United States Government Accountability Office

GAO Report to Congressional Requesters

DRUG SAFETY 

Improvement Needed 

in FDA’s Postmarket 

Decision-making and 

Oversight Process 

March 2006 

 

GAO-06-402 
What GAO Found

United States Government Accountability Office

Why GAO Did This Study

Highlights

Accountability Integrity Reliability

 March 2006

DRUG SAFETY

Improvement Needed in FDA’s 

Postmarket Decision-making and 

Oversight Process 

Highlights of GAO-06-402, a report to the 

Chairman, Committee on Finance, United 

States Senate and the Chairman,

Committee on Energy and Commerce, 

House of Representatives 

In 2004, several high-profile drug

safety cases raised concerns about

the Food and Drug

Administration’s (FDA) ability to 

manage postmarket drug safety 

issues. In some cases there have

been disagreements within FDA 

about how to address safety issues. 

In this report GAO (1) describes 

FDA’s organizational structure and 

process for postmarket drug safety 

decision making, (2) assesses the 

effectiveness of FDA’s postmarket 

drug safety decision-making

process, and (3) assesses the steps

FDA is taking to improve 

postmarket drug safety decision 

making. GAO conducted an 

organizational review and case 

studies of four drugs with safety 

issues: Arava, Baycol, Bextra, and 

Propulsid. 

What GAO Recommends

To improve the decision-making

process for postmarket drug safety, 

GAO suggests that the Congress 

consider expanding FDA’s 

authority to require drug sponsors 

to conduct postmarket studies 

when needed. GAO also 

recommends that FDA 

systematically track postmarket

drug safety issues, revise and 

implement its draft policy on major 

postmarket safety decisions, 

improve the dispute resolution 

process, and clarify ODS’s role in

scientific advisory committees. In 

its comments on a draft of this 

report, FDA stated that GAO’s 

conclusions were reasonable. FDA 

did not comment on GAO’s 

recommendations. 

Two organizationally distinct FDA offices, the Office of New Drugs (OND) 

and the Office of Drug Safety (ODS), are involved in postmarket drug safety

activities. OND, which holds responsibility for approving drugs, is involved 

in safety activities throughout the life cycle of a drug, and it has the decisionmaking responsibility to take regulatory actions concerning the postmarket 

safety of drugs. OND works closely with ODS to help it make postmarket 

decisions. ODS, with a primary focus on postmarket safety, serves primarily

as a consultant to OND and does not have independent decision-making 

responsibility. ODS has been reorganized several times over the years. 

There has been high turnover of ODS directors in the past 10 years, with 

eight different directors of the office and its predecessors. In the four drug 

case studies GAO examined, GAO observed that the postmarket safety

decision-making process was complex and iterative. 

FDA lacks clear and effective processes for making decisions about, and 

providing management oversight of, postmarket safety issues. The process

has been limited by a lack of clarity about how decisions are made and about 

organizational roles, insufficient oversight by management, and data 

constraints. GAO observed that there is a lack of criteria for determining 

what safety actions to take and when to take them. Certain parts of ODS’s 

role in the process are unclear, including ODS’s participation in FDA’s 

scientific advisory committee meetings organized by OND. Insufficient 

communication between ODS and OND has been an ongoing concern and 

has hindered the decision-making process. ODS does not track information 

about ongoing postmarket safety issues, including the recommendations that 

ODS staff make for safety actions. FDA faces data constraints in making 

postmarket safety decisions. There are weaknesses in the different types of 

data available to FDA, and FDA lacks authority to require certain studies and

has resource limitations for obtaining data. 

Some of FDA’s initiatives, such as the establishment of a Drug Safety 

Oversight Board, a draft policy on major postmarket decision making, and 

the identification of new data sources, may improve the postmarket safety 

decision-making process, but will not address all gaps. FDA’s newly created 

Drug Safety Oversight Board may help provide oversight of important, highlevel safety decisions, but it does not address the lack of systematic tracking

of ongoing safety issues. Other initiatives, such as FDA’s draft policy on 

major postmarket decisions and regular meetings between OND divisions 

and ODS, may help improve the clarity and effectiveness of the process, but 

they are not fully implemented. FDA has not clarified ODS’s role in certain 

scientific advisory committee meetings. FDA’s dispute resolution processes 

for disagreements about postmarket safety decisions have not been used. 

FDA is taking steps to identify additional data sources, but data constraints 

remain. 

www.gao.gov/cgi-bin/getrpt?GAO-06-402.

To view the full product, including the scope 

and methodology, click on the link above. 

For more information, contact Marcia Crosse, 

(202) 512-7119, crossem@gao.gov. 
Contents 

Letter 1

Results in Brief 4 

Background 6

Two Distinct FDA Units Involved in Postmarket Drug Safety 

Activities 12

FDA Lacks a Clear and Effective Decision-making Process for 

Postmarket Drug Safety 18 

FDA Initiatives Are an Improvement, but Will Not Address All Gaps 29 

Conclusions 36

Matter for Congressional Consideration 36 

Recommendations for Executive Action 36 

Agency Comments and Our Evaluation 37 

Appendix I Regulatory History and FDA Decision-making 

Process for Arava 39 

Background and Summary 39 

Chronology 39

Appendix II Regulatory History and FDA Decision-making 

Process for Baycol 43 

Background and Summary 43 

Chronology 43

Appendix III Regulatory History and FDA Decision-making 

Process for Bextra 46 

Background and Summary 46 

Chronology 46

Appendix IV Regulatory History and FDA Decision-making 

Process for Propulsid 51 

Background and Summary 51 

Chronology 51

Appendix V Comments from the Food and Drug Administration 58 

Page i GAO-06-402 FDA Postmarket Drug Safety
Appendix VI GAO Contact and Staff Acknowledgments 62 

Figures 

Figure 1: FDA Organizational Structure for Postmarket Drug Safety 9 

Abbreviations 

AERS Adverse Event Reporting System 

CDER Center for Drug Evaluation and Research 

DDRE Division of Drug Risk Evaluation 

DSaRM Drug Safety and Risk Management Advisory Committee 

DSB Drug Safety Oversight Board 

FDA Food and Drug Administration 

HHS Department of Health and Human Services 

HRT Hormone Replacement Therapy 

NSAID Nonsteroidal Anti-inflammatory Drug 

ODS Office of Drug Safety 

OND Office of New Drugs 

OPaSS Office of Pharmacoepidemiology and Statistical Science 

PDUFA Prescription Drug User Fee Act 

SRS Spontaneous Reporting System 

This is a work of the U.S. government and is not subject to copyright protection in the 

United States. It may be reproduced and distributed in its entirety without further 

permission from GAO. However, because this work may contain copyrighted images or 

other material, permission from the copyright holder may be necessary if you wish to 

reproduce this material separately. 

Page ii GAO-06-402 FDA Postmarket Drug Safety
United States Government Accountability Office

Washington, DC 20548 

March 31, 2006 

The Honorable Charles E. Grassley 

Chairman 

Committee on Finance 

United States Senate 

The Honorable Joe Barton 

Chairman 

Committee on Energy and Commerce 

House of Representatives 

In 2004, several high-profile drug safety cases raised concerns about the 

Food and Drug Administration’s (FDA) management of safety issues 

concerning drugs that have been approved for marketing.1

 At 

congressional hearings in September 2004, FDA was criticized for taking 

too long to tell physicians and patients about studies linking the use of 

antidepressants among children to an increased risk of suicidal behavior. 

Similarly, at a congressional hearing in November 2004, it was alleged that 

FDA did not act quickly enough on evidence it obtained in 2001 about the 

cardiovascular risks of Vioxx, an anti-inflammatory drug.2

 In these cases 

and others there were disagreements within FDA about how to address 

safety issues. There were also reports that some FDA scientists were 

discouraged by supervisors from raising questions about the safety of 

certain drugs. 

Problems with FDA’s postmarket drug safety program have been raised 

before. There have been numerous reviews by external and internal 

groups dating back over 30 years that have identified problems with the 

federal government’s postmarket drug surveillance program and that have 

 1

FDA is an agency within the Department of Health and Human Services (HHS).

2

Vioxx was voluntarily withdrawn from the market by its manufacturer in September 2004.

Page 1 GAO-06-402 FDA Postmarket Drug Safety
made recommendations for improvement.3

 Following passage of the 

Prescription Drug User Fee Act of 1992 (PDUFA),4

 additional concerns 

were raised about drug safety. Under PDUFA, drug companies 

(“sponsors”) began paying fees to FDA, which used the funds to hire more 

drug application reviewers and make other changes in order to speed up 

the drug review process. As a result, FDA was able to review drug 

applications and approve new drugs for marketing more rapidly than 

before. However, the increased attention to timely drug approval decisions 

led to increased attention to monitoring of postmarket safety as well, 

which was reflected in the 2002 reauthorization of PDUFA.5

 The 2002 act 

states that FDA should continue to strengthen and improve the review and

monitoring of drug safety, and the PDUFA goals, incorporated by 

reference into the act, state that FDA will allocate almost $71 million over 

a 5-year period for postmarket drug safety. FDA subsequently increased its 

risk management activities,6

 drafted guidance for industry to help drug 

companies assess and minimize drug risks, and used PDUFA revenues to 

upgrade its system for adverse event reporting and to acquire external 

sources of data. In late 2004 and 2005, in response to the safety issues 

raised in the case of Vioxx and other drugs, FDA announced plans to 

further strengthen its management of postmarket drug safety. These 

initiatives, some of which are in an early stage of implementation, include

launching a new Web page to make public information on emerging drug 

safety issues while FDA evaluates them, finalizing the risk management 

 3

See, for example, National Research Council, Report of the International Conference of 

Adverse Reactions Reporting Systems (Washington, D.C.: National Academies of Science,

1971); FDA, Program Review of the Division of Epidemiology and Surveillance (DES) in 

the Office of Epidemiology and Biometrics (OEB) (Washington, D.C.: 1993); HHS, Office 

of Inspector General, Review of the Food and Drug Administration’s Handling of Adverse

Drug Reaction Reports (Washington, D.C.: 1999). In November 2004, FDA announced that

it would contract with the Institute of Medicine to evaluate the current drug safety system. 

This study is currently in progress.

4

Pub. L. No. 102-571, 106 Stat. 4491. 

5

Pub. L. No. 107-188, 116 Stat. 594. 

6

In an effort to address drug risks, FDA works with industry to develop risk management 

plans and postapproval risk management studies. Risk management plans may include

labeling, targeted education and outreach such as medication guides and training 

programs, reminder systems such as consent forms and special data collection systems, 

and performance-linked access systems such as restricted distribution and limited 

prescribing or dispensing. 

Page 2 GAO-06-402 FDA Postmarket Drug Safety
guidance for industry,7

 and making other organizational and policy process 

changes. 

In light of the recent controversy about drug safety, you asked us to 

conduct a review of FDA’s current organizational structure and decisionmaking process for postmarket drug safety. In this report we (1) describe 

FDA’s organizational structure and process for postmarket drug safety 

decision making, (2) assess the effectiveness of the postmarket drug safety

decision-making process, and (3) assess steps FDA is taking to improve 

postmarket drug safety decision making. 

To describe FDA’s organizational structure and process for postmarket 

drug safety decision making, we analyzed FDA’s organizational charts and 

annual reports, the roles and responsibilities of staff working on drug 

safety, documents describing internal FDA policies and procedures, and 

other relevant FDA documents. Our review focused on two offices within 

FDA’s Center for Drug Evaluation and Research (CDER) that are involved

in postmarket drug safety activities: the Office of New Drugs (OND) and 

the Office of Drug Safety (ODS). We interviewed ODS, OND, and other 

CDER managers and staff about their roles, responsibilities, workloads, 

and the process for postmarket drug safety decision making. We also 

interviewed former FDA officials and drug safety experts from outside 

FDA. To assess the effectiveness of the postmarket drug safety decisionmaking process, we analyzed documents describing internal FDA policies 

and procedures and interviewed FDA officials. In order to obtain an indepth understanding of FDA’s policies and procedures, we conducted case 

studies of four drugs—Arava, Baycol, Bextra, and Propulsid—that help to 

illustrate the current decision-making process.8

 Each of these drugs 

presented significant postmarket safety issues that FDA acted upon in 

recent years, and they reflect differences in the type of adverse event or 

potential safety problem associated with the drug, the safety actions taken, 

 7

In March 2005, FDA issued three guidance documents for industry: HHS, FDA, Guidance 

for Industry: Premarketing Risk Assessment; Guidance for Industry: Development and 

Use of Risk Minimization Action Plans; and Guidance for Industry: Good

Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (Rockville, Md.:

2005). 

8

FDA approved Arava to treat arthritis; Baycol to treat high cholesterol; Propulsid to treat

nighttime heartburn; and Bextra to relieve pain. Baycol, Bextra, and Propulsid have since

been withdrawn from the market (in August 2001, April 2005, and March 2000, 

respectively), and the warnings on Arava’s label were strengthened (most recently in March 

2004). In this report we also refer to other drugs that had safety issues for purposes of

illustration, but they were not part of our case studies.

Page 3 GAO-06-402 FDA Postmarket Drug Safety
and the OND and ODS staff involved. For our case studies we reviewed 

relevant FDA documents and conducted interviews with OND and ODS 

staff and former FDA staff who were directly involved in the cases. We 

focused on (1) significant postmarket drug safety regulatory actions; 

(2) analyses that ODS conducted on the safety concerns; and (3) internal 

FDA meetings, especially those that involved ODS.9

 We did not examine 

other elements of the postmarket drug safety decision-making process, 

such as internal OND meetings. In some cases there may be gaps in our 

description of events because there was no documentation available about 

that point in the process. We also did not evaluate the scientific validity of 

FDA’s data, methodologies, or decisions in these or other cases. Our cases 

cannot be generalized to FDA’s deliberations about postmarket drug safety

issues for other drugs. Finally, to assess FDA’s actions to improve 

postmarket drug safety decision making, we reviewed relevant FDA 

documents and interviewed FDA officials and outside drug safety experts. 

We conducted our review from December 2004 through March 2006 in 

accordance with generally accepted government auditing standards. 

Two organizationally distinct FDA offices, OND and ODS, are involved in 

postmarket drug safety activities. OND, which holds responsibility for 

approving drugs, is involved in safety activities throughout the life cycle of

a drug, and it has the decision-making responsibility to take regulatory 

actions concerning the postmarket safety of drugs. OND staff include 

physicians, pharmacologists, toxicologists, and microbiologists who are 

focused on providing health care practitioners and patients with a range of

drugs for treatment of a specific disease or condition. OND’s work and its 

pace are driven by PDUFA goals that FDA make drug approvability 

decisions within certain time frames. OND works closely with ODS to 

make postmarket drug safety decisions. In contrast to OND’s broad 

perspective, ODS’s primary focus is on postmarket drug safety. ODS 

serves primarily as a consultant to OND and does not have independent 

decision-making responsibility. ODS has been reorganized several times 

over the years, and its Division of Drug Risk Evaluation (DDRE) is the 

primary unit responsible for postmarket safety surveillance. The Division’s 

safety evaluators, who are generally pharmacists, review and analyze 

adverse event reports. Its epidemiologists, taking a population-based 

Results in Brief 

 9

FDA verified the major postmarket regulatory actions we identified for each drug. ODS 

and OND staff also told us which internal meetings were significant in the decision-making 

process. 

Page 4 GAO-06-402 FDA Postmarket Drug Safety
perspective, analyze adverse events in the context of drug utilization, and 

conduct postmarket drug safety research in collaboration with scientists 

outside of FDA. There has been high turnover of ODS directors in the past 

10 years, with eight different directors of the office and its various 

predecessors. In our case studies we observed that the decision-making 

process for postmarket drug safety is complex, involving input from a 

variety of FDA staff and organizational units and information sources, but 

the central focus of the process is the iterative interaction between OND 

and ODS. 

