Drug Safety: FDA Needs to Further Address Shortcomings in Its	 
Postmarket Decision-making Process (22-MAR-07, GAO-07-599T).	 
                                                                 
GAO 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.					 
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-07-599T					        
    ACCNO:   A67129						        
  TITLE:     Drug Safety: FDA Needs to Further Address Shortcomings in
Its Postmarket Decision-making Process				 
     DATE:   03/22/2007 
  SUBJECT:   Consumer protection				 
	     Data collection					 
	     Data integrity					 
	     Decision making					 
	     Drugs						 
	     Pharmaceutical industry				 
	     Pharmacological research				 
	     Prescription drugs 				 
	     Product safety					 
	     Safety regulation					 
	     Safety standards					 

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GAO-07-599T

   

     * [1]Background
     * [2]FDA Lacked a Clear and Effective Decision-making Process for

          * [3]Decision-making Process on Drug Safety Lacked Clarity about
          * [4]A Lack of Communication and Limited Oversight Hindered the D
          * [5]Data Constraints Contributed to Difficulty in Making Postmar

     * [6]FDA's Initiatives to Improve Postmarket Drug Safety Decision

          * [7]Order by Mail or Phone

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

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, [8]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.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).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.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.

1The report is available online at
[9]www.gao.gov/cgi-bin/getrpt?GAO-06-402 .

2ODS 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.

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.

3FDA 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.

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)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)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.

4Adverse event is the term used by FDA to refer to any untoward medical
event associated with the use of a drug in humans.

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.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.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.

5Observational 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.

6Health 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.

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.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.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.

7These committees are either mandated by legislation or are established at
the discretion of the Department of Health and Human Services.

821 U.S.C. S 355(e). FDA may propose withdrawal when, for example, it
determines through experience, tests, or other data that a drug is unsafe
under the conditions of use approved in its application, there is a lack
of substantial evidence that the drug will have the effect that it
purports to have or that is suggested in its labeling, or required patent
information is not timely filed. Prior to withdrawal, FDA would need to
notify the affected parties and provide an opportunity for a hearing.
Approval may be suspended immediately, prior to a hearing, if the
Secretary of Health and Human Services finds that continued marketing of a
particular drug constitutes an imminent hazard to the public health.

9At 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.

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.10 Our observations were
consistent with two previous internal FDA reports on the agency's internal
deliberations regarding Propulsid and the diabetes drug Rezulin.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.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.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.14

10Propulsid's label was modified multiple times, including the addition of
a boxed warning, to warn consumers and professionals about cardiovascular
risks.

11Rezulin was removed from the market in 2000 because of its risk for
liver toxicity.

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.

12ODS is responsible for setting the agenda for meetings of the Drug
Safety and Risk Management Advisory Committee.

13The 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.

14Similarly, other senior-level CDER staff, including ODS and OND
managers, did not agree with the ODS staff's conclusions and
recommendation.

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.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.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.

15This 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.

16In 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.

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.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 2003.18 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.

17This was a joint meeting of the Arthritis Advisory Committee and the
Drug Safety and Risk Management Advisory Committee.

18Postmarket 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).

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 2006.19 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.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.21

19Institute 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).

20The draft policy is entitled "Process for Decision-Making Regarding
Major Postmarketing Safety-Related Actions."

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.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.

           o 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.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.
           o 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.

           o 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.

           o 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.

21In 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).

22HHS, 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).

23The 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.

           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 [email protected] . 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.
			  
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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,
[email protected].

Highlights of [18]GAO-07-599T , a testimony before the Subcommittee on
Oversight and Investigations, Committee on Energy and Commerce, House of
Representatives

March 22, 2007

DRUGSAFETY

FDA Needs to Further Address Shortcomings in Its Postmarket
Decision-making Process

In 2004, several high-profile drug safety cases raised concerns about the
Food and Drug Administration's (FDA) ability to manage postmarket drug
safety issues. In some cases there 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.

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.

References

Visible links
8. http://www.gao.gov/cgi-bin/getrpt?GAO-06-402
9. http://www.gao.gov/cgi-bin/getrpt?www.gao.gov/cgi-bin/getrpt?GAO-06-402
  18. http://www.gao.gov/cgi-bin/getrpt?GAO-07-599T
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