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Testimony: 

Before the Subcommittee on Oversight and Investigations, Committee on 
Energy and Commerce, House of Representatives: 

United States Government Accountability Office: 

GAO: 

For Release on Delivery Expected at 9:30 a.m. EDT: 

March 22, 2007: 

Drug Safety: 

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

Statement of Marcia Crosse: 
Director, Health Care: 

GAO-07-599T: 

GAO Highlights: 

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

Why GAO Did This Study: 

In 2004, several high-profile drug safety cases raised concerns about 
the Food and Drug Administrationís (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 FDAís postmarket 
decision-making process. This testimony is based on Drug Safety: 
Improvement Needed in FDAís 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). ONDís 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 FDAís initiatives since 
March 2006 to improve its decision-making process for this testimony, 
GAO interviewed FDA officials and reviewed FDA documents in February 
and March 2007. 

What GAO Found: 

In its March 2006 report, GAO found that FDA lacked clear and effective 
processes for making decisions about, and providing management 
oversight of, postmarket drug safety issues. There was a lack of 
clarity about how decisions were made and about organizational roles, 
insufficient oversight by management, and data constraints. GAO 
observed that there was a lack of criteria for determining what safety 
actions to take and when to take them. Certain parts of ODSís role in 
the process were unclear, including ODSís 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 Aravaís 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 FDAís 
access to data was constrained by both its authority to require certain 
studies and its limited resources. 

During the course of GAOís 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 FDAís 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 ODSís 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 GAOís 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 FDAís authority to require drug sponsors to 
conduct postmarket studies, as needed, to collect additional data on 
drug safety concerns. 

[Hyperlink, http://www.gao.gov/cgi-bin/getrpt?GAO-07-599T]. 

To view the full product, including the scope and methodology, click on 
the link above. For more information, contact Marcia Crosse, (202) 512-
7119, crossem@gao.gov. 

[End of section] 

Mr. Chairman and Members of the Subcommittee, 

I am pleased to be here today as you examine the Food and Drug 
Administration's (FDA) process for decision making regarding postmarket 
drug safety issues. In 2004, several high-profile drug safety cases 
raised concerns about FDA's ability to manage postmarket drug safety 
issues. Those cases showed that there were disagreements and potential 
delays within FDA about how to address serious safety problems. My 
remarks today are based on GAO's March 2006 report on FDA's postmarket 
decision-making process (Drug Safety: Improvement Needed in FDA's 
Postmarket Decision-making and Oversight Process, GAO-06-402). I will 
also discuss a number of FDA initiatives to improve its decision-making 
process, including some that respond to the recommendations we made in 
that report.[Footnote 1] 

In carrying out the work for our report between December 2004 and March 
2006, we focused on two offices within FDA's Center for Drug Evaluation 
and Research (CDER) that are involved in postmarket drug safety 
activities: the Office of New Drugs (OND) and the Office of Drug Safety 
(ODS).[Footnote 2] While there is some overlap in the activities of OND 
and ODS, they have different organizational characteristics and 
perspectives on postmarket drug safety. OND is involved in postmarket 
drug safety activities as one aspect of its larger responsibility to 
review new drug applications, and it has the ultimate responsibility to 
take regulatory action concerning the postmarket safety of drugs. ODS 
is primarily focused on postmarket drug safety, which includes the 
review of reports of adverse reactions to drugs. ODS operates primarily 
in a consultant capacity to OND and does not have any independent 
decision-making responsibility. 

For our report, we interviewed ODS, OND, and other CDER managers and 
staff, as well as drug safety experts from outside FDA. We also 
analyzed documents describing internal FDA policies and procedures. In 
order to obtain an in-depth understanding of FDA's policies and 
procedures, we conducted case studies of four drugs--Arava, Baycol, 
Bextra, and Propulsid--that help to illustrate the decision-making 
process.[Footnote 3] Each of these drugs presented significant 
postmarket safety issues that FDA acted upon in recent years, and they 
reflect differences in the type of adverse event or potential safety 
problem associated with each drug, the safety actions taken, and the 
OND and ODS staff involved. To follow up with FDA about its responses 
to our recommendations and its initiatives to improve its postmarket 
safety decision-making process, we interviewed four FDA managers, 
including CDER's Associate Director for Safety Policy and 
Communication, in February and March 2007. We did not evaluate the 
effectiveness of FDA's efforts to respond to our recommendations. All 
of our work was conducted in accordance with generally accepted 
government auditing standards. 

