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Report to Congressional Requesters:

March 2006:

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

GAO-06-402:

GAO Highlights:

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: 

Why GAO Did This Study:

In 2004, several high-profile drug safety cases raised concerns about 
the Food and Drug Administrations (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 FDAs organizational structure and process for postmarket 
drug safety decision making, (2) assesses the effectiveness of FDAs 
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 Found:

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 ODSs role in the process are unclear, including 
ODSs participation in FDAs 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 FDAs 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. FDAs 
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 FDAs 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 ODSs role in certain scientific 
advisory committee meetings. FDAs 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. 

What GAO Recommends:

To improve the decision-making process for postmarket drug safety, GAO 
suggests that the Congress consider expanding FDAs 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 
ODSs role in scientific advisory committees. In its comments on a 
draft of this report, FDA stated that GAOs conclusions were 
reasonable. FDA did not comment on GAOs recommendations.

To view the full product, including the scope and methodology, click on 
the link above. For more information, contact Marcia Crosse, (202) 512-
7119, [Hyperlink crossem@gao.gov].

[End of Section]

Contents:

Letter:

Results in Brief:

Background:

Two Distinct FDA Units Involved in Postmarket Drug Safety Activities:

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

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

Conclusions:

Matter for Congressional Consideration:

Recommendations for Executive Action:

Agency Comments and Our Evaluation:

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

Background and Summary:

Chronology:

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

Background and Summary:

Chronology:

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

Background and Summary:

Chronology:

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

Background and Summary:

Chronology:

Appendix V: Comments from the Food and Drug Administration:

Appendix VI: GAO Contact and Staff Acknowledgments:

Figures:

Figure 1: FDA Organizational Structure for Postmarket Drug Safety:

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: 

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.[Footnote 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.[Footnote 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.[Footnote 3] Following passage of 
the Prescription Drug User Fee Act of 1992 (PDUFA),[Footnote 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.[Footnote 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,[Footnote 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,[Footnote 7] and 
making other organizational and policy process changes.

In light of the recent controversy about drug safety, you asked us to 
conduct a review of FDA's current organizational structure and 
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.[Footnote 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.[Footnote 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.

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.

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)[Footnote 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),[Footnote 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.[Footnote 12]

CDER, the largest of FDA's five centers, is the organizational entity 
within FDA that oversees the review of marketing applications for new 
drugs and the postmarket monitoring of drugs once they are 
marketed.[Footnote 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.[Footnote 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.[Footnote 15] ODS is a much smaller office than OND, with 
fiscal year 2005 expenditures of $26.9 million and 106 staff. In fiscal 
year 2005, $7.6 million of ODS's expenditures were from PDUFA funds. 
ODS staff evaluate and monitor drug risks and promote the safe use of 
drugs. While ODS is involved in both premarket and postmarket drug 
safety issues, its primary focus is on postmarket safety.

An important part of the drug approval and postmarket monitoring 
process is the advice FDA receives from 16 human-drug-related 
scientific advisory committees, composed of experts and consumer 
representatives from outside FDA.[Footnote 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.

Figure 1: FDA Organizational Structure for Postmarket Drug Safety:

[See PDF for image]

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.

[End of figure]

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.[Footnote 17] Adverse event 
reports become part of FDA's computerized database known as the Adverse 
Event Reporting System (AERS).[Footnote 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.[Footnote 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,[Footnote 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.

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.[Footnote 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.[Footnote 
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.[Footnote 
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.[Footnote 24]

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.

FDA estimates that 51 percent of OND's work time is devoted to drug 
safety, either premarket or postmarket.[Footnote 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.

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.[Footnote 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.[Footnote 27] Finally, 
safety evaluators and epidemiologists interact with international 
colleagues on drug safety issues.

ODS operates primarily in a consultant capacity to OND and does not 
have any independent decision-making responsibility. When there is a 
safety concern, ODS staff conduct an analysis and produce a written 
report for OND called a consult. Safety consults conducted by DDRE 
staff include analyses of adverse event reports and assessments of 
postmarket study designs and risk management plans.[Footnote 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;[Footnote 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.

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,[Footnote 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.

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.[Footnote 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.[Footnote 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.[Footnote 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.[Footnote 34]

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.

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.[Footnote 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.[Footnote 36] Similarly, after the 
diabetes drug Rezulin was removed from the market in 2000 because of 
its risk for liver toxicity, a CDER report focused on Rezulin also 
recommended that a consistent approach to postmarket drug safety be 
developed, including what regulatory actions should occur to address 
postmarket drug safety concerns, and when they should occur.