FDA lacks a clear and effective process for making decisions about, and 

providing management oversight of, postmarket drug safety issues. The 

process has been limited by a lack of clarity about how decisions are made 

and about organizational roles, insufficient oversight by management, and

data constraints. We observed that there is a lack of criteria for 

determining what safety actions to take and when to take them. Certain 

parts of ODS’s role in the process are unclear, including ODS’s 

participation in scientific advisory committee meetings that are organized

by OND to discuss specific drugs. While ODS staff have presented their 

analyses during some of these meetings, our case studies and others 

provide examples of the exclusion of ODS staff. Insufficient 

communication between ODS and OND’s divisions has been an ongoing 

concern and has hindered the decision-making process. Specifically, ODS 

does not always know how OND has responded to ODS’s safety analyses 

and recommendations. ODS management does not systematically track 

information about the recommendations its staff make and OND’s 

response to them. This limits the ability of ODS management to provide 

effective oversight so that FDA can ensure that safety concerns are 

addressed and resolved in a timely manner. FDA faces data constraints 

that contribute to the difficulty in making postmarket safety decisions. For 

example, FDA relies on clinical trials, reports of adverse drug reactions, 

and studies following the use of drugs in ongoing medical care in order to

evaluate safety concerns and support its decisions, but each type of data

has weaknesses. FDA also lacks authority to require certain studies and 

has resource limitations for obtaining data. 

Some of FDA’s initiatives, such as the establishment of a Drug Safety

Oversight Board (DSB), a draft policy on major postmarket drug safety 

decision making, and the identification of new data sources, may improve 

the postmarket drug safety decision-making process, but they will not 

address all the gaps we identified. FDA’s newly created DSB may help 

provide oversight of important, high-level safety decisions; however, it 

does not address the lack of systematic tracking of safety issues and their 

Page 5 GAO-06-402 FDA Postmarket Drug Safety
resolution. Other initiatives such as FDA’s draft policy on major 

postmarket decisions and regular meetings between OND divisions and 

ODS may help improve the clarity and effectiveness of the process, but 

they are incomplete, and do not clarify ODS’s role in certain scientific 

advisory committee meetings. FDA’s dispute resolution processes to help 

resolve organizational and individual disagreements over postmarket drug 

safety decisions have not been used and may not be viewed as sufficiently

independent. FDA is taking steps to identify additional data sources, 

including data on Medicare beneficiaries using drugs covered by the new 

prescription drug benefit, but data constraints remain. 

To help improve the decision-making process for postmarket drug safety, 

we suggest that the Congress consider expanding FDA’s authority to 

require drug sponsors to conduct postmarket studies when additional data

are needed. We are also making recommendations to the Commissioner of 

FDA to improve the process by establishing a mechanism for 

systematically tracking postmarket drug safety issues, revising and 

implementing FDA’s draft policy on major postmarket drug safety 

decisions, improving CDER’s dispute resolution process, and clarifying 

ODS’s role in FDA’s scientific advisory committee meetings. 

In commenting on a draft of this report, FDA stated that the conclusions 

reached by GAO were reasonable and consistent with actions that it has 

already begun or planned. FDA did not comment on our 

recommendations. 

Before a drug can be marketed in the United States, its sponsor must 

demonstrate to FDA that the drug is safe and effective for its intended use.

Because no drug is absolutely safe—there is always some risk of an 

adverse reaction—FDA approves a drug for marketing when the agency

judges that its known benefits outweigh its known risks. After a drug is on

the market, FDA continues to assess its risks and benefits. FDA reviews 

reports of adverse drug reactions (adverse events)

10 related to the drug and 

information from studies about the drug, including clinical trials and 

studies following the use of drugs in ongoing medical care (observational

Background 

Postmarket Drug Safety 

and FDA’s Role 

 10Adverse event is the technical term used by FDA to refer to any untoward medical event 

associated with the use of a drug in humans. 

Page 6 GAO-06-402 FDA Postmarket Drug Safety
studies),11 conducted by the drug’s sponsor, FDA, or other researchers. If 

FDA has information that a drug on the market may pose a significant 

health risk to consumers, it weighs the effect of the adverse events against 

the benefit of the drug to determine what actions, if any, are warranted. 

This decision-making process is complex and encompasses many factors, 

such as the medical importance and utility of the drug, the drug’s extent of 

usage, the severity of the disease being treated, the drug’s efficacy in 

treating this disease, and the availability of other drugs to treat the same 

disorder.12

CDER, the largest of FDA’s five centers, is the organizational entity within 

FDA that oversees the review of marketing applications for new drugs and 

the postmarket monitoring of drugs once they are marketed.13 Within 

CDER there are several key offices involved in activities related to 

postmarket drug safety. OND is the largest of the offices with fiscal year 

2005 expenditures of $110.6 million and 715 staff. In fiscal year 2005, more 

than half of OND’s expenditures, or $57.2 million, came from PDUFA 

funds. OND’s staff evaluate new drugs for efficacy and safety to decide if a 

drug should be approved for marketing. OND also makes decisions about 

actions to take when there are postmarket safety issues with a drug (for 

example, revising the label to include adverse event information or having

FDA withdraw approval for marketing). For safety questions, OND 

interacts with several FDA offices and divisions, but primarily with ODS.14

 11Observational studies can provide information about the association between certain 

drug exposures and adverse events. In observational studies, the investigator does not 

control the therapy, but observes and evaluates ongoing medical care. In contrast, in 

clinical trials the investigator controls the therapy to be received by participants and can 

test for causal relationships. 

12The risk/benefit calculation is different for each drug. For example, FDA is likely to be 

more tolerant of adverse events if the drug is the only drug that treats a life-threatening

condition than it is for a drug that is one of many drugs for treating a less serious condition. 

13CDER also oversees the review of marketing applications for therapeutic biological 

products, such as antibodies that are produced in a laboratory to eliminate foreign 

substances such as bacteria or toxins. 

14Other FDA offices and divisions that are involved in safety activities include: the Division 

of Drug Marketing, Advertising, and Communication, which assesses whether drug

information provided by drug sponsors is truthful, balanced, and accurately communicated;

the Office of Pediatric Therapeutics, which is responsible for pediatric ethical, and safety 

issues that arise either before or after a drug has been approved for use in children; and the 

Office of Compliance, which is responsible for inspections of drug sponsors and 

manufacturers to ensure adherence to current good manufacturing practices and 

appropriate monitoring of adverse events. 

Page 7 GAO-06-402 FDA Postmarket Drug Safety
ODS is currently located within the Office of Pharmacoepidemiology and

Statistical Science (OPaSS), which is organizationally parallel to OND and 

also contains the Office of Biostatistics.15 ODS is a much smaller office 

than OND, with fiscal year 2005 expenditures of $26.9 million and 106 

staff. In fiscal year 2005, $7.6 million of ODS’s expenditures were from 

PDUFA funds. ODS staff evaluate and monitor drug risks and promote the 

safe use of drugs. While ODS is involved in both premarket and 

postmarket drug safety issues, its primary focus is on postmarket safety. 

An important part of the drug approval and postmarket monitoring 

process is the advice FDA receives from 16 human-drug-related scientific 

advisory committees, composed of experts and consumer representatives 

from outside FDA.16 Considered by FDA as important in helping the agency

accomplish its mission and maintaining public trust, these advisory 

committees provide expert advice to the agency on a range of issues, 

including safety. The committees are largely organized according to 

specialized medical areas or conditions such as cardiovascular disease, 

gastrointestinal conditions, or oncology. In 2002, FDA established the 

Drug Safety and Risk Management Advisory Committee (DSaRM), 1 of the 

16 human-drug-related scientific advisory committees, to specifically

advise FDA on drug safety and risk management issues. The committee is 

composed of individuals from outside FDA with experience in the areas of 

medication errors, risk communication, risk perception, risk management, 

clinical trial methodology, evidence-based medicine, biometrics, and 

pharmacoepidemiology. Since it was established, DSaRM has met nine 

times, with four of those meetings held jointly with another drug-related 

scientific advisory committee. DSaRM members have also been asked to

participate in other scientific advisory committees when safety issues 

were discussed. ODS sets the agenda for DSaRM meetings, whereas OND 

sets the agenda for the other scientific advisory committee meetings. 

Figure 1 describes the offices and external advisory committees involved

in postmarket drug safety at FDA. 

 15The Office of Biostatistics provides support on research methods and statistics. 

16These committees are either mandated by legislation or are established at the discretion 

of HHS. 

Page 8 GAO-06-402 FDA Postmarket Drug Safety
Figure 1: FDA Organizational Structure for Postmarket Drug Safety 

Source: Based on FDA’s and CDER’s organizational charts.

Organizational reporting

FDA Office of the 

Commissioner

Center for Drug

Evaluation 

and Research (CDER)

4 other centers

Office of New Drugs

(OND)

Office of 

Pharmacoepidemiology 

and Statistical 

Science (OPaSS)

Office of Drug Safety

(ODS)

Office of Biostatistics

Advisory reporting

Scientific Advisory Committees: 

16 human-drug-related committees, 

composed of outside experts and 

consumer representatives

Note: The scientific advisory committees referred to in this report include the following: Drug Safety 

and Risk Management Advisory Committee, Psychopharmacologic Drugs Advisory Committee, and 

Arthritis Advisory Committee. 

FDA’s Postmarket Drug 

Safety Authority 

In terms of postmarket drug safety surveillance, FDA has the authority to 

require that drug sponsors report adverse events to FDA with different 

reporting schedules based on the seriousness of the event and whether the 

event has been previously identified and is included in the drug’s label.

Sponsors must report serious, unlabeled adverse events to FDA within 15 

days of learning about them. Sponsors are required to report other adverse 

events quarterly for 3 years, then annually thereafter in the form of 

periodic adverse event reports. In addition, health care providers and 

Page 9 GAO-06-402 FDA Postmarket Drug Safety
patients can voluntarily submit adverse event reports to FDA through its 

MedWatch program.17 Adverse event reports become part of FDA’s 

computerized database known as the Adverse Event Reporting System 

(AERS).18

FDA has the authority to withdraw the approval of a drug on the market 

for safety-related and other reasons, although it rarely does so.19 Since 

2000 there have been 10 drug withdrawals for safety reasons, and in all of 

these cases the drug’s sponsor voluntarily removed the drug from the 

market. FDA does not have explicit authority to require that drug sponsors 

take other safety actions; however, when FDA identifies a potential 

problem, sponsors generally negotiate with FDA to develop a mutually 

agreeable remedy to avoid other regulatory action. For example, if FDA 

determines that an approved drug may produce adverse events not 

previously identified, FDA and the sponsor may negotiate on revised 

labeling for the drug,20 and then FDA may issue an accompanying Public 

Health Advisory for patients and health care providers that describes the 

safety information. FDA may also request that the sponsor restrict the 

distribution of the drug in order to minimize a significant risk associated 

with the drug. 

 17MedWatch is an FDA program for receiving reports of adverse events from and providing 

safety information to healthcare professionals and the public. MedWatch provides clinical 

information about safety issues involving medical products, including prescription and 

over-the-counter drugs, biologics, medical and radiation-emitting devices, and special 

nutritional products (e.g., medical foods, dietary supplements, and infant formulas). 

18FDA receives over 400,000 reports of adverse events each year. Some adverse event 

reports are not entered into AERS, such as periodic reports for drugs that have been

approved for more than 3 years and that are considered nonserious. 

1921 U.S.C. § 355(e). FDA may propose withdrawal when, for example, it determines

through experience, tests, or other data that a drug is unsafe under the conditions of use 

approved in its application, there is a lack of substantial evidence that the drug will have 

the effect that it purports to have or that is suggested in its labeling, or required patent 

information is not timely filed. Prior to withdrawal, FDA would need to notify the affected 

parties and provide an opportunity for a hearing. Approval may be suspended immediately, 

prior to a hearing, if the Secretary of Health and Human Services finds that continued 

marketing of a particular drug constitutes an imminent hazard to the public health. FDA

used this authority once, to withdraw the drug phenformin from the market in 1977. 

Phenformin was used to treat diabetes and was associated with a life-threatening buildup 

of lactic acid in the blood. 

20The labeling of a drug can be changed, for example, by adding information to the

“Warnings Section.” 

Page 10 GAO-06-402 FDA Postmarket Drug Safety
FDA has limited authority to require that sponsors conduct postmarket 

safety studies; it may impose such a requirement during the premarket 

phase of drug development in two situations, and in one during the 

postmarket phase. In two situations, FDA has the authority to require that

sponsors commit to conducting postmarketing studies as a condition of 

approval. First, FDA’s program for accelerated approval of new drugs for 

serious or life-threatening illnesses (referred to as “subpart H drugs”) 

allows FDA to more quickly approve drugs showing meaningful 

therapeutic benefit with the caveat that the sponsor will conduct or finish 

studies after the drug is marketed.21 Such drugs may be made available to 

the public sooner but with less complete safety information than the 

normal review process requires for approval. Second, in cases where 

human efficacy studies of a drug may not be ethical or feasible, FDA may 

rely on animal studies alone to approve the use of a drug and require 

postmarket studies as a condition of approval when studies on humans 

become feasible and ethical.22 For example, FDA approved a drug in 2003 

that is used as a treatment for patients who have been exposed to a 

chemical nerve agent called Soman. Evidence of the effectiveness of this 

drug was obtained from animals alone because it is unethical to perform 

such studies in humans. In either situation, FDA may withdraw approval of 

these drugs if, for example, postmarket clinical studies fail to verify 

clinical benefits, the sponsor fails to perform postmarketing studies with 

due diligence, or postmarketing restrictions (for example, restricted 

distribution) are inadequate to assure safe use of the drug.23 Finally, under 

certain conditions, after a drug is approved, FDA can also require that 

drug sponsors conduct postmarket studies of marketed drugs when such 

 2121 C.F.R. § 314.510 (2005). 

2221 C.F.R. § 314.610(b)(1) (2005). 

2321 C.F.R. § 314.530(a)(1)–(3); 21 C.F.R. § 314.620(a)(1)–(3) (2005). 

Page 11 GAO-06-402 FDA Postmarket Drug Safety
studies are needed to provide adequate labeling to ensure the safe and 

effective use of these drugs in children.24

Two distinct FDA offices are involved in postmarket drug safety activities.

While there is some overlap in their activities, they have different 

organizational characteristics and perspectives on postmarket drug safety. 

OND is involved in postmarket drug safety activities as one aspect of its 

larger responsibility to review new drug applications, and it has the 

decision-making responsibility for postmarket drug safety. ODS has a 

primary focus on postmarket drug safety and provides consultation to 

OND. ODS has been reorganized several times over the years, and there 

has been an absence of stable leadership. FDA’s postmarket drug safety 

decision-making process is complex, involving iterative interactions 

between OND and ODS. 

Since OND is responsible for approving or disapproving drug applications, 

its staff are involved in safety activities throughout the life cycle of a drug 

(that is, premarket and postmarket), and it has the ultimate responsibility 

to take regulatory action concerning the postmarket safety of drugs. OND 

is organized into six offices that evaluate drugs and drug products, and 

within these offices are 17 review divisions organized by medical specialty

(for example, oncology or dermatology). OND’s staff includes physicians, 

pharmacologists, toxicologists, and microbiologists. The key decision 

makers in OND—division directors and office directors—are physicians. 

In general, OND staff take a clinical perspective in their work. According 

to the Director of the office, OND’s medical staff have expertise in medical 

specialties as well as drug regulation, which he said gave them the ability 

to integrate issues related to the disease, available therapy, effectiveness 

of the drug, and relative safety. He also told us that OND staff are focused 

on meeting patient needs and providing health care practitioners and 

Two Distinct FDA

Units Involved in 

Postmarket Drug 

Safety Activities 

OND Has Decision-making 

Responsibility for 

Postmarket Drug Safety 

 24According to the Pediatric Research Equity Act of 2003, FDA may require drug 

manufacturers to develop information regarding the safety, effectiveness, dosing, and 

administration of marketed drugs if (1) the drug is used by a substantial number of 

pediatric patients for the labeled indications, and the absence of adequate labeling could 

pose significant risks to pediatric patients; or (2) the drug would represent a meaningful 

therapeutic benefit over existing therapies for pediatric patients for claimed indications, 

and the absence of adequate labeling could pose significant risks to pediatric patients. 

21 U.S.C. § 355c. This authority may be used only after FDA has been unsuccessful in 

obtaining necessary pediatric information under other authority. These studies have 

resulted in new pediatric labels with important dosing or safety information.

Page 12 GAO-06-402 FDA Postmarket Drug Safety
patients with a range of drugs for treatment of a specific disease or 

condition. Finally, an important characteristic of OND’s organization is 

that OND’s work and its pace are driven in part by PDUFA goals to 

complete its review of drug applications within certain time frames. 

