Drug Safety
FDA Needs to Further Address Shortcomings in Its Postmarket Decision-making Process Gao ID: GAO-07-599T March 22, 2007GAO was asked to testify on the effectiveness of the Food and Drug Administration's (FDA) postmarket decision-making process. This testimony is based on Drug Safety: Improvement Needed in FDA's Postmarket Decision-making and Oversight Process, GAO-06-402 (March 31, 2006). The report focused on the complex interaction between two offices within FDA that are involved in postmarket drug safety activities: the Office of New Drugs (OND), and the Office of Drug Safety (ODS). OND's primary responsibility is to review new drug applications, but it is also involved in monitoring the safety of marketed drugs. ODS is focused primarily on postmarket drug safety issues. ODS is now called the Office of Surveillance and Epidemiology. For its report, GAO reviewed FDA policies, interviewed FDA staff, and conducted case studies of four drugs with safety issues: Arava, Baycol, Bextra, and Propulsid. To gather information on FDA's initiatives since March 2006 to improve its decision-making process for this testimony, GAO interviewed FDA officials and reviewed FDA documents in February and March 2007.
In its March 2006 report, GAO found that FDA lacked clear and effective processes for making decisions about, and providing management oversight of, postmarket drug safety issues. There was a lack of clarity about how decisions were made and about organizational roles, insufficient oversight by management, and data constraints. GAO observed that there was 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 were unclear, including ODS's participation in the meetings of scientific advisory committees organized by OND to discuss safety issues for specific drugs. In the case of Arava, for example, ODS staff were not allowed to present their analysis of postmarket safety at an advisory committee meeting held to review Arava's safety risks and benefits. Insufficient communication between ODS and OND hindered the decision-making process. ODS management did not systematically track information about ongoing postmarket safety issues, including the recommendations that ODS staff made for safety actions. GAO also found that FDA faced data constraints that contributed to the difficulty in making postmarket safety decisions. GAO found that there were weaknesses in the different types of data available to FDA, and FDA's access to data was constrained by both its authority to require certain studies and its limited resources. During the course of GAO's work for its March 2006 report, FDA began a variety of initiatives to improve its postmarket drug safety decision-making process, including the establishment of the Drug Safety Oversight Board. FDA also commissioned the Institute of Medicine to examine the drug safety system, including FDA's oversight of postmarket drug safety. GAO recommended in its March 2006 report that FDA take four steps to improve its decision-making process for postmarket safety. GAO recommended that FDA revise and implement its draft policy on the decision-making process for major postmarket safety actions, improve its process to resolve disagreements over safety decisions, clarify ODS's role in scientific advisory committees, and systematically track postmarket drug safety issues. FDA has initiatives underway and under consideration that, if implemented, could address three of GAO's four recommendations. Because none of these initiatives was fully implemented as of March 2007, it was too early to evaluate their effectiveness. In the 2006 report GAO also suggested that Congress consider expanding FDA's authority to require drug sponsors to conduct postmarket studies, as needed, to collect additional data on drug safety concerns.
GAO-07-599T, Drug Safety: FDA Needs to Further Address Shortcomings in Its Postmarket Decision-making Process
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Testimony:
Before the Subcommittee on Oversight and Investigations, Committee on
Energy and Commerce, House of Representatives:
United States Government Accountability Office:
GAO:
For Release on Delivery Expected at 9:30 a.m. EDT:
March 22, 2007:
Drug Safety:
FDA Needs to Further Address Shortcomings in Its Postmarket Decision-
making Process:
Statement of Marcia Crosse:
Director, Health Care:
GAO-07-599T:
GAO Highlights:
Highlights of GAO-07-599T, a testimony before the Subcommittee on
Oversight and Investigations, 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 were disagreements within FDA
about how to address these issues.