In addition to a lack of criteria for safety actions, we observed a 
lack of clarity related to ODS's recommendations. In practice, ODS 
often makes written recommendations about safety actions to OND but 
there is some confusion over this role, according to several ODS 
managers, and there is no policy that explicitly states whether ODS's 
role includes this responsibility. The case of Arava illustrates this 
confusion. In 2002, the OND review division responsible for Arava, a 
drug used to treat rheumatoid arthritis, requested that ODS review 
postmarket data for cases of serious liver toxicity associated with its 
use. The ODS staff who worked on this analysis recommended that Arava 
be withdrawn from the market because they concluded that the risk for 
serious liver toxicity exceeded its benefits. The OND Division Director 
responsible for Arava felt that ODS should not have included a 
recommendation in its consult because he argued that this was the 
responsibility of OND, not ODS. Some of the confusion may be the result 
of ODS's evolving role in postmarket drug safety. A current and a 
former ODS manager told us that in the past, ODS's safety consults were 
technical documents summarizing adverse events with minimal data 
analysis and few recommendations. Over time the consults have become 
more detailed with sophisticated data analyses and more recommendations 
about what safety action is needed (for example, label change, 
medication guide, drug withdrawal).

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.[Footnote 
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.[Footnote 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.[Footnote 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.[Footnote 40] In 
December 2004, ODS epidemiologists communicated to the CDER Director 
their position that ODS's role should include the responsibility of 
presenting all relevant ODS data at advisory committee meetings. 
According to an FDA official, there was no written response to this 
request. However, in our interviews, the Directors of CDER and OND told 
us that in retrospect they felt it was a mistake for FDA to have 
restricted the ODS epidemiologist from presenting his safety 
information at the meeting.

Several ODS managers that we interviewed told us that there is also a 
lack of clarity regarding the role of the epidemiologist in postmarket 
drug safety work. Despite the fact that ODS's epidemiologists have some 
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.[Footnote 41] For example, in 
that review some epidemiologists indicated that they should be able to 
maintain an independent approach to their research and the publication 
of their research. However, some OND review division directors 
indicated that the work of the epidemiologists should be considered 
within the context of CDER's overall regulatory mission. Further, the 
epidemiologists' research conclusions do not necessarily reflect the 
conclusions of FDA but may be perceived as such by the medical 
community. ODS managers indicated that a current challenge for FDA is 
to determine how it should use its epidemiologists and what their work 
products should be. According to the current ODS Director, efforts are 
needed to help OND better understand what epidemiologists can do. The 
epidemiologists themselves have asked for greater clarity about their 
role and a stronger voice in decision making.

A Lack of Communication and Limited Oversight Hinders the 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.

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,[Footnote 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.[Footnote 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.[Footnote 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.[Footnote 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 hyaluronidase[Footnote 46] with two local anesthetics in 
preparation for cataract surgery. Because local anesthetics can lead to 
cardiac events, the ODS safety evaluator who reviewed this case 
concluded that the causal role of hyaluronidase alone could not be 
established.

FDA may also use data from clinical trials and observational studies to 
support postmarket drug safety decisions, but each source has 
weaknesses that constrain the usefulness of the data provided. Clinical 
trials, in particular randomized clinical trials, are considered the 
"gold standard" for assessing evidence about efficacy and safety 
because they are considered the strongest method by which one can 
determine whether new drugs work.[Footnote 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.[Footnote 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.[Footnote 49]

Despite the weaknesses of clinical trials and observational studies, 
evidence from both types of studies helps inform FDA's postmarket drug 
safety decision-making process. For example, clinical trials conducted 
by drug sponsors for their own purposes sometimes provide information 
for FDA's evaluation of postmarket drug safety issues. For instance, 
drug sponsors sometimes conduct clinical trials for drugs already 
marketed in order to seek approval for a new or expanded use.[Footnote 
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.[Footnote 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.[Footnote 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.[Footnote 53]

FDA's access to postmarket clinical trial and observational data, 
however, is limited by its authority and available resources. As 
described previously, FDA does not have broad authority to require that 
a drug sponsor conduct an observational study or clinical trial for the 
purpose of investigating a specific postmarket safety concern. One 
senior FDA official and several outside drug safety experts told us 
that FDA needs greater authority to 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.

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.[Footnote 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.

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.[Footnote 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.[Footnote 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.[Footnote 
57]

According to an FDA policy document, the DSB will identify, track, and 
oversee the management of important drug safety issues. Important drug 
safety issues include serious side effects identified after a drug's 
approval that have the potential to significantly alter the drug's 
benefit-to-risk analysis or significantly affect physicians' 
prescribing decisions. According to an FDA official, ODS and OND submit 
monthly reports of safety issues for discussion by the DSB to be used 
in setting the agenda for the meetings. In addition, at any time 
individuals within and outside of FDA can submit issues to be 
considered by contacting a DSB member or the executive director. The 
FDA official said that the DSB will not be involved in the ongoing 
process of postmarket surveillance and decision making about drug 
safety issues, but rather will be involved with ensuring that broader 
safety issues--such as ongoing delays in changing a label--are 
effectively resolved. The DSB may also develop standards for certain 
kinds of safety-related actions, such as when a drug warrants a boxed 
warning or a medication guide.[Footnote 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.

