Drug Safety: Improvement Needed in FDA's Postmarket		 
Decision-making and Oversight Process (31-MAR-06, GAO-06-402).	 
                                                                 
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.			 
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-06-402 					        
    ACCNO:   A50564						        
  TITLE:     Drug Safety: Improvement Needed in FDA's Postmarket      
Decision-making and Oversight Process				 
     DATE:   03/31/2006 
  SUBJECT:   Consumer protection				 
	     Decision making					 
	     Drugs						 
	     Pharmaceutical industry				 
	     Pharmacological research				 
	     Prescription drugs 				 
	     Product safety					 
	     Safety regulation					 
	     Safety standards					 

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GAO-06-402

     

     * Results in Brief
     * Background
          * Postmarket Drug Safety and FDA's Role
          * FDA's Postmarket Drug Safety Authority
     * Two Distinct FDA Units Involved in Postmarket Drug Safety Ac
          * OND Has Decision-making Responsibility for Postmarket Drug S
          * ODS Serves as a Consultant to OND
          * Postmarket Drug Safety Decision Making Is Complex and Iterat
     * FDA Lacks a Clear and Effective Decision-making Process for
          * Decision-making Process on Drug Safety Lacks Clarity about C
          * A Lack of Communication and Limited Oversight Hinders the De
          * Data Constraints Contribute to Difficulty in Making Postmark
     * FDA Initiatives Are an Improvement, but Will Not Address All
          * DSB May Provide Broad Oversight, but Systematic Tracking Is
          * Other Process and Organizational Initiatives Are Promising,
          * Dispute Resolution Processes Have Not Been Used
          * FDA Is Taking Steps to Identify Additional Data Sources, but
     * Conclusions
     * Matter for Congressional Consideration
     * Recommendations for Executive Action
     * Agency Comments and Our Evaluation
     * Background and Summary
     * Chronology
          * September 1998
               * March 2001
               * March 2002
               * August 2002
               * October 2002
               * November 2002
               * December 2002
               * March 2003
               * June 2003
               * October 2003
               * March 2004
     * Background and Summary
     * Chronology
          * June 1997
               * January 1999
               * May 1999
               * December 1999
               * June 2000
               * July 2000
               * November 2000
               * April 2001
               * May 2001
               * July 2001
               * August 2001
     * Background and Summary
     * Chronology
          * November 2001
               * September 2002
               * November 2002
               * April 2003
               * July 2003
               * March 2004
               * April 2004
               * June 2004
               * August 2004
               * October 2004
               * December 2004
               * February 2005
               * April 2005
     * Background and Summary
     * Chronology
          * July 1993
               * January 1995
               * February 1995
               * September 1995
               * January 1996
               * August 1996
               * June 1997
               * August 1997
               * September 1997
               * October 1997
               * November 1997
               * December 1997
               * May 1998
               * June 1998
               * July 1998
               * November 1998
               * May 1999
               * June 1999
               * November 1999
               * January 2000
               * March 2000
               * April 2000
               * March 2002
     * GAO Contact
     * Acknowledgments
     * GAO's Mission
     * 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

Report to Congressional Requesters

United States Government Accountability Office

GAO

March 2006

DRUG SAFETY

Improvement Needed in FDA's Postmarket Decision-making and Oversight
Process

GAO-06-402

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
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

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protection in the United States. It may be reproduced and distributed in
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separately.

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 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 guidance for industry,7 and making other
organizational and policy process changes.

1FDA is an agency within the Department of Health and Human Services
(HHS).

2Vioxx was voluntarily withdrawn from the market by its manufacturer in
September 2004.

3See, 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.

4Pub. L. No. 102-571, 106 Stat. 4491.

5Pub. L. No. 107-188, 116 Stat. 594.

6In 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.

In light of the recent controversy about drug safety, you asked us to
conduct a review of FDA's current organizational structure and
decision-making 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 decision-making process,
we analyzed documents describing internal FDA policies and procedures and
interviewed FDA officials. In order to obtain an in-depth 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, 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.

7In 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).

8FDA 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.

                                Results in Brief

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 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.

9FDA 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.

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 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.

                                   Background

Postmarket Drug Safety and FDA's Role

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
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

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.

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 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.

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.

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.

Figure 1: FDA Organizational Structure for Postmarket Drug Safety

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
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. S: 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."

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 studies
are needed to provide adequate labeling to ensure the safe and effective
use of these drugs in children.24

2121 C.F.R. S: 314.510 (2005).

2221 C.F.R. S: 314.610(b)(1) (2005).

2321 C.F.R. S: 314.530(a)(1)-(3); 21 C.F.R. S: 314.620(a)(1)-(3) (2005).

      Two Distinct FDA Units Involved in Postmarket Drug Safety Activities

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.

OND Has Decision-making Responsibility for Postmarket Drug Safety

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 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.

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. S: 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.

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).

ODS Serves as a Consultant to OND

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 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
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.

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

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
DDRE-initiated 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 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
peer-reviewed journals.

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.

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 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.

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.

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 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

31For more information on events related to FDA's decision-making
processes on Arava, Baycol, Bextra, and Propulsid, see apps. I-IV.