GAO was asked to testify on the effectiveness of FDA‘s postmarket
decision-making process. This testimony is based on Drug Safety:
Improvement Needed in FDA‘s Postmarket Decision-making and Oversight
Process, GAO-06-402 (March 31, 2006). The report focused on the complex
interaction between two offices within FDA that are involved in
postmarket drug safety activities: the Office of New Drugs (OND), and
the Office of Drug Safety (ODS). OND‘s primary responsibility is to
review new drug applications, but it is also involved in monitoring the
safety of marketed drugs. ODS is focused primarily on postmarket drug
safety issues. ODS is now called the Office of Surveillance and
Epidemiology.
For its report, GAO reviewed FDA policies, interviewed FDA staff, and
conducted case studies of four drugs with safety issues: Arava, Baycol,
Bextra, and Propulsid. To gather information on FDA‘s initiatives since
March 2006 to improve its decision-making process for this testimony,
GAO interviewed FDA officials and reviewed FDA documents in February
and March 2007.
What GAO Found:
In its March 2006 report, GAO found that FDA lacked clear and effective
processes for making decisions about, and providing management
oversight of, postmarket drug safety issues. There was a lack of
clarity about how decisions were made and about organizational roles,
insufficient oversight by management, and data constraints. GAO
observed that there was 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 were unclear, including ODS‘s participation in the meetings
of scientific advisory committees organized by OND to discuss safety
issues for specific drugs. In the case of Arava, for example, ODS staff
were not allowed to present their analysis of postmarket safety at an
advisory committee meeting held to review Arava‘s safety risks and
benefits. Insufficient communication between ODS and OND hindered the
decision-making process. ODS management did not systematically track
information about ongoing postmarket safety issues, including the
recommendations that ODS staff made for safety actions. GAO also found
that FDA faced data constraints that contributed to the difficulty in
making postmarket safety decisions. GAO found that there were
weaknesses in the different types of data available to FDA, and FDA‘s
access to data was constrained by both its authority to require certain
studies and its limited resources.
During the course of GAO‘s work for its March 2006 report, FDA began a
variety of initiatives to improve its postmarket drug safety decision-
making process, including the establishment of the Drug Safety
Oversight Board. FDA also commissioned the Institute of Medicine to
examine the drug safety system, including FDA‘s oversight of postmarket
drug safety. GAO recommended in its March 2006 report that FDA take
four steps to improve its decision-making process for postmarket
safety. GAO recommended that FDA revise and implement its draft policy
on the decision-making process for major postmarket safety actions,
improve its process to resolve disagreements over safety decisions,
clarify ODS‘s role in scientific advisory committees, and
systematically track postmarket drug safety issues. FDA has initiatives
underway and under consideration that, if implemented, could address
three of GAO‘s four recommendations. Because none of these initiatives
was fully implemented as of March 2007, it was too early to evaluate
their effectiveness. In the 2006 report GAO also suggested that
Congress consider expanding FDA‘s authority to require drug sponsors to
conduct postmarket studies, as needed, to collect additional data on
drug safety concerns.
[Hyperlink, http://www.gao.gov/cgi-bin/getrpt?GAO-07-599T].
To view the full product, including the scope and methodology, click on
the link above. For more information, contact Marcia Crosse, (202) 512-
7119, crossem@gao.gov.
[End of section]
Mr. Chairman and Members of the Subcommittee,
I am pleased to be here today as you examine the Food and Drug
Administration's (FDA) process for decision making regarding postmarket
drug safety issues. In 2004, several high-profile drug safety cases
raised concerns about FDA's ability to manage postmarket drug safety
issues. Those cases showed that there were disagreements and potential
delays within FDA about how to address serious safety problems. My
remarks today are based on GAO's March 2006 report on FDA's postmarket
decision-making process (Drug Safety: Improvement Needed in FDA's
Postmarket Decision-making and Oversight Process, GAO-06-402). I will
also discuss a number of FDA initiatives to improve its decision-making
process, including some that respond to the recommendations we made in
that report.[Footnote 1]
In carrying out the work for our report between December 2004 and March
2006, we 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).[Footnote 2] While there is some overlap in the activities of OND
and ODS, 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 ultimate responsibility to
take regulatory action concerning the postmarket safety of drugs. ODS
is primarily focused on postmarket drug safety, which includes the
review of reports of adverse reactions to drugs. ODS operates primarily
in a consultant capacity to OND and does not have any independent
decision-making responsibility.