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.[Footnote 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.[Footnote 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.[Footnote 
61] The process stops at the division level if a decision is reached 
that a major safety action is not needed.[Footnote 62] Otherwise, the 
recommendation is discussed at higher levels of management in CDER. An 
Office Action Meeting would then be held to recommend a course of 
action to the CDER director, although it is possible that there still 
could be disagreement at the office level. A final meeting, called the 
Decisional Meeting, would then be held to decide a course of action, 
and would include the CDER director as well as office-and division- 
level staff. It is not clear how the new DSB will be integrated into 
the draft policy on major postmarket drug safety decision making, and 
FDA officials told us they are still trying to determine how to do this.

Other initiatives may improve the decision-making process, but these 
efforts have not been fully implemented. For example, ODS has 
established a Process Improvement Team to assess the safety consult 
process, including how OND asks questions about postmarket safety 
concerns and how ODS should answer the questions. OND has established a 
similar team to assess the overall process for reviewing postmarket 
safety information, including the consult process. Both teams plan to 
make recommendations; for example, the OND representative chairing the 
OND team told us the OND team plans to recommend which office (OND or 
ODS) should have responsibility for certain postmarket tasks, such as 
reviewing periodic adverse event reports. According to the OND chair, 
the OND team expects to finalize its recommendations by the end of 
March 2006. According to the ODS Director, the ODS team's work was 
still in progress as of January 2006 and would not be completed for 
about 6 months. In February 2006, ODS established a new Process 
Improvement Team to identify best practices for safety evaluators in 
order to make sure there is standardization of their work (for example, 
reviewing of adverse event reports). The ODS Director estimated that 
the work of this team would be completed in 3 to 4 months.

FDA officials told us that they have proposed reorganizing CDER to 
dissolve OPaSS and have the director of ODS report to the CDER 
director. FDA plans to implement this reorganization in May 2006. In 
the meantime, ODS has taken some other steps to improve communication 
and oversight of safety issues. According to the ODS Director, the DDRE 
Director recently instituted regular meetings between the safety 
evaluators in his division and the OND review divisions in order to 
discuss drug safety issues, including ongoing consults, issues that 
DDRE staff have not yet provided consultation on, and how safety issues 
have been resolved. According to the DDRE Director, over half of OND's 
review divisions have participated in these regular meetings to date. 
The Director of ODS also acknowledged that ODS needs to have a better 
way to track safety issues as they are emerging. He told us that ODS is 
developing a tracking system that is currently being tested and is 
expected to become operational in 2006. The Director also said he had 
plans to build up the immediate office of ODS by adding an associate 
director of operations and staff responsible for working on 
relationships with other federal agencies (for example, National 
Institutes of Health) and contractors. He has decided to hold regular 
meetings with the ODS deputy director and division directors for the 
specific purpose of discussing the status of drug safety problems.

Despite the efforts that FDA has made to improve its postmarket drug 
safety decision-making process, the role of ODS in advisory committee 
meetings (other than DSaRM) has not been clarified. The role of ODS in 
scientific advisory committee meetings is not discussed in the draft 
policy on major postmarket drug safety decisions or in other policy 
documents. In addition, according to the ODS Director, the role of 
epidemiologists in ODS requires further clarification. A Process 
Improvement Team that was formed to address this issue was suspended, 
and the ODS Director said that other ways to approach this issue are 
being evaluated.

Dispute Resolution Processes Have Not Been Used:

The DSB and a pilot program have not been used as of February 2006 to 
help resolve organizational and individual disagreements that occur 
within CDER over safety decisions and may not be viewed as sufficiently 
independent. According to an FDA policy document, the DSB will resolve 
organizational disputes over approaches to drug safety. According to an 
FDA official, as of February 2006, however, the DSB had not handled any 
such formal disputes. An FDA official told us that, as an example, ODS 
might believe that a drug should come off the market but OND does not 
agree, and resolving this matter could be handled by the DSB. Although 
DSB members who were involved with a drug product's approval or safety 
review will be recused from the DSB's decision-making process 
concerning that drug, the current DSB membership includes CDER managers 
who oversee the drug approval and safety review processes, which may 
limit the ability of the DSB to provide neutral, independent advice in 
the handling of organizational disputes. In addition, decisions made by 
the DSB will serve as recommendations to the CDER director, 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,[Footnote 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.[Footnote 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.[Footnote 
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.