FDA estimates that 51 percent of OND’s work time is devoted to drug 

safety, either premarket or postmarket.25 In the drug development or 

premarket phase, OND staff review safety and efficacy data from 

sponsors’ animal studies and human clinical trials to decide whether or 

not to approve a drug. In some cases OND identifies safety concerns at the 

time of approval that it believes can be managed, for example, by 

educating patients and providers or restricting distribution to certain 

populations. In these cases, OND works with ODS and the sponsor to 

develop a risk management plan to outline these strategies. OND may also 

request, or in cases where FDA has the authority, require that a sponsor 

conduct a postmarketing study as a condition of approval. 

After a drug is on the market, OND receives information about safety 

issues related to a drug’s use and takes appropriate regulatory action. OND 

receives information about safety issues in several ways. First, OND staff 

receive notification of adverse event reports for drugs to which they are

assigned and they review the periodic adverse event reports that are 

submitted by drug sponsors. Second, OND staff review safety information 

that is submitted to FDA when a sponsor seeks approval for a new use or 

formulation of a drug, and monitor completion of postmarket studies. 

OND also partners with ODS and other CDER offices for information and 

analysis to help it make postmarket drug safety decisions. When 

considering postmarket drug safety issues, OND staff use evidence found

in clinical trials. For example, one OND manager told us that OND staff 

typically review adverse event data related to a drug, obtain a consult from 

ODS, and then review any clinical trial data. Then, if necessary, OND 

makes a decision about what action should be taken, which may include 

negotiating with a sponsor to change a drug’s label, restricting its 

distribution, or proposing to withdraw the drug’s approval. 

 25Theresa M. Mullin, Ph.D., Office of Planning, Office of Commissioner, FDA, “Estimating 

CDER Resources Devoted to Safety” (presentation to FDA Science Board Advisory 

Committee, Apr. 15, 2005). 

Page 13 GAO-06-402 FDA Postmarket Drug Safety
ODS serves primarily as a consultant to OND and has an overall goal of 

reducing preventable deaths and injuries associated with the use of drugs 

with a primary focus on postmarket drug safety. ODS also provides 

consultation to OND on premarket safety issues, including risk

management issues.26 Although FDA’s postmarket drug safety office has 

been reorganized several times over the years, the consultant role of the 

office has remained consistent. ODS was formed in 2002 when FDA 

combined the Office of Postmarketing Drug Risk Assessment with the 

MedWatch program (from the Office of Training and Communications) 

and with patient labeling and risk communication functions (from the 

Division of Drug Marketing, Advertising, and Communications). ODS was 

established within the new Office of Pharmacoepidemiology and 

Statistical Science (OPaSS). OPaSS was made equivalent to OND within 

the CDER organizational structure. 

ODS Serves as a 

Consultant to OND 

ODS is composed of a small management team and three divisions. 

According to the ODS Director, the management team consists of the 

director, deputy director, an associate director for regulatory affairs, and 

an associate director for science and medicine. ODS’s three divisions are: 

the Division of Drug Risk Evaluation (DDRE), the Division of Surveillance, 

Research, and Communication Support, and the Division of Medication 

Errors and Technical Support. The Division of Surveillance, Research, and 

Communication Support is involved with the acquisition and analysis of 

data related to drug safety. This division also reviews consumer-oriented 

materials for content and patient-friendly language, such as medication 

guides, which are dispensed with drugs that have serious safety concerns. 

This division also disseminates safety information to the medical 

community and general public through the MedWatch Web site. The 

Division of Medication Errors and Technical Support is responsible for 

conducting premarketing reviews of all proprietary names and labels of 

drugs in order to minimize medication errors due to similar names or 

confusion related to the labeling and packaging of drugs. This division also

provides postmarketing review and analysis of medication errors. 

ODS’s DDRE is the primary unit responsible for postmarket drug safety 

surveillance. Its staff of 47 include safety evaluators, who are generally

pharmacists, and epidemiologists, with many having either a Ph.D. in 

epidemiology or an M.D. with epidemiologic training. The division’s safety 

evaluators are assigned to cover specific groups or classes of marketed 

 26PDUFA goals apply to ODS’s premarket consultative work. 

Page 14 GAO-06-402 FDA Postmarket Drug Safety
drugs. They primarily review reports of individual adverse events from 

AERS in order to detect safety signals. The division’s epidemiologists work 

collaboratively with the safety evaluators, using population-level data to 

analyze potential safety signals and put them into context. They also 

review the published literature and conduct research through the use of 

contracts and other agreements with researchers outside of government, 

health care utilization databases, and surveillance systems.27 Finally, safety 

evaluators and epidemiologists interact with international colleagues on

drug safety issues. 

ODS operates primarily in a consultant capacity to OND and does not have 

any independent decision-making responsibility. When there is a safety 

concern, ODS staff conduct an analysis and produce a written report for 

OND called a consult. Safety consults conducted by DDRE staff include 

analyses of adverse event reports and assessments of postmarket study 

designs and risk management plans.28 In fiscal year 2004, DDRE completed 

approximately 600 safety consults. A majority of DDRE’s consults are 

requested by OND. In fiscal year 2004, 71 percent of DDRE’s consults were 

requested by OND; 22 percent were requested by other sources;29 and 

7 percent were self-initiated by DDRE. Over time, the proportion of DDREinitiated consults has declined while the proportion of OND-requested 

consults has increased. 

In general, ODS staff take a population-based perspective in their work, 

which ODS staff we spoke with contrasted with the clinical perspective of

OND. They look at how a drug is being used in the general population and 

its side effects, and they base their safety analyses on adverse event 

reports, observational studies, and other population-based data sources. 

ODS staff do not typically use clinical trial data for their safety analyses 

and conclusions. In their postmarket work, ODS staff also do not operate 

under PDUFA drug review goals and therefore do not face the same kinds 

 27For example, FDA has used data from the IMS Health National Prescription Audit 

database and the National Electronic Injury Surveillance System: Cooperative Adverse 

Drug Events Surveillance System (NEISS-CADES).

28In addition to these safety consults, ODS’s Division of Medication Errors and Technical 

Support provides consults on medication errors, drug names, and labeling, while ODS’s

Division of Surveillance, Research, and Communication Support provides consults on drug 

use data. 

29ODS has also done consults for other FDA centers (for example, Center for Devices and 

Radiological Health), other federal agencies (for example, National Institutes of Health), 

international health agencies (for example, World Health Organization), and others. 

Page 15 GAO-06-402 FDA Postmarket Drug Safety
of deadlines that OND staff face. Furthermore, ODS staff have sometimes 

taken an academic research approach to safety work, for example, 

publishing case reports about adverse events or safety analyses in peerreviewed journals. 

There has been high turnover of ODS directors—there have been eight 

different directors of the office and its various predecessors—in the past 

10 years. Four of the directors have been “acting” directors, not permanent 

ones. From February to September 2002 and again from October 2003 to 

January 2005, the Director of OPaSS also served as the Acting Director of 

ODS. The Director of CDER, as well as staff within and outside of ODS, 

told us that the lack of consistent leadership of ODS has had a negative 

effect on the work and morale of staff. One ODS staff member told us that 

since drug safety issues often take a fair amount of time to resolve, it is 

important to have consistency in leadership so that the leaders are 

knowledgeable of ongoing issues. In October 2005 FDA appointed a 

permanent director of ODS from within the organization, the first 

permanent director since October 2003. 

Postmarket Drug Safety 

Decision Making Is 

Complex and Iterative 

The decision-making process for postmarket drug safety is complex, 

involving input from a variety of FDA staff and organizational units and 

information sources, but the central focus of the process is the iterative 

interaction between OND and ODS. As we have described, ODS safety 

consults can be initiated within ODS or requested by OND, but typically 

OND requests them. OND often requests an analysis because of 

information it receives from the drug’s sponsor about a safety concern. 

ODS safety evaluators then search AERS for all relevant cases and develop 

a summary of individual cases from the reports. The safety evaluators 

assess the cases to determine whether the adverse events are drug-related

and whether there are any common trends or risk factors. ODS 

epidemiologists sometimes collaborate with the safety evaluators by 

estimating how frequently an adverse event occurs among the population 

exposed to a particular drug,30 and they compare this estimate with how 

frequently the same event occurs in a population not treated by the drug.

The epidemiologists also might use information from observational studies 

and drug use analyses to analyze the safety issue. When completed, ODS 

 30This is called a “reporting rate” and is calculated by dividing the number of reported cases 

of a particular adverse event by a measure of the drug’s utilization, such as the number of 

dispensed prescriptions. FDA has contracts with outside companies to obtain information 

about drug utilization across various health care settings. 

Page 16 GAO-06-402 FDA Postmarket Drug Safety
staff summarize their analysis in a written consult. The ODS division 

director of the staff who worked on the consult typically reviews the 

consult and either signs it, indicating agreement, or writes a memorandum 

explaining what part he or she disagrees with and why. According to FDA 

officials, OND staff within the review divisions usually decide what 

regulatory action should occur, if any, by considering the results of the 

safety analysis in the context of other factors such as the availability of

other similar drugs and the severity of the condition the drug is designed 

to treat. Several CDER staff, including OND and ODS staff, that we 

interviewed told us that most of the time there is agreement within FDA 

about what safety actions should be taken. At other times, however, OND 

and ODS disagree about whether the postmarket data are adequate to 

establish the existence of a safety problem or support a recommended 

regulatory action. In those cases, sometimes OND requests additional 

analyses by ODS and sometimes there is involvement from other FDA 

organizations. In some cases, OND seeks the advice of FDA’s scientific 

advisory committees, including DSaRM, for decisions about postmarket 

drug safety. The recommendations of the advisory committees do not bind

the agency to any decision. According to FDA officials, if a decision is 

made by OND that a safety action is warranted, then OND staff generally 

work with the drug’s sponsor to implement it. 

There was sometimes a lack of consensus in our drug case studies, and we 

observed that ODS often performed a series of related analyses about the 

same safety concerns for OND over a significant period of time.31 As an 

illustration of this iterative decision-making process, OND requested in 

2002 that ODS analyze cases of serious skin reactions associated with the 

pain reliever Bextra after the drug’s sponsor had communicated with OND 

about this potential risk. ODS staff searched the AERS database and found 

several related cases for review. They estimated the occurrence of 

reported cases of serious skin reactions among Bextra users by using the 

cases and drug utilization data. On the basis of their analysis, ODS 

recommended that Bextra’s label be updated to include this risk, and OND 

followed the recommendation by working with the sponsor to update the 

label in 2002. Between 2002 and 2004, ODS staff conducted five other 

analyses of the occurrence of serious skin reactions associated with 

Bextra, including two that were requested by OND. In March 2004, ODS 

staff recommended that Bextra carry a boxed warning about its risks of 

 31For more information on events related to FDA’s decision-making processes on Arava,

Baycol, Bextra, and Propulsid, see apps. I–IV. 

Page 17 GAO-06-402 FDA Postmarket Drug Safety
serious skin reactions. The ODS staff based their recommendation on their 

finding that Bextra’s risk for serious skin reactions was 8 to 13 times 

higher than that for other similar drugs and 20 times higher than the 

incidence rate in the population.32 The ODS Division Directors who 

reviewed the analysis and recommendation agreed, but the OND review 

division responsible for Bextra did not initially agree. About 5 months 

later, the OND review division decided a boxed warning was warranted, 

after ODS performed another analysis requested by OND, comparing 

Bextra’s risk with several other similar drugs, including Mobic.

33 ODS 

found no reported cases of serious skin reactions associated with Mobic. 

In 2005, a joint meeting of FDA’s Arthritis Advisory Committee and DSaRM 

was held to discuss the postmarket safety of several anti-inflammatory 

drugs including Bextra, with a focus on their cardiovascular risks. The 

committees recommended, after presentations by FDA staff and others, 

that Bextra should remain on the market. A few months later, FDA asked 

the sponsor to withdraw the drug from the market because, in part, its risk 

for serious skin reactions appeared to be greater than for other similar 

anti-inflammatory drugs.34

FDA’s postmarket drug safety decision-making process has been limited

by a lack of clarity, insufficient oversight by management, and data 

constraints. We observed that there is a lack of established criteria for 

determining what safety actions to take and when. Aspects of ODS’s role 

in the process are unclear, including its role in participating in scientific 

advisory committee meetings organized by OND. A lack of communication 

between ODS and OND’s review divisions and limited oversight of 

postmarket drug safety issues by ODS management has hindered the 

decision-making process. FDA relies primarily on three types of data 

sources—adverse event reports, clinical trial studies, and observational 

studies—in its postmarket decision making. Each data source has 

FDA Lacks a Clear 

and Effective 

Decision-making 

Process for 

Postmarket Drug 

Safety 

 32A boxed warning is placed in a prominently displayed box on a drug’s label when there 

are serious safety problems associated with a drug, such as those that may lead to serious 

injury or death. Advertisements that serve to remind health care professionals of a drug’s 

availability (called “reminder ads”) are not allowed for drugs with boxed warnings. 

33In April 2004, prior to the boxed warning, the label was changed to include a statement in 

the warnings section that fatalities due to serious skin reactions had been reported. This 

change did not include a boxed warning. 

34The OND and OPaSS Directors posted a memorandum on FDA’s Web site explaining this

decision. 

Page 18 GAO-06-402 FDA Postmarket Drug Safety
weaknesses, however. FDA also faces constraints in requiring certain 

studies and obtaining data. 

Decision-making Process 

on Drug Safety Lacks 

Clarity about Criteria for 

Action and the Role of 

ODS 

While acknowledging the complexity of the postmarket drug safety 

decision-making process, we observed in our interviews with OND and 

ODS staff and in our case studies that the process lacked clarity about 

how drug safety decisions are made and about the role of ODS. If FDA had 

established criteria for certain postmarket drug safety decisions, then 

some of the disagreements we observed in our case studies could have 

possibly been resolved more quickly. For example, in the case of Bextra,

as described earlier, ODS and OND staff disagreed about whether the 

degree of risk warranted a boxed warning, the most serious warning 

placed in the labeling of a prescription medication. As another example, 

there were differing opinions over taking stronger actions against 

Propulsid, the nighttime heartburn medication which was associated with 

cardiovascular side effects, or whether to modify the label. Between 1995

and 1997, Propulsid’s label had been modified, including the addition of a 

boxed warning, to warn consumers and professionals about the 

cardiovascular side effects of the drug. In June 1997 a task force within 

FDA, including OND and ODS staff, was convened to further evaluate the 

efficacy and safety of Propulsid. FDA staff, including task force members, 

later met to discuss several regulatory options, including proposing further 

label modifications, presenting the agency’s concerns to an advisory 

committee, and proposing to withdraw approval of Propulsid. According 

to a former OND manager, as a result of this meeting, FDA decided to seek 

further label modifications. Some staff, from both OND and ODS, however, 

supported stronger actions at this time, including proceeding with 

proposing a withdrawal of approval.35 According to several FDA officials, 

in the absence of established criteria, decisions about safety actions are 

often based on the case-by-case judgments of the individuals reviewing the 

data. 

Our observations are consistent with previous FDA reviews. In 2000, two 

internal CDER reports based on interviews that FDA conducted with staff 

indicated that an absence of established criteria for determining what 

safety actions to take, and when, posed a challenge for making postmarket 

 35Subsequent changes to the boxed warning were made in 1998 and a medication guide was

implemented in 1998. FDA decided in November 1999 that an advisory committee meeting 

would be scheduled to discuss how to reduce the occurrence of adverse events with 

Propulsid, but before it was held the drug’s sponsor withdrew the drug from the market.

Page 19 GAO-06-402 FDA Postmarket Drug Safety
drug safety decisions. The reports recognized the need to establish criteria 

to help guide such decisions. In a review of the safety issues concerning

Propulsid, CDER staff recommended that a standardized approach to 

postmarket drug safety issues be established, by addressing various issues 

such as how to determine when to incorporate safety issues into labeling 

and when stronger actions should supersede further labeling changes. 

According to the report, several staff noted frustration with the numerous 

changes made to Propulsid’s label that were mostly ineffective in reducing 

the number of cardiovascular adverse events.36 Similarly, after the diabetes

drug Rezulin was removed from the market in 2000 because of its risk for 

liver toxicity, a CDER report focused on Rezulin also recommended that a 

consistent approach to postmarket drug safety be developed, including 

what regulatory actions should occur to address postmarket drug safety 

concerns, and when they should occur. 

