies in a timely manner. 

FDA has the authority to require postmarketing study commitments in 

certain situations (e.g., accelerated approval), but most postmarketing 

study commitments are requested by FDA and agreed to by drug 

applicants. The Food and Drug Administration Modernization Act of 

1997 (FDAMA) provided FDA with new authorities for monitoring 

certain types of postmarketing studies. FDAMA requires that drug 

applicants submit annual status reports (ASRs) that provide 

information on the status of certain postmarketing studies. Some of the 

information from these reports is considered public information. 

Reviewers within FDA’s Center for Drug Evaluation and Research 

(CDER) are charged with validating the accuracy of these reports. 

We reviewed FDA’s database of postmarketing study commitments for 

new drug applications approved during fiscal years 1990 through 2004. 

We also examined documents regarding postmarketing study 

commitments that drug applicants submitted to FDA in fiscal year 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS i 
EXE CUTIVE S U MMAR Y 

2004. We interviewed project managers in CDER. Finally, we reviewed 

FDA policies and procedures regarding postmarketing commitments. 

EXTENT OF COMMITMENTS 

Forty-eight percent of new drug applications approved from fiscal years 

1990 through 2004 involved at least one postmarketing study 

commitment. 

FDA classified 74 percent of these postmarketing study commitments as 

clinical studies. Ninety-one percent of postmarketing commitments 

were requested by FDA and agreed to by drug applicants as opposed to 

being required by statute or regulation. 

Approved new molecular entities tended to have more postmarketing 

study commitments than other approved new drug applications. 

Two of fifteen review divisions at FDA accounted for 40 percent of the 

postmarketing study commitments from fiscal years 1990 through 2004. 

FINDING 

FDA cannot readily identify whether or how timely postmarketing 

study commitments are progressing toward completion. 

About one-third of ASRs were missing or incomplete. 

o Thirty-five percent of the 336 ASRs that were or should have been 

submitted in fiscal year 2004 were missing entirely or contained no 

information on open postmarketing study commitments. 

Thirty-nine percent were missing one or more items of required 

information. 

ASRs contain information of limited utility. 

o Even complete ASRs lack information that would be useful in 

monitoring the progress of postmarketing study commitments. 

o FDA has limited recourse when drug applicants do not submit 

required information or do not demonstrate progress in completing 

their postmarketing study commitments. 

FDA lacks an effective management information system for monitoring 

postmarketing study commitments. 

o FDA reviewers cannot easily identify which annual reports should 

include ASRs for outstanding postmarketing study commitments. 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS ii 
EXE CUTIVE S U MMAR Y

o FDA utilizes a confusing numbering system to identify 

postmarketing study commitments, and drug applicants do not 

always provide numbers for commitments they address in ASRs. 

o FDA frequently does not populate the fields of its database of 

postmarketing study commitments with information from 

commitment letters and ASRs that could assist reviewers in 

tracking the progress of commitments. 

Monitoring postmarketing study commitments is not a top priority at FDA. 

o FDA reviewers indicated to us that monitoring postmarketing study 

commitments is not generally considered a top priority at FDA. 

Our analysis showed that FDA validated only 30 percent of ASRs 

submitted in fiscal year 2004; five review divisions did not validate 

any ASRs. 

RECOMMENDATIONS 

To better determine whether and how timely postmarketing study 

commitments are progressing toward completion, FDA should: 

o Instruct drug applicants to provide additional, meaningful 

information in their ASRs; 

o Improve the management information system for monitoring 

postmarketing study commitments so that it provides timely, 

accurate, and useful information; and 

o Ensure that postmarketing study commitments are being 

monitored and that ASRs are being validated. 

AGENCY COMMENTS 

FDA disagreed with our finding that it cannot readily identify whether 

and how timely postmarketing study commitments are progressing 

toward completion. The agency emphasized both the seriousness with 

which it takes its obligation to monitor the progress of postmarketing 

study commitments and that it makes some information regarding the 

commitments publicly available. 

FDA concurred with two of our three recommendations. Specifically, 

FDA agreed with our recomendations to improve the management 

information system for monitoring postmarketing study commitments 

and to ensure that postmarketing study commitments are being 

monitored and ASRs are validated. The agency highlighted ongoing 

OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS iii 
EXE CUTIVE S U MMAR Y 

efforts to enhance its postmarketing study commitment database and 

reporting capabilities, train its review division staff on ASR validation 

procedures, and standardize the process by which postmarketing study 

commitments are requested and reviewed. 

FDA disagreed with our recommendation that it instruct drug 

applicants to provide additional, meaningful information in their ASRs, 

citing that implementing such a recommendation would require new 

regulations. 

OFFICE OF INSPECTOR GENERAL RESPONSE 

In disagreeing with our finding, FDA highlighted several areas in which 

it has made improvements. We appreciate that FDA has taken steps to 

improve its monitoring of postmarketing study commitments. However, 

our review of the postmarketing study commitment database and 

annual status reports, as well as our interviews with agency officials, 

demonstrated that FDA cannot readily identify whether or how timely 

postmarketing study commitments are progressing toward completion 

for the period of our review. 

We recognize that our recommendation that FDA instruct drug 

applicants to provide additional, meaningful information in their ASRs 

could require regulatory changes. In response, we added language to 

our recommendation acknowledging that FDA may need to seek 

regulatory changes to improve its system for monitoring postmarketing 

study commitments. 

We also made other minor changes to our report based on FDA’s 

technical comments. 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS iv 
Δ T ABLE OF CONTENTS 

EXECUTIVE SUMMARY ..................................... i

INTR O D U C T I ON ........................................... 1

EXTENT OF COMM ITMENTS ............................... 8

FINDI N G .................................................. 11

FDA cannot readily identify progress ...................... 11

 Missing or incomplete information........................ 11

 Limited utility of information............................ 12

Ineffective mangement information system................. 14

 Monitoring is not a top priority .......................... 17

RECOM M E NDATI O NS ..................................... 19

 Agency comments ...................................... 21

Office of Inspector General response ....................... 22

ENDN OTE S ............................................... 23

APPENDIXES ............................................. 29

A: Methodology........................................ 29

B: Data Tables ........................................ 32

C: Agency Comments ................................... 35

ACKN O W LEDGMENTS .................................... 38
ΔINTROD UCT ION

 INTRODU C TION 

OBJECTIVES 

1. To determine the extent to which new drug applications involve 

postmarketing study commitments with the Food and Drug 

Administration (FDA). 

2. To determine how and the extent to which FDA monitors open 

postmarketing study commitments for new drug applications. 

BACKGROUND 

The Importance of Postmarketing Studies 

FDA requires all new drugs to undergo clinical testing to demonstrate 

their safety and efficacy prior to approval for sale in the United States.1 

However, these premarket clinical trials involve relatively small 

numbers of individuals compared to the actual numbers who will 

eventually use the drugs. Therefore, it is possible that additional 

information regarding the safe and effective use of any drug may not be 

fully known until the drug has been approved and then prescribed to 

larger numbers of individuals in the general population. It is especially 

likely that information regarding rare side effects will not be fully 

known based on premarket trials. 

To learn more about the risks, benefits, and optimal use of an approved 

drug, drug applicants may conduct additional studies after a drug is 

already on the market.2 These studies, known as postmarketing 

studies, may evaluate a drug’s safety, efficacy, pharmacology, 

toxicology, and/or manufacturing controls, among other factors. It is 

common for a drug to be involved in multiple postmarketing studies. 

Although postmarketing studies provide important information about 

drugs, FDA does not consider them essential to drug approvals except in 

limited circumstances, such as to support accelerated approval 

applications or for required pediatric studies.3 Based on the results of 

postmarketing studies, FDA may approve changes to a drug’s label, 

approve a drug for new uses, require changes in a drug’s manufacturing 

process, or, in rare cases, seek to withdraw a drug from the market. 