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 
information[Footnote 66] from other organizations about their active 
surveillance programs[Footnote 67] 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.

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:

* establish a mechanism for systematically tracking ODS's 
recommendations and subsequent safety actions;

* with input from the DSB and the Process Improvement Teams, revise and 
implement the draft policy on major postmarket drug safety decisions;

* improve CDER's dispute resolution process by revising the pilot 
program to increase its independence; and:

* clarify ODS's role in FDA's scientific advisory committee meetings 
involving postmarket drug safety issues.

Agency Comments and Our Evaluation:

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 crossem@gao.gov. Contact points for our 
Offices of Congressional Relations and Public Affairs may be found on 
the last page of this report. GAO staff who made major contributions to 
this report are listed in appendix VI.

Signed By:

Marcia Crosse:
Director, Health Care:

[End of section]

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

Background and Summary:

Arava was approved for marketing in 1998. Arava is indicated in adults 
for the treatment of active rheumatoid arthritis to reduce the signs 
and symptoms of the disease, slow down damage to joints, and improve 
physical function. Arava has been associated with cases of serious 
liver injury, some of which have been fatal.

In this case, the Office of Drug Safety (ODS)[Footnote 68] 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.

Chronology:

September 1998:

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.

March 2001:

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 Products[Footnote 69] 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.

March 2002:

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.

August 2002:

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.

October 2002:

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.

November 2002:

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 benefits[Footnote 70] 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.

December 2002:

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.

March 2003:

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,[Footnote 71] 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.

June 2003:

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.

October 2003:

The sponsor issued a Dear Healthcare Professional letter explaining the 
labeling changes approved in June 2003.

March 2004:

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.[Footnote 72]

FDA sent a letter to Public Citizen denying its request to remove Arava 
from the U.S. market.

[End of section]

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

Background and Summary:

Baycol was approved for marketing in 1997. Baycol is a member of the 
class of drugs known as statins that lower cholesterol levels in the 
body. Baycol was associated with rhabdomyolysis, a severe adverse 
reaction involving the breakdown of muscle fibers, which can lead to 
death.

In this case, the Office of Drug Safety (ODS) and the Office of New 
Drugs (OND) agreed from the outset (spring 2001) that adverse event 
reports received for high-dose Baycol were alarming.[Footnote 73] 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.

Chronology:

June 1997:

FDA approved Baycol for marketing (doses up to 0.3 mg).[Footnote 74] 
The original label stated that rhabdomyolysis had been reported with 
the use of other statins.

January 1999:

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.

May 1999:

FDA approved the 0.4 mg dose of Baycol.

December 1999:

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.

June 2000:

At the request of OND's Division of Endocrine and Metabolic Drug 
Products,[Footnote 75] 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.

July 2000:

FDA approved the 0.8 mg dose of Baycol.

November 2000:

FDA approved the addition of a patient package insert for 
Baycol.[Footnote 76]

April 2001:

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.

May 2001:

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.

July 2001:

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.[Footnote 
77]

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.

August 2001:

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.

[End of section]

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

Background and Summary:

Bextra was approved for marketing in 2001. Bextra was part of the class 
of drugs known as the COX-2 selective nonsteroidal anti-inflammatory 
drugs (NSAID). Bextra was approved to relieve the symptoms of 
osteoarthritis and rheumatoid arthritis in adults, and to relieve 
painful menstrual cycles. Bextra was associated with serious, 
potentially fatal skin reactions, including Stevens-Johnson Syndrome 
and toxic epidermal necrolysis. Bextra was also later associated with 
an increased risk of serious cardiovascular events, similar to the 
other approved COX-2 drugs.

In this case, after the Office of Drug Safety (ODS)[Footnote 78] 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.

Chronology:

November 2001:

FDA approved Bextra for marketing.

September 2002:

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,[Footnote 79] 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.

November 2002:

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.

April 2003:

The Division of Pediatrics and Therapeutics[Footnote 80] 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.

July 2003:

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.

March 2004:

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,[Footnote 81] 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.

April 2004:

Bextra's label was changed to include the statement that fatalities due 
to serious skin reaction had been reported.

June 2004:

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.

August 2004:

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.

October 2004:

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.

December 2004:

FDA announced that Bextra would carry a boxed warning for serious skin 
reactions.[Footnote 82] The sponsor also issued a Dear Healthcare 
Professional letter explaining these changes.

February 2005:

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.

April 2005:

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.[Footnote 83] 
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.

[End of section]

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

Background and Summary:

Propulsid was approved for marketing in 1993. Propulsid was indicated 
for use in adults for the symptomatic relief of nighttime heartburn due 
to gastroesophageal reflux disease. Propulsid was associated with 
serious cardiac arrhythmias, including reports of death, and most of 
these adverse events occurred in patients who were taking other 
medications or suffering from underlying conditions known to increase 
the risk of cardiac arrhythmia.