For our report, we interviewed ODS, OND, and other CDER managers and
staff, as well as drug safety experts from outside FDA. We also
analyzed documents describing internal FDA policies and procedures. 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 decision-making
process.[Footnote 3] 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 each drug, the safety actions taken, and the
OND and ODS staff involved. To follow up with FDA about its responses
to our recommendations and its initiatives to improve its postmarket
safety decision-making process, we interviewed four FDA managers,
including CDER's Associate Director for Safety Policy and
Communication, in February and March 2007. We did not evaluate the
effectiveness of FDA's efforts to respond to our recommendations. All
of our work was conducted in accordance with generally accepted
government auditing standards.
In summary, we found that FDA lacked a clear and effective process for
making decisions about, and providing management oversight of,
postmarket drug safety issues. There was a lack of clarity about how
decisions were made and about organizational roles, insufficient
oversight by management, and data constraints. We observed that there
was a lack of criteria for determining what safety actions to take and
when to take them, which likely contributed to disagreements over
decisions about postmarket safety. Certain parts of ODS's role in the
process were unclear, including ODS's participation in scientific
advisory committee meetings that were organized by OND to discuss
specific drugs. Although ODS staff presented their analyses during some
of these meetings, we found examples of the exclusion of ODS staff from
making presentations at several meetings. For example, in 2003 ODS
staff, who had recommended that Arava be removed from the market, were
not allowed to discuss their analysis of Arava's postmarket safety data
at a scientific advisory committee meeting. This meeting was held to
review Arava's safety risks and benefits in the context of other
similar drugs. Insufficient communication between ODS and OND's
divisions was an ongoing concern and hindered the decision-making
process. For example, ODS did not always know how OND had responded to
ODS's safety analyses and recommendations. ODS management did not
systematically track information about the recommendations its staff
made and OND's response. This limited the ability of ODS management to
provide effective oversight so that FDA could ensure that safety
concerns were addressed and resolved in a timely manner. FDA faced data
constraints that contributed to the difficulty in making postmarket
safety decisions. In the absence of specific authority to require drug
sponsors to conduct postmarket studies, FDA has often relied on drug
sponsors voluntarily agreeing to conduct these studies. However, these
studies have not consistently been completed. FDA was also limited in
the resources it had available to obtain data from outside sources.
FDA has undertaken a variety of initiatives to improve its postmarket
drug safety decision-making process. Prior to the completion of our
report in March 2006, FDA commissioned the Institute of Medicine (IOM)
to examine the drug safety system, including FDA's oversight of
postmarket drug safety. FDA also established the Drug Safety Oversight
Board in CDER and made other internal changes. Since March 2006, FDA
has continued to address its oversight and decision-making
shortcomings. In January 2007, FDA issued a detailed response to IOM's
recommendations. In our 2006 report, we recommended that FDA revise and
implement its draft policy on the decision-making process for major
postmarket safety actions, improve its process to resolve disagreements
over safety decisions, clarify ODS's role in scientific advisory
committees, and systematically track postmarket drug safety issues. FDA
has since begun to implement initiatives that we believe could address
the goals of three of the four recommendations in our 2006 report. FDA
has made revisions to, but not finalized, its draft policy on major
postmarket drug safety decisions. FDA has not improved its process to
resolve disagreements over safety decisions and the agency is
developing but has not finalized guidance to clarify ODS's role in
scientific advisory committees. FDA is in the process of implementing a
tracking system. Although FDA's initiatives are positive steps, they
are not yet fully implemented and it is too soon to evaluate their
effectiveness.