Most postmarketing studies provide information that leads to labeling 

changes, such as how optimal dosing may differ across patient 

populations. 

Given the valuable information that postmarketing studies can provide, 

it is not surprising that they are becoming increasingly common. 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 1 
INTROD UCT ION 

A 1996 Office of Inspector General (OIG) report found that the 

percentage of new drugs with postmarketing study commitments 

increased from the early 1970s through the early 1990s.4 FDA’s report 

to Congress on postmarketing study commitments in April 2002 found a 

similar trend.5 

At the same time, members of Congress, FDA, and others have raised 

concerns that drug applicants are not fulfilling their postmarketing 

study commitments in a timely manner.6,7 

Types of Postmarketing Studies 

There are three main types of postmarketing studies: (1) studies 

required by FDA, (2) studies requested by FDA and agreed to by drug 

applicants, and (3) voluntary studies. The latter two are the most 

common types of postmarketing studies. 

Studies required by FDA. In certain situations, FDA has the statutory or 

regulatory authority to require drug applicants to conduct 

postmarketing studies.8 These postmarketing study commitments are 

the least common. 

Studies requested by FDA and agreed to by drug applicants. Although FDA 

can request that drug applicants conduct postmarketing studies at any 

time, most requests for postmarketing studies are made prior to drug 

approval, when FDA has leverage over drug applicants who are eager to 

obtain approval for their products. Manufacturers not only agree to 

these commitments in writing, but FDA also lists the commitments in 

final approval letters. However, FDA does not have any authority to 

sanction drug applicants that fail to conduct these studies. These are 

the most common postmarketing study commitments. 

Voluntary studies. Voluntary studies are studies that drug applicants 

conduct on their own initiative. 

FDA’s Monitoring of Postmarketing Study Commitments 

Section 130(a) of Title I of the Food and Drug Administration 

Modernization Act of 1997 (FDAMA) added section 506B to the Food, 

Drug, and Cosmetic Act and provided FDA with new authorities for 

monitoring certain postmarketing studies associated with drugs and 

biologics.9 Congress enacted this section in response to concerns 

expressed by FDA and the public about the timeliness with which 

postmarketing studies were being completed and the need to update 

drug labeling with information obtained from such studies.10 Section 

506B of FDAMA contains two particularly relevant provisions: 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 2 
INTROD UCT ION

(1) it requires reporting on the status of certain postmarketing studies, 

and (2) it establishes that certain information in these reports is 

considered public information.11,12 These reports, known as annual 

status reports (ASRs), are intended to be a key tool for FDA to use in 

monitoring postmarketing study commitments. 

In October 2000, FDA issued final regulations on the nature and 

contents of ASRs for open postmarketing study commitments required 

under FDAMA.13 Pursuant to the regulations, the types of 

commitments for which drug applicants must submit ASRs are studies 

that address: (1) clinical safety, (2) clinical efficacy, (3) clinical 

pharmacology, and (4) nonclinical pharmacology.14 This requirement 

covers all studies required by FDA and all studies requested by FDA 

and agreed to by drug applicants, except for chemistry, manufacturing, 

and control studies.15 The requirement excludes voluntary studies. 

Throughout this report, we use the terms commitment and 

postmarketing study commitment to refer only to postmarketing studies 

that require annual reporting under FDAMA. 

Pursuant to regulation, ASRs must contain the following information:16 

o Applicant name 

o Product name 

o Application number 

o Date of U.S. approval 

o Date of postmarketing study commitment 

o Description of postmarketing study commitment 

o Schedule for completion of and reporting on the postmarketing 

commitment 

o Status of the commitment 

o Pending: The study has not started, but is not behind schedule. 

o Ongoing: The study is ahead of or on schedule. 

o Delayed: The study is behind the original schedule. 

o Terminated: The study was ended before completion, but a final 

report has not been submitted to FDA. 

OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 3 
INTROD UCT ION 

o Submitted: The study was completed or terminated and a final 

report was submitted to FDA for review. 

o Explanation of the status of the study 

Drug applicants must submit ASRs within 60 days of the anniversary of 

the approval of a new drug application.17 Generally, ASRs can be found 

in larger reports, known as annual reports, which are submitted by 

drug applicants and contain information concerning changes in 

manufacturing practices and labeling, among other things. FDA’s goal 

is to review ASRs within 90 days of receipt.18 The main focus of FDA 

reviews is to validate the accuracy of the information in the ASRs; 

however, FDA also determines whether drug applicants are making 

adequate progress toward fulfilling their commitments. FDA may 

follow up with drug applicants regarding these reports as necessary, 

such as for late and/or incomplete reports. 

In April 2001, FDA issued draft guidance to industry that elaborates on 

the regulatory requirements for the content of ASRs.19 This guidance 

was finalized in February 2006 (after the period of our review).20 

The Prescription Drug User Fee Act of 2002, which reauthorized user 

fees for the review of new drug applications, also provided FDA with 

additional tools to improve compliance with postmarketing 

commitments. The law amended section 506B of the Federal Food, 

Drug, and Cosmetic Act to require the Secretary to inform the public if 

and when drug applicants fail to fulfill such commitments.21 In 

November 2004, FDA announced that it had contracted with the 

Institute of Medicine to study the effectiveness of the drug safety 

system with an emphasis on the postmarket phase.22 In February 2005, 

FDA announced the creation of the Drug Safety Board to oversee drug 

safety issues, in which postmarketing studies can play a part.23 

Center for Drug Evaluation and Research Procedures 

Within FDA, the Center for Drug Evaluation and Research (CDER) is 

responsible for reviewing new drug applications and for monitoring 

postmarketing study commitments for drugs. Reviewers within CDER’s 

Office of New Drugs (OND) have the lead responsibility for reviewing 

new drug applications and ASRs for postmarketing study commitments. 

Typically, the reviewer who reviewed a new drug application also 

reviews any associated ASRs. CDER reviewers have backgrounds in 

various disciplines, including pharmacy, chemistry, and medicine, 

among others. There are multiple review divisions within OND. 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 4 
INTROD UCT ION 

In 1996, CDER issued procedures for tracking and monitoring 

postmarketing commitments.24 CDER is in the process of updating 

these procedures. In 2001, CDER implemented a new database to track 

and monitor the status of postmarketing commitments. To foster public 

accountability in completing these commitments, portions of this 

database are available to the public on the FDA Web site.25 

In March 2005, CDER issued procedures for reviewing ASRs for 

postmarketing study commitments. These procedures require reviewers 

to complete worksheets that document that they verified the accuracy of 

the information in the ASRs. Reviewers must indicate on the 

worksheets whether they agree with the status of commitments and 

explanations of status as reported by drug applicants.26 

After a final study report is submitted, CDER procedure calls for a 

review to determine whether a given commitment has been fulfilled; if it 

has, CDER sends a fulfillment letter to the drug applicant.27 

Prior Office of Inspector General Reports 

In May 1996, OIG issued a report assessing the effectiveness of FDA’s 

monitoring of postmarketing study commitments for drugs.28 This 

inspection found that the number of new drugs with postmarking 

commitments was increasing, but that FDA lacked both formal 

procedures for monitoring these commitments and an effective 

management tool to track the status of commitments. The inspection 

attributed these vulnerabilities to competing priorities, limited 

resources, and an inability to enforce compliance. 

In March 2003, OIG issued a report assessing how FDA manages the 

new drug application review process.29 This inspection found that 

reviewers were often uncertain about what types of postmarketing 

commitments to request of drug applicants prior to drug approval. 

Recent FDA Initiatives 

Over the past several years, FDA has changed the way it monitors 

postmarketing study commitments. FDA has: (1) implemented a new 

database to track the status of postmarketing study commitments, 

(2) issued new procedures for tracking and reviewing commitments, 

(3) received additional authorities to require drug applicants to report 

annually on the progress of their commitments and publicly disclose 

information from these reports, (4) issued new procedures for reviewing 

annual status reports, and (5) issued guidance for industry regarding 

status reports for postmarketing study commitments. 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 5 
INTROD UCT ION

METHODOLOGY 

Our analysis involved several data sources and methods. (For a 

complete description of our methodology, see Appendix A.) 

We reviewed FDA’s database of postmarketing study commitments for 

new drug applications approved from fiscal years 1990 through 2004. 

Because the database does not consistently show when postmarketing 

study commitments were initiated, we linked each postmarketing study 

commitment to the fiscal year in which its new drug application was 

approved. We performed trend analyses by year, study type, study 

category, review division, and study status. We conducted the same 

trend analyses for postmarketing study commitments associated with 

new molecular entities (NMEs), a subset of new drug applications for 

drugs that contain active ingredients never before approved for 

marketing in the United States. 

We reviewed annual reports that FDA received from drug applicants in 

fiscal year 2004 that did or should have contained ASRs for open 

postmarketing study commitments. We matched the postmarketing 

studies listed in these ASRs to commitments in FDA’s database of 

postmarketing study commitments and analyzed the ASRs for 

completeness and accuracy. We also reviewed all available FDA 

validations and other supporting documentation associated with fiscal 

year 2004 ASRs. 

We also reviewed all fulfillment letters issued by FDA in fiscal year 

2004. For a subset of commitments fulfilled in fiscal year 2004, we 

obtained additional documentation from FDA, which we reviewed to 

determine reasons for lateness and the extent of FDA followup. 

We interviewed project managers at 14 of the 16 review divisions within 

CDER. We did not speak to reviewers at the two divisions that oversee 

therapeutic biologic drugs, which were excluded from the scope of this 

inspection.30 We used a structured questionnaire to conduct the 

interviews; this questionnaire addressed policies and procedures, 

challenges, and recommendations regarding monitoring postmarketing 

study commitments. We conducted all interviews by telephone. 

Finally, we reviewed all relevant policies, procedures, and guidance 

documents for postmarketing study commitments issued by FDA. We 

used these documents to better understand the process for monitoring 

postmarketing study commitments. 

OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 6 
INTROD UCT ION 

We conducted this evaluation in accordance with the “Quality 

Standards for Inspections” issued by the President’s Council on 

Integrity and Efficiency and the Executive Council on Integrity and 

Efficiency. 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 7 
Δ EXTENT OF COMMITMENTS 

In this section we provide a summary of the extent and nature of 

postmarketing study commitments associated with new drug 

applications approved from fiscal years 1990 through 2004. 

For additional information, see Appendix B. 

Forty-eight percent of new drug applications approved from fiscal years 

1990 through 2004 involved at least one postmarketing study commitment. 

On an annual basis, the percentage of approved new drug applications 

with at least one commitment ranged from a low of 26 percent (in 1990) to 

a high of 71 percent (in 2004). From fiscal years 1995 through 2003, the 

percentage of approved new drug applications with at least one 

commitment was fairly constant. (See Chart 1 below.) 

Chart 1. Percentage of New Drug Applications With at Least 

One Postmarketing Study Commitment, by Fiscal Year, 

1990–2004 

0 

10 

20 

30 

40 

50 

60 

70 

80 

199019911992199319941995199619971998199920002001200220032004 

Year 

Percentage of 

New Drug 

Applications 

Source: Office of Inspector General analysis of FDA data, 2005. 

FDA classified 74 percent of postmarketing study commitments from fiscal 

years 1990 through 2004 as clinical. Ninety-one percent of postmarketing 

commitments were requested by FDA and agreed to by drug applicants as 

opposed to being required. 

Clinical postmarketing studies involve an approved drug being 

administered to humans and evaluated for safety and/or efficacy. (See 

Table 1 on the following page.) 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 8 
EXTENT OF COMMITME N TS 

Table 1. Postmarketing Study Commitments by Nature 

From Fiscal Years 1990–2004 

Nature of Postmarketing 

Study Commitment 

Number of Postmarketing 

Study Commitments 

Percentage of Postmarketing 

Study Commitments 

Clinical 

Pediatric*

Nonclinical

All Others

1,732 

326 

255 

 40

74 

14 

11 

2

 Total 2,353 ** 

*Pediatric studies are considered clinical studies, but are tracked separately in FDA's database.

** Column does not sum to 100 due to rounding.

Source: Office of Inspector General analysis of FDA data, 2005.

Further, the overwhelming majority of postmarketing study 

commitments from the period of our review were requested by FDA. 

(See Table 2 below.) Drug applicants agree to conduct requested study 

commitments in writing, and FDA lists the commitments in final 

approval letters. 

Table 2. Postmarketing Study Commitments by Type 

From Fiscal Years 1990–2004 

Type of Postmarketing 

Study Commitment 

Number of Postmarketing 

Study Commitments 

Percentage of Postmarketing 

Study Commitments 

Requested by FDA 

Accelerated Approval*

Deferred Pediatric*

Animal Efficacy*

2,132

 118

 102

 1

 91 

5 

4 

 < 1

 Total 2,353 100 

* Full explanations of these postmarketing study commitment types can be found in endnote 8. 

Source: Office of Inspector General analysis of FDA data, 2005. 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 9 
EXTENT OF COMMITME N TS 

Approved new molecular entities tended to have more postmarketing study 

commitments than other approved new drug applications. 

NMEs are approved drugs that contain active ingredients that have never 

been approved for marketing in the United States. Because less is known 

about these entirely new drugs, it is perhaps not surprising that, on 

average, NMEs tended to be associated with more postmarketing study 

commitments than other new drug applications. (See Chart 2 below.) 

Chart 2. Average Numbers of Commitments for 

NME and Non-NME New Drug Applications, by Fiscal Year, 

1990–2004 

0 

1 

2 

3 

4 

5 

6 

7 

199019911992199319941995199619971998199920002001200220032004 

Year 

Nu

mber of Co

m

mitments

NMEs 

non-NMEs 

Source: Office of Inspector General analysis of FDA data, 2005. 

Two of fifteen review divisions within CDER accounted for 40 percent of the 

postmarketing study commitments from fiscal years 1990 through 2004. 

During the period of our inquiry, the Division of Anti-Viral Drug 

Products oversaw 26 percent of the postmarketing study commitments 

and the Division of Special Pathogen and Immunologic Drug Products 

oversaw 14 percent of postmarketing study commitments. None of the 

other CDER review divisions oversaw more than 10 percent of 

postmarketing study commitments. (See Appendix B, Table 2, for 

additional information.) 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 10 
Δ FINDING 

FDA cannot readily identify whether or how timely 

postmarketing study commitments are 

progressing toward completion 

About one-third of ASRs were missing or incomplete 

ASRs are intended to be a key source of information for FDA and an 

important tool for monitoring postmarketing study commitments. 

Of the 336 ASRs that, according to FDA, were or should have been 

submitted by drug applicants in fiscal year 2004, 35 percent (119) were 

either missing entirely or contained no information on open 

postmarketing study commitments; some stated explicitly that no open 

postmarketing study commitments existed when, in fact, they did. 

(See Table 3 below.) 

Table 3. Classification of ASRs That Were or Should Have 

Been Submitted in Fiscal Year 2004 

Description of ASR Number of ASRs Percentage of ASRs 

ASR Not Submitted by Drug 

Applicant

ASR Did Not Contain Information 

on Open Postmarketing Study 

Commitments

ASR Contained Information on at 

Least One, but Not Necessarily All 

Open Postmarketing Study 

Commitments 

 27

 92

217

 8 

27 

65

 Total 336 100 

Source: Office of Inspector General analysis of FDA data, 2005. 