  FDA Lacks a Clear and Effective Decision-making Process for Postmarket Drug
                                     Safety

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 weaknesses, however. FDA
also faces constraints in requiring certain studies and obtaining data.

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.

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
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.

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.

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.

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 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.

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.

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 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.

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.

A Lack of Communication and Limited Oversight Hinders the Decision-making
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).

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,
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
anti-inflammatory 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.

42Adverse event data are the primary basis for postmarket safety actions
ranging from labeling changes to withdrawal.

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 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
population-based 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

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. Drug-induced 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.

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 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 anti-inflammatory
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
population-based 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

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.

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 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 long-term 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.

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).

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 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.

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).

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 Initiatives Are an Improvement, but Will Not Address All Gaps

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.

DSB May Provide Broad Oversight, but Systematic Tracking Is Still Needed

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 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

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).

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 DSB has plans to form subcommittees to look at policy
development in this and other areas.

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.

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
Decision-Making 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 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.

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.

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 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.

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.

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, 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 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.

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.

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. The
working group's review of the request for information was still ongoing as
of March 2006.

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.

                                  Conclusions

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.

                     Matter for Congressional Consideration

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.

                      Recommendations for Executive Action

To improve the postmarket drug safety decision-making process, we
recommend that the Commissioner of FDA take the following four actions:

           o  establish a mechanism for systematically tracking ODS's
           recommendations and subsequent safety actions;
           o  with input from the DSB and the Process Improvement Teams,
           revise and implement the draft policy on major postmarket drug
           safety decisions;
           o  improve CDER's dispute resolution process by revising the pilot
           program to increase its independence; and
           o  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 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 [email protected] . 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

           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 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 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 mid-December 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 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.

           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.

           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 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 dose-related, 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.

           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-to-benefit 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 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 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
           non-life-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.

           At the request of OND, ODS staff compared Bextra's rate of serious
           skin reactions with the reporting rates of Celebrex, Vioxx, and
           Mobic, anti-inflammatory 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-to-benefit 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, 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.

           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. 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 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.

           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 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 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.

           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.

           Marcia Crosse, (202) 512-7119 or [email protected]

           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.

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                       Agency Comments and Our Evaluation

Appendix I: ReDecision Appendix I: Regulatory History and FDA
Decision-making Process for Arava

                             Background and Summary

                                   Chronology

  September 1998

  March 2001

1The 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.

  March 2002

  August 2002

  October 2002

  November 2002

2This division is now called the Division of Anesthesia, Analgesia, and
Rheumatology Products.

3This 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.

  December 2002

  March 2003

4The presentation also included a summary of data from other sources
including the sponsor, and an analysis of AERS called data mining.

  June 2003

  October 2003

  March 2004

5FDA requested information about the use of Arava in children from its
sponsor, on the basis of the Pediatric Research Equity Act of 2003.

Appendix II: ReDecision Appendix II: Regulatory History and FDA
Decision-making Process for Baycol

                             Background and Summary

                                   Chronology

  June 1997

  January 1999

  May 1999

  December 1999

1The 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.

2The sponsor only marketed the 0.2 and 0.3 mg doses in the United States.

  June 2000

  July 2000

  November 2000

  April 2001

  May 2001

3The Division of Endocrine and Metabolic Drug Products is now called the
Division of Metabolism and Endocrinology Products.

4A 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.

  July 2001

  August 2001

5ODS'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.

Appendix III: RegDecision Appendix III: Regulatory History and FDA
Decision-making Process for Bextra

                             Background and Summary

                                   Chronology

  November 2001

  September 2002

1The 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.

2The Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug
Products is now called the Division of Anesthesia, Analgesia, and
Rheumatology Products.

  November 2002

  April 2003

  July 2003

3This 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.

  March 2004

  April 2004

  June 2004

4Used 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.

  August 2004

  October 2004

  December 2004

  February 2005

  April 2005

5A new warning regarding Bextra's cardiovascular risk was also added to
Bextra's label at this time.

6FDA 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.

Appendix IV: Regulatory History and FDA Decision-making Process for
Propulsid

                             Background and Summary

                                   Chronology

  July 1993

  January 1995

1The 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.

2Torsade de pointes is a type of serious cardiac arrhythmia.

3FDA now maintains adverse event reports in the Adverse Event Reporting
System (AERS).

  February 1995

  September 1995

  January 1996

  August 1996

4The division is now called the Division of Gastroenterology Products.

5Nizoral tablets, Sporanox capsules, Monistat IV, and Tao capsules were
contraindicated with Propulsid.

6A few reports and studies in the medical literature also suggested that
Propulsid may cause cardiac arrhythmias.

  June 1997

  August 1997

  September 1997

7Any use of a drug not described in the label is termed off-label use.

  October 1997

  November 1997

  December 1997

  May 1998

  June 1998

  July 1998

  November 1998

  May 1999

8Used 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.

9Unit-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.

  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).

  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.

Appendix V: Comments from the Food and Drug Administration Appendix V:
Comments from the Food and Drug Administration

Appendix VI: St Appendix VI: GAO Contact and Staff Acknowledgments

                                  GAO Contact

                                Acknowledgments

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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

March 2006

DRUG SAFETY

Improvement Needed in FDA's Postmarket Decision-making and Oversight
Process

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 decision-making 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, high-level 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.
*** End of document. ***