Background:
Because no drug is absolutely safe, 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 4] related to the drug and information from clinical
studies about the drug that are conducted by the drug's sponsor. FDA
also reviews adverse events from studies that follow the use of drugs
in ongoing medical care (observational studies)[Footnote 5] that are
carried out 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.
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. After a drug is on the
market, OND staff receive 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.[Footnote 6]
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. When consulting with OND
on a safety issue, ODS staff search for all relevant case reports of
adverse events and assess them to determine whether or not the drug
caused the adverse event and whether there are any common trends or
risk factors. ODS staff might also 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.
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. Then, if
necessary, OND staff make a decision about what action should be taken.
Several CDER staff, including staff from OND and ODS, 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 staff 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, OND staff sometimes request 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, which are composed of experts and consumer representatives
from outside FDA.[Footnote 7] In 2002, FDA established the Drug Safety
and Risk Management Advisory Committee, 1 of the 16 human-drug-related
scientific advisory committees, to specifically advise FDA on drug
safety and risk management issues. The recommendations of the advisory
committees do not bind the agency to any decision.
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 8] In almost all cases of drug withdrawals for safety
reasons, the drug's sponsor has voluntarily removed the drug from the
market. For example, in 2001 Baycol's sponsor voluntarily withdrew the
drug from the market after meeting with FDA to discuss reports of
adverse events, including some reports of fatalities.[Footnote 9] 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. Negotiations may result in
revised drug labeling or restricted distribution. FDA has limited
authority to require that sponsors conduct postmarket safety studies.
FDA Lacked a Clear and Effective Decision-making Process for Postmarket
Drug Safety:
In our March 2006 report, we found that FDA's postmarket drug safety
decision-making process was limited by a lack of clarity, insufficient
oversight by management, and data constraints. We observed that there
was a lack of established criteria for determining what safety actions
to take and when, and aspects of ODS's role in the process were
unclear. A lack of communication between ODS and OND's review divisions
and limited oversight of postmarket drug safety issues by ODS
management hindered the decision-making process. FDA's decisions
regarding postmarket drug safety were also made more difficult by the
constraints it faced in obtaining data.
Decision-making Process on Drug Safety Lacked Clarity about Criteria
for Action and the Role of ODS:
While acknowledging the complexity of the postmarket drug safety
decision-making process, we found through our interviews with OND and
ODS staff and in our case studies that the process lacked clarity about
how drug safety decisions were made and about the role of ODS. If FDA
had established criteria for determining what safety actions to take
and when, then some of the disagreements we observed in our case
studies might have been resolved more quickly. In the absence of
established criteria, several FDA officials told us that decisions
about safety actions were often based on the case-by-case judgments of
the individuals reviewing the data. For example, in the case of Bextra,
ODS and OND staff disagreed about whether the degree of risk for
serious skin reactions warranted a boxed warning, the most serious
warning placed in the labeling of a prescription medication. Similarly,
in the case of Propulsid, some staff, from both OND and ODS, supported
proposing a withdrawal of approval because of the cardiovascular side
effects of the drug while others believed label modifications were
warranted.[Footnote 10] Our observations were consistent with two
previous internal FDA reports on the agency's internal deliberations
regarding Propulsid and the diabetes drug Rezulin.[Footnote 11] In
those reviews FDA indicated that an absence of established criteria for
determining what safety actions to take, and when to take them, posed a
challenge for making postmarket drug safety decisions.
