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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 Administration’s (FDA) ability to manage postmarket
drug safety issues. In some cases there have been disagreements within
FDA about how to address safety issues. In this report GAO (1)
describes FDA’s organizational structure and process for postmarket
drug safety decision making, (2) assesses the effectiveness of FDA’s
postmarket drug safety decision-making process, and (3) assesses the
steps FDA is taking to improve postmarket drug safety decision making.
GAO conducted an organizational review and case studies of four drugs
with safety issues: Arava, Baycol, Bextra, and Propulsid.
What GAO 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 ODS’s role in the process are unclear, including
ODS’s participation in FDA’s scientific advisory committee meetings
organized by OND. Insufficient communication between ODS and OND has
been an ongoing concern and has hindered the decision-making process.
ODS does not track information about ongoing postmarket safety issues,
including the recommendations that ODS staff make for safety actions.
FDA faces data constraints in making postmarket safety decisions. There
are weaknesses in the different types of data available to FDA, and FDA
lacks authority to require certain studies and has resource limitations
for obtaining data.
Some of FDA’s initiatives, such as the establishment of a Drug Safety
Oversight Board, a draft policy on major postmarket decision making,
and the identification of new data sources, may improve the postmarket
safety decision-making process, but will not address all gaps. FDA’s
newly created Drug Safety Oversight Board may help provide oversight of
important, high-level safety decisions, but it does not address the
lack of systematic tracking of ongoing safety issues. Other
initiatives, such as FDA’s draft policy on major postmarket decisions
and regular meetings between OND divisions and ODS, may help improve
the clarity and effectiveness of the process, but they are not fully
implemented. FDA has not clarified ODS’s role in certain scientific
advisory committee meetings. FDA’s dispute resolution processes for
disagreements about postmarket safety decisions have not been used. FDA
is taking steps to identify additional data sources, but data
constraints remain.
What GAO Recommends:
To improve the decision-making process for postmarket drug safety, GAO
suggests that the Congress consider expanding FDA’s authority to
require drug sponsors to conduct postmarket studies when needed. GAO
also recommends that FDA systematically track postmarket drug safety
issues, revise and implement its draft policy on major postmarket
safety decisions, improve the dispute resolution process, and clarify
ODS’s role in scientific advisory committees. In its comments on a
draft of this report, FDA stated that GAO’s conclusions were
reasonable. FDA did not comment on GAO’s recommendations.
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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