In summary, we found that FDA lacked a clear and effective process for 
making decisions about, and providing management oversight of, 
postmarket drug safety issues. There was a lack of clarity about how 
decisions were made and about organizational roles, insufficient 
oversight by management, and data constraints. We observed that there 
was a lack of criteria for determining what safety actions to take and 
when to take them, which likely contributed to disagreements over 
decisions about postmarket safety. Certain parts of ODS's role in the 
process were unclear, including ODS's participation in scientific 
advisory committee meetings that were organized by OND to discuss 
specific drugs. Although ODS staff presented their analyses during some 
of these meetings, we found examples of the exclusion of ODS staff from 
making presentations at several meetings. For example, in 2003 ODS 
staff, who had recommended that Arava be removed from the market, were 
not allowed to discuss their analysis of Arava's postmarket safety data 
at a scientific advisory committee meeting. This meeting was held to 
review Arava's safety risks and benefits in the context of other 
similar drugs. Insufficient communication between ODS and OND's 
divisions was an ongoing concern and hindered the decision-making 
process. For example, ODS did not always know how OND had responded to 
ODS's safety analyses and recommendations. ODS management did not 
systematically track information about the recommendations its staff 
made and OND's response. This limited the ability of ODS management to 
provide effective oversight so that FDA could ensure that safety 
concerns were addressed and resolved in a timely manner. FDA faced data 
constraints that contributed to the difficulty in making postmarket 
safety decisions. In the absence of specific authority to require drug 
sponsors to conduct postmarket studies, FDA has often relied on drug 
sponsors voluntarily agreeing to conduct these studies. However, these 
studies have not consistently been completed. FDA was also limited in 
the resources it had available to obtain data from outside sources. 

FDA has undertaken a variety of initiatives to improve its postmarket 
drug safety decision-making process. Prior to the completion of our 
report in March 2006, FDA commissioned the Institute of Medicine (IOM) 
to examine the drug safety system, including FDA's oversight of 
postmarket drug safety. FDA also established the Drug Safety Oversight 
Board in CDER and made other internal changes. Since March 2006, FDA 
has continued to address its oversight and decision-making 
shortcomings. In January 2007, FDA issued a detailed response to IOM's 
recommendations. In our 2006 report, we recommended that FDA revise and 
implement its draft policy on the decision-making process for major 
postmarket safety actions, improve its process to resolve disagreements 
over safety decisions, clarify ODS's role in scientific advisory 
committees, and systematically track postmarket drug safety issues. FDA 
has since begun to implement initiatives that we believe could address 
the goals of three of the four recommendations in our 2006 report. FDA 
has made revisions to, but not finalized, its draft policy on major 
postmarket drug safety decisions. FDA has not improved its process to 
resolve disagreements over safety decisions and the agency is 
developing but has not finalized guidance to clarify ODS's role in 
scientific advisory committees. FDA is in the process of implementing a 
tracking system. Although FDA's initiatives are positive steps, they 
are not yet fully implemented and it is too soon to evaluate their 
effectiveness. 

Background: 

Because no drug is absolutely safe, FDA approves a drug for marketing 
when the agency judges that its known benefits outweigh its known 
risks. After a drug is on the market, FDA continues to assess its risks 
and benefits. FDA reviews reports of adverse drug reactions (adverse 
events)[Footnote 4] related to the drug and information from clinical 
studies about the drug that are conducted by the drug's sponsor. FDA 
also reviews adverse events from studies that follow the use of drugs 
in ongoing medical care (observational studies)[Footnote 5] that are 
carried out by the drug's sponsor, FDA, or other researchers. If FDA 
has information that a drug on the market may pose a significant health 
risk to consumers, it weighs the effect of the adverse events against 
the benefit of the drug to determine what actions, if any, are 
warranted. 