In addition to a lack of criteria for safety actions, we observed a lack of 

clarity related to ODS’s recommendations. In practice, ODS often makes 

written recommendations about safety actions to OND but there is some 

confusion over this role, according to several ODS managers, and there is 

no policy that explicitly states whether ODS’s role includes this 

responsibility. The case of Arava illustrates this confusion. In 2002, the 

OND review division responsible for Arava, a drug used to treat 

rheumatoid arthritis, requested that ODS review postmarket data for cases 

of serious liver toxicity associated with its use. The ODS staff who worked 

on this analysis recommended that Arava be withdrawn from the market 

because they concluded that the risk for serious liver toxicity exceeded its

benefits. The OND Division Director responsible for Arava felt that ODS 

should not have included a recommendation in its consult because he 

argued that this was the responsibility of OND, not ODS. Some of the 

confusion may be the result of ODS’s evolving role in postmarket drug 

safety. A current and a former ODS manager told us that in the past, ODS’s 

safety consults were technical documents summarizing adverse events 

with minimal data analysis and few recommendations. Over time the 

consults have become more detailed with sophisticated data analyses and 

more recommendations about what safety action is needed (for example, 

label change, medication guide, drug withdrawal). 

 36One staff member noted that the numerous labeling changes made it increasingly difficult 

to use Propulsid as labeled because of the numerous contraindications. 

Page 20 GAO-06-402 FDA Postmarket Drug Safety
ODS’s role in scientific advisory committee meetings is also unclear. 

According to the OND Director, OND is responsible for setting the agenda 

for the advisory committee meetings, with the exception of DSaRM. This 

includes who is to present and what issues will be discussed by the 

advisory committees. For the advisory committees (other than DSaRM) it 

is unclear when ODS staff will participate. While ODS staff have presented 

their postmarket drug safety analyses during some advisory committee 

meetings, our case study of Arava, and another case involving

antidepressant drugs, provide examples of the exclusion of ODS staff. For 

example, in March 2003, the Arthritis Advisory Committee met to review 

the efficacy of Arava, and its safety in the context of all available drugs to

treat rheumatoid arthritis.37 The OND review division responsible for Arava 

presented its own analysis of postmarket drug safety data at the meeting, 

but did not allow the ODS staff—who had recommended that Arava be 

removed from the market—to present their analysis because it felt that 

ODS’s review did not have scientific merit. Specifically, the OND review 

division felt that some of the cases in the ODS review did not meet the 

definition of acute liver failure, the safety issue on which the review was 

focused. The OND division also believed that in some of the cases ODS 

staff inappropriately concluded that liver failure resulted from exposure to 

Arava.38 After the meeting, ODS epidemiologists and safety evaluators 

asked the ODS and OPaSS Directors to clarify ODS’s role involving 

postmarket drug safety issues, including its role at advisory committee 

meetings.39 According to an FDA official, there was no written response to 

this request. 

As another example of ODS’s unclear role in scientific advisory 

committees, in February 2004 an ODS epidemiologist was not allowed to 

present his analysis of safety data at a joint meeting of the 

Psychopharmacologic Drugs Advisory Committee and the Pediatric 

Subcommittee of the Anti-Infective Drugs Advisory Committee that was 

held to discuss reports of suicidal thoughts and actions in children with 

 37The committee was asked to consider whether the data presented by the drug’s sponsor

supported improvement in physical function and whether the drug’s labeling needed to be

updated to add any additional warning about liver toxicity. 

38Similarly, other senior-level CDER staff, including ODS and OND managers, did not agree 

with the ODS staff’s conclusions and recommendation. 

39Specifically, they recommended that as a matter of policy, ODS staff should present

postmarket safety data at these meetings or if such data are presented by a non-ODS staff 

member, then ODS staff should play an integral role in preparing the presentation content. 

Page 21 GAO-06-402 FDA Postmarket Drug Safety
major depressive disorder during clinical trials for various antidepressant 

drugs. According to statements by FDA officials at a congressional 

hearing, OND believed that the ODS staff member’s analysis, which 

showed a relationship between the use of antidepressants and suicidal 

thoughts and behaviors in children, was too preliminary to be presented in 

detail. The analysis was based on pediatric clinical trial data that FDA 

requested from the sponsors of several antidepressant drugs. FDA had 

asked the sponsors to identify suicide-related events using specific 

methods, and then ODS was asked to analyze all of the submitted data.

OND later decided that the sponsors may have been inconsistent in their 

classification approaches and asked outside experts to perform additional 

reviews of all the cases by rating whether particular events could be 

classified as suicidal. The staff member who performed the ODS review, 

however, believed that the available data were sufficient to conclude a

relationship between the use of antidepressants and suicidal thoughts and

behaviors in pediatrics and to recommend further safety actions. In his 

consult, the ODS staff member also concluded that while additional 

analyses would yield valuable information, they would also take several 

more months to complete. In light of this delay, he recommended an 

interim plan to discourage the use of all but one antidepressant in the 

treatment of pediatric major depressive disorders.40 In December 2004, 

ODS epidemiologists communicated to the CDER Director their position 

that ODS’s role should include the responsibility of presenting all relevant 

ODS data at advisory committee meetings. According to an FDA official, 

there was no written response to this request. However, in our interviews, 

the Directors of CDER and OND told us that in retrospect they felt it was a 

mistake for FDA to have restricted the ODS epidemiologist from 

presenting his safety information at the meeting.

Several ODS managers that we interviewed told us that there is also a lack

of clarity regarding the role of the epidemiologist in postmarket drug 

safety work. Despite the fact that ODS’s epidemiologists have some 

 40In March 2004, FDA asked drug sponsors of 10 antidepressants to include stronger

cautions and warnings about the need to monitor pediatric and adult patients for the 

worsening of depression and the emergence of suicidal thoughts and behavior. The

additional review of the clinical trial data, performed by an expert panel assembled at 

Columbia University, was completed in July 2004. In September 2004, a joint meeting was 

held with the Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory

Committee to discuss FDA’s analysis of the reclassified data. FDA announced in October 

2004 that it had requested that drug sponsors of all antidepressants add a boxed warning to

the labels describing the increased risk of suicidal thoughts and behaviors in pediatric 

patients. 

Page 22 GAO-06-402 FDA Postmarket Drug Safety
defined responsibilities, there appears to be some confusion about the 

scope of their activities and a lack of understanding on the part of OND 

about their role and capabilities. A prior review of postmarket drug safety 

identified similar issues.41 For example, in that review some 

epidemiologists indicated that they should be able to maintain an 

independent approach to their research and the publication of their 

research. However, some OND review division directors indicated that the 

work of the epidemiologists should be considered within the context of 

CDER’s overall regulatory mission. Further, the epidemiologists’ research 

conclusions do not necessarily reflect the conclusions of FDA but may be 

perceived as such by the medical community. ODS managers indicated 

that a current challenge for FDA is to determine how it should use its 

epidemiologists and what their work products should be. According to the 

current ODS Director, efforts are needed to help OND better understand 

what epidemiologists can do. The epidemiologists themselves have asked 

for greater clarity about their role and a stronger voice in decision making. 

A Lack of Communication 

and Limited Oversight 

Hinders the Decisionmaking Process 

A lack of communication between ODS and OND’s review divisions and 

limited oversight of postmarket drug safety issues by ODS management 

have also hindered the decision-making process. The frequency and extent

of communication between ODS and OND’s divisions on postmarket drug 

safety vary. ODS and OND staff often described their relationship with 

each other as generally collaborative, with effective communication. But 

both ODS and OND staff said sometimes there were communication 

problems, and this has been an ongoing concern. For example, according 

to some current and former ODS staff, OND does not always adequately 

communicate the key question or point of interest to ODS when it requests 

a consult, and as ODS works on the consult there is sometimes little 

interaction between the two offices. After a consult is completed and sent 

to OND, ODS staff reported that OND sometimes does not respond in a 

timely manner or at all. Several ODS staff characterized this as consults 

falling into a “black hole” or “abyss.” OND’s Director told us that OND staff 

probably do not “close the loop” in responding to ODS’s consults, which 

includes explaining why certain ODS recommendations are not followed. 

In some cases CDER managers and OND staff criticized the methods used 

in ODS consults and told us that the consults were too lengthy and 

academic. 

 41FDA, Program Review of the Division of Epidemiology and Surveillance (DES) in the

Office of Epidemiology and Biometrics (OEB), (Washington, D.C.: 1993). 

Page 23 GAO-06-402 FDA Postmarket Drug Safety
ODS management has not effectively overseen postmarket drug safety 

issues, and as a result, it is unclear how FDA can know that important 

safety concerns have been addressed and resolved in a timely manner. 

According to a former ODS Director, the small size of ODS’s management 

team has presented a challenge for effective oversight of postmarket drug 

safety issues. Another problem is the lack of systematic information on 

drug safety issues. According to the ODS Director, ODS currently 

maintains a database of consults that can provide certain types of 

information such as the total count, the types of consults that ODS staff 

conducted, and the ODS staff that wrote the consults. But it does not 

include information about whether ODS staff have made 

recommendations for safety actions and how the safety issues were 

handled and resolved, including whether recommended safety actions 

were implemented by OND. For example, ODS was unable to provide us

with a summary of the recommendations for safety actions that its staff 

made in 2004 because it was not tracking such information. 

Data Constraints 

Contribute to Difficulty in 

Making Postmarket Safety 

Decisions 

Data constraints—such as weaknesses in data sources and limitations in 

requiring certain studies and obtaining data—contribute to FDA’s 

difficulty in making postmarket drug safety decisions. OND and ODS use 

three different sources of data to make postmarket drug safety decisions. 

They include adverse event reports, clinical trial studies, and observational 

studies. While data from each source have weaknesses that contribute to 

the difficulty in making postmarket drug safety decisions, evidence from 

more than one source can help inform the postmarket decision-making 

process. The availability of these data sources is constrained, however, 

because of FDA’s limited authority to require drug sponsors to conduct 

postmarket studies and its resources. 

While decisions about postmarket drug safety are often based on adverse 

event reports,

42 FDA cannot establish the true frequency of adverse events 

in the population with AERS data. The inability to calculate the true 

frequency makes it hard to establish the magnitude of a safety problem, 

 42Adverse event data are the primary basis for postmarket safety actions ranging from

labeling changes to withdrawal.

Page 24 GAO-06-402 FDA Postmarket Drug Safety
and it makes comparisons of risks across similar drugs difficult.43 In 

addition, it can be difficult to attribute adverse events to particular drugs 

when there is a relatively high incidence rate in the population for the 

medical condition.44 For example, ODS staff analyzed adverse event 

reports of serious cardiovascular events among users of the antiinflammatory drug Vioxx in a 2001 consult. However, because Vioxx was 

used to treat arthritis, which occurs more frequently among older adults,

and because of the relatively high rate of cardiovascular events among the 

elderly, ODS staff concluded that the postmarket data available at that 

time were not sufficient to establish that Vioxx was causally related to 

serious cardiovascular adverse events.

45 With AERS data it is also difficult 

to attribute adverse events to the use of particular drugs because the 

AERS reports may be confounded by other factors, such as other drug 

exposures. For example, one AERS report described a patient who 

developed cardiac arrest after he was given the drug hyaluronidase46 with 

two local anesthetics in preparation for cataract surgery. Because local

anesthetics can lead to cardiac events, the ODS safety evaluator who 

reviewed this case concluded that the causal role of hyaluronidase alone

could not be established.

FDA may also use data from clinical trials and observational studies to 

support postmarket drug safety decisions, but each source has

weaknesses that constrain the usefulness of the data provided. Clinical 

trials, in particular randomized clinical trials, are considered the “gold 

standard” for assessing evidence about efficacy and safety because they

are considered the strongest method by which one can determine whether 

 43This is due, in part, to the underreporting of adverse events and inconsistency in how

those reporting define cases. These limitations have been reported elsewhere. See, for

example, David J. Graham, Patrick C. Waller, and Xavier Kurz, “A View from Regulatory

Agencies,” in Pharmacoepidemiology, ed. Brian L. Strom (Chichester: John Wiley & Sons, 

Ltd., 2000), pp. 109–124. 

44AERS data are useful when an adverse event is relatively rare, such as liver toxicity. Druginduced liver toxicity is the major reason for regulatory actions concerning drugs, including 

withdrawal from the market, restrictions on use, and warnings to physicians. 

45The sponsor of Vioxx voluntarily removed it from the market in 2004 because one of its

postmarket clinical trials showed a causal relationship between the use of Vioxx and 

serious cardiovascular events. However, some researchers and some FDA staff believe that 

previous studies, including a clinical trial completed by the sponsor, supported an earlier 

withdrawal of Vioxx or restrictions on its use. 

46This drug promotes the dispersion of other drugs, for example, speeding the onset of

action for an anesthetic. 

Page 25 GAO-06-402 FDA Postmarket Drug Safety
new drugs work.47 However, clinical trials also have weaknesses. Clinical 

trials typically have too few enrolled patients to detect serious adverse 

events associated with a drug that occur relatively infrequently in the 

population being studied. They are usually carried out on homogenous 

populations of patients that often do not reflect the types of patients who 

will actually take the drugs, including those who have other medical 

problems or take other medications. In addition, clinical trials are often 

too short in duration to identify adverse events that may occur only after 

long use of the drug.48 This is particularly important for drugs used to treat 

chronic conditions where patients are taking the medications for the long 

term. Observational studies, which use data obtained from populationbased sources, can provide FDA with information about the population 

effect and risk associated with the use of a particular drug. Because they

are not controlled experiments, however, there is the possibility that the 

results can be biased or confounded by other factors.49

Despite the weaknesses of clinical trials and observational studies, 

evidence from both types of studies helps inform FDA’s postmarket drug 

safety decision-making process. For example, clinical trials conducted by

drug sponsors for their own purposes sometimes provide information for 

FDA’s evaluation of postmarket drug safety issues. For instance, drug 

sponsors sometimes conduct clinical trials for drugs already marketed in 

order to seek approval for a new or expanded use.50 These studies may 

 47In these trials, patients are randomly assigned to either receive the drug or a different

treatment, and differences in results between the two groups can typically be attributed to 

the drug. 

48FDA has generally recommended that 1500 patients be exposed to a drug intended for 

long-term treatment of non-life-threatening conditions. While between 300 and 600 of these 

patients should be exposed for 6 months and 100 exposed for 1 year, others will have 

shorter-term exposure. See HHS, FDA, Guidance for Industry: Premarketing Risk 

Assessment (Rockville, Md.: 2005).

49The limitations of observational studies have been discussed and debated in the literature 

and were recently illustrated in the case of hormone replacement therapy (HRT). While 

observational studies had indicated a positive effect of HRT, in 2002 the Women’s Health 

Initiative study, a clinical trial, demonstrated the opposite, and found that HRT may in fact

increase the risk of heart disease, cancer, and other diseases. A review of the observational 

studies suggested that selection bias probably accounted for the positive effect of HRT, 

that is, women who chose to take the hormone replacement drug were different from 

women who did not. For example, they tended to be healthier and better educated. 

50In such cases, clinical trial data, including adverse event reports from trials, are submitted 

to FDA while at the same time FDA receives postmarket adverse event reports from

sponsors or from other sources, such as health care providers, and all of this information is

factored into decisions about whether to approve new or expanded uses for the drug. 

Page 26 GAO-06-402 FDA Postmarket Drug Safety
also be conducted to support claims about the additional benefits of a 

drug, and their results sometimes reveal safety information about a 

marketed drug. For example, to support the addition of a claim for the 

lower risk of gastrointestinal outcomes (such as ulcers and bleeding), 

Vioxx’s sponsor conducted a clinical trial that found a greater number of 

heart attacks in patients taking Vioxx compared with another antiinflammatory drug, naproxen. This safety information was later added to 

Vioxx’s labeling.51 In addition to relying on sponsors, ODS partners with 

researchers outside of FDA to conduct postmarket observational studies 

through cooperative agreements and contracts. For example, several 

cooperative agreements supported a study of Propulsid using populationbased databases from two managed care organizations and one state 

Medicaid program, before and after warnings on contraindications were 

added to the drug’s label in 1998.52 The cooperative agreement researchers, 

which included ODS staff, measured the prevalence of contraindicated use 

of Propulsid, and found that a 1998 labeling change warning about the 

contraindication did not significantly decrease the percentage of users 

who should not have been prescribed this drug.53

FDA’s access to postmarket clinical trial and observational data, however, 

is limited by its authority and available resources. As described previously, 

FDA does not have broad authority to require that a drug sponsor conduct 

an observational study or clinical trial for the purpose of investigating a 

specific postmarket safety concern. One senior FDA official and several 

outside drug safety experts told us that FDA needs greater authority to 

 51This study was not designed to study cardiovascular events but it has been proposed that

FDA could use the studies that sponsors conduct for marketed drugs to explicitly study 

emerging safety concerns. 

