GAO-07-856T, Drug Safety: Further Actions Needed to Improve FDA's Postmarket Decision-making Process


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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.

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