In this case there was general agreement about the safety concern 
between the Office of New Drugs (OND) and the Office of Drug Safety 
(ODS),[Footnote 84] 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.

Chronology:

July 1993:

FDA approved Propulsid for marketing in tablet form.

January 1995:

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 pointes[Footnote 85] in FDA's 
MedWatch Spontaneous Reporting System (SRS)[Footnote 86] and identified 
potential risk factors, including cardiac history and the concomitant 
use of several other drugs. OND's Division of Gastrointestinal and 
Coagulation Drug Products[Footnote 87] agreed with ODS that this was a 
safety concern.

February 1995:

Propulsid's label was revised to state that it was contraindicated with 
certain other drugs[Footnote 88] 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.

September 1995:

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.

January 1996:

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.[Footnote 89] 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.

August 1996:

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.

June 1997:

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.

August 1997:

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.

September 1997:

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.[Footnote 
90] 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.

October 1997:

An ODS safety evaluator reported that there were additional cases of 
serious, cardiovascular adverse events among children who were 
prescribed Propulsid.

November 1997:

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.

December 1997:

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.

May 1998:

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.

June 1998:

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.

July 1998:

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.

November 1998:

FDA implemented a medication guide[Footnote 91] and unit-dose 
packaging[Footnote 92] for Propulsid.

May 1999:

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.[Footnote 93]

June 1999:

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.

November 1999:

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.

January 2000:

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.

March 2000:

FDA announced that the sponsor would withdraw Propulsid from the U.S. 
market as of July 14, 2000. FDA also announced that its scheduled 
public advisory committee meeting was cancelled.

April 2000:

The sponsor announced that it would make Propulsid available to certain 
patients through an investigational limited-access program, approved by 
FDA.

March 2002:

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.

[End of section]

Appendix V: Comments from the Food and Drug Administration:

Department Of Health & Human Services:

Food and Drug Administration: 
Rockville MD 20857:

March 14 2006:

Marcia Crosse: 
Director, Health Care: 
U.S. Government Accountability Office: Washington, DC 20548:

Dear Ms. Crosse:

Enclosed are the Food and Drug Administration's (FDA) comments on the 
U.S. Government Accountability Office's draft report entitled, "DRUG 
SAFETY: Improvement Needed in FDA's Postmarket Decision-Making and 
Oversight Process" (GAO-06-402). These comments represent the tentative 
position of the agency and are subject to reevaluation when the final 
version of this report is received.

FDA appreciates the opportunity to comment on this draft report before 
its publication.

Sincerely,

Signed By:

Andrew C. von Eschenbach, M.D.
Acting Commissioner of Food and Drugs:

Enclosure:

Comments by CDER on the Government Accountability Office's (GAO) Draft 
Report, DRUG SAFETY: Improvement Needed in FDA's Postmarket Decision- 
Making and Oversight Process (GAO-06-402):

Introduction:

The Center for Drug Evaluation and Research (CDER) appreciates the 
opportunity to comment on GAO's draft report which focuses on 
postmarketing drug safety issues. This document has two sections: 
general comments about topics discussed in the document and specific 
comments related to items of fact in the report.

Overall, CDER believes that the report is well done and that the 
conclusions reached are reasonable and consistent with actions we 
already have underway or planned. In particular, CDER has several 
initiatives that are discussed in the GAO report and are in the process 
of being implemented. These initiatives are aimed at strengthening the 
management of identified safety issues to assure that the decisions are 
made promptly, and are based on all of the relevant expertise in CDER, 
including the staff in the Office of New Drugs (OND) and the Office of 
Drug Safety (ODS).

General Comments by CDER on the Government Accountability Office's 
(GAO) Draft Report, DRUG SAFETY: Improvement Needed in FDA's Postmarket 
Decision-Making and Oversight Process (GAO-06-402):

Complexity of Decisionmaking and Quality of Data:

Throughout the report, GAO makes statements that appear critical of 
CDER's drug safety processes, implying that they are too complex and 
the data on which they rest are sometimes unreliable. For example, GAO 
states that the decision-making process for postmarket drug safety is 
complex, and is limited by a lack of clarity, insufficient oversight by 
management, and data constraints. CDER believes that the evaluation of 
drug safety (i.e., determining whether a drug is likely to have caused 
an event and how often that occurs), and then weighing that against a 
drug's value is intrinsically complex. This complex balancing of risks 
and benefits, based upon whatever data are available, is the task CDER 
is required to perform every day. This cannot be changed, and CDER 
should not be criticized for the task it faces. Although there is no 
single formula for how best to make such important determinations, as 
GAO recognizes in the report, CDER is working to improve its processes 
for addressing these complex issues.

