Drug Safety
Further Actions Needed to Improve FDA's Postmarket Decision-making Process Gao ID: GAO-07-856T May 9, 2007In 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 FDA's oversight of drug safety. This testimony is based on Drug Safety: Improvement Needed in FDA's Postmarket Decision-making and Oversight Process, GAO-06-402 (Mar. 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 in February and March 2007, and received updated information from FDA in May 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. 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 FDA's access to data was constrained by both its limited authority to require drug sponsors to conduct postmarket studies and its limited resources for acquiring data from other external sources. 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 and that, if implemented, could address three of GAO's four recommendations. 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-07-856T, Drug Safety: Further Actions Needed to Improve FDA's Postmarket Decision-making Process
This is the accessible text file for GAO report number GAO-07-856T
entitled 'Drug Safety: Further Actions Needed to Improve FDA's
Postmarket Decision-making Process' which was released on May 9, 2007.
This text file was formatted by the U.S. Government Accountability
Office (GAO) to be accessible to users with visual impairments, as part
of a longer term project to improve GAO products' accessibility. Every
attempt has been made to maintain the structural and data integrity of
the original printed product. Accessibility features, such as text
descriptions of tables, consecutively numbered footnotes placed at the
end of the file, and the text of agency comment letters, are provided
but may not exactly duplicate the presentation or format of the printed
version. The portable document format (PDF) file is an exact electronic
replica of the printed version. We welcome your feedback. Please E-mail
your comments regarding the contents or accessibility features of this
document to Webmaster@gao.gov.
This is a work of the U.S. government and is not subject to copyright
protection in the United States. It may be reproduced and distributed
in its entirety without further permission from GAO. Because this work
may contain copyrighted images or other material, permission from the
copyright holder may be necessary if you wish to reproduce this
material separately.
Testimony:
Before the Subcommittee on Health, Committee on Energy and Commerce,
House of Representatives:
United States Government Accountability Office:
GAO:
For Release on Delivery Expected at 10:00 a.m. EDT:
May 9, 2007:
Drug Safety:
Further Actions Needed to Improve FDA's Postmarket Decision-making
Process:
Statement of Marcia Crosse:
Director, Health Care:
GAO-07-856T:
GAO Highlights:
Highlights of GAO-07-856T, a testimony before the Subcommittee on
Health, 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 FDA‘s oversight of drug safety. This
testimony is based on Drug Safety: Improvement Needed in FDA‘s
Postmarket Decision-making and Oversight Process, GAO-06-402 (Mar. 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 in February and March 2007, and received
updated information from FDA in May 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. 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 FDA‘s access to data was constrained by both
its limited authority to require drug sponsors to conduct postmarket
studies and its limited resources for acquiring data from other
external sources.
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 and that, if implemented, could
address three of GAO‘s four recommendations. 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-07-856T].
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 safety of our nation's
drug supply. 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. 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's 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, and received updated
information from FDA in May 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. 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 has 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 has also had limited available resources 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.
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. OND is a much larger office
than ODS. In fiscal year 2005, OND had 715 staff and expenditures of
$110.6 million. More than half of OND's expenditures in fiscal year
2005, or $57.2 million, came from user fees paid by drug sponsors under
the Prescription Drug User Fee Amendments of 2002.[Footnote 6] ODS had
106 staff in fiscal year 2005 and expenditures of $26.9 million, with
$7.6 million from prescription drug user fees.
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 7] 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 8] 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 9] 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 10] 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 have also been made more difficult by
the constraints it faces 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. 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.
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 Have 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--have
contributed to FDA's difficulty in making postmarket drug safety
decisions. OND and ODS have used three different sources of data to
make postmarket drug safety decisions, including adverse event reports,
clinical trial studies, and observational studies. While data from each
source have weaknesses that have contributed 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 has been 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 have often been based on
adverse event reports, FDA cannot establish the true frequency of
adverse events in the population with data from adverse event reports.
The inability to calculate the true frequency makes it hard to
establish the magnitude of a safety problem, and comparisons of risks
across similar drugs are difficult.[Footnote 13] In addition, it is
difficult to attribute adverse events to particular drugs when there is
a relatively high incidence rate in the population for the medical
condition. It is 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 constrain 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 14] 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.
We have found that FDA's access to postmarket clinical trial and
observational data is 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 15]
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 have 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 16] 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 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
17] 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 would be discussed by involved OND and ODS managers,
beginning at the division level, and documented.[Footnote 18] 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. Because the CDER Director is involved in determining whether
the process will be initiated, appoints a panel chair to review the
case, and makes the final decision on how the dispute should be
resolved, we found that the pilot program does not offer CDER staff 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 19]
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 goal of many of the
recommendations made by GAO and IOM.[Footnote 20] In that response, FDA
stated that it would take steps to improve the "culture of safety" in
CDER, reduce tension between preapproval and postapproval 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 were fully implemented as of May 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 21] 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 May 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 May 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.
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.
[End of section]
Related GAO Products:
Drug Safety: FDA Needs to Further Address Shortcomings in Its
Postmarket Decision-making Process. GAO-07-599T. Washington, D.C.:
March 22, 2007.
Pediatric Drug Research: Studies Conducted under Best Pharmaceuticals
for Children Act. GAO-07-557. Washington, D.C.: March 22, 2007.
Prescription Drugs: Improvements Needed in FDA's Oversight of Direct-
to-Consumer Advertising. GAO-07-54. Washington, D.C.: November 16,
2006.
Internet Pharmacies: Some Pose Safety Risks for Consumers and Are
Unreliable in Their Business Practices. GAO-04-888T. Washington, D.C.:
June 17, 2004.
Internet Pharmacies: Some Pose Safety Risks for Consumers. GAO-04-820.
Washington, D.C.: June 17, 2004.
Antibiotic Resistance: Federal Agencies Need to Better Focus Efforts to
Address Risk to Humans from Antibiotic Use in Animals. GAO-04-490.
Washington, D.C.: April 22, 2004.
Pediatric Drug Research: Food and Drug Administration Should More
Efficiently Monitor Inclusion of Minority Children. GAO-03-950.
Washington, D.C.: September 26, 2003.
Women's Health: Women Sufficiently Represented in New Drug Testing, but
FDA Oversight Needs Improvement. GAO-01-754. Washington, D.C.: July 6,
2001.
FOOTNOTES
[1] The report is available online at www.gao.gov/cgi-bin/getrpt?GAO-06-
402. See Related GAO Products at the end of this statement for other
GAO reports about FDA's oversight of prescription drugs.
[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] Pub. L. No. 107-188 § 501 et. seq., 116 Stat. 687.
[7] 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.
[8] These committees are either mandated by legislation or are
established at the discretion of the Department of Health and Human
Services (HHS).
[9] 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.
[10] 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.
[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] 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 Brian L.
Strom, ed., Pharmacoepidemiology (Chichester: John Wiley & Sons, Ltd.,
2000), pp. 109-124.
[14] 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.
[15] This was a joint meeting of the Arthritis Advisory Committee and
the Drug Safety and Risk Management Advisory Committee.
[16] 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).
[17] A. Baciu, K. Stratton, and S. P. Burke, eds., Institute of
Medicine of the National Academies, Committee on the Assessment of the
U.S. Drug Safety System, The Future of Drug Safety: Promoting and
Protecting the Health of the Public (Washington, D.C.: Sept. 22, 2006).
[18] The draft policy is entitled "Process for Decision-Making
Regarding Major Postmarketing Safety-Related Actions."
[19] 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).
[20] 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).
[21] 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.
GAO's Mission:
The Government Accountability Office, the audit, evaluation and
investigative arm of Congress, exists to support Congress in meeting
its constitutional responsibilities and to help improve the performance
and accountability of the federal government for the American people.
GAO examines the use of public funds; evaluates federal programs and
policies; and provides analyses, recommendations, and other assistance
to help Congress make informed oversight, policy, and funding
decisions. GAO's commitment to good government is reflected in its core
values of accountability, integrity, and reliability.
Obtaining Copies of GAO Reports and Testimony:
The fastest and easiest way to obtain copies of GAO documents at no
cost is through GAO's Web site (www.gao.gov). Each weekday, GAO posts
newly released reports, testimony, and correspondence on its Web site.
To have GAO e-mail you a list of newly posted products every afternoon,
go to www.gao.gov and select "Subscribe to Updates."
Order by Mail or Phone:
The first copy of each printed report is free. Additional copies are $2
each. A check or money order should be made out to the Superintendent
of Documents. GAO also accepts VISA and Mastercard. Orders for 100 or
more copies mailed to a single address are discounted 25 percent.
Orders should be sent to:
U.S. Government Accountability Office 441 G Street NW, Room LM
Washington, D.C. 20548:
To order by Phone: Voice: (202) 512-6000 TDD: (202) 512-2537 Fax: (202)
512-6061:
To Report Fraud, Waste, and Abuse in Federal Programs:
Contact:
Web site: www.gao.gov/fraudnet/fraudnet.htm E-mail: fraudnet@gao.gov
Automated answering system: (800) 424-5454 or (202) 512-7470:
Congressional Relations:
Gloria Jarmon, Managing Director, JarmonG@gao.gov (202) 512-4400 U.S.
Government Accountability Office, 441 G Street NW, Room 7125
Washington, D.C. 20548:
Public Affairs:
Paul Anderson, Managing Director, AndersonP1@gao.gov (202) 512-4800
U.S. Government Accountability Office, 441 G Street NW, Room 7149
Washington, D.C. 20548:
