Department of Health and Human Services

OFFICE OF 

INSPECTOR GENERAL 

FDA M
S  ONITORING OF 

P S
OSTMARKETING  TUDY 

C
OMMITMENTS

Daniel R. Levinson

Inspector General 

June 2006 

OEI-01-04-00390
 Office of Inspector General 

http://oig.hhs.gov 
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as amended, is to protect the integrity of the Department of Health and Human Services 
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community, and issues fraud alerts and other industry guidance.  I N T R O D U C T I O N
  E X E C U T I V E   S U M M A R 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 FDAs Center for Drug Evaluation and Research 
(CDER) are charged with validating the accuracy of these reports. 
We reviewed FDAs 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 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  i  E X E C U T I V E   S U M M A R 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. 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  ii  EE XX EE CC UU TT II VV EE    SS UU MM MM AA RR YY
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 
OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  iii  E X E C U T I V E   S U M M A R 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 FDAs 
technical comments. 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  iv    T A B L E   O F   C O N T E N T S  

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

I N T RO DUC T IO N  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  1

E X T E N T  O F  C O M MI T M E N T S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  8

F I N D IN G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  11

FDA cannotreadily identify progress  . . . . . . . . . . . . . . . . . . . . . .  11

  Missing orincomplete information. . . . . . . . . . . . . . . . . . . . . . . .  11

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

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

  Monitoring is not a toppriority  . . . . . . . . . . . . . . . . . . . . . . . . . .  17

R E C O MMEN D A T ION S  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  19

  Agencycomments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  21

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

E N D NO T ES  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  23

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

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

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

C:  AgencyComments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  35

A C K NO WL E D G M E N T S  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  38
 I N T R O D U C T I O N
  I N T R O D U C T I O N  

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 drugs 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 drugs label, 
approve a drug for new uses, require changes in a drugs 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.   
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  1  I N T R O D U C T I O N  
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 FDAs 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. 
FDAs 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: 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  2  II NN TT RR OO DD UU CC TT II OO NN
(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. 
OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  3  I N T R O D U C T I O N  
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.  FDAs 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 CDERs 
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. 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  4  I N T R O D U C T I O N  
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 FDAs 
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. 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  5  II NN TT RR OO DD UU CC TT II OO NN

METHODOLOGY 
Our analysis involved several data sources and methods. (For a 
complete description of our methodology, see Appendix A.) 
We reviewed FDAs 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 FDAs 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. 
OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  6  I N T R O D U C T I O N  
We conducted this evaluation in accordance with the Quality 
Standards for Inspections issued by the Presidents Council on 
Integrity and Efficiency and the Executive Council on Integrity and 
Efficiency. 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  7    E X T E N T   O F   C O M M I T M E N T S  

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, 
19902004 
80 
70 
g 
u 60 
Dr
of New cations  4500  
ge pli
ap 30 
ntA
e
c 20 
er
P
10 
0 
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 
9 9 9 9 9 9 9 9 9 9 0 0 0 0 0
9 9 9 9 9 9 9 9 9 9 0 0 0 0 0
1 1 1 1 1 1 1 1 1 1 2 2 2 2 2
Year 
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.) 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  8  E X T E N T   O F   C O M M I T M E N T S  

Table 1.  Postmarketing Study Commitments by Nature 
From Fiscal Years 19902004 
Nature of Postmarketing            Number of Postmarketing  Percentage of Postmarketing 
Study Commitment  Study Commitments  Study Commitments 
Clinical  1,732  74 
Pediatric* 326  14 
Nonclinical 255  11 
All Others      40 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 19902004 
Type of Postmarketing  Number of Postmarketing  Percentage of Postmarketing 
Study Commitment  Study Commitments  Study Commitments 
Requested by FDA  2,132  91 
Accelerated Approval*  118 5 
Deferred Pediatric*  102 4 
Animal Efficacy*  1  < 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. 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  9  E X T E N T   O F   C O M M I T M E N T S  

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, 
19902004 
7 
6 
s
nt
me 5 
mit
m 4 
o NMEs 
C
of  3  non-NMEs 
er 
b 2 
m
u
N 1 
0 
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 
9 9 9 9 9 9 9 9 9 9 0 0 0 0 0
9 9 9 9 9 9 9 9 9 9 0 0 0 0 0
1 1 1 1 1 1 1 1 1 1 2 2 2 2 2
Year 
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.) 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  10    F I N D I N G  

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 
  27  8 
Applicant
ASR Did Not Contain Information 
on Open Postmarketing Study   92 27 
Commitments
ASR Contained Information on at 
Least One, but Not Necessarily All 
217 65
Open Postmarketing Study 
Commitments 
     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 FDAs 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 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  11  F I N D I N G  
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  Number of Postmarketing  Percentage of Postmarketing 
Missing Elements  Study Commitments  Study Commitments 
7      1  < 1  
6      3  < 1  
5  9 1 
4   49 6 
3   54 7 
2   68 9 
1  123 16 
0  481 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 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  12  F I N D I N G  
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 
o Date of postmarketing study
regulatory requirements.  It 	
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 othersincluding dates of submission 
of study protocols, completion of participant enrollment, completion of 
the study, and submission of the final study reportas common and 
important to determining study progress.33  Additionally, the guidance 
states that in providing an explanation of any commitments 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 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  13  F I N D I N G

