Drug Safety: Further Actions Needed to Improve FDA's Postmarket  
Decision-making Process (09-MAY-07, GAO-07-856T).		 
                                                                 
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.		 
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-07-856T					        
    ACCNO:   A69367						        
  TITLE:     Drug Safety: Further Actions Needed to Improve FDA's     
Postmarket Decision-making Process				 
     DATE:   05/09/2007 
  SUBJECT:   Consumer protection				 
	     Decision making					 
	     Drugs						 
	     Pharmaceutical industry				 
	     Pharmacological research				 
	     Prescription drugs 				 
	     Product safety					 
	     Safety regulation					 
	     Safety standards					 

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GAO-07-856T

   

     * [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 Have Contributed to Difficulty in Making Po

     * [6]FDA's Initiatives to Improve Postmarket Drug Safety Decision
     * [7]Related GAO Products

          * [8]Order by Mail or Phone

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

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, [9]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.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, 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.

1The 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.

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. 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.

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.

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.

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.

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 2002.6 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.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.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.

6Pub. L. No. 107-188 S 501 et. seq., 116 Stat. 687.

7Health 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.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.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.

8These committees are either mandated by legislation or are established at
the discretion of the Department of Health and Human Services (HHS).

921 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.

10At 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
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.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.

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

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

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.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.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.

13This 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.

14In 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 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.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 2003.16 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.

15This was a joint meeting of the Arthritis Advisory Committee and the
Drug Safety and Risk Management Advisory Committee.

16Postmarket 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 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 2006.17 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.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.19

17A. 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).

18The draft policy is entitled "Process for Decision-Making Regarding
Major Postmarketing Safety-Related Actions."

19In 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).

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.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.

           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.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.
		   
20HHS, 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).

21The 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.

           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 May 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 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 [11][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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           November 16, 2006.

           Internet Pharmacies: Some Pose Safety Risks for Consumers and Are
           Unreliable in Their Business Practices. [15]GAO-04-888T .
           Washington, D.C.: June 17, 2004.

           Internet Pharmacies: Some Pose Safety Risks for Consumers.
           [16]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.
           [17]GAO-04-490 . Washington, D.C.: April 22, 2004.

           Pediatric Drug Research: Food and Drug Administration Should More
           Efficiently Monitor Inclusion of Minority Children. [18]GAO-03-950
           . Washington, D.C.: September 26, 2003.

           Women's Health: Women Sufficiently Represented in New Drug
           Testing, but FDA Oversight Needs Improvement. [19]GAO-01-754 .
           Washington, D.C.: July 6, 2001.
		   
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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,
[email protected].

Highlights of [27]GAO-07-856T , a testimony before the Subcommittee on
Health, Committee on Energy and Commerce, House of Representatives

May 9, 2007

DRUG SAFETY

Further Actions Needed to Improve FDA's 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 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.

References

Visible links
9. http://www.gao.gov/cgi-bin/getrpt?GAO-06-402
  11. [email protected]
  12. http://www.gao.gov/cgi-bin/getrpt?GAO-07-599T
  13. http://www.gao.gov/cgi-bin/getrpt?GAO-07-557
  14. http://www.gao.gov/cgi-bin/getrpt?GAO-07-54
  15. http://www.gao.gov/cgi-bin/getrpt?GAO-04-888T
  16. http://www.gao.gov/cgi-bin/getrpt?GAO-04-820
  17. http://www.gao.gov/cgi-bin/getrpt?GAO-04-490
  18. http://www.gao.gov/cgi-bin/getrpt?GAO-03-950
  19. http://www.gao.gov/cgi-bin/getrpt?GAO-01-754
  20. http://www.gao.gov/
  27. http://www.gao.gov/cgi-bin/getrpt?GAO-07-856T
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