Of the 788 commitments listed in the ASRs from fiscal year 2004 that 

could be matched with commitments in FDA’s database of 

postmarketing study commitments, 39 percent (307) were missing one 

or more items of required information. (See Table 4 on the following 

page.) For example, drug applicants did not provide a status for 

8 percent of commitments (65) and did not provide an explanation of 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 11 
F I NDING 

status for 10 percent of commitments (78). (See Appendix B, Table 3, 

for additional information.) 

For an additional 14 percent of commitments (110), drug applicants 

wrote something about the status of their commitments but did not 

provide one of the status definitions (i.e., pending, ongoing, delayed, 

terminated, and submitted) that are required by regulation.31 For 

example, we reviewed ASRs that identified the status of commitments 

as “the final report of the study will be available by the end of the year,” 

and “the data is currently being analyzed.” If drug applicants do not 

provide one of the standard status definitions, FDA may not be able to 

post accurate information about the status of commitments on its public 

Web site of postmarketing study commitments. 

Table 4. Number of Required Elements Missing From 

Fiscal Year 2004 ASRs, per Postmarketing Study Commitment 

Number of 

Missing Elements 

Number of Postmarketing 

Study Commitments 

Percentage of Postmarketing 

Study Commitments 

7 

6 

5

4

3

2

1 

0 

1

3

 9

 49

 54

 68

123

481

 < 1 

 < 1 

1 

6 

7 

9 

16 

61

 Total 788 100 

Source: Office of Inspector General analysis of FDA data, 2005. 

ASRs contain information of limited utility 

Even complete ASRs often lacked information that would be useful in 

monitoring the progress of postmarketing study commitments. Of the 

FDA officials we interviewed at the 14 review divisions, officials at 

9 told us that the inadequacy of information even on complete ASRs 

poses a major or moderate challenge to their ability to effectively 

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F I NDING 

monitor the progress of postmarketing study commitments. Some of the 

FDA reviewers we interviewed indicated that the information provided 

on ASRs does not assist in ensuring progress of postmarketing study 

commitments. For example, one official we interviewed categorized the 

current process for monitoring postmarketing study commitments as 

“very shallow” because, although validating ASRs provides information 

on whether FDA agrees with the status of commitments, it does not 

necessarily serve to move commitments toward completion. 

In 2001, FDA released draft 

guidance to industry on how to Nine elements required to be

reported on ASRs for open complete ASRs for postmarketing postmarketing study commitments 

study commitments.32 This 

guidance, finalized in February o Applicant name 

o Product name 2006, reiterates and provides o Application number 

additional detail about the o Date of U.S. approval 

regulatory requirements. It o Date of postmarketing study

commitment 

includes a section on the content o Description of postmarketing 

and format of ASRs and provides study commitment 

o Original schedule for completing detailed information on the nine the postmarketing study

required items of information that, commitment 

pursuant to regulations, must be o Status of the commitment 

o Explanation of the status reported for each open 

postmarketing study commitment. Source: 21 CFR § 314.81(b)(2)(vii). 

(See the box to the right.) The 

regulations require drug applicants to report a schedule for completion 

and reporting of the postmarketing study commitment. The regulations 

also recommend that the schedule contain certain milestones, including 

projected dates of initiation for different phases of the studies. FDA 

recognizes these milestones and others—including dates of submission 

of study protocols, completion of participant enrollment, completion of 

the study, and submission of the final study report—as “common and 

important to determining study progress.”33 Additionally, the guidance 

states that in providing an explanation of any commitment’s status, a 

drug applicant should briefly explain the progress of the commitment 

with regard to its original schedule.34 

Our review of ASRs found that they frequently lacked the information 

and detail either required or recommended by regulation. For example, 

many of the ASRs we reviewed provided none of the milestone dates 

recommended by the regulations, and others included information on 

only some of the dates. Further, even when drug applicants explained 

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F I NDING

the status of commitments, the explanations often lacked detail. We 

saw examples of drug applicants simply listing the status of the 

commitment (e.g., pending) as both the status and the explanation of 

the status. 

The inadequacy of information on ASRs makes it difficult for FDA 

reviewers to readily identify the data they actually require to monitor 

the progress of postmarketing study commitments effectively. Not only 

are the most substantive aspects of the ASRs often lacking detail, but 

further, ASRs do not give reviewers complete pictures of the progress of 

postmarketing study commitments. Rather, reviewers must evaluate 

additional reports—including study protocols, progress reports, and 

final reports—submitted by drug applicants over the past year(s). 

However, ASRs do not include information that would link 

commitments with those reports. FDA does not require drug applicants 

to include in ASRs the dates on which they submitted additional 

information or to where they submitted that information. Officials told 

us that having this information readily available would make it easier 

to locate the documents they need to review. One official said that, 

currently, finding the information necessary to review open 

postmarketing study commitments is like “looking for a needle in a 

haystack.” 

Section 130(a) of Title 1 of FDAMA does not provide any enforcement 

authority to FDA for instances in which drug applicants do not submit 

required information or demonstrate progress in completing their 

postmarketing study commitments. As a practical matter, FDA officials 

have two options for short-term action in such cases: (1) sending letters 

and (2) placing phone calls to drug applicants. Although many of the FDA 

officials we interviewed stated that letters or phone calls may often be 

enough to get drug applicants to submit the information FDA is 

requesting, in some cases these options are ineffective. 

FDA lacks an effective management information system for monitoring 

postmarketing study commitments 

Difficulty identifying overdue ASRs. Although FDA management provides 

review divisions with some reports for monitoring the status of 

postmarketing study commitments, there appears to be a low level of 

awareness of these reports in the review divisions and the reports may 

be of limited utility. The FDA officials we interviewed in the review 

divisions indicated that they cannot readily identify which annual 

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F I NDING

reports have associated open postmarketing commitments and, 

therefore, should contain ASRs. The reviewers we interviewed told us 

that they must either cross-reference the postmarketing commitment 

database for open postmarketing study commitments or rely on 

informal tools (e.g., knowledge of FDA employees or informal lists) to 

determine whether an approved new drug application has open 

postmarketing commitments requiring the submission of an ASR. 

Several FDA officials we interviewed stated that they only know reports 

will be late when drug applicants call to tell them. Of the FDA officials 

we interviewed at the 14 review divisions, officials at 8 stated that the 

current tracking system poses either a major or moderate challenge to 

their ability to effectively monitor the progress of postmarketing study 

commitments. 

Our review of ASRs uncovered additional barriers to using the 

postmarketing study commitment database to determine when ASRs 

are overdue. We compared the list of ASRs FDA reported as having 

been submitted or not submitted in fiscal year 2004 with the database of 

postmarketing study commitments. This comparison showed that not 

all of the open commitments in the database were accounted for in 

ASRs.35 FDA reported that some of these commitments were for drugs 

that had been withdrawn from the market; yet the database did not 

capture this information. Further, FDA reported that some 

commitments were not reported on because of drug applicant mergers or 

other reasons. Nonetheless, the regulations require that ASRs be 

submitted annually until a final study report has been submitted to 

FDA and the drug applicant has been notified that the study 

commitment has been fulfilled.36 The regulations provide no exceptions 

for drug applications that have experienced changes in ownership. 

Confusing numbering system. FDA uses a confusing numbering system 

for postmarketing study commitments. At the time of a drug’s approval, 

FDA numbers any commitments for that drug sequentially starting 

with “1.” In addition, when FDA approves a subsequent supplemental 

application for the same drug, it again numbers any commitments 

sequentially starting with “1.” These numbers appear in the drug 

approval letters sent to drug applicants and in FDA’s database of 

postmarketing study commitments. 