The decision-making process for postmarket drug safety is complex, 
involving input from a variety of FDA staff and organizational units 
and information sources, but the central focus of the process is the 
iterative interaction between OND and ODS. After a drug is on the 
market, OND staff receive information about safety issues in several 
ways. First, OND staff receive notification of adverse event reports 
for drugs to which they are assigned and they review the periodic 
adverse event reports that are submitted by drug sponsors.[Footnote 6] 
Second, OND staff review safety information that is submitted to FDA 
when a sponsor seeks approval for a new use or formulation of a drug, 
and monitor completion of postmarket studies. When consulting with OND 
on a safety issue, ODS staff search for all relevant case reports of 
adverse events and assess them to determine whether or not the drug 
caused the adverse event and whether there are any common trends or 
risk factors. ODS staff might also use information from observational 
studies and drug use analyses to analyze the safety issue. When 
completed, ODS staff summarize their analysis in a written consult. 
According to FDA officials, OND staff within the review divisions 
usually decide what regulatory action should occur, if any, by 
considering the results of the safety analysis in the context of other 
factors such as the availability of other similar drugs and the 
severity of the condition the drug is designed to treat. Then, if 
necessary, OND staff make a decision about what action should be taken. 

Several CDER staff, including staff from OND and ODS, told us that most 
of the time there is agreement within FDA about what safety actions 
should be taken. At other times, however, OND and ODS staff disagree 
about whether the postmarket data are adequate to establish the 
existence of a safety problem or support a recommended regulatory 
action. In those cases, OND staff sometimes request additional analyses 
by ODS and sometimes there is involvement from other FDA organizations. 
In some cases, OND seeks the advice of FDA's scientific advisory 
committees, which are composed of experts and consumer representatives 
from outside FDA.[Footnote 7] In 2002, FDA established the Drug Safety 
and Risk Management Advisory Committee, 1 of the 16 human-drug-related 
scientific advisory committees, to specifically advise FDA on drug 
safety and risk management issues. The recommendations of the advisory 
committees do not bind the agency to any decision. 

FDA has the authority to withdraw the approval of a drug on the market 
for safety-related and other reasons, although it rarely does 
so.[Footnote 8] In almost all cases of drug withdrawals for safety 
reasons, the drug's sponsor has voluntarily removed the drug from the 
market. For example, in 2001 Baycol's sponsor voluntarily withdrew the 
drug from the market after meeting with FDA to discuss reports of 
adverse events, including some reports of fatalities.[Footnote 9] FDA 
does not have explicit authority to require that drug sponsors take 
other safety actions; however, when FDA identifies a potential problem, 
sponsors generally negotiate with FDA to develop a mutually agreeable 
remedy to avoid other regulatory action. Negotiations may result in 
revised drug labeling or restricted distribution. FDA has limited 
authority to require that sponsors conduct postmarket safety studies. 

FDA Lacked a Clear and Effective Decision-making Process for Postmarket 
Drug Safety: 

In our March 2006 report, we found that FDA's postmarket drug safety 
decision-making process was limited by a lack of clarity, insufficient 
oversight by management, and data constraints. We observed that there 
was a lack of established criteria for determining what safety actions 
to take and when, and aspects of ODS's role in the process were 
unclear. A lack of communication between ODS and OND's review divisions 
and limited oversight of postmarket drug safety issues by ODS 
management hindered the decision-making process. FDA's decisions 
regarding postmarket drug safety were also made more difficult by the 
constraints it faced in obtaining data. 

Decision-making Process on Drug Safety Lacked Clarity about Criteria 
for Action and the Role of ODS: 

While acknowledging the complexity of the postmarket drug safety 
decision-making process, we found through our interviews with OND and 
ODS staff and in our case studies that the process lacked clarity about 
how drug safety decisions were made and about the role of ODS. If FDA 
had established criteria for determining what safety actions to take 
and when, then some of the disagreements we observed in our case 
studies might have been resolved more quickly. In the absence of 
established criteria, several FDA officials told us that decisions 
about safety actions were often based on the case-by-case judgments of 
the individuals reviewing the data. For example, in the case of Bextra, 
ODS and OND staff disagreed about whether the degree of risk for 
serious skin reactions warranted a boxed warning, the most serious 
warning placed in the labeling of a prescription medication. Similarly, 
in the case of Propulsid, some staff, from both OND and ODS, supported 
proposing a withdrawal of approval because of the cardiovascular side 
effects of the drug while others believed label modifications were 
warranted.[Footnote 10] Our observations were consistent with two 
previous internal FDA reports on the agency's internal deliberations 
regarding Propulsid and the diabetes drug Rezulin.[Footnote 11] In 
those reviews FDA indicated that an absence of established criteria for 
determining what safety actions to take, and when to take them, posed a 
challenge for making postmarket drug safety decisions. 

We also found that ODS's role in scientific advisory committee meetings 
was unclear. According to the OND Director, OND is responsible for 
setting the agenda for the advisory committee meetings, with the 
exception of the Drug Safety and Risk Management Advisory 
Committee.[Footnote 12] This includes who is to present and what issues 
will be discussed by the advisory committees. For the advisory 
committees (other than the Drug Safety and Risk Management Advisory 
Committee) it was unclear when ODS staff would participate. Although 
ODS staff presented their postmarket drug safety analyses during some 
advisory committee meetings, our case study of Arava provided an 
example of the exclusion of ODS staff. In March 2003, FDA's Arthritis 
Advisory Committee met to review the efficacy of Arava, and its safety 
in the context of all available drugs to treat rheumatoid 
arthritis.[Footnote 13] The OND review division responsible for Arava 
presented its own analysis of postmarket drug safety data at the 
meeting, but did not allow the ODS staff--who had recommended that 
Arava be removed from the market--to present their analysis because it 
felt that ODS's review did not have scientific merit. Specifically, the 
OND review division felt that some of the cases in the ODS review did 
not meet the definition of acute liver failure, the safety issue on 
which the review was focused.[Footnote 14] 

A Lack of Communication and Limited Oversight Hindered the Decision- 
making Process: 

A lack of communication between ODS and OND's review divisions and 
limited oversight of postmarket drug safety issues by ODS management 
also hindered the decision-making process. ODS and OND staff often 
described their relationship with each other as generally 
collaborative, with effective communication, but both ODS and OND staff 
told us that there had been communication problems on some occasions, 
and that this had been an ongoing concern. For example, according to 
some ODS staff, OND did not always adequately communicate the key 
question or point of interest to ODS when it requested a consult, and 
as ODS worked on the consult there was sometimes little interaction 
between the two offices. After a consult was completed and sent to OND, 
ODS staff reported that OND sometimes did not respond in a timely 
manner or at all. Several ODS staff characterized this as consults 
falling into a "black hole" or "abyss." OND's Director told us that OND 
staff probably do not "close the loop" in responding to ODS's consults, 
which includes explaining why certain ODS recommendations were not 
followed. In some cases CDER managers and OND staff criticized the 
methods used in ODS consults and told us that the consults were too 
lengthy and academic. 

ODS management had not effectively overseen postmarket drug safety 
issues, and as a result, it was unclear how FDA could know that 
important safety concerns had been addressed and resolved in a timely 
manner. A former ODS Director told us that the small size of ODS's 
management team presented a challenge for effective oversight of 
postmarket drug safety issues. Another problem was the lack of 
systematic information on drug safety issues. According to the ODS 
Director, ODS maintained a database of consults that provided some 
information about the consults that ODS staff conducted, but it did not 
include information about whether ODS staff made recommendations for 
safety actions and how the safety issues were handled and resolved, 
such as whether recommended safety actions were implemented by OND. 

Data Constraints Contributed to Difficulty in Making Postmarket Safety 
Decisions: 

Data constraints--such as weaknesses in data sources and FDA's limited 
ability to require certain studies and obtain additional data-- 
contributed to FDA's difficulty in making postmarket drug safety 
decisions. OND and ODS used three different sources of data to make 
postmarket drug safety decisions. They included adverse event reports, 
clinical trial studies, and observational studies. While data from each 
source had weaknesses that contributed to the difficulty in making 
postmarket drug safety decisions, evidence from more than one source 
could have helped inform the postmarket decision-making process. The 
availability of these data sources was constrained, however, because of 
FDA's limited authority to require drug sponsors to conduct postmarket 
studies and its resources. 