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 reportsincluding study protocols, progress reports, and 
final reportssubmitted 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 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  14  F I N D I N G

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 drugs 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 FDAs 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 FDAs database 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  15  F I N D I N G

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 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  16  F I N D I N G

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 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  17  FDA reviewers sometimes agreed with drug applicants even when the 
applicants failed to provide one of the status options required by the 
regulations. 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  18  F I N D I N G S  
  R E C O M M E N D A T I O N S  

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 FDAs tools for 
monitoring postmarketing study commitmentsASRs and its 
management information systemmay 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 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  19  R E C O M M E N D A 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 FDAs 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.   
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  20  RR EE CC OO MM MM EE NN DD AA TT II OO NN SS  
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 marketa remedy 
available to FDA only in limited circumstancesthe 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. 
OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  21  R E C O M M E N D A 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 FDAs  
technical comments. 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  22    E N D N O T E 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 FDAs 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 SurveillanceLack 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 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  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. 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  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 StudiesImplementation 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 StudiesImplementation 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 StudiesImplementation of Section 130 of the Food and 
Drug Administration Modernization Act of 1997, February 2006. 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  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, FDAs 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). 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  26  32 Department of Health & Human Services, Food and Drug 
Administration, Draft Guidance, Guidance for Industry, Reports on the 
Status of Postmarketing StudiesImplementation 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 StudiesImplementation 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 StudiesImplementation 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 StudiesImplementation 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 StudiesImplementation 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 cross-
referenced 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. 
  OEI-01-04-00390  FDAS MONITORING OF POSTMARKETING STUDY COMMITMENTS  27  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 CDERs 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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METHODOLOGY 
Analysis of FDAs 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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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 FDAs 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 
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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) FDAs 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. 
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DATA TABLES

Appendix Table 1.  New Drug Applications With Postmarketing Study 
Commitments, by Fiscal Year, 19902004 
Number of New  Percentage of New 
Number of  Drug Applications  Drug Applications 
Year of 
New Drug  With at Least One  With at Least One 
Drug Approval 
Applications  Postmarketing  Postmarketing 
Study Commitment  Study Commitment 
1990  70  18  26 
1991  62 26  42 
1992  86 38  44 
1993  84 23  27 
1994  63 37  59 
1995  71 32  45 
1996  120 65  54 
1997  124 61  49 
1998  107 47  44 
1999  77 39  51 
2000  106 60  57 
2001  71 36  51 
2002  64 34  53 
2003  86 40  47 
2004  93 66  71
     Overall  1,284  622  48 
Source:  Office of Inspector General analysis of FDA data, 2005. 
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Appendix Table 2.  Postmarketing Study Commitments by 
Review Division From Fiscal Years 19902004 
Number of  Percentage of 
Postmarketing  Postmarketing 
CDER Review Division 
Study  Study 
Commitments  Commitments 
Anti-Viral Drug Products  601  26 
Special Pathogen and Immunologic Drug Products  335 14 
Oncology Drug Products  197 8 
Neuropharmacological Drug Products  189 8 
Metabolic and Endocrine Drug Products  153 7 
Anesthetic, Critical Care, and Addiction Drug Products  129 5 
Gastro-Intestinal and Coagulation Drug Products  117 5 
Dermatologic and Dental Drug Products  115 5 
Medical Imaging and Radiopharmaceutical Drug Products  102 4 
Anti-Infective Drug Products  101 4 
Reproductive and Urologic Drug Products  91 4 
Anti-Inflammatory, Analgesic, and Opthalmologic Drug Products  77 3 
Over-the-Counter Drug Products  68 3 
Cardio-Renal Drug Products  38 2 
Pulmonary and Allergy Drug Products  40 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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Appendix Table 3.  Required Elements Missing From 
Fiscal Year 2004 ASRs, per Postmarketing Study Commitment 
Number of Postmarketing  Percentage of Postmarketing 
Element  Study Commitments for  Study Commitments for 
Which Element Was Missing  Which Element Was Missing* 
Date of U.S. Approval  149 19 
Date of Study Commitment  145 18 
Schedule  141 18 
Explanation of Status  78 10 
Applicant Name  75 10 
Status of Commitment  65 8 
Description of Commitment  18 2 
Application Number  10 1 
Product Name  6  < 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 
Number of Validations  Percentage of Validations 
Submission and Validation 
Less Than 90 Days  29  45 
Between 91 and 180 Days  19 29 
More Than 180 Days  17 26
     Total  65  100 
Source:  Office of Inspector General analysis of FDA data, 2005. 
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Agency Comments 
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 A P P E N D I X   ~   C  

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 A P P E N D I X   ~   C  

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 A P P E N D I X   ~   A  
  A C K N O W L E D G M E N T S  

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: 
Aimee 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 
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