Further complicating matters is that drug applicants do not always 

number the commitments they address in their ASRs; even when they 

do so, the numbers do not always match the numbers in FDA’s database 

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F I NDING

of postmarketing study commitments. As commitments are fulfilled, 

drug applicants may renumber remaining commitments, so that if 

commitments “1” and “2” are fulfilled, a drug applicant may list the 

original commitment “3” as commitment “1” in an ASR. 

We observed that the commitment numbers and descriptions used in 

ASRs did not always match the commitment numbers and descriptions 

in the FDA database. In addition, we saw examples of FDA using 

different commitment numbers in its validations of ASRs than it used in 

the database of postmarketing study commitments. Having to 

cross-reference multiple sources to determine the correct identifiers for 

postmarketing study commitments adds to the already burdensome task 

of tracking postmarketing study commitments. 

FDA has recently adopted new procedures to minimize confusion 

regarding how to number postmarketing study commitments. However, 

this new process still relies on drug applicants to number commitments 

consistently over time. 

Database inconsistently populated. FDA frequently does not populate the 

fields of its database of postmarketing study commitments with 

information from commitment letters and ASRs that could assist 

reviewers in tracking the progress of commitments. We observed that 

database fields that should contain protocol submission dates, original 

projected completion dates, study start dates, and current projected 

completion dates are not always populated. For example, out of a total 

of 2,353 commitments in the database, study start dates were present 

for only 6 percent (132) and original projected completion dates were 

present for only 21 percent (484). Without this information readily 

available, it is difficult for reviewers to determine whether studies are 

on schedule. In addition, FDA generally does not record in its database 

the dates on which drug applicants make final report submissions; only 

3 percent of commitments classified by FDA as “fulfilled” in the 

database listed the final report submission date. Without this 

information, it is not possible to readily determine the length of time it 

takes for drug applicants to complete postmarketing study 

commitments or whether they are being completed at all. 

To determine whether drug applicants are completing their 

postmarketing study commitments early, on time, or late, we attempted 

to analyze postmarketing study commitments deemed by FDA to have 

been fulfilled in fiscal year 2004.37 Because of missing data, we were 

able to determine the timeliness of only 18 of the 145 commitments 

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F I NDING

fulfilled in fiscal year 2004.38 Of these 18 commitments, 3 were 

completed on time or early; the other 15 were completed, on average, 

about 5 months late. 

According to FDA officials, commitments that predated FDAMA and the 

2001 reporting regulations may not have had study schedules 

established at the time of approval and, therefore, would not necessarily 

have commitment schedule dates within the database. We observed 

that the prevalence of commitment schedule dates in the database has 

improved since the 2001 reporting regulations were enacted. However, 

the regulations called for all commitments, including those that predate 

FDAMA, to submit ASRs that included schedules.39 

Because the database of postmarketing study commitments is not 

populated with these dates, the public Web site on postmarketing study 

commitments may not keep the public and the medical community 

informed of the status of postmarketing obligations. 

Monitoring postmarketing study commitments is not a top priority at FDA 

Of the FDA officials we interviewed at the 14 review divisions, officials 

at 9 said that the current priority of monitoring postmarketing study 

commitments poses a major or moderate challenge to their ability to 

effectively monitor the progress of the studies. FDA officials told us 

that, among other things, reviewing drug applications and documenting 

FDA/industry meetings are higher priorities than reviewing 

postmarketing study commitments and ASRs. Further, central OND 

management provides project managers with regular updates on 

upcoming Prescription Drug User Fee Act goals and other priority 

items; however, no centrally generated report addresses postmarketing 

study commitments and their progress toward completion. Many of the 

FDA officials we interviewed told us that when they prioritize their 

workloads, they simply lack the resources to accomplish all of the tasks 

assigned to them. 

FDA validated only 30 percent (65) of the 217 ASRs that were actually 

submitted by drug applicants in fiscal year 2004 and included at least 

one open postmarketing study commitment. Five review divisions did 

not validate any of the ASRs they were charged with overseeing in fiscal 

year 2004. Further, even when ASRs were validated, FDA frequently 

did not meet its goal of completing ASR reviews within 90 days of 

receipt and often appeared to fall short of meeting FDA requirements 

for monitoring postmarketing study commitments. (See Appendix B, 

Table 4, for additional information.) For example, we observed that 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 17 
FDA reviewers sometimes agreed with drug applicants even when the 

applicants failed to provide one of the status options required by the 

regulations. 

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ΔF I NDING S 

 RECOMME NDA TIONS 

We recognize that FDA reviewers have multiple priorities in addition to 

monitoring postmarketing study commitments and that FDA faces 

limited staffing resources. We also recognize that FDA has taken steps 

to improve its monitoring system for postmarketing study commitments 

and has other initiatives underway. For example, in March 2005, FDA 

finalized an internal manual of policies and procedures regarding 

postmarketing study commitments and ASRs.40 FDA is also in the 

process of redesigning its database of postmarketing study 

commitments and enhancing the postmarketing study commitment 

reporting system to make monitoring more efficient. 

Postmarketing studies are important tools for gathering information 

about the risks, benefits, and optimal uses of drugs that may not be 

fully known until the drugs are approved and prescribed in the general 

population. Yet, we have identified shortcomings in the extent to which 

information is reported, the utility of the information that is collected, 

and the effectiveness of the current management information system. 

Taken together, these vulnerabilities raise concerns that FDA’s tools for 

monitoring postmarketing study commitments—ASRs and its 

management information system—may not ensure that postmarketing 

study commitments are progressing toward completion. 

Based on our review, we believe that FDA should take additional steps 

to improve the system for monitoring postmarketing study 

commitments so as to be able to readily identify whether and how 

timely postmarketing study commitments are progressing toward 

completion. Toward that end, we recommend that FDA: 

Instruct Drug Applicants to Provide Additional, Meaningful Information in 

Their ASRs 

FDA should instruct drug applicants to provide in their ASRs when and 

where they submitted reports on their open postmarketing study 

commitments. FDA officials must review these other reports to 

determine the progress of commitments. 

While the regulations currently require drug applicants to report a 

schedule for completion and reporting of the postmarketing study 

commitment, they recommend but do not require that applicants 

provide in their ASRs relevant dates of key milestones. Such milestones 

could include: (1) submissions of study protocols, (2) completion of 

participant enrollment, (3) completion of studies, and (4) submissions of 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 19 
R E C O MMENDA T I O N S 

final reports. Toward this end, FDA may want to seek regulatory 

change to require a greater a level of detail in ASRs. 

Improve the Management Information System for Monitoring Postmarketing 

Study Commitments So That It Provides Timely, Accurate, and Useful 

Information 

FDA should take several steps to improve its management information 

system: 

o Ensure that commitments are numbered uniquely and logically. 

The current numbering of postmarketing study commitments can 

create confusion and lead to misidentifying commitments. An 

effective numbering system would assign a unique identifier at the 

time of approval. FDA could then instruct drug applicants to use 

those unique identifiers on any submissions made to the agency, 

and FDA could use the identifiers in its management information 

system and on all correspondence regarding postmarketing study 

commitments. 

o Ensure that the database is populated with useful information. 

Some information on postmarketing study commitments is already 

entered into FDA’s database. FDA should also populate its 

database with, at a minimum, the following items: (1) study start 

dates, (2) original scheduled completion dates, and (3) final report 

submission dates. 

Further, FDA should consider populating the database with 

additional information, including: (1) references to reports 

submitted by drug applicants, (2) numbers of participants enrolled 

while commitments are “ongoing,” and (3) information pertaining to 

why commitments are “delayed,” whenever applicable. 

o Enhance the current reporting capability that identifies late ASRs 

and outstanding commitments. 

There appears to be a low level of awareness within the review 

divisions of the reports that identify late ASRs and outstanding 

commitments. Furthermore, these reports may be of limited utility. 