Role of PDUFA Goals in the Drug Review Process:

The GAO refers to OND's work and its pace being driven by PDUFA goals. 
We believe that this is a bit misleading and should be changed to state 
that OND's work and its pace are driven "in part" by PDUFA goals. OND 
has other statutory and regulatory drivers of their work, as well as a 
mission to protect the public health, which all of the staff in OND 
take very seriously.

In addition, this section of your report focuses on ODS' role in 
postmarket drug safety. ODS is also active in premarket safety review. 
For example, OND and ODS are required to meet to discuss drug safety 
before each new drug is approved. The purpose of the meeting is to 
discuss the safety database at the time of each drug's approval and 
facilitate postmarketing safety assessment. In addition, ODS is 
involved throughout the premarket review when there are specific safety 
issues, risk management issues, and risk management programs under 
consideration. For example, ODS was involved in the premarket reviews 
of Bosentan, Revlimid, Palladone, and Exubera.

When ODS' work occurs during the premarket period, ODS works with OND 
to meet the PDUFA goals. The goals, therefore, apply when ODS is 
reviewing a risk management plan for a drug yet to be approved, as 
illustrated by the examples above.

Role of ODS and OND in Drug Safety:

Throughout, the report refers to the ODS as a "consultant to OND." This 
understates the importance and value that ODS adds in evaluating drug 
safety issues. CDER considers ODS and OND to be co-equal partners in 
the identification and timely resolution of drug safety issues. One 
goal of the processes that CDER is putting into place around drug 
safety (processes you summarize in your document) is to foster that 
partnership.

Role of the Drug Safety Oversight Board (DSB) in Drug Safety:

CDER agrees with many of the comments about the potential impact of the 
DSB on the management of postmarketing safety issues, including 
standard setting. The DSB has reviewed current mechanisms CDER has for 
identifying drug safety concerns and discussed ways to enhance tracking 
of safety by CDER. Because the DSB membership includes balanced 
representation from OND and ODS leadership, these discussions can 
facilitate the implementation of CDER-wide actions on safety.

Role of ODS and OND in Advisory Committee Meetings:

The report recommends that the ODS role in Advisory Committee meetings 
be `clarified'. For instance, it states that ODS sets the agenda for 
the Drug Safety and Risk Management Advisory Committee (DSaRM) meetings 
and OND sets the agenda for all other scientific advisory committee 
meetings. In many cases, however, ODS and other groups in CDER are 
actively involved in the setting of the agendas for meetings of other 
committees besides DSaRM. For example, FDA's Office of Pediatric 
Therapeutics sets the agenda for the Pediatric Advisory Committee with 
OND and ODS input. The agenda for the Peripheral and Central Nervous 
System Drugs Advisory Committee meeting for Tysabri (natalizumab), and 
the presentations by both OND and ODS reflected the partnership between 
OND and ODS, despite the fact that this meeting was not a joint meeting 
with DSaRM. The reality is that when safety issues arise in CDER today 
where ODS expertise is important, they are included in the planning of 
Advisory Committee meetings.

The GAO report also includes two cases where OND and ODS did not agree 
on what ODS should present to the advisory committee. It is implied 
that such disagreements occur frequently, but this is not, in fact, the 
case. When appropriate, ODS staff present their postmarketing safety 
reviews at advisory committee meetings organized by OND (see the 
example cited above for Tysabri). ODS also presented at a recent 
Peripheral and Central Nervous System Drugs Advisory Committee meeting 
on August 4, 2005, that discussed the NDA for MT 100 (naproxen sodium 
and meteclopramide hydrochloride) for the acute treatment of migraine 
headache with or without aura. In the vast majority of cases, OND and 
ODS work cooperatively on advisory committee presentations, regardless 
of who organized the meeting.

Arava Case Study:

There is additional information regarding Arava that was not reflected 
in GAO's case study. In two meetings attended by approximately 20 
people from OND and ODS, there was a wide-ranging discussion of the 
postmarketing cases of liver injury, with a full opportunity for 
discussion by all participants. ODS' concerns were taken very 
seriously, and in the end the consensus of the group was that the 
reports were unconvincing and represented at most a few drug-related 
injuries. These conclusions were also supported by the Advisory 
Committee and outside experts. This case study is one example of how 
the process in CDER can work to achieve consensus around a complicated 
safety issue.

[End of Section]

Appendix VI: GAO Contact and Staff Acknowledgments:

GAO Contact:

Marcia Crosse, (202) 512-7119 or[Hyperlink crossem@gao.gov]:

Acknowledgments:

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.