We also found that ODS's role in scientific advisory committee meetings
was unclear. According to the OND Director, OND is responsible for
setting the agenda for the advisory committee meetings, with the
exception of the Drug Safety and Risk Management Advisory
Committee.[Footnote 12] This includes who is to present and what issues
will be discussed by the advisory committees. For the advisory
committees (other than the Drug Safety and Risk Management Advisory
Committee) it was unclear when ODS staff would participate. Although
ODS staff presented their postmarket drug safety analyses during some
advisory committee meetings, our case study of Arava provided an
example of the exclusion of ODS staff. In March 2003, FDA's 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 13] 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.[Footnote 14]
A Lack of Communication and Limited Oversight Hindered 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
also hindered the decision-making process. ODS and OND staff often
described their relationship with each other as generally
collaborative, with effective communication, but both ODS and OND staff
told us that there had been communication problems on some occasions,
and that this had been an ongoing concern. For example, according to
some ODS staff, OND did not always adequately communicate the key
question or point of interest to ODS when it requested a consult, and
as ODS worked on the consult there was sometimes little interaction
between the two offices. After a consult was completed and sent to OND,
ODS staff reported that OND sometimes did 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 were 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 had not effectively overseen postmarket drug safety
issues, and as a result, it was unclear how FDA could know that
important safety concerns had been addressed and resolved in a timely
manner. A former ODS Director told us that the small size of ODS's
management team presented a challenge for effective oversight of
postmarket drug safety issues. Another problem was the lack of
systematic information on drug safety issues. According to the ODS
Director, ODS maintained a database of consults that provided some
information about the consults that ODS staff conducted, but it did not
include information about whether ODS staff made recommendations for
safety actions and how the safety issues were handled and resolved,
such as whether recommended safety actions were implemented by OND.
Data Constraints Contributed to Difficulty in Making Postmarket Safety
Decisions:
Data constraints--such as weaknesses in data sources and FDA's limited
ability to require certain studies and obtain additional data--
contributed to FDA's difficulty in making postmarket drug safety
decisions. OND and ODS used three different sources of data to make
postmarket drug safety decisions. They included adverse event reports,
clinical trial studies, and observational studies. While data from each
source had weaknesses that contributed to the difficulty in making
postmarket drug safety decisions, evidence from more than one source
could have helped inform the postmarket decision-making process. The
availability of these data sources was 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 were often based on
adverse event reports, FDA could not establish the true frequency of
adverse events in the population with data from adverse event reports.
The inability to calculate the true frequency made it hard to establish
the magnitude of a safety problem, and comparisons of risks across
similar drugs were difficult.[Footnote 15] In addition, it would have
been difficult to attribute adverse events to particular drugs when
there was a relatively high incidence rate in the population for the
medical condition. It was also difficult to attribute adverse events to
the use of particular drugs because data from adverse event reports may
have been confounded by other factors, such as other drug exposures.
FDA can also use available data from clinical trials and observational
studies to support postmarket drug safety decisions. Although each
source presents weaknesses that constrained the usefulness of the data
provided, having data from more than one source can help improve FDA's
decision-making ability. 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 16] 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. For example, they
do not often include 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. 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. For example, in the case of Propulsid, an observational study
showed that a 1998 labeling change warning about contraindications did
not significantly decrease the percentage of users in one population
who should not have been prescribed this drug. Because they are not
controlled experiments, however, there is the possibility that the
results can be biased or confounded by other factors.
We found that FDA's access to postmarket clinical trial and
observational data was limited by its authority and available
resources. 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. For example, during a
February 2005 scientific advisory committee meeting, some FDA staff and
committee members 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.[Footnote
17]
Lacking specific authority to require drug sponsors to conduct
postmarket studies, FDA has often relied on drug sponsors voluntarily
agreeing to conduct these studies. But the postmarket studies that drug
sponsors agreed to conduct have not consistently been completed. One
study estimated that the completion rate of postmarket studies,
including those that sponsors had voluntarily agreed to conduct, rose
from 17 percent in the mid-1980s to 24 percent between 1991 and
2003.[Footnote 18] FDA has little leverage to ensure that these studies
are carried out.
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. Under the cooperative agreement
program, FDA collaborated with outside researchers in order to access a
wide range of population-based data and conduct research on drug
safety. Annual funding for this program was less than $1 million from
fiscal year 2002 through fiscal year 2005. In 2006, FDA awarded four
contracts for a total cost of $1.6 million per year to replace the
cooperative agreements.