An enhanced management information system could generate 

reports that would enable reviewers to readily identify approved 

new drug applications for which ASRs are due as well as those with 

open commitments that are behind schedule. 

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R E C O MMENDA T I O N S 

Ensure That Postmarketing Study Commitments Are Being Monitored and 

That ASRs Are Being Validated 

FDA must ensure that reviewers are meeting their oversight 

responsibilities for postmarketing study commitments. Although FDA 

faces competing priorities and limited staffing resources, ensuring that 

postmarketing studies are being completed in a timely manner is crucial 

to ensuring that the public and the medical community are aware of the 

risks, benefits, and optimal uses of approved drugs. To this end, FDA 

must ensure that reviewers have the information, tools, and time they 

need to complete this important task. 

FDA should also consider seeking authority to obtain additional 

recourse options in cases of postmarketing study commitments that lag 

far behind schedule or for which required documents are not submitted. 

Currently, short of withdrawing a drug from the market—a remedy 

available to FDA only in limited circumstances—the only short-term, 

practical options available to FDA in dealing with drug applicants that 

do not comply with the terms of their commitments are sending letters 

and placing phone calls. Providing FDA reviewers with additional tools, 

such as the ability to impose monetary fines, may send a signal to drug 

applicants that there are consequences when postmarketing study 

commitments are not fulfilled. 

AGENCY COMMENTS 

FDA disagreed with our finding that it cannot readily identify whether 

and how timely postmarketing study commitments are progressing 

toward completion. The agency emphasized both the seriousness with 

which it takes its obligation to monitor the progress of postmarketing 

study commitments and that it makes some information regarding the 

commitments publicly available. 

FDA concurred with two of our three recommendations. Specifically, 

FDA agreed with our recomendations to improve the management 

information system for monitoring postmarketing study commitments 

and to ensure that postmarketing study commitments are being 

monitored and ASRs are validated. The agency highlighted ongoing 

efforts to enhance its postmarketing study commitment database and 

reporting capabilities, train its review division staff on ASR validation 

procedures, and standardize the process by which postmarketing study 

commitments are requested and reviewed. 

OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 21 
R E C O MMENDA T I O N S 

FDA disagreed with our recommendation that it instruct drug 

applicants to provide additional, meaningful information in their ASRs, 

stating that implementing such a recommendation would require new 

regulations. 

See Appendix C for complete agency comments. 

OFFICE OF INSPECTOR GENERAL RESPONSE 

In disagreeing with our finding, FDA highlighted several areas in which 

it has made improvements. We appreciate that FDA has taken steps to 

improve its monitoring of postmarketing study commitments. However, 

our review of the postmarketing study commitment database and 

annual status reports, as well as our interviews with agency officials, 

demonstrated that FDA cannot readily identify whether or how timely 

postmarketing study commitments are progressing toward completion 

for the period of our review. 

We recognize that our recommendation that FDA instruct drug 

applicants to provide additional, meaningful information in their ASRs 

could require regulatory changes. In response, we added language to 

our recommendation acknowledging that FDA may need to seek 

regulatory changes to improve its system for monitoring postmarketing 

study commitments. 

We also made other minor changes to our report based on FDA’s 

technical comments. 

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Δ ENDNOTE S 

1 Federal Food, Drug, and Cosmetic Act of 1938, as amended. 

21 U.S.C. § 355. 

2 Drug applicants typically are pharmaceutical or biotechnology 

companies seeking FDA’s approval to market a new drug by submitting a 

new drug application. 

3 Department of Health & Human Services, Food and Drug 

Administration, “Report to Congress on Postmarketing Studies 

[FDAMA 130],” April 2002. 

4 Department of Health & Human Services, Office of Inspector General, 

“Postmarketing Studies of Prescription Drugs” (OEI-03-94-00760), 

May 1996. 

5 Department of Health & Human Services, Food and Drug 

Administration, “Report to Congress on Postmarketing Studies 

[FDAMA 130],” April 2002. 

6 Department of Health & Human Services, Food and Drug 

Administration, “Report to Congress on Postmarketing Studies 

[FDAMA 130],” April 2002, p. 1. 

7 See, for example: Henderson, D. June 1, 2005. “Speedy drug-review 

process ‘broken.’” Boston Globe: D3. 

Also see: Fontanarosa, P.B., Rennie, D., and DeAngelis, C.D. 

December 1, 2004. “Postmarketing Surveillance—Lack of vigilance, lack 

of trust.” Journal of the American Medical Association 292 (21): 

2647-2650. 

8 The following are the four situations in which FDA can require drug 

applicants to conduct postmarketing studies: 

Accelerated approval. FDA may approve a drug based on a surrogate 

clinical endpoint. For example, FDA may approve a cancer drug based 

on the surrogate endpoint that the drug reduces tumor size, instead of 

the endpoint of increased life expectancy. In such cases, FDA requires 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 23 
the applicant to conduct postmarketing studies to verify the safety and 

efficacy of the drug after it is on the market. FDA may withdraw the 

drug if the studies do not demonstrate effectiveness, raise safety 

concerns, or are not completed with due diligence. 

See 21 U.S.C. 356, 21 CFR § 314.510, and 21 CFR § 314.530. 

Deferred pediatric studies. FDA requires all new drugs that are likely 

to be used in pediatric patients to demonstrate, prior to approval, their 

safety and efficacy in relevant pediatric populations. However, FDA 

may defer this requirement until after the drug is approved for use in 

adults. When FDA grants a deferral, it requires the applicant to 

conduct postmarketing studies to demonstrate the safety and efficacy of 

the drug in pediatric participants. If the applicant fails to conduct such 

studies, FDA may consider the drug misbranded and may authorize an 

injunction, seizure, or other action. See: Pediatric Research Equity Act 

of 2003; 21 CFR § 314.55; 21 U.S.C. §§ 331-334; and 63 Federal 

Register 66,631, December 2, 1998, Regulations Requiring 

Manufacturers to Assess the Safety and Effectiveness of New Drugs 

and Biological Products in Pediatric Patients. 

Animal efficacy rule. FDA may approve a drug based solely on animal 

studies when clinical studies in humans cannot be conducted ethically. 

Under these circumstances, FDA requires the applicant to conduct 

postmarketing studies to verify and assess the safety and efficacy of the 

drug in humans. If the applicant fails to perform the studies with due 

diligence, FDA may withdraw the drug. See 21 CFR § 314.610 and 

21 CFR § 314.620. 

Determination to revoke approval. FDA may require an applicant to 

conduct a postmarketing study after the drug is already approved if 

information is needed to determine whether the approval of the drug 

should be revoked. This is typically used for cases in which there is a 

serious concern about safety. (FDA does not track these situations in 

its database of postmarketing study commitments.) 

See 21 U.S.C. §§ 355(e) and 355(k). 

9 21 U.S.C. § 356b. 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 24 
10 Department of Health & Human Services, Food and Drug 

Administration, “Report to Congress on Postmarketing Studies 

[FDAMA 130],” April 2002. 

11 21 U.S.C. § 356b. 

12 Prior to FDAMA, drug applicants were required to report on 

postmarketing studies. 21 CFR § 314.81. However, Section 130(a) of 

Title I of FDAMA (1) requires applicants to provide more detailed 

information on the status of their commitments and (2) made certain 

information publicly available. 

13 65 Federal Register 64,607, October 30, 2000, Postmarketing Studies 

for Approved Human Drug and Licensed Biological Products; Status 

Reports. 

14 21 CFR § 314.81(b)(2)(vii). 

15 Although these studies are excluded from FDAMA, they still must be 

reported to FDA under a different reporting requirement, 

21 CFR § 314.81(b)(2)(viii). 

16 21 CFR § 314.81(b)(2)(vii). 

17 21 CFR § 314.81(b)(2). 