(290431):

[End of Section]

FOOTNOTES:

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

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

[3] See, for example, National Research Council, Report of the 
International Conference of Adverse Reactions Reporting Systems 
(Washington, D.C.: National Academies of Science, 1971); FDA, Program 
Review of the Division of Epidemiology and Surveillance (DES) in the 
Office of Epidemiology and Biometrics (OEB) (Washington, D.C.: 1993); 
HHS, Office of Inspector General, Review of the Food and Drug 
Administration's Handling of Adverse Drug Reaction Reports (Washington, 
D.C.: 1999). In November 2004, FDA announced that it would contract 
with the Institute of Medicine to evaluate the current drug safety 
system. This study is currently in progress.

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

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

[6] In an effort to address drug risks, FDA works with industry to 
develop risk management plans and postapproval risk management studies. 
Risk management plans may include labeling, targeted education and 
outreach such as medication guides and training programs, reminder 
systems such as consent forms and special data collection systems, and 
performance-linked access systems such as restricted distribution and 
limited prescribing or dispensing.

[7] In March 2005, FDA issued three guidance documents for industry: 
HHS, FDA, Guidance for Industry: Premarketing Risk Assessment; Guidance 
for Industry: Development and Use of Risk Minimization Action Plans; 
and Guidance for Industry: Good Pharmacovigilance Practices and 
Pharmacoepidemiologic Assessment (Rockville, Md.: 2005).

[8] FDA approved Arava to treat arthritis; Baycol to treat high 
cholesterol; Propulsid to treat nighttime heartburn; and Bextra to 
relieve pain. Baycol, Bextra, and Propulsid have since been withdrawn 
from the market (in August 2001, April 2005, and March 2000, 
respectively), and the warnings on Arava's label were strengthened 
(most recently in March 2004). In this report we also refer to other 
drugs that had safety issues for purposes of illustration, but they 
were not part of our case studies.

[9] FDA verified the major postmarket regulatory actions we identified 
for each drug. ODS and OND staff also told us which internal meetings 
were significant in the decision-making process. 

[10] Adverse event is the technical term used by FDA to refer to any 
untoward medical event associated with the use of a drug in humans.

[11] Observational 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.

[12] The 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.

[13] CDER 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.

[14] Other 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. 

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

[16] These committees are either mandated by legislation or are 
established at the discretion of HHS. 

[17] MedWatch 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). 

[18] FDA 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.

[19] 21 U.S.C.  355(e). FDA may propose withdrawal when, for example, 
it determines through experience, tests, or other data that a drug is 
unsafe under the conditions of use approved in its application, there 
is a lack of substantial evidence that the drug will have the effect 
that it purports to have or that is suggested in its labeling, or 
required patent information is not timely filed. Prior to withdrawal, 
FDA would need to notify the affected parties and provide an 
opportunity for a hearing. Approval may be suspended immediately, prior 
to a hearing, if the Secretary of Health and Human Services finds that 
continued marketing of a particular drug constitutes an imminent hazard 
to the public health. FDA used this authority once, to withdraw the 
drug phenformin from the market in 1977. Phenformin was used to treat 
diabetes and was associated with a life-threatening buildup of lactic 
acid in the blood.

[20] The labeling of a drug can be changed, for example, by adding 
information to the "Warnings Section."

[21] 21 C.F.R.  314.510 (2005).

[22] 21 C.F.R.  314.610(b)(1) (2005).

[23] 21 C.F.R.  314.530(a)(1)-(3); 21 C.F.R.  314.620(a)(1)-(3) 
(2005).

[24] According to the Pediatric Research Equity Act of 2003, FDA may 
require drug manufacturers to develop information regarding the safety, 
effectiveness, dosing, and administration of marketed drugs if (1) the 
drug is used by a substantial number of pediatric patients for the 
labeled indications, and the absence of adequate labeling could pose 
significant risks to pediatric patients; or (2) the drug would 
represent a meaningful therapeutic benefit over existing therapies for 
pediatric patients for claimed indications, and the absence of adequate 
labeling could pose significant risks to pediatric patients. 21 U.S.C. 
 355c. This authority may be used only after FDA has been unsuccessful 
in obtaining necessary pediatric information under other authority. 
These studies have resulted in new pediatric labels with important 
dosing or safety information.

[25] Theresa 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).

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

[27] For 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).

[28] In 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.

[29] ODS 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.

[30] This 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.

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

[32] A 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. 

[33] In 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.

[34] The OND and OPaSS Directors posted a memorandum on FDA's Web site 
explaining this decision.

[35] Subsequent 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. 

[36] One staff member noted that the numerous labeling changes made it 
increasingly difficult to use Propulsid as labeled because of the 
numerous contraindications. 

[37] The 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.

[38] Similarly, other senior-level CDER staff, including ODS and OND 
managers, did not agree with the ODS staff's conclusions and 
recommendation. 

[39] Specifically, 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. 

[40] In 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. 

[41] FDA, Program Review of the Division of Epidemiology and 
Surveillance (DES) in the Office of Epidemiology and Biometrics (OEB), 
(Washington, D.C.: 1993). 

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

[43] This 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.

[44] AERS 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. 

[45] The 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.

[46] This drug promotes the dispersion of other drugs, for example, 
speeding the onset of action for an anesthetic.

[47] In 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. 

[48] FDA 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).

[49] The 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.

[50] In 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.

[51] This 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. 

[52] A 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.

[53] 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).

[54] Postmarket 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). 

[55] See 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).

[56] According 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.

[57] FDA also makes information publicly available concerning certain 
emerging safety information through its Web page, which reflects the 
input of the DSB.

[58] Used 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.

[59] According 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. 

[60] ODS 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.

[61] This 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.

[62] Management 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.

[63] Created 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.

[64] See H.R. Conf. Rep. No. 109-255, at 100 (2005) (accompanying H.R. 
2744). 

[65] The conferees directed FDA to report to the Appropriations 
Committees on its proposed use of the funds. The report is currently 
under review within FDA. 

[66] Department 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,[Hyperlink http:// 
www.fbo.gov/servlet/Documents/R/1154711] (downloaded February 27, 
2006). 

[67] Active 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.

[68] The names of the postmarket safety and new drug offices changed 
during the time period studied. For the sake of clarity and consistency 
we used ODS and OND--the current names--when referring to these 
offices. 

[69] This division is now called the Division of Anesthesia, Analgesia, 
and Rheumatology Products.

[70] This conclusion was based on an analysis of Adverse Event 
Reporting System (AERS) reports, the usage of Arava in the population, 
and a review of the literature and efficacy from preapproval clinical 
trials. 

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

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

[73] The names of the postmarket safety and new drug offices changed 
during the time period studied. For the sake of clarity and consistency 
we used ODS and OND--the current names--when referring to these offices.

[74] The sponsor only marketed the 0.2 and 0.3 mg doses in the United 
States.

[75] The Division of Endocrine and Metabolic Drug Products is now 
called the Division of Metabolism and Endocrinology Products. 

[76] A patient package insert is an additional part of the professional 
labeling of a drug that provides important information to the consumer 
and may be distributed to patients when the drug is dispensed. It is 
required for a few drugs, such as oral contraceptives, and voluntary 
for other drugs.

[77] ODS's analysis was finalized on August 17, 2001. It did not 
contain a recommendation for regulatory action. The safety review 
included a critique of two epidemiologic studies that the sponsor 
conducted to examine the risk of myopathy (for example, muscle aching 
or muscle weakness) subsequent to statin use in a managed care 
organization, using its automated claims data. The ODS staff who wrote 
the consult concluded that the studies did not alleviate the concerns 
raised by the spontaneous report data. The Acting Division Director of 
ODS who reviewed the consult concurred with the review. 

[78] The names of the postmarket safety and new drug offices changed 
during the time period studied. for the sake of clarity and consistency 
we used ODS and OND-the current names-when referring to these offices.

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

[80] This division is now called the Division of Pediatric Drug 
Development and is located within CDER's Office of Counter-Terrorism 
and Pediatric Drug Development. This division has responsibility for 
determining what kinds of pediatric studies are needed to develop 
information about certain marketed drugs, such as the appropriate 
dosing for pediatric use.

[81] Used primarily for outpatient drugs that have serious safety 
concerns, medication guides are required to be dispensed with each 
prescription. They contain information specifically for the patient, 
such as the most important information the patient should know about a 
drug. 

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

[83] FDA posted a memo on its Web site, written by the Directors of OND 
and OPaSS, explaining why FDA decided to ask Bextra's sponsor to 
withdraw the drug from the market.

[84] The names of the postmarket safety and new drug offices changed 
during the time period studied. For the sake of clarity and consistency 
we used ODS and OND--the current names--when referring to these offices.

[85] Torsade de pointes is a type of serious cardiac arrhythmia.

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

[87] The division is now called the Division of Gastroenterology 
Products.

[88] Nizoral tablets, Sporanox capsules, Monistat IV, and Tao capsules 
were contraindicated with Propulsid. 

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

[90] Any use of a drug not described in the label is termed off-label 
use. 

[91] Used primarily for outpatient drugs that have serious safety 
concerns, medication guides are required to be dispensed with each 
prescription. They contain information specifically for the patient, 
such as the most important information the patient should know about a 
drug. 

[92] Unit-dose packaging includes a single dose, individually packaged 
and labeled. According to an FDA official, this type of packaging is 
believed to help prevent medication errors.

[93] The 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). 

[94] In April 2000, the sponsor announced that it would make Propulsid 
available to patients who met specific eligibility criteria through an 
investigational limited-access program.

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