FDA's Initiatives to Improve Postmarket Drug Safety Decision Making:
Prior to the completion of our March 2006 report, FDA began several
initiatives to improve its postmarket drug safety decision-making
process. Most prominently, FDA commissioned the Institute of Medicine
(IOM) to convene a committee of experts to assess the current system
for evaluating postmarket drug safety, including FDA's oversight of
postmarket safety and its processes. IOM issued its report in September
2006.[Footnote 19] FDA also had underway several organizational changes
that we discussed in our 2006 report. For example, FDA established the
Drug Safety Oversight Board to help provide oversight and advice to the
CDER Director on the management of important safety issues. The board
is involved with ensuring that broader safety issues, such as ongoing
delays in changing a label, are effectively resolved. FDA also drafted
a policy that was designed to ensure that all major postmarket safety
recommendations--including those that involve disagreements--would be
discussed by involved OND and ODS managers, beginning at the division
level.[Footnote 20] The draft policy states that decisions about major
postmarket safety recommendations would be documented. 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--including the failure to take a drug safety action--that
could have a significant negative effect on public health. In that
program, the CDER Director would decide whether the process should be
initiated, appoint the chair for a panel to review the case, and make
the final decision on how the dispute should be resolved. Because the
CDER Director is involved in determining whether the process will begin
and makes the final decision, the pilot program did not offer employees
an independent forum for resolving disputes. FDA also began to explore
ways to access additional data sources that it can obtain under its
current authority, such as data on Medicare beneficiaries' experience
with prescription drugs covered under the prescription drug
benefit.[Footnote 21]
Since our report, FDA has made efforts to improve its postmarket safety
decision-making and oversight process. In its written response to the
IOM recommendations, FDA agreed with the goals of many of the
recommendations made by GAO and IOM.[Footnote 22] In that response, FDA
stated that it would take steps to improve the "culture of safety" in
CDER, reduce tension between pre-approval and post-approval staff,
clarify the roles and responsibilities of pre-and postmarket staff, and
improve methods for resolving scientific disagreements.
FDA has also begun several initiatives since our March 2006 report that
we believe could address three of our four recommendations. Because
none of these initiatives was fully implemented as of March 2007, it
was too early to evaluate their effectiveness.
* To make the postmarket safety decision-making process clearer and
more effective, we recommended that FDA revise and implement its draft
policy on major postmarket drug safety decisions. CDER has made
revisions to the draft policy, but has not yet finalized and
implemented it. CDER's Associate Director for Safety Policy and
Communication told us that the draft policy provides guidance for
making major postmarket safety decisions, including identifying the
decision-making officials for safety actions and ensuring that the
views of involved FDA staff are documented. According to the Associate
Director, the revised draft does not now discuss decisions for more
limited safety actions, such as adding a boxed warning to a drug's
label.[Footnote 23] As a result, fewer postmarket safety
recommendations would be required to be discussed by involved OND and
ODS managers than envisioned in the draft policy we reviewed for our
2006 report. Separately, FDA has instituted some procedures that are
consistent with the goals of the draft policy. For example, ODS staff
now participate in regular, bimonthly safety meetings with each of the
review divisions in OND.
* To help resolve disagreements over safety decisions, we recommended
that FDA improve CDER's dispute resolution process by revising the
pilot program to increase its independence. FDA had not revised its
pilot dispute resolution program as of March 2007, and FDA officials
told us that the existing program had not been used by any CDER staff
member.
* To make the postmarket safety decision-making process clearer, we
recommended that FDA clarify ODS's role in FDA's scientific advisory
committee meetings involving postmarket drug safety issues. According
to an FDA official, the agency intends to, but had not yet, drafted a
policy that will describe what safety information should be presented
and how such information should be presented at scientific advisory
committee meetings. The policy is also expected to clarify ODS's role
in planning for, and participating in, meetings of FDA's scientific
advisory committees.