18 Department of Health & Human Services, Food and Drug 

Administration, “Guidance for Industry, Reports on the Status of 

Postmarketing Studies—Implementation of Section 130 of the Food and 

Drug Administration Modernization Act of 1997,” February 2006, p. 14. 

19 Department of Health & Human Services, Food and Drug 

Administration, Draft Guidance, “Guidance for Industry, Reports on the 

Status of Postmarketing Studies—Implementation of Section 130 of the 

Food and Drug Administration Modernization Act of 1997,” April 2001. 

20 Department of Health & Human Services, Food and Drug 

Administration, “Guidance for Industry, Reports on the Status of 

Postmarketing Studies—Implementation of Section 130 of the Food and 

Drug Administration Modernization Act of 1997,” February 2006. 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 25 
21 21 U.S.C. § 356b(d). 

22 Department of Health & Human Services, Food and Drug 

Administration, Press Release, “FDA Acts to Strengthen the Safety 

Program for Marketed Drugs,” November 5, 2004. 

23 Department of Health & Human Services, Press Release, “Reforms 

Will Improve Oversight and Openness at FDA,” February 15, 2005. 

24 Food and Drug Administration, Center for Drug Evaluation and 

Research, Manual of Policies and Procedures, “Procedures for Tracking 

and Reviewing Phase 4 Commitments,” effective date October 1, 1996. 

25 Postmarketing study commitment database available online at 

http://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm. Last accessed 

May 19, 2006. 

26 Food and Drug Administration, Center for Drug Evaluation and 

Research, Manual of Policies and Procedures, “Procedures for Completing 

and Processing the Form ‘Annual Report Review: Postmarketing Study 

Commitment Summary,’” effective date March 16, 2005. 

27 Food and Drug Administration, Center for Drug Evaluation and 

Research, Manual of Policies and Procedures, “Procedures for Tracking 

and Reviewing Phase 4 Commitments,” effective date October 1, 1996. 

28 Department of Health & Human Services, Office of Inspector 

General, “Postmarketing Studies of Prescription Drugs” 

(OEI-03-94-00760), May 1996. 

29 Department of Health & Human Services, Office of Inspector 

General, “FDA’s Review Process for New Drug Applications” 

(OEI-01-01-00590), March 2003. 

30 On October 1, 2003, FDA transferred certain product oversight 

responsibilities from the Center for Biologics Evaluation and Research 

(CBER) to CDER. CBER postmarketing commitments and its review 

divisions were excluded from this review. 

31 21 CFR § 314.81(b)(2)(vii)(a)(8). 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 26 
32 Department of Health & Human Services, Food and Drug 

Administration, Draft Guidance, “Guidance for Industry, Reports on the 

Status of Postmarketing Studies—Implementation of Section 130 of the 

Food and Drug Administration Modernization Act of 1997,” April 2001. 

33 Department of Health & Human Services, Food and Drug 

Administration, Draft Guidance, “Guidance for Industry, Reports on the 

Status of Postmarketing Studies—Implementation of Section 130 of the 

Food and Drug Administration Modernization Act of 1997,” April 2001, 

p. 14. 

The finalized guidance is consistent with the draft guidance. 

See Department of Health & Human Services, Food and Drug 

Administration, “Guidance for Industry, Reports on the Status of 

Postmarketing Studies—Implementation of Section 130 of the Food and 

Drug Administration Modernization Act of 1997,” February 2006, p. 12. 

34 Department of Health & Human Services, Food and Drug 

Administration, Draft Guidance, “Guidance for Industry, Reports on the 

Status of Postmarketing Studies—Implementation of Section 130 of the 

Food and Drug Administration Modernization Act of 1997,” April 2001, 

p. 15. 

The finalized guidance is consistent with the draft guidance. 

See Department of Health & Human Services, Food and Drug 

Administration, “Guidance for Industry, Reports on the Status of 

Postmarketing Studies—Implementation of Section 130 of the Food and 

Drug Administration Modernization Act of 1997,” February 2006, p. 14. 

35 We reviewed ASRs submitted in fiscal year 2004 and compared the 

commitments addressed in the reports to the commitments listed in the 

database of postmarketing study commitments. We identified examples 

of new drug applications and postmarketing commitments that were 

listed in the database and, therefore, would have required ASRs; yet 

ASRs were missing for some of these new drug applications. (We crossreferenced the database to a list, provided to us by CDER, of all annual 

reports that should have included an update on postmarketing study 

commitments in fiscal year 2004.) We requested that CDER look into 

some of the missing ASRs. 

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36 21 CFR § 314.81(b)(2)(vii). 

37 CDER provided us with a list of 160 commitments associated with 

68 unique new drug applications that were fulfilled in fiscal year 2004; 

we were able to analyze 145 of these commitments associated with 

59 unique new drug applications. The others were excluded because they 

were outside the period of our inquiry and/or could not be matched to 

commitments in CDER’s database of postmarketing study commitments. 

38 When the original projected completion date and/or the final report 

submission date were not available, we could not determine the amount 

of time it took for postmarketing study commitments to be fulfilled. 

39 65 Federal Register 64,607, 64,608, October 30, 2000, Postmarketing 

Studies for Approved Human Drug and Licensed Biological Products; 

Status Reports. 

40 Food and Drug Administration, Center for Drug Evaluation and 

Research, Manual of Policies and Procedures, “Procedures for Completing 

and Processing the Form ‘Annual Report Review: Postmarketing Study 

Commitment Summary,’” effective date March 16, 2005. 

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Δ APPENDIX ~ A 

METHODOLOGY 

Analysis of FDA’s Postmarketing Database 

We obtained from the Food and Drug Administration (FDA) its data on 

the status of all postmarketing study commitments associated with new 

drug applications issued between October 1, 1989, and September 30, 

2004. To obtain additional data on these commitments, we requested 

that FDA link the database of postmarketing study commitments to its 

Oracle-based management information system, which contains 

information including drugs’ approval dates, drugs’ review divisions, 

whether drugs are new molecular entities (NMEs), and types of 

commitments. 

Our analysis of postmarketing study commitments is based on a 

population of 2,353 commitments. The database actually contained 

2,381 unique postmarketing study commitments, but we excluded 

28 because they were associated with new drug applications approved 

before October 1, 1989, and therefore, outside the scope of our review. 

We did include in our analysis 279 studies that are associated with 

more than one new drug application. 

One limitation of the database is that it does not generally contain the 

dates on which commitments were initiated (most, but not all, 

commitments are made at the time of drug approval). Therefore, to 

associate commitments with fiscal years, we linked each commitment to 

the approval date of its associated new drug application. 

The database has additional limits. First, it does not contain many 

dates that would be useful in monitoring postmarketing study 

commitments. Further, prior to the implementation of the Food and 

Drug Administration Modernization Act of 1997 (FDAMA), 

postmarketing study commitments were not required to have schedules. 

Therefore, one cannot determine whether postmarketing study 

commitments associated with new drug applications from 2001 or 

earlier are, or were, on schedule. 

We used Microsoft Excel® to perform various trend analyses. We 

conducted trend analyses of postmarketing study commitments 

associated with new drug applications by fiscal year, study type, study 

category, review division, and study status. We conducted the same 

trend analyses for postmarketing study commitments associated with 

NMEs, which are a subset of new drug applications. 

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APP E N D I X ~ A 

Review of ASRs and Corresponding FDA Reviews 

We obtained from FDA a list of the 336 annual reports that were or 

should have been received from drug applicants in fiscal year 2004 and 

that should have contained annual status reports (ASRs) for open 

postmarketing study commitments. We classified these submissions 

based on whether they contained required information. We reviewed all 

commitments listed in the 217 ASRs in which drug applicants actually 

provided information on their open postmarketing study commitments. 