52A boxed warning was first added to Propulsid’s label in 1995, which contraindicated its

use in patients taking drugs that affected Propulsid’s metabolism. FDA expanded the boxed 

warning in 1998 to include additional contraindicated drugs. The boxed warning also stated

that the use of Propulsid was contraindicated in patients with certain medical conditions,

such as heart disease, that could predispose them to cardiac arrhythmias. FDA also issued 

a press release about the changes, and the drug’s sponsor distributed a letter to 800,000

health care professionals informing them of the revised label. In 2000 FDA announced the

decision to hold an advisory committee meeting to discuss the safety of Propulsid and 

ways to reduce the occurrence of adverse events associated with Propulsid. The sponsor

withdrew the drug in 2000, before the scheduled meeting, but ODS staff told us that they 

were planning to present the study findings at the meeting. 

53See W. Smalley, D. Shatin, D.K. Wysowski, et al., “Contraindicated Use of Cisapride: 

Impact of Food and Drug Administration Regulatory Action,” Journal of the American 

Medical Association, vol. 284, no. 23 (2000). 

Page 27 GAO-06-402 FDA Postmarket Drug Safety
require such studies. Long-term clinical trials may be needed to answer 

safety questions about risks associated with the long-term use of drugs, 

such as those that are widely used to treat chronic conditions. For 

example, during a February 2005 scientific advisory committee meeting,

some FDA staff and members of the Arthritis Advisory Committee and 

DSaRM indicated that there was a need for better information on the longterm use of anti-inflammatory drugs and discussed how a long-term trial 

might be designed to study the cardiovascular risks associated with the 

use of these drugs. As another example, FDA approved Protopic and 

Elidel, both eczema creams, in December 2000 and December 2001,

respectively. Since their approval, FDA has received reports of lymphoma 

and skin cancer in children and adults treated with these creams. In March 

2005, FDA announced that it would require label changes for the creams, 

including a boxed warning about the potential cancer risk. An ODS 

epidemiologist told us that FDA has been trying for several years to get the 

sponsor to do long-term studies of these drugs, but that it has been 

difficult to negotiate. 

In the absence of specific authority, FDA often relies on drug sponsors 

voluntarily agreeing to conduct such postmarket studies. But the 

postmarket studies that drug sponsors agree to conduct have not 

consistently been completed. For example, one study estimated that the 

completion rate of postmarket studies, including those that sponsors have 

voluntarily agreed to conduct, rose from 17 percent in the mid-1980s to 

24 percent between 1991 and 2003.54 FDA has little leverage to ensure that 

these studies are carried out, for example, by imposing administrative 

penalties. 

In terms of resource limitations, several FDA staff (including CDER 

managers) and outside drug safety experts told us that in the past ODS has 

not had enough resources for cooperative agreements to support its 

postmarket drug surveillance program. Annual funding for this program 

was less than $1 million from fiscal year 2002 through fiscal year 2005. In 

October 2005 FDA awarded four contracts to replace the cooperative 

agreements, and FDA announced that these contracts would allow FDA to 

more quickly access population-level data and a wider range of data 

sources. The total amount of the contracts, awarded from 2005 to 2010, is 

 54Postmarket studies for approved drugs and biologics are included in the percent 

calculations. See: Tufts Center for the Study of Drug Development (Kenneth I. Kaitin, ed.),

“FDA Requested Postmarketing Studies in 73% of Recent New Drug Approvals,” Impact 

Report: Analysis and Insight into Critical Drug Development Issues, vol. 6, no. 4 (2004). 

Page 28 GAO-06-402 FDA Postmarket Drug Safety
about $5.4 million, which averages about $1.1 million per year, a slight 

increase from fiscal year 2005 funding. The new contracts will provide 

access to data from a variety of health care settings including health 

maintenance organizations, preferred provider organizations, and state 

Medicaid programs. 

According to an FDA official, FDA does not conduct its own clinical trials

because of the high cost associated with carrying out such studies and 

because FDA does not have the infrastructure needed to conduct them. It

was recently estimated that clinical trials designed to study long-term drug 

safety could cost between $3 million and $7 million per trial.55 The 

estimated cost of just one such trial would exceed the amount FDA has 

currently allocated ($1.1 million) for its contracts with researchers outside 

of FDA. 

FDA has undertaken several initiatives to improve the postmarket drug 

safety decision-making process, but these are unlikely to address all the 

gaps. FDA’s newly created Drug Safety Oversight Board (DSB) may help 

provide oversight of important, high-level safety decisions, but it does not 

address the need for systematic tracking of ongoing safety issues. Other 

initiatives, such as FDA’s draft policy on major postmarket drug safety 

decisions and communication initiatives may help improve the clarity and

effectiveness of the process, but they have not been fully implemented. 

FDA’s dispute resolution processes to help resolve disagreements over 

safety decisions have not been used and may not be viewed as sufficiently

independent. FDA is taking steps to identify additional data sources for 

postmarket drug safety studies, and expects to use additional funds for 

this purpose, but FDA still faces data constraints. 

FDA’s DSB, created in the spring of 2005, may help provide oversight of 

important, high-level safety decisions within CDER; however, there is still 

a need for systematic tracking of ongoing safety issues. FDA established 

the DSB to help provide independent oversight and advice to the CDER 

Director on the management of important safety issues. The DSB reports 

directly to the head of CDER and consists primarily of FDA officials from 

FDA Initiatives Are an 

Improvement, but Will 

Not Address All Gaps 

DSB May Provide Broad 

Oversight, but Systematic 

Tracking Is Still Needed 

 55See D. Carpenter, “A Proposal for Financing Postmarketing Drug Safety Studies By 

Augmenting FDA User Fees,” Health Affairs—Web Exclusive, 

http://content.healthaffairs.org/cgi/content/full/hlthaff.w5.469/DC1 (downloaded October 

18, 2005). 

Page 29 GAO-06-402 FDA Postmarket Drug Safety
within CDER and other FDA centers. According to an FDA policy 

document, the DSB includes 11 voting members from CDER, with 

3 representatives from ODS and 3 from OND. Currently the OND and ODS

Directors are voting members. It also includes representatives from other 

federal agencies.56 DSB members who conducted the primary preapproval 

review of the drug or who were involved with a drug’s approval or 

postmarket safety review will not be allowed to vote on issues concerning 

that drug. As of February 2006, the DSB was meeting regularly and an FDA 

official told us that it is expected to meet monthly. The meetings are not 

open to the public, but FDA posts abbreviated summaries of the meeting 

minutes on its Web site.57

According to an FDA policy document, the DSB will identify, track, and 

oversee the management of important drug safety issues. Important drug 

safety issues include serious side effects identified after a drug’s approval

that have the potential to significantly alter the drug’s benefit-to-risk 

analysis or significantly affect physicians’ prescribing decisions. According 

to an FDA official, ODS and OND submit monthly reports of safety issues 

for discussion by the DSB to be used in setting the agenda for the 

meetings. In addition, at any time individuals within and outside of FDA 

can submit issues to be considered by contacting a DSB member or the 

executive director. The FDA official said that the DSB will not be involved 

in the ongoing process of postmarket surveillance and decision making 

about drug safety issues, but rather will be involved with ensuring that 

broader safety issues—such as ongoing delays in changing a label—are 

effectively resolved. The DSB may also develop standards for certain kinds 

of safety-related actions, such as when a drug warrants a boxed warning 

or a medication guide.58 The FDA official acknowledged that safety-related

decisions are still based on individual judgments and lack consistency. The 

 56According to FDA policy documents, the DSB will have representation from outside FDA, 

including a member from another HHS agency (for example, National Institutes of Health) 

and a non-HHS health care providing agency (for example, Department of Veterans 

Affairs). The board may also consult with other scientific experts and representatives of 

patient and consumer groups as needed. 

57FDA also makes information publicly available concerning certain emerging safety 

information through its Web page, which reflects the input of the DSB.

58Used primarily for outpatient drugs that have serious safety concerns, medication guides

are required to be dispensed with each prescription. They contain safety information 

specifically for the patient, such as the most important information the patient should 

know about a drug. 

Page 30 GAO-06-402 FDA Postmarket Drug Safety
DSB has plans to form subcommittees to look at policy development in 

this and other areas. 

The DSB may help provide high-level oversight of safety issues, but it does 

not address the problem of the lack of systematic tracking of safety issues 

and their resolution. Information about the resolution of safety issues 

identified by ODS staff is still not available to ODS management nor to the 

DSB. 

Other Process and 

Organizational Initiatives 

Are Promising, but Not 

Fully Implemented 

FDA’s draft policy on major postmarket drug safety decision making and 

other process and organizational initiatives may make the process clearer

and more effective, but these efforts have not been fully implemented. 

Several years ago, FDA drafted a policy entitled “Process for DecisionMaking Regarding Major Postmarketing Safety-Related Actions” that could 

help improve the decision-making process, but as of February 2006, this 

policy has not been finalized and implemented. The draft policy was 

designed to ensure that all major postmarket safety recommendations, 

such as the market withdrawal of a drug, would be discussed by involved 

CDER managers, starting at the division level.

59 The draft policy states that 

CDER staff, including ODS staff, are to write a detailed memorandum 

describing their recommendation for a major safety action.60 If the 

immediate supervisor disagrees, he or she prepares a memorandum 

explaining the nature of the differences, and then the division director 

prepares a memorandum indicating how the issue should be resolved. In

some cases the supervisor and division director may be the same person. 

A Division Consensus Meeting is to be convened for every 

recommendation regardless of whether there is initial agreement between 

the staff member making the recommendation and the supervisor and 

division director.61 The process stops at the division level if a decision is 

 59According to the draft policy, major postmarket safety-related actions also include 

restrictions on a drug’s distribution and boxed warnings. Some recommendations included

in risk minimization action plans are also considered major postmarket safety-related 

actions under this draft policy, such as reminder systems that are intended to facilitate 

reduced-risk prescribing and use. 

60ODS staff (and staff from other consultant divisions) are to discuss their intended 

recommendation with the appropriate OND review division before drafting the 

memorandum. The draft policy states that these discussions are not intended to unduly

influence the recommendation, but should be viewed as opportunities to exchange

information and enhance communication. 

61This meeting includes staff and managers from the involved divisions, such as the OND 

review division responsible for the drug and the ODS division making the recommendation.

Page 31 GAO-06-402 FDA Postmarket Drug Safety
reached that a major safety action is not needed.

62 Otherwise, the 

recommendation is discussed at higher levels of management in CDER. An 

Office Action Meeting would then be held to recommend a course of 

action to the CDER director, although it is possible that there still could be 

disagreement at the office level. A final meeting, called the Decisional 

Meeting, would then be held to decide a course of action, and would 

include the CDER director as well as office- and division- level staff. It is 

not clear how the new DSB will be integrated into the draft policy on 

major postmarket drug safety decision making, and FDA officials told us 

they are still trying to determine how to do this. 

Other initiatives may improve the decision-making process, but these 

efforts have not been fully implemented. For example, ODS has 

established a Process Improvement Team to assess the safety consult 

process, including how OND asks questions about postmarket safety 

concerns and how ODS should answer the questions. OND has established 

a similar team to assess the overall process for reviewing postmarket 

safety information, including the consult process. Both teams plan to make 

recommendations; for example, the OND representative chairing the OND 

team told us the OND team plans to recommend which office (OND or 

ODS) should have responsibility for certain postmarket tasks, such as 

reviewing periodic adverse event reports. According to the OND chair, the 

OND team expects to finalize its recommendations by the end of March 

2006. According to the ODS Director, the ODS team’s work was still in 

progress as of January 2006 and would not be completed for about 

6 months. In February 2006, ODS established a new Process Improvement 

Team to identify best practices for safety evaluators in order to make sure 

there is standardization of their work (for example, reviewing of adverse 

event reports). The ODS Director estimated that the work of this team 

would be completed in 3 to 4 months. 

FDA officials told us that they have proposed reorganizing CDER to 

dissolve OPaSS and have the director of ODS report to the CDER director. 

FDA plans to implement this reorganization in May 2006. In the meantime, 

ODS has taken some other steps to improve communication and oversight 

of safety issues. According to the ODS Director, the DDRE Director 

 62Management above the division level, including the OND, ODS, and CDER directors, 

would be briefed about the matter even if division-level officials decide not to proceed with 

a safety action. The process would continue, however, if the CDER director does not agree

with the decision that a major safety action is not needed. In addition, the process would 

continue if the decision is appealed. 

Page 32 GAO-06-402 FDA Postmarket Drug Safety
recently instituted regular meetings between the safety evaluators in his 

division and the OND review divisions in order to discuss drug safety 

issues, including ongoing consults, issues that DDRE staff have not yet 

provided consultation on, and how safety issues have been resolved. 

According to the DDRE Director, over half of OND’s review divisions have 

participated in these regular meetings to date. The Director of ODS also 

acknowledged that ODS needs to have a better way to track safety issues 

as they are emerging. He told us that ODS is developing a tracking system 

that is currently being tested and is expected to become operational in 

2006. The Director also said he had plans to build up the immediate office

of ODS by adding an associate director of operations and staff responsible 

for working on relationships with other federal agencies (for example, 

National Institutes of Health) and contractors. He has decided to hold 

regular meetings with the ODS deputy director and division directors for 

the specific purpose of discussing the status of drug safety problems. 

Despite the efforts that FDA has made to improve its postmarket drug 

safety decision-making process, the role of ODS in advisory committee 

meetings (other than DSaRM) has not been clarified. The role of ODS in 

scientific advisory committee meetings is not discussed in the draft policy 

on major postmarket drug safety decisions or in other policy documents. 

In addition, according to the ODS Director, the role of epidemiologists in 

ODS requires further clarification. A Process Improvement Team that was 

formed to address this issue was suspended, and the ODS Director said 

that other ways to approach this issue are being evaluated.

Dispute Resolution 

Processes Have Not Been 

Used 

The DSB and a pilot program have not been used as of February 2006 to 

help resolve organizational and individual disagreements that occur within 

CDER over safety decisions and may not be viewed as sufficiently 

independent. According to an FDA policy document, the DSB will resolve 

organizational disputes over approaches to drug safety. According to an 

FDA official, as of February 2006, however, the DSB had not handled any 

such formal disputes. An FDA official told us that, as an example, ODS 

might believe that a drug should come off the market but OND does not 

agree, and resolving this matter could be handled by the DSB. Although 

DSB members who were involved with a drug product’s approval or safety

review will be recused from the DSB’s decision-making process 

concerning that drug, the current DSB membership includes CDER 

managers who oversee the drug approval and safety review processes, 

which may limit the ability of the DSB to provide neutral, independent 

advice in the handling of organizational disputes. In addition, decisions 

made by the DSB will serve as recommendations to the CDER director, 

Page 33 GAO-06-402 FDA Postmarket Drug Safety
who is the final decision maker. This reporting chain may further limit the 

independence of the DSB since the CDER director manages the overall

drug approval and safety review processes. 

In addition to the DSB, a pilot program for dispute resolution procedures 

has not been used by CDER staff as of February 2006. In November 2004 

FDA implemented a pilot program for dispute resolution that is designed 

for individual CDER staff to have their views heard when they disagree

with a decision that could have a significant negative effect on public 

health, such as a proposed safety action or the failure to take a safety 

action. Any CDER employee can initiate the process, but the CDER 

ombudsman,63 in consultation with the CDER director, determines 

whether a dispute warrants formal review. If the CDER director and 

ombudsman decide to proceed, the CDER director would establish a panel

of three or four members, one of which the CDER employee initiating the

process would nominate. The panel would review the case and make a 

recommendation to the CDER director, who would then decide how the 

dispute should be resolved. Like the DSB, the pilot program also does not 

offer employees an independent forum for resolving disputes. The CDER 

director decides whether the process should be initiated, appoints the 

chair of the panel, and is the final adjudicator. 

FDA Is Taking Steps to 

Identify Additional Data 

Sources, but Constraints 

Remain 

FDA is taking steps to identify additional data sources that it may obtain 

with its current authority and resources. In fiscal year 2006, FDA expects 

to use $10 million for this purpose consistent with direction in the 

Conference Report accompanying FDA’s fiscal year 2006 appropriation.64

The Conference Report specified that a $10 million increase over the prior

year was provided for drug safety activities, including $5 million for ODS 

and $5 million for drug safety activities within CDER. The conferees 

intended for the increases to be used for FDA’s highest-priority drug safety

needs that were not funded in fiscal year 2005, such as acquiring access to 

additional databases beyond those that will be accessed through its new 

contracts.65 The ODS Director told us that ODS plans to use the $5 million 

 63Created in 1995, the role of the CDER ombudsman includes investigating complaints and 

resolving issues and disputes. The CDER ombudsman receives complaints directly from

the drug industry, the public, and CDER staff. 

64See H.R. Conf. Rep. No. 109-255, at 100 (2005) (accompanying H.R. 2744). 

65The conferees directed FDA to report to the Appropriations Committees on its proposed 

use of the funds. The report is currently under review within FDA. 

Page 34 GAO-06-402 FDA Postmarket Drug Safety
to hire staff, specifically safety evaluators and technical support staff. The 

other $5 million is to be used for postmarket drug safety work throughout 

CDER and those plans had not been finalized as of February 2006. The 

Director of ODS said that given the high cost of planning and conducting

observational studies, only one or two studies can be funded each year. 

According to the ODS Director, FDA has started to work with the Centers 

for Medicare & Medicaid Services to obtain access to data on Medicare 

beneficiaries’ experience with prescription drugs covered under the new 

prescription drug benefit, which began in 2006. This data source may 

provide information about drug utilization for a very large population of 

Medicare recipients and can potentially be linked to claims data, providing

information about patients’ medical outcomes. According to the ODS 

Director, a team of ODS staff has been working with the Centers for 

Medicare & Medicaid Services to determine what data elements ODS 

would seek to access; however, it is uncertain how useful the data will be 

because there are potential data reliability issues. For example, it is 

unclear whether ODS will be able to do medical chart reviews to verify 

medical outcomes. Additionally, in April 2005 FDA requested information66

from other organizations about their active surveillance programs67 in the 

United States for identifying serious adverse events. In its request, FDA 

noted that it was seeking information related to these programs because 

active surveillance would strengthen and complement the tools it 

currently has to monitor postmarket drug safety. As an example, FDA 

noted interest in learning about systems that can identify specific acute 

outcomes for which a drug is frequently considered as a potential cause,

such as acute liver failure and serious skin reactions. According to the 

ODS Director, a working group within ODS is currently evaluating the 

responses to the request for information; however, it is unlikely that they 

will fund any of these active surveillance systems in 2006 because FDA 

needs to ensure that such systems are able to identify drug safety concerns 

earlier compared to other data sources before the agency invests in them. 

 66Department of Health and Human Services, Food and Drug Administration, Office of

Acquisitions and Grants Services, “Request for Information on Active Surveillance 

Programs in the United States for the Identification of Clinically Serious Adverse Events 

Associated with Medical Products,” published on April 11, 2005, 

http://www.fbo.gov/servlet/Documents/R/1154711 (downloaded February 27, 2006). 

67Active surveillance has been defined by others as the regular periodic collection of case 

reports from health care providers or facilities. By contrast, passive surveillance refers to

adverse event reports provided at the discretion of a health care provider. 

Page 35 GAO-06-402 FDA Postmarket Drug Safety
The working group’s review of the request for information was still 

ongoing as of March 2006. 

Postmarket drug safety decision making at FDA is a complex process that 

sometimes results in disagreements, as observed in our case studies. 

Scientific disagreements may be expected in a large regulatory agency, 

especially given the different professional orientations of the key players, 

OND and ODS, and the inherent limitations of the available data. However, 

because of the potential public health consequences of FDA’s decisions 

about postmarket drug safety issues, it is important to come to a decision 

quickly. In our review, we observed opportunities for improving the clarity 

and oversight of the process and strengthening the information used for 

decision making. FDA has recently made some important organizational 

and policy changes, but more could be done to improve management 

oversight of postmarket drug safety issues, to improve the dispute 

resolution process, and to strengthen the collaboration between OND and 

ODS. In order to address the serious limitations of the data, FDA will need 

to continue its efforts to develop useful observational studies and to 

access and use additional healthcare databases. However, even if FDA is 

successful in expanding its data sources for postmarket drug safety 

surveillance, it would still benefit from information from long-term clinical 

trials of certain drugs and the additional authority to require that these 

studies be carried out. 

To improve the decision-making process for postmarket drug safety, the 

Congress should consider expanding FDA’s authority to require drug 

sponsors to conduct postmarket studies, such as clinical trials or 

observational studies, as needed, to collect additional data on drug safety 

concerns. 

To improve the postmarket drug safety decision-making process, we 

recommend that the Commissioner of FDA take the following four actions: 

• establish a mechanism for systematically tracking ODS’s 

recommendations and subsequent safety actions; 

Conclusions 

Matter for 

Congressional 

Consideration 

Recommendations for 

Executive Action 

• with input from the DSB and the Process Improvement Teams, revise and 

implement the draft policy on major postmarket drug safety decisions; 

• improve CDER’s dispute resolution process by revising the pilot program 

to increase its independence; and 

Page 36 GAO-06-402 FDA Postmarket Drug Safety
• clarify ODS’s role in FDA’s scientific advisory committee meetings 

involving postmarket drug safety issues. 

FDA reviewed a draft of this report and provided comments, which are 

reprinted in appendix V. FDA also provided technical comments, which 

we incorporated as appropriate. 

FDA commented that our conclusions were reasonable and consistent 

with actions that it has already begun or planned. FDA did not comment 

on our recommendations. In addition, FDA made six comments about 

specific aspects of our draft report. First, concerning our description of 

the complexity of the postmarket decision-making process, FDA stated 

that the draft report implied the process is too complex and that FDA 

should not be criticized for its difficult task of weighing the risks and 

benefits associated with drugs with the data available to the agency. We 

agree with FDA that postmarket drug safety issues are inherently complex. 

For that reason, we believe that FDA needs to have greater clarity about

how decisions are made and to establish more effective oversight of the 

decision-making process. Furthermore, we believe that our report fairly 

characterizes the limitations of the data that FDA relies on in this complex 

process. Because of the data limitations, we believe that FDA needs 

greater authority to access certain kinds of postmarket safety data.

Second, FDA noted that factors other than PDUFA goals influence OND’s 

work and its pace. FDA also stated that ODS plays a role in certain 

premarket safety activities and that PDUFA goals also apply to these 

activities. We clarified these points in the report. Third, FDA stated that 

referring to ODS as a consultant to OND understates the role of ODS in 

drug safety and that CDER considers ODS and OND to be equal partners in 

the identification and timely resolution of drug safety issues. As we stated 

in the draft report, we found that the central focus of the process is the 

iterative interaction between OND and ODS. Nonetheless, ODS does not 

have any independent decision-making responsibility while OND has the 

ultimate responsibility to make decisions about regulatory actions 

concerning the postmarket safety of drugs. Further, both OND and ODS 

refer to ODS reports on drug safety as consults. For these reasons, we 

believe that our description of ODS as a consultant to OND is accurate. 

Fourth, FDA agreed with our statements about the role of the DSB and 

indicated that the DSB has reviewed current mechanisms for identifying 

safety issues and discussed ways to enhance the tracking of those issues. 

Fifth, FDA commented that our examples of ODS staff being excluded 

from advisory committee meetings imply that such disagreements occur 

Agency Comments 

and Our Evaluation 

Page 37 GAO-06-402 FDA Postmarket Drug Safety
frequently. FDA stated that this is not the case, and that OND and ODS 

work cooperatively in the vast majority of cases. However, our work 

demonstrates a need for further clarification of ODS’s role. Finally, FDA 

commented that our case study chronology for Arava was incomplete 

because it did not describe two meetings. We provided additional 

clarification in the report about the meetings in the chronology for Arava.

As we agreed with your offices, unless you publicly announce the contents 

of this report earlier, we plan no further distribution of it until 30 days 

from the date of this letter. We will then send copies to others who are 

interested and make copies available to others who request them. 

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

me at (202) 512-7119 or crossem@gao.gov. Contact points for our Offices 

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

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

are listed in appendix VI.

Marcia Crosse 

Director, Health Care 

Page 38 GAO-06-402 FDA Postmarket Drug Safety
Appendix I: Re

Decision

gulatory History and FDA 

-making Process for Arava 

Page 39 GAO-06-402

Appendix I: Regulatory History and FDA 

Decision-making Process for Arava 

Background and 

Summary 

Arava was approved for marketing in 1998. Arava is indicated in adults for 

the treatment of active rheumatoid arthritis to reduce the signs and 

symptoms of the disease, slow down damage to joints, and improve 

physical function. Arava has been associated with cases of serious liver 

injury, some of which have been fatal.

In this case, the Office of Drug Safety (ODS)1

 identified a serious safety 

signal—hepatic failure and fatal hepatitis—associated with Arava in March 

2001. A citizen’s petition in 2002 spurred further inquiry into the issue. An 

ODS analysis of adverse event reports concluded that Arava was 

associated with a substantial increased risk of liver failure and 

recommended removal from the market, but the Office of New Drugs 

(OND) disagreed. OND established an internal panel of senior staff and 

hired outside consultants to further review the reports of liver failure, and 

both the panel and outside consultants concluded that in most cases Arava 

was not causally related to liver failure. In 2003 a Food and Drug 

Administration (FDA) advisory committee meeting was held to discuss 

Arava and ODS staff were not allowed to present their analysis. FDA 

approved revised labeling of Arava in 2003 that strengthened the drug’s 

warnings, and it remained on the market as of February 2006.

FDA approved Arava for marketing. At approval there was a known risk of 

liver toxicity (hepatotoxicity); in clinical trials Arava was associated with 

elevated liver enzymes in a significant number of patients. This

information was included in the original label.

During routine surveillance of incoming adverse event reports, an ODS 

safety evaluator had identified 11 cases of hepatic failure and fatal 

hepatitis associated with the use of Arava. The safety evaluator 

recommended that Arava’s label mention more extensive liver damage, 

such as liver-related fatalities. The ODS Division Director who reviewed 

the consult concurred with the findings and recommendation, but the 

OND Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug 

Chronology 

September 1998 

March 2001 

 1

The names of the postmarket safety and new drug offices changed during the time period

studied. For the sake of clarity and consistency we used ODS and OND—the current 

names—when referring to these offices. 

FDA Postmarket Drug Safety
Appendix I: Regulatory History and FDA 

Decision-making Process for Arava 

Products2 did not. OND did not agree with the findings or recommendation 

because officials were uncertain about the causal relationship between 

Arava and liver damage in the case reports and they believed that the 

current label was adequate for communicating risk about hepatotoxicity.

Public Citizen, a national nonprofit public interest organization, filed a 

petition requesting that FDA immediately remove Arava from the U.S. 

market. Public Citizen said that a significantly higher number of serious 

adverse events, including fatal liver toxicity, had been associated with 

Arava, compared with another drug used to treat patients with rheumatoid 

arthritis. In response to the petition, OND requested that ODS review 

postmarket data for serious hepatic events and liver failure since the 

approval of Arava. 

ODS and OND staff met to discuss ODS’s preliminary work in response to 

the Public Citizen request. ODS’s preliminary review concluded that Arava

was associated with a substantially increased risk for acute liver failure 

and recommended removal from the market. OND disagreed with the 

review. 

Because of the disagreements about causality, OND established a panel of

senior-level Center for Drug Evaluation and Research (CDER) staff, which 

included managers from OND and ODS. The panel met twice to review 

U.S. postmarket reports of 16 cases of acute liver failure and to vote on the 

probability that Arava caused the liver injury. The majority of panel 

members voted that Arava was likely to be causally related to liver failure

in only 2 of the cases. 

ODS staff finalized their review on Arava and sent the consult to OND. The 

report included the recommendation to remove Arava from the market 

because the authors believed that the risks of Arava greatly exceeded its 

benefits3

 and because the available risk management strategies (for 

example, label changes and periodic liver enzyme monitoring) had been

shown to be ineffective in minimizing risk for other drugs. The ODS 

Division Director who reviewed the consult concurred with the findings 

March 2002 

August 2002 

October 2002 

November 2002 

 2

This division is now called the Division of Anesthesia, Analgesia, and Rheumatology 

Products. 

3

This conclusion was based on an analysis of Adverse Event Reporting System (AERS) 

reports, the usage of Arava in the population, and a review of the literature and efficacy 

from preapproval clinical trials. 

Page 40 GAO-06-402 FDA Postmarket Drug Safety
Appendix I: Regulatory History and FDA 

Decision-making Process for Arava 

and recommendation. The ODS Director and the Office of 

Pharmacoepidemiology and Statistical Science (OPaSS) Director also 

reviewed the consult. Both disagreed with the findings and 

recommendation. 

At the request of OND, an ODS safety evaluator reviewed adverse event 

reports of liver injury associated with Arava from outside the United 

States. The ODS safety evaluator, who did not work on the prior analysis 

of the U.S. cases, analyzed 13 cases of liver failure and concluded that 

there was a possible association between the use of Arava and the 

development of liver failure. The safety evaluator also concluded that 

these findings were consistent with the earlier ODS findings in the 16 U.S.

liver failure cases. The ODS Division Director who reviewed the consult 

concurred with the findings. 

Because of the disagreement on Arava’s safety, OND had hired outside 

consultants, including two hepatologists, to further review Arava’s safety 

profile. The hepatology consultants completed their analysis, which 

included a review of the U.S. reports of acute liver failure, by midDecember 2002. They identified no definite cases of Arava-induced liver 

failure, but found some cases to be possibly related to Arava.

FDA’s Arthritis Advisory Committee met to review Arava’s benefit-to-risk 

profile and ways to improve risk management, and to discuss whether 

Arava should be approved for a claim of improvement in physical function. 

OND presented its own analysis of the postmarket safety data,

4

 and did not 

allow ODS staff to present their analysis of postmarket safety data. A 

former OND manager told us that OND believed that the ODS analysis did 

not have scientific merit. 

FDA’s Advisory Committee voted unanimously that Arava’s benefits in 

rheumatoid arthritis outweighed its potential risks and that its risks were 

no greater than other similar drugs. The committee also voted that Arava

should be approved for a claim of improvement in physical function. 

ODS’s epidemiologists and safety evaluators submitted a letter to the ODS 

and OPaSS Directors, expressing their concerns with the Arthritis 

Advisory Committee meeting. They recommended that ODS staff should 

December 2002 

March 2003 

 4

The presentation also included a summary of data from other sources including the

sponsor, and an analysis of AERS called data mining. 

Page 41 GAO-06-402 FDA Postmarket Drug Safety
Appendix I: Regulatory History and FDA 

Decision-making Process for Arava 

present postmarket safety data at advisory committee meetings and that 

there should be a policy that defines the role of ODS at all advisory 

committee meetings involving postmarket safety issues. 

CDER’s Director and Deputy Director sent a memo about ODS’s 

November 2002 consult to the ODS Director, an ODS Division Director, 

and the OPaSS Director. The memo criticized the quality of ODS’s consult 

and stated that ODS had analyzed postmarket data on Arava with a “bias 

toward concluding that the risk is as large as possible.” The memo also 

included the general expectations for an ODS consult. For example, it 

stated that consults should include a summary of the strengths and 

weaknesses of the analytic approach used to evaluate postmarket data. 

FDA approved revised labeling of Arava to support the claim of improved 

physical function. The revised labeling also stated that rare cases of severe 

liver injury, including cases with fatal outcomes, had been reported in 

Arava users. OND decided that although the liver toxicity risk was very 

rare, the accumulated evidence provided support for strengthening the 

warnings on the label. 

OND asked the sponsor to submit liver-related adverse events within 

15 days rather than annually, on the basis of an ODS request. 

The sponsor issued a Dear Healthcare Professional letter explaining the 

labeling changes approved in June 2003. 

Information was added to Arava’s label about the use of Arava in pediatric 

populations, including instances of liver-related adverse reactions from 

pediatric study reports.5

FDA sent a letter to Public Citizen denying its request to remove Arava 

from the U.S. market. 

June 2003 

October 2003 

March 2004 

 5

FDA requested information about the use of Arava in children from its sponsor, on the

basis of the Pediatric Research Equity Act of 2003. 

Page 42 GAO-06-402 FDA Postmarket Drug Safety
Appendix II: Re

Decision

gulatory History and FDA 

-making Process for Baycol

Page 43 GAO-06-402

Appendix II: Regulatory History and FDA 

Decision-making Process for Baycol 

Background and 

Summary 

Baycol was approved for marketing in 1997. Baycol is a member of the 

class of drugs known as statins that lower cholesterol levels in the body.

Baycol was associated with rhabdomyolysis, a severe adverse reaction

involving the breakdown of muscle fibers, which can lead to death. 

In this case, the Office of Drug Safety (ODS) and the Office of New Drugs 

(OND) agreed from the outset (spring 2001) that adverse event reports 

received for high-dose Baycol were alarming.1

 At the request of OND, ODS 

conducted an analysis that verified the increased safety risk associated 

with Baycol, but it did not make specific recommendations for action. 

Shortly thereafter, OND and ODS met with the sponsor and the Food and 

Drug Administration (FDA) communicated to the sponsor that it was 

considering withdrawing the high-dose Baycol from the market. In August

2001 the sponsor voluntarily withdrew all doses of Baycol. 

FDA approved Baycol for marketing (doses up to 0.3 mg).2

 The original 

label stated that rhabdomyolysis had been reported with the use of other 

statins. 

FDA approved a change in the warnings section of Baycol’s label to 

indicate that rare cases of rhabdomyolysis had been reported with Baycol 

and other drugs in the class. FDA also approved adding a new 

subsection—postmarketing adverse event reports (including 

rhabdomyolysis)—to the label. 

FDA approved the 0.4 mg dose of Baycol. 

FDA approved a change in Baycol’s label, requested by the sponsor, to 

include a contraindication with gemfibrozil (a member of a class of drugs 

called fibrates, which also lower cholesterol). The combined use of Baycol 

and gemfibrozil was contraindicated because of the risk for 

rhabdomyolysis. The sponsor issued a Dear Healthcare Professional letter 

shortly thereafter, explaining the labeling changes. 

Chronology 

June 1997 

January 1999 

May 1999 

December 1999 

 1

The names of the postmarket safety and new drug offices changed during the time period

studied. For the sake of clarity and consistency we used ODS and OND—the current 

names—when referring to these offices. 

2

The sponsor only marketed the 0.2 and 0.3 mg doses in the United States. 

FDA Postmarket Drug Safety
Appendix II: Regulatory History and FDA 

Decision-making Process for Baycol

At the request of OND’s Division of Endocrine and Metabolic Drug 

Products,3

 ODS completed a postmarketing safety review of 

rhabdomyolysis resulting from the combined use of statins and fibrates. 

OND requested the review because sponsors of other statins (not Baycol) 

were seeking over-the-counter status for their drugs. ODS safety 

evaluators and an epidemiologist analyzed reports from the Adverse Event 

Reporting System (AERS) and calculated reporting rates of 

rhabdomyolysis for Baycol and other statins when taken alone, and in

combination with gemfibrozil. The reporting rate for Baycol combined 

with gemfibrozil was higher than that of other statins combined with 

gemfibrozil. But the reporting rate for Baycol alone was only slightly 

higher compared with the other statins. On the basis of their findings and

the severity of rhabdomyolysis as a clinical diagnosis, the ODS staff 

recommended that the statins not be granted over-the-counter designation. 

The ODS Division Director who reviewed the consult concurred. In 

agreement with ODS’s position, OND decided to discuss with the sponsor 

sending stronger messages to healthcare professionals about the adverse 

reaction. 

FDA approved the 0.8 mg dose of Baycol. 

FDA approved the addition of a patient package insert for Baycol.4

An ODS safety evaluator contacted the OND medical officer responsible 

for Baycol about reports of fatal rhabdomyolysis associated with Baycol,

especially at the 0.8 mg dose, since ODS’s last consult in 2000. The medical 

officer agreed the data were alarming and asked for more analysis. At 

about the same time, the sponsor notified OND about a dose-related 

occurrence of adverse events. 

FDA approved several revisions to labeling for Baycol, including an 

emphasis that the correct starting dose of Baycol should be 0.4 mg 

because of the increased risk of rhabdomyolysis at higher doses. The 

June 2000 

July 2000 

November 2000 

April 2001 

May 2001 

 3

The Division of Endocrine and Metabolic Drug Products is now called the Division of 

Metabolism and Endocrinology Products. 

4

A patient package insert is an additional part of the professional labeling of a drug that 

provides important information to the consumer and may be distributed to patients when

the drug is dispensed. It is required for a few drugs, such as oral contraceptives, and

voluntary for other drugs.

Page 44 GAO-06-402 FDA Postmarket Drug Safety
Appendix II: Regulatory History and FDA 

Decision-making Process for Baycol

sponsor issued a Dear Healthcare Professional letter explaining the 

changes. 

OND and ODS staff met with the sponsor to discuss concerns over the 

safety of Baycol. An ODS epidemiologist presented an analysis of fatal 

cases of rhabdomyolysis associated with the 0.8 mg dose of Baycol 

compared with Lipitor, another statin, and compared with the 0.4 mg dose 

of Baycol. ODS found that the risk of fatal rhabdomyolysis was higher for 

Baycol than for Lipitor. ODS also found that the risk appeared to be doserelated, with twice as many of the fatalities among patients taking the 

highest daily dose—0.8 mg—of Baycol (without concomitant gemfibrozil) 

compared with the lower dose—0.4 mg.5

At the meeting, FDA communicated to the sponsor that it was considering 

several safety actions to address its concerns about Baycol, including the

withdrawal of the 0.8 mg dose, and a boxed warning with information 

about not exceeding a dosage of 0.4 mg daily and a contraindication with 

gemfibrozil. 

OND and ODS staff met with the sponsor again to discuss their ongoing 

concerns over the safety of Baycol, particularly concerns about the risk of 

rhabdomyolysis at higher doses or in combination with gemfibrozil. The 

sponsor proposed to (1) voluntarily withdraw the 0.8 mg dose in the 

United States, (2) add a boxed warning on the label about not exceeding a 

dose of 0.4 mg daily, and (3) add a boxed warning on the label for 

contraindicated use of Baycol and gemfibrozil. FDA asked the sponsor for 

a comprehensive analysis of the 0.4 mg dose. 

A week later, FDA announced that the sponsor voluntarily withdrew all 

doses of Baycol from the United States market and the sponsor issued a 

Dear Healthcare Professional letter explaining its decision. 

July 2001 

August 2001 

 5

ODS’s analysis was finalized on August 17, 2001. It did not contain a recommendation for 

regulatory action. The safety review included a critique of two epidemiologic studies that

the sponsor conducted to examine the risk of myopathy (for example, muscle aching or 

muscle weakness) subsequent to statin use in a managed care organization, using its 

automated claims data. The ODS staff who wrote the consult concluded that the studies did 

not alleviate the concerns raised by the spontaneous report data. The Acting Division 

Director of ODS who reviewed the consult concurred with the review. 

Page 45 GAO-06-402 FDA Postmarket Drug Safety
Appendix III: Reg

Decision

ulatory History and FDA 

-making Process for Bextra 

Page 46 GAO-06-402

Appendix III: Regulatory History and FDA 

Decision-making Process for Bextra 

Background and 

Summary 

Bextra was approved for marketing in 2001. Bextra was part of the class of 

drugs known as the COX-2 selective nonsteroidal anti-inflammatory drugs 

(NSAID). Bextra was approved to relieve the symptoms of osteoarthritis 

and rheumatoid arthritis in adults, and to relieve painful menstrual cycles. 

Bextra was associated with serious, potentially fatal skin reactions, 

including Stevens-Johnson Syndrome and toxic epidermal necrolysis. 

Bextra was also later associated with an increased risk of serious 

cardiovascular events, similar to the other approved COX-2 drugs. 

In this case, after the Office of Drug Safety (ODS)1

 did an analysis of 

serious skin reactions associated with Bextra in 2002, Bextra’s label was 

modified. ODS continued to do a series of analyses of adverse events 

associated with Bextra from 2003 to 2004, recommending in 2004 that 

there be a boxed warning, the most serious warning, on the label, but the 

Office of New Drugs (OND) disagreed. OND changed its position after 

ODS did a comparison, at OND’s request, of Bextra’s rate of serious skin 

reactions with the reporting rates of other similar drugs. A boxed warning 

was added to Bextra’s label in late 2004. In February 2005, two scientific 

advisory committees that met primarily about the cardiovascular risks 

associated with the COX-2 NSAIDs voted that Bextra’s overall risk-tobenefit profile supported continued marketing. But a few months later the 

Food and Drug Administration (FDA) came to a different conclusion and 

announced that the overall risk-to-benefit profile of Bextra was not 

favorable, and as a result requested that it be withdrawn from the market, 

which it was in April 2005. 

FDA approved Bextra for marketing. 

The sponsor had identified the occurrence of serious skin reactions, 

proposed adding information about this risk to the label, and proposed 

issuing a Dear Healthcare Professional letter. At the request of OND’s 

Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products,2

Chronology 

November 2001 

September 2002 

 1

The names of the postmarket safety and new drug offices changed during the time period

studied. For the sake of clarity and consistency we used ODS and OND—the current 

names—when referring to these offices. 

2

The Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products is now

called the Division of Anesthesia, Analgesia, and Rheumatology Products. 

FDA Postmarket Drug Safety
Appendix III: Regulatory History and FDA 

Decision-making Process for Bextra 

ODS staff reviewed reports of serious skin reactions in the Adverse Event 

Reporting System (AERS) for Bextra. They compared Bextra’s reporting

rate of serious skin reactions with rates for Vioxx and Celebrex (other 

COX-2 NSAIDs), and the incidence in the general population. The ODS 

staff agreed that the label should be changed and that a Dear Healthcare 

Professional letter should be issued because the rates for Bextra were 

higher than those for Vioxx, Celebrex, and the general population. The 

ODS Division Director that reviewed the consult and OND concurred with 

the findings.

FDA announced an updated label describing the risk for serious skin 

reactions associated with Bextra and that Bextra was contraindicated in

patients with histories of allergic reactions to sulfa, a substance that 

Bextra contains. The sponsor issued a Dear Healthcare Professional letter 

explaining the updated label. 

The Division of Pediatrics and Therapeutics3

 had asked ODS for a 

recommendation on whether Bextra should be studied in pediatric 

populations for the treatment of acute pain, as proposed by the sponsor. 

ODS staff recommended that Bextra not be studied in pediatric 

populations because of its risk of serious skin reactions in the adult 

population. In addition, ODS staff analyzed data from the National Center 

for Health Statistics and found that serious skin reactions generally occur 

more commonly in children than adults. The ODS Acting Division Director 

that reviewed the consult agreed with the analysis and recommendation as

did the Division of Pediatrics and Therapeutics. However, OND disagreed 

with the recommendation and supported the study of Bextra in pediatric 

populations because staff in OND felt this drug could have value in certain

pediatric populations, such as patients who cannot tolerate other NSAIDs. 

Ultimately, Bextra was not studied in children in part because, according

to a former OND manager, OND deferred to ODS’s judgment on this 

recommendation. 

ODS staff updated their original analysis and concluded that the reporting 

rates for serious skin reactions associated with Bextra remained markedly 

elevated above the incidence in the general population and above the rates 

for Celebrex and Vioxx. ODS staff recommended adding another skin 

November 2002 

April 2003 

July 2003 

 3

This division is now called the Division of Pediatric Drug Development and is located 

within CDER’s Office of Counter-Terrorism and Pediatric Drug Development. This division 

has responsibility for determining what kinds of pediatric studies are needed to develop 

information about certain marketed drugs, such as the appropriate dosing for pediatric use. 

Page 47 GAO-06-402 FDA Postmarket Drug Safety
Appendix III: Regulatory History and FDA 

Decision-making Process for Bextra 

reaction to the warnings in the label and the ODS Acting Division Director 

that reviewed the consult concurred. Although OND did not respond to the 

consult, a former OND manager told us that it would not have been 

important to add this skin reaction to the label since the label already 

included the most severe forms of skin reactions.

ODS staff updated their assessment of the risks of serious skin reactions 

associated with Bextra, on the basis of additional AERS reports, and 

commented on a risk management plan submitted by the sponsor. They 

recommended to OND several stronger safety actions, including a boxed 

warning and a medication guide,4

 because the risk remained elevated

compared with the incidence in the general population and relative to 

Celebrex and Vioxx (for example, 13-fold relative to Vioxx). The ODS staff 

stated that very little was known about the risk factors for serious skin 

reactions, making them difficult to avoid. In addition, they recommended 

that OND consider the clinical circumstances in which Bextra had a 

favorable benefit-to-risk profile relative to other treatment alternatives. 

Two ODS Division Directors that reviewed the consult concurred, but 

OND did not agree that Bextra needed stronger safety actions at this time. 

Bextra’s label was changed to include the statement that fatalities due to

serious skin reaction had been reported. 

At the request of OND, ODS staff compared Bextra’s reporting rate of 

serious skin reactions with an antibiotic drug’s reporting rate because 

both Bextra and the antibiotic contained sulfa and both drugs were 

contraindicated in patients with known allergies to sulfa. ODS staff 

compared the reporting rates, but indicated in their consult that it was 

inappropriate to compare an antibiotic marketed for more than 30 years 

and was used for acute, potentially life-threatening illnesses with a 

recently marketed pain reliever that was generally used for a chronic nonlife-threatening illness. The ODS Division Director that reviewed the 

consult concurred. However, the OND medical officer involved in the case 

maintained it was an appropriate comparison. ODS staff found a higher 

reporting rate for serious skin reactions associated with Bextra when 

compared with the rate for the antibiotic drug. 

March 2004 

April 2004 

June 2004 

 4

Used primarily for outpatient drugs that have serious safety concerns, medication guides

are required to be dispensed with each prescription. They contain information specifically 

for the patient, such as the most important information the patient should know about a 

drug. 

Page 48 GAO-06-402 FDA Postmarket Drug Safety
Appendix III: Regulatory History and FDA 

Decision-making Process for Bextra 

At the request of OND, ODS staff compared Bextra’s rate of serious skin 

reactions with the reporting rates of Celebrex, Vioxx, and Mobic, antiinflammatory drugs that are used to treat arthritis. ODS staff concluded 

that Bextra’s reporting rate continued to be elevated compared with the 

other drugs, including Mobic, which had no reported cases of serious skin 

reactions. As a result of this analysis, and the reports of death (at least 

four deaths have been associated with Bextra), OND asked Bextra’s 

sponsor for a boxed warning about this risk, which it previously did not 

support. 

The sponsor issued a Dear Healthcare Professional letter summarizing the 

serious skin reactions associated with Bextra and stated that it had 

proposed an updated label to FDA to expand previous warnings about the 

skin reactions. 

FDA announced that Bextra would carry a boxed warning for serious skin 

reactions.5

 The sponsor also issued a Dear Healthcare Professional letter 

explaining these changes. 

A joint meeting of FDA’s Arthritis Advisory Committee and the Drug 

Safety and Risk Management Advisory Committee was held. The meeting

was focused primarily on the cardiovascular risks of the COX-2 selective

NSAIDs, including Bextra. The advisory committees voted (17 yes, 13 no, 

2 abstentions) that Bextra’s overall risk-to-benefit profile supported 

continued marketing. 

After reviewing information from multiple sources, which included 

specific votes and recommendations that the advisory committees made in

February 2005, FDA announced its conclusion that Bextra’s overall risk-tobenefit profile was not favorable and, as a result, requested that the 

sponsor voluntarily withdraw Bextra from the market.6

 FDA concluded 

that in addition to its cardiovascular risk (similar to the other COX-2 

drugs), Bextra already carried a boxed warning for serious skin reactions. 

While the other COX-2 drugs also had a risk for these serious skin 

reactions, the reporting rate appeared to be greater for Bextra. In addition, 

August 2004 

October 2004 

December 2004 

February 2005 

April 2005 

 5

A new warning regarding Bextra’s cardiovascular risk was also added to Bextra’s label at

this time. 

6

FDA posted a memo on its Web site, written by the Directors of OND and OPaSS, 

explaining why FDA decided to ask Bextra’s sponsor to withdraw the drug from the 

market. 

Page 49 GAO-06-402 FDA Postmarket Drug Safety
Appendix III: Regulatory History and FDA 

Decision-making Process for Bextra 

the occurrence of the skin reactions was unpredictable, for example, 

occurring after both short- and long-term use, making attempts to manage 

this risk difficult. Also, there were no data supporting a unique therapeutic 

benefit for Bextra over other available NSAIDs, which could have offset 

the increased risk of serious skin reactions. 

The sponsor agreed to withdraw the drug in the United States. 

Page 50 GAO-06-402 FDA Postmarket Drug Safety
A

Deci

ppendix IV: Regulatory History and FDA

sion-making Process for Propulsid 

Page 51 GAO-06-402

Appendix IV: Regulatory History and FDA 

Decision-making Process for Propulsid 

Background and 

Summary 

Propulsid was approved for marketing in 1993. Propulsid was indicated for 

use in adults for the symptomatic relief of nighttime heartburn due to 

gastroesophageal reflux disease. Propulsid was associated with serious 

cardiac arrhythmias, including reports of death, and most of these adverse 

events occurred in patients who were taking other medications or 

suffering from underlying conditions known to increase the risk of cardiac 

arrhythmia. 

In this case there was general agreement about the safety concern 

between the Office of New Drugs (OND) and the Office of Drug Safety

(ODS),1

 but differing opinions within the Food and Drug Administration 

(FDA) over what safety actions should be taken regarding the drug. In 

1997 FDA decided to continue to work with the sponsor to make changes

to the drug’s label, which included a boxed warning, but some staff felt 

stronger actions were needed. An FDA-supported study later found that 

the boxed warning did not significantly deter use of the drug with 

contraindicated drugs or medical conditions. During this case, a task force 

within FDA was formed to help evaluate Propulsid’s safety and efficacy, 

and ODS staff conducted numerous analyses and made multiple 

recommendations for stronger safety actions, including a market 

withdrawal. The sponsor voluntarily removed the drug from the market in

2000. Propulsid is currently available through a limited-access program to 

ensure that only certain patients receive the medication. 

FDA approved Propulsid for marketing in tablet form. 

The sponsor submitted information to the Center for Drug Evaluation and

Research (CDER) about reports of cardiac arrhythmias associated with 

the use of Propulsid. Subsequently, an ODS safety evaluator identified and 

reviewed 12 reports of torsade de pointes2

 in FDA’s MedWatch 

Spontaneous Reporting System (SRS)3

 and identified potential risk factors, 

including cardiac history and the concomitant use of several other drugs. 

Chronology 

July 1993 

January 1995 

 1

The names of the postmarket safety and new drug offices changed during the time period

studied. For the sake of clarity and consistency we used ODS and OND—the current 

names—when referring to these offices. 

2

Torsade de pointes is a type of serious cardiac arrhythmia. 

3

FDA now maintains adverse event reports in the Adverse Event Reporting System (AERS).

FDA Postmarket Drug Safety
Appendix IV: Regulatory History and FDA

Decision-making Process for Propulsid 

OND’s Division of Gastrointestinal and Coagulation Drug Products4 agreed 

with ODS that this was a safety concern. 

Propulsid’s label was revised to state that it was contraindicated with 

certain other drugs5

 which, when taken with Propulsid, can increase the 

concentration of Propulsid and lead to arrhythmias. A clinical study 

conducted by the sponsor provided this evidence. The label was also 

revised to include information about other risk factors, including a history 

of cardiac disease. The sponsor issued a Dear Healthcare Professional 

letter with similar information. 

FDA approved Propulsid for marketing in liquid form. 

A boxed warning was added to Propulsid’s label, specifying its 

contraindication with other drugs. The boxed warning also included the 

statement that some of the reported adverse events had resulted in death.

The sponsor issued a Dear Healthcare Professional letter in October with 

similar information. 

An ODS epidemiologist identified and analyzed 46 adverse event reports of 

patients who developed serious cardiac arrhythmias while using 

Propulsid, from July 1993 through early October 1995, and concluded that 

many patients who developed arrhythmias had histories of cardiac and 

renal conditions. Most patients who developed arrhythmias were not 

taking contraindicated medications; as a result, the epidemiologist 

concluded that Propulsid may itself cause arrhythmias.6

 The 

epidemiologist recommended that risk factors, such as histories of 

significant cardiac and renal disease, should be displayed in the label’s 

warning with the same emphasis as the contraindicated drugs. The ODS 

Division Director concurred with the consult. 

At the request of OND, an ODS safety evaluator searched SRS for all 

adverse event reports associated with Propulsid in children aged 19 years 

and younger. Although Propulsid was not approved for use in children, it 

had been prescribed to children (for example, in newborn infants for 

February 1995 

September 1995 

January 1996 

August 1996 

 4

The division is now called the Division of Gastroenterology Products. 

5

Nizoral tablets, Sporanox capsules, Monistat IV, and Tao capsules were contraindicated 

with Propulsid. 

6

A few reports and studies in the medical literature also suggested that Propulsid may 

cause cardiac arrhythmias. 

Page 52 GAO-06-402 FDA Postmarket Drug Safety
Appendix IV: Regulatory History and FDA

Decision-making Process for Propulsid 

feeding problems such as reflux). Six children were reported to have had 

cardiac arrhythmias with the use of Propulsid and several other children 

had other cardiovascular events. The safety evaluator also reported that 

the estimated usage of Propulsid in children was increasing steadily. 

FDA rejected the sponsor’s application for a pediatric indication for 

Propulsid. 

OND established a task force within FDA to evaluate the safety and 

efficacy of Propulsid. The task force included members from OND and 

ODS. At its initial meeting, the task force decided to gather information 

from several sources, including the reviews done by ODS, in order to 

accurately assess the safety of Propulsid. 

As agreed in the June 1997 Propulsid task force meeting, an ODS 

epidemiologist reviewed adverse event reports of Propulsid users with 

serious arrhythmias. The epidemiologist found that in about half of the 

cases, patients had taken contraindicated drugs with Propulsid and that a 

high proportion of the remaining cases had medical problems that may 

have predisposed them to arrhythmias. The epidemiologist recommended 

that the risk factors, such as predisposing medical problems, should be 

displayed in the label’s warning with the same emphasis as the 

contraindicated drugs and that the recommended dosage should not be 

exceeded. The ODS Division Director who reviewed the consult 

concurred. 

The task force on Propulsid met for the second time. The group discussed 

information that was gathered on the safety of Propulsid. An ODS 

epidemiologist summarized her August 1997 consult, including her 

recommendation that predisposing medical problems should be displayed 

in the label’s warnings similar to the contraindicated drugs and that the 

recommended dosage should not be exceeded. She also noted that 

Propulsid was primarily being prescribed for off-label use.7

 Other relevant

studies were discussed, including a clinical trial study where 3 out of 32 

healthy elderly volunteers had abnormal electrocardiogram results after 

exposure to Propulsid alone. 

June 1997 

August 1997 

September 1997 

 7

Any use of a drug not described in the label is termed off-label use. 

Page 53 GAO-06-402 FDA Postmarket Drug Safety
Appendix IV: Regulatory History and FDA

Decision-making Process for Propulsid 

An ODS safety evaluator reported that there were additional cases of 

serious, cardiovascular adverse events among children who were 

prescribed Propulsid. 

FDA approved a rapidly disintegrating tablet form of Propulsid for 

marketing. 

The task force on Propulsid met and decided to seek further input from a 

CDER-wide group about pursuing the following regulatory actions: adding 

the risk for cardiac arrhythmias with the use of Propulsid alone (for 

example, without taking contraindicated drugs) to the label; holding an 

advisory committee meeting; and withdrawing approval of all Propulsid 

formulations. 

OND’s Division of Gastrointestinal and Coagulation Drug Products 

consulted another OND division that was responsible for the drug Seldane 

to find out what information would be required to withdraw the approval

of a drug since FDA had initiated proceedings to withdraw its approval of 

Seldane in 1996 for a similar cardiovascular side effect. That division 

recommended that data be gathered to support the assertion that 

Propulsid was still being coprescribed with contraindicated drugs despite 

the boxed warning and Dear Healthcare Professional letters.

At the request of OND, an ODS epidemiologist evaluated the sponsor’s 

epidemiological study on risk of serious cardiac arrhythmias among 

Propulsid users. In this study the researchers concluded that serious 

cardiac arrhythmias were not associated with Propulsid. The ODS 

epidemiologist outlined several major limitations with the study, including

the potential for the misclassification of arrhythmia in patients not 

diagnosed by an electrocardiogram. 

A meeting was held in CDER to discuss FDA’s regulatory options for 

Propulsid. This meeting included some senior-level managers in CDER and 

an FDA attorney. The OND medical officer responsible for Propulsid 

presented his concerns, including his conclusion that Propulsid should be 

removed from the market. Proceeding with a withdrawal from the market 

was discussed at the meeting. FDA continued to work with the sponsor to 

change Propulsid’s label. Some staff believed that stronger safety actions 

were needed. 

An ODS epidemiologist summarized reports of 186 patients who developed 

serious cardiac disorders and arrhythmias (including deaths) with and 

without contraindicated drugs from July 1993 through early May 1998. The 

October 1997 

November 1997 

December 1997 

May 1998 

Page 54 GAO-06-402 FDA Postmarket Drug Safety
Appendix IV: Regulatory History and FDA

Decision-making Process for Propulsid 

ODS epidemiologist recommended to OND that the boxed warning should 

state that serious arrhythmias had occurred in Propulsid users who had 

not been taking contraindicated drugs, and that an accompanying Dear 

Healthcare Professional letter should be issued.

The ODS epidemiologist also recommended that Propulsid’s labeling 

should state that the safety and effectiveness of Propulsid had not been 

demonstrated in pediatric patients for any indication. 

FDA announced revisions to the boxed warning that strengthened its 

warnings and precautions, and the sponsor issued a Dear Healthcare 

Professional letter explaining the revisions. The changes included the 

statement that Propulsid was contraindicated in patients with medical 

problems known to predispose them to arrhythmias, such as heart disease.

The revision also stated that other therapies for heartburn should be used

before Propulsid, and that the safety and effectiveness in pediatric patients 

had not been established. Also, the revised boxed warning included the 

statement that cardiac adverse events, including sudden death, had 

occurred among Propulsid users who were not taking contraindicated 

drugs. 

An ODS epidemiologist summarized cardiac adverse event reports from 

the beginning of Propulsid’s marketing (July 1993) through May 1998. 

There were 187 reports, including 38 deaths. 

FDA implemented a medication guide8

 and unit-dose packaging9 for 

Propulsid. 

An ODS epidemiologist worked on a study to evaluate labeling compliance 

among Propulsid users, which was carried out through ODS’s cooperative 

agreement program. The study ultimately found that the boxed warning 

June 1998 

July 1998 

November 1998 

May 1999 

 8

Used primarily for outpatient drugs that have serious safety concerns, medication guides

are required to be dispensed with each prescription. They contain information specifically 

for the patient, such as the most important information the patient should know about a 

drug. 

9

Unit-dose packaging includes a single dose, individually packaged and labeled. According

to an FDA official, this type of packaging is believed to help prevent medication errors. 

Page 55 GAO-06-402 FDA Postmarket Drug Safety
Appendix IV: Regulatory History and FDA

Decision-making Process for Propulsid 

did not significantly deter the use of Propulsid with contraindicated drugs

or medical conditions.10

The sponsor issued a Dear Healthcare Professional letter with information 

about revisions to the boxed warning. The revisions included two new 

contraindications and a new drug interaction. Similar revisions were 

incorporated into the medication guide. 

An ODS epidemiologist analyzed and summarized the reports of Propulsid 

users who developed cardiovascular problems, including deaths, in four 

separate consults. The reports included adult and pediatric patients who 

took Propulsid with and without contraindicated drugs and medical 

conditions. The ODS epidemiologist recommended to OND that other 

contraindications should be added to the label, including one for patients 

with structural heart defects. 

The ODS epidemiologist recommended that OND consider several safety 

actions, including asking the sponsor to conduct a clinical or 

epidemiological study on the association between Propulsid and cardiac 

adverse events in its users, and removing Propulsid from the market. 

ODS and OND staff and the CDER Director met to discuss further options 

for regulatory actions. It was decided that FDA would hold a public 

advisory committee meeting to discuss ways to reduce the occurrence of

adverse events with Propulsid. The preliminary results of the cooperative 

agreement study were going to be presented at the advisory committee 

meeting. 

FDA announced further revisions to the boxed warning and that a public

advisory committee meeting was scheduled for April. The label revision 

included new recommendations for performing diagnostic tests and a new 

contraindication for patients with electrolyte disorders. Similar revisions 

were incorporated into the medication guide. The sponsor issued a Dear 

Healthcare Professional letter explaining these revisions. 

June 1999 

November 1999 

January 2000 

 10The study was published in 2000. See W. Smalley, D. Shatin, D.K. Wysowski, et al.,

“Contraindicated Use of Cisapride: Impact of Food and Drug Administration Regulatory 

Action,” Journal of the American Medical Association, vol. 284, no. 23 (2000). 

Page 56 GAO-06-402 FDA Postmarket Drug Safety
Appendix IV: Regulatory History and FDA

Decision-making Process for Propulsid 

FDA announced that the sponsor would withdraw Propulsid from the U.S. 

market as of July 14, 2000.11 FDA also announced that its scheduled public 

advisory committee meeting was cancelled. 

The sponsor announced that it would make Propulsid available to certain

patients through an investigational limited-access program, approved by 

FDA. 

An ODS epidemiologist summarized reports of adverse events, including 

cardiovascular events, among patients enrolled in the limited-access 

program. The epidemiologist recommended that the availability of 

Propulsid should not be expanded from the limited-access program to a 

restricted distribution. The ODS Division Director who reviewed the 

consult agreed. The drug’s availability was not expanded. 

March 2000 

April 2000 

March 2002 

 11In April 2000, the sponsor announced that it would make Propulsid available to patients 

who met specific eligibility criteria through an investigational limited-access program. 

Page 57 GAO-06-402 FDA Postmarket Drug Safety
Appendix V: Comments from the Food and Appendix V Drug Administration : Comments from the Food and 

Drug Administration 

Page 58 GAO-06-402 FDA Postmarket Drug Safety
Appendix V: Comments from the Food and

Drug Administration 

Page 59 GAO-06-402 FDA Postmarket Drug Safety
Appendix V: Comments from the Food and

Drug Administration 

Page 60 GAO-06-402 FDA Postmarket Drug Safety
Appendix V: Comments from the Food and

Drug Administration 

Page 61 GAO-06-402 FDA Postmarket Drug Safety
Appendix VI: 

St

GAO Contact and 

aff Acknowledgments

Page 62 GAO-06-402

Appendix VI: GAO Contact and Staff 

Acknowledgments 

GAO Contact Marcia Crosse, (202) 512-7119 or crossem@gao.gov

In addition to the contact named above, Martin T. Gahart, Assistant 

Director; Anne Dievler; Pamela Dooley; Cathleen Hamann; and Julian 

Klazkin made key contributions to this report. 

FDA Postmarket Drug Safety

Acknowledgments 

(290431) 
GAO’s Mission The Government Accountability Office, the audit, evaluation and 

investigative arm of Congress, exists to support Congress in meeting its 

constitutional responsibilities and to help improve the performance and 

accountability of the federal government for the American people. GAO 

examines the use of public funds; evaluates federal programs and policies; 

and provides analyses, recommendations, and other assistance to help

Congress make informed oversight, policy, and funding decisions. GAO’s 

commitment to good government is reflected in its core values of 

accountability, integrity, and reliability. 

The fastest and easiest way to obtain copies of GAO documents at no cost

is through GAO’s Web site (www.gao.gov). Each weekday, GAO posts 

newly released reports, testimony, and correspondence on its Web site. To

have GAO e-mail you a list of newly posted products every afternoon, go 

to www.gao.gov and select “Subscribe to Updates.” 

The first copy of each printed report is free. Additional copies are $2 each. 

A check or money order should be made out to the Superintendent of 

Documents. GAO also accepts VISA and Mastercard. Orders for 100 or 

more copies mailed to a single address are discounted 25 percent. Orders 

should be sent to: 

U.S. Government Accountability Office 

441 G Street NW, Room LM 

Washington, D.C. 20548 

To order by Phone: Voice: (202) 512-6000 

TDD: (202) 512-2537 

Fax: (202) 512-6061 

Contact: 

Web site: www.gao.gov/fraudnet/fraudnet.htm

E-mail: fraudnet@gao.gov

Automated answering system: (800) 424-5454 or (202) 512-7470 

Gloria Jarmon, Managing Director, JarmonG@gao.gov (202) 512-4400 

U.S. Government Accountability Office, 441 G Street NW, Room 7125 

Washington, D.C. 20548 

Paul Anderson, Managing Director, AndersonP1@gao.gov (202) 512-4800

U.S. Government Accountability Office, 441 G Street NW, Room 7149 

Washington, D.C. 20548 

Obtaining Copies of 

GAO Reports and 

Testimony

Order by Mail or Phone 

To Report Fraud,

Waste, and Abuse in 

Federal Programs 

Congressional 

Relations 

Public Affairs 

PRINTED ON RECYCLED PAPER