* To help ensure that safety concerns were addressed and resolved in a
timely manner, we recommended that FDA establish a mechanism for
systematically tracking ODS's recommendations and subsequent safety
actions. As of March 2007, FDA was in the process of implementing the
Document Archiving, Reporting and Regulatory Tracking System (DARRTS)
to track such information on postmarket drug safety issues. Among many
other uses, DAARTS will track ODS's safety recommendations and the
responses to them. CDER's Associate Director for Safety Policy and
Communication told us that DAARTS would be fully operational by the end
of April 2007.
We also suggested in our report that Congress consider expanding FDA's
authority to require drug sponsors to conduct postmarket studies in
order to ensure that the agency has the necessary information, such as
clinical trial and observational data, to make postmarket decisions.
Mr. Chairman, this concludes my prepared remarks. I would be pleased to
respond to any questions that you or other members of the Subcommittee
may have.
For further information regarding this testimony, please contact Marcia
Crosse 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 testimony. Martin T. Gahart, Assistant Director;
Pamela Dooley; and Cathleen Hamann made key contributions to this
statement.
FOOTNOTES
[1] The report is available online at [Hyperlink,
http://www.gao.gov/cgi-bin/getrpt?GAO-06-402].
[2] ODS was renamed the Office of Surveillance and Epidemiology in May
2006. For the purposes of this testimony, we are referring to this
office by its former name.
[3] 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.
[4] Adverse event is the term used by FDA to refer to any untoward
medical event associated with the use of a drug in humans.
[5] 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.
[6] Health care providers and patients can voluntarily submit adverse
event reports to FDA. Adverse event reports become part of FDA's
computerized database known as the Adverse Event Reporting System.
[7] These committees are either mandated by legislation or are
established at the discretion of the Department of Health and Human
Services.
[8] 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.
[9] At this meeting FDA communicated to the sponsor that it was
considering proceeding with a withdrawal of the highest dose of Baycol
because of its increased risk for a severe adverse event involving the
breakdown of muscle fibers.
[10] Propulsid's label was modified multiple times, including the
addition of a boxed warning, to warn consumers and professionals about
cardiovascular risks.
[11] Rezulin was removed from the market in 2000 because of its risk
for liver toxicity.
[12] ODS is responsible for setting the agenda for meetings of the Drug
Safety and Risk Management Advisory Committee.
[13] 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. Ultimately, the label was strengthened in
2003 to state that rare cases of severe liver injury, including cases
of fatal outcomes, had been reported in Arava users.
[14] Similarly, other senior-level CDER staff, including ODS and OND
managers, did not agree with the ODS staff's conclusions and
recommendation.
[15] 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, D.J. Graham, P.C.
Waller, and X. Kurz, "A View from Regulatory Agencies," in
Pharmacoepidemiology, ed. Brian L. Strom (Chichester: John Wiley &
Sons, Ltd., 2000), pp. 109-124.
[16] 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.
[17] This was a joint meeting of the Arthritis Advisory Committee and
the Drug Safety and Risk Management Advisory Committee.
[18] 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).
[19] Institute of Medicine of the National Academies, Committee on the
Assessment of the U.S. Drug Safety System, Editors A. Baciu, K.
Stratton, and S.P. Burke, The Future of Drug Safety: Promoting and
Protecting the Health of the Public (Washington, DC: Sept. 22, 2006).
[20] The draft policy is entitled "Process for Decision-Making
Regarding Major Postmarketing Safety-Related Actions."
[21] In October 2006, the Centers for Medicare & Medicaid Services
published a proposed rule that would, when finalized, facilitate access
by FDA and others to information about prescription drugs covered by
Medicare. See 71 Fed. Reg. 61445 (Oct. 18, 2006).
[22] HHS, FDA, The Future of Drug Safety--Promoting and Protecting the
Health of the Public: FDA's Response to the Institute of Medicine's
2006 Report (Rockville, Md.: January 2007).
[23] The original draft policy included the market withdrawal of a
drug, restrictions on a drug's distribution, and boxed warnings as
major postmarket drug safety decisions.
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