Because we determined that the numbering of commitments in ASRs 

was not always consistent with the numbering of commitments in the 

database of postmarketing study commitments, we attempted to match 

each commitment listed in an ASR to a commitment in the database by 

using the descriptions of the commitments. We found 788 commitments 

for which there were matches, and excluded all remaining commitments 

from our analysis. We used a set protocol to extract information from 

the reports into a Microsoft Access® database. 

We also reviewed all available FDA validations and other supporting 

documentation associated with postmarketing study commitments for 

fiscal year 2004 ASRs. FDA provided us with 66 validation forms, of 

which we excluded 1 because it addressed only control, manufacturing, 

and chemistry studies; these were outside the scope of our review. We 

reviewed this documentation to determine (1) the extent to which the 

reviews were completed on time and (2) the extent to which FDA 

reviewers concurred with progress on commitments as reported by drug 

applicants. We used a set protocol to extract information from these 

documents into a Microsoft Access® database. 

Review of FDA Fulfillment Letters 

To determine how long it takes to complete postmarketing study 

commitments, we reviewed all FDA fulfillment letters issued in fiscal 

year 2004. FDA sends fulfillment letters to drug applicants to 

acknowledge completed commitments. We had to review fulfillment 

letters because the dates associated with postmarketing study 

commitments, including fulfillment dates, were not required in ASRs 

before the implementation of FDAMA and, therefore, were not 

consistently tracked in FDA’s database of postmarketing study 

commitments. 

FDA provided us with fulfillment letters for 160 postmarketing 

commitments that were associated with 68 unique new drug 

applications. We excluded 15 commitments because they were either 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 30 
APP E N D I X ~ A 

not listed in the database or there was a discrepancy between the 

details in the fulfillment letters and the descriptions in the database 

that led us to question whether there was actually a match. Of the 

remaining 145 commitments, we had to exclude 127 for which we could 

not determine the original scheduled completion dates and/or the dates 

on which final reports were submitted; this left us with 18 commitments 

to analyze. 

Case Studies 

Based on our analysis of the fiscal year 2004 fulfillment letters for 

postmarketing study commitments, we identified the nine commitments 

that were fulfilled the latest. We obtained all ASRs and corresponding 

FDA reviews associated with these commitments from the time the 

commitments were made through fulfillment, as well as any additional 

correspondence regarding those commitments. We reviewed this 

documentation to determine: (1) why commitments were late and (2) 

the extent to which FDA reviewers concurred with the progress of 

commitments as reported by drug applicants. We also attempted to 

determine the extent to which FDA reviewers followed up with drug 

applicants regarding any issues the reviewers may have had with the 

commitments. 

Interviews With FDA Officials 

We interviewed project managers at 14 of the 16 review divisions within 

FDA. We did not interview officials at the two divisions responsible for 

overseeing therapeutic biologic drugs because these drugs were outside 

the scope of our inspection. 

We used a structured questionnaire to conduct the interviews. The 

questionnaire addressed: (1) FDA’s policies and procedures for 

monitoring postmarketing study commitments, (2) the challenges FDA 

faces in monitoring postmarketing study commitments, and 

(3) recommendations for improving the process of monitoring 

postmarketing study commitments. We conducted all interviews by 

telephone. 

Review of FDA Policies, Procedures, and Guidance Documents 

We obtained and reviewed all relevant policies, procedures, and 

guidance documents for postmarketing study commitments issued by 

FDA. We used these documents to better understand the process for 

monitoring postmarketing study commitments. 

OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 31 
Δ APPENDIX ~ B 

DATA TABLES

Appendix Table 1. New Drug Applications With Postmarketing Study 

Commitments, by Fiscal Year, 1990–2004 

Year of 

Drug Approval 

Number of 

New Drug 

Applications 

Number of New 

Drug Applications 

With at Least One 

Postmarketing 

Study Commitment 

Percentage of New 

Drug Applications 

With at Least One 

Postmarketing 

Study Commitment 

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

 70

 62

 86

 84

 63

 71

 120

 124

 107

 77

 106

 71

 64

 86

 93

 18 

26 

38 

23 

37 

32 

65 

61 

47 

39 

60 

36 

34 

40 

66 

26 

42 

44 

27 

59 

45 

54 

49 

44 

51 

57 

51 

53 

47 

71

 Overall 1,284 622 48 

Source: Office of Inspector General analysis of FDA data, 2005. 

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APP E N D I X ~ B 

Appendix Table 2. Postmarketing Study Commitments by 

Review Division From Fiscal Years 1990–2004 

CDER Review Division 

Number of 

Postmarketing 

Study 

Commitments 

Percentage of 

Postmarketing 

Study 

Commitments 

Anti-Viral Drug Products

Special Pathogen and Immunologic Drug Products

Oncology Drug Products

Neuropharmacological Drug Products

Metabolic and Endocrine Drug Products

Anesthetic, Critical Care, and Addiction Drug Products

Gastro-Intestinal and Coagulation Drug Products

Dermatologic and Dental Drug Products

Medical Imaging and Radiopharmaceutical Drug Products

Anti-Infective Drug Products

Reproductive and Urologic Drug Products

Anti-Inflammatory, Analgesic, and Opthalmologic Drug Products

Over-the-Counter Drug Products

Cardio-Renal Drug Products

Pulmonary and Allergy Drug Products

 601

 335

 197

 189

 153

 129

 117

 115

 102

 101

 91

 77

 68

 38

 40

 26 

14 

8 

8 

7 

5 

5 

5 

4 

4 

4 

3 

3 

2 

2

 Total 2,353 100 

Note: This table attributes postmarketing study commitments to the CDER review divisions that existed between 1990 

and 2004.

Source: Office of Inspector General analysis of FDA data, 2005.

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APP E N D I X ~ B 

Appendix Table 3. Required Elements Missing From 

Fiscal Year 2004 ASRs, per Postmarketing Study Commitment 

Element 

Number of Postmarketing 

Study Commitments for 

Which Element Was Missing 

Percentage of Postmarketing 

Study Commitments for 

Which Element Was Missing* 

Date of U.S. Approval 

Date of Study Commitment 

Schedule 

Explanation of Status

Applicant Name

Status of Commitment

Description of Commitment

Application Number

Product Name

149

145

141

 78

 75

 65

 18

 10

 6 

19 

18 

18 

10 

10 

8 

2 

1 

< 1 

* Column does not sum to 100 because rows are independent of one another. 

Source: Office of Inspector General analysis of FDA data, 2005. 

Appendix Table 4. Length of Time It Took FDA 

to Validate Fiscal Year 2004 ASRs 

Length of Time Between 

Submission and Validation Number of Validations Percentage of Validations 

Less Than 90 Days 

Between 91 and 180 Days 

More Than 180 Days 

29

19

17

 45 

29 

26

 Total 65 100 

Source: Office of Inspector General analysis of FDA data, 2005. 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 34 
Δ APPENDIX C 

Agency Comments 

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APP E N D I X ~ C 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 36 
APP E N D I X ~ C 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 37 
ΔAPP E N D I X ~ A 

 ACKNOWLEDGMENTS 

This report was prepared under the direction of Joyce M. Greenleaf, 

Regional Inspector General for Evaluation and Inspections in the 

Boston regional office, and Russell W. Hereford, Deputy Regional 

Inspector General. Other principal Office of Evaluation and Inspections 

staff who contributed include: 

Aimée Golbitz, Team Leader 

Christopher Galvin, Program Analyst 

Michael Flood, Program Analyst 

Ayana Everett, Program Specialist 

Linda Hall Moody, Program Specialist 

Genevieve Nowolinski, Program Specialist 

Elise Stein, Director, Public Health and Human Services 

 OE I-01-04-00 390 F DA’ S MO N I T O R I N G O F P OST M ARKE T I NG S TUDY C O M M I TMEN TS 38