While decisions about postmarket drug safety were often based on 
adverse event reports, FDA could not establish the true frequency of 
adverse events in the population with data from adverse event reports. 
The inability to calculate the true frequency made it hard to establish 
the magnitude of a safety problem, and comparisons of risks across 
similar drugs were difficult.[Footnote 15] In addition, it would have 
been difficult to attribute adverse events to particular drugs when 
there was a relatively high incidence rate in the population for the 
medical condition. It was also difficult to attribute adverse events to 
the use of particular drugs because data from adverse event reports may 
have been confounded by other factors, such as other drug exposures. 

FDA can also use available data from clinical trials and observational 
studies to support postmarket drug safety decisions. Although each 
source presents weaknesses that constrained the usefulness of the data 
provided, having data from more than one source can help improve FDA's 
decision-making ability. Clinical trials, in particular randomized 
clinical trials, are considered the "gold standard" for assessing 
evidence about efficacy and safety because they are considered the 
strongest method by which one can determine whether new drugs 
work.[Footnote 16] However, clinical trials also have weaknesses. 
Clinical trials typically have too few enrolled patients to detect 
serious adverse events associated with a drug that occur relatively 
infrequently in the population being studied. They are usually carried 
out on homogenous populations of patients that often do not reflect the 
types of patients who will actually take the drugs. For example, they 
do not often include those who have other medical problems or take 
other medications. In addition, clinical trials are often too short in 
duration to identify adverse events that may occur only after long use 
of the drug. This is particularly important for drugs used to treat 
chronic conditions where patients are taking the medications for the 
long term. Observational studies, which use data obtained from 
population-based sources, can provide FDA with information about the 
population effect and risk associated with the use of a particular 
drug. For example, in the case of Propulsid, an observational study 
showed that a 1998 labeling change warning about contraindications did 
not significantly decrease the percentage of users in one population 
who should not have been prescribed this drug. Because they are not 
controlled experiments, however, there is the possibility that the 
results can be biased or confounded by other factors. 

We found that FDA's access to postmarket clinical trial and 
observational data was limited by its authority and available 
resources. FDA does not have broad authority to require that a drug 
sponsor conduct an observational study or clinical trial for the 
purpose of investigating a specific postmarket safety concern. One 
senior FDA official and several outside drug safety experts told us 
that FDA needs greater authority to require such studies. Long-term 
clinical trials may be needed to answer safety questions about risks 
associated with the long-term use of drugs. For example, during a 
February 2005 scientific advisory committee meeting, some FDA staff and 
committee members indicated that there was a need for better 
information on the long-term use of anti-inflammatory drugs and 
discussed how a long-term trial might be designed to study the 
cardiovascular risks associated with the use of these drugs.[Footnote 
17] 

Lacking specific authority to require drug sponsors to conduct 
postmarket studies, FDA has often relied on drug sponsors voluntarily 
agreeing to conduct these studies. But the postmarket studies that drug 
sponsors agreed to conduct have not consistently been completed. One 
study estimated that the completion rate of postmarket studies, 
including those that sponsors had voluntarily agreed to conduct, rose 
from 17 percent in the mid-1980s to 24 percent between 1991 and 
2003.[Footnote 18] FDA has little leverage to ensure that these studies 
are carried out. 

In terms of resource limitations, several FDA staff (including CDER 
managers) and outside drug safety experts told us that in the past ODS 
has not had enough resources for cooperative agreements to support its 
postmarket drug surveillance program. Under the cooperative agreement 
program, FDA collaborated with outside researchers in order to access a 
wide range of population-based data and conduct research on drug 
safety. Annual funding for this program was less than $1 million from 
fiscal year 2002 through fiscal year 2005. In 2006, FDA awarded four 
contracts for a total cost of $1.6 million per year to replace the 
cooperative agreements. 

FDA's Initiatives to Improve Postmarket Drug Safety Decision Making: 

Prior to the completion of our March 2006 report, FDA began several 
initiatives to improve its postmarket drug safety decision-making 
process. Most prominently, FDA commissioned the Institute of Medicine 
(IOM) to convene a committee of experts to assess the current system 
for evaluating postmarket drug safety, including FDA's oversight of 
postmarket safety and its processes. IOM issued its report in September 
2006.[Footnote 19] FDA also had underway several organizational changes 
that we discussed in our 2006 report. For example, FDA established the 
Drug Safety Oversight Board to help provide oversight and advice to the 
CDER Director on the management of important safety issues. The board 
is involved with ensuring that broader safety issues, such as ongoing 
delays in changing a label, are effectively resolved. FDA also drafted 
a policy that was designed to ensure that all major postmarket safety 
recommendations--including those that involve disagreements--would be 
discussed by involved OND and ODS managers, beginning at the division 
level.[Footnote 20] The draft policy states that decisions about major 
postmarket safety recommendations would be documented. FDA implemented 
a pilot program for dispute resolution that is designed for individual 
CDER staff to have their views heard when they disagree with a 
decision--including the failure to take a drug safety action--that 
could have a significant negative effect on public health. In that 
program, the CDER Director would decide whether the process should be 
initiated, appoint the chair for a panel to review the case, and make 
the final decision on how the dispute should be resolved. Because the 
CDER Director is involved in determining whether the process will begin 
and makes the final decision, the pilot program did not offer employees 
an independent forum for resolving disputes. FDA also began to explore 
ways to access additional data sources that it can obtain under its 
current authority, such as data on Medicare beneficiaries' experience 
with prescription drugs covered under the prescription drug 
benefit.[Footnote 21] 

Since our report, FDA has made efforts to improve its postmarket safety 
decision-making and oversight process. In its written response to the 
IOM recommendations, FDA agreed with the goals of many of the 
recommendations made by GAO and IOM.[Footnote 22] In that response, FDA 
stated that it would take steps to improve the "culture of safety" in 
CDER, reduce tension between pre-approval and post-approval staff, 
clarify the roles and responsibilities of pre-and postmarket staff, and 
improve methods for resolving scientific disagreements. 

FDA has also begun several initiatives since our March 2006 report that 
we believe could address three of our four recommendations. Because 
none of these initiatives was fully implemented as of March 2007, it 
was too early to evaluate their effectiveness. 

* To make the postmarket safety decision-making process clearer and 
more effective, we recommended that FDA revise and implement its draft 
policy on major postmarket drug safety decisions. CDER has made 
revisions to the draft policy, but has not yet finalized and 
implemented it. CDER's Associate Director for Safety Policy and 
Communication told us that the draft policy provides guidance for 
making major postmarket safety decisions, including identifying the 
decision-making officials for safety actions and ensuring that the 
views of involved FDA staff are documented. According to the Associate 
Director, the revised draft does not now discuss decisions for more 
limited safety actions, such as adding a boxed warning to a drug's 
label.[Footnote 23] As a result, fewer postmarket safety 
recommendations would be required to be discussed by involved OND and 
ODS managers than envisioned in the draft policy we reviewed for our 
2006 report. Separately, FDA has instituted some procedures that are 
consistent with the goals of the draft policy. For example, ODS staff 
now participate in regular, bimonthly safety meetings with each of the 
review divisions in OND. 

* To help resolve disagreements over safety decisions, we recommended 
that FDA improve CDER's dispute resolution process by revising the 
pilot program to increase its independence. FDA had not revised its 
pilot dispute resolution program as of March 2007, and FDA officials 
told us that the existing program had not been used by any CDER staff 
member. 

* To make the postmarket safety decision-making process clearer, we 
recommended that FDA clarify ODS's role in FDA's scientific advisory 
committee meetings involving postmarket drug safety issues. According 
to an FDA official, the agency intends to, but had not yet, drafted a 
policy that will describe what safety information should be presented 
and how such information should be presented at scientific advisory 
committee meetings. The policy is also expected to clarify ODS's role 
in planning for, and participating in, meetings of FDA's scientific 
advisory committees. 

* To help ensure that safety concerns were addressed and resolved in a 
timely manner, we recommended that FDA establish a mechanism for 
systematically tracking ODS's recommendations and subsequent safety 
actions. As of March 2007, FDA was in the process of implementing the 
Document Archiving, Reporting and Regulatory Tracking System (DARRTS) 
to track such information on postmarket drug safety issues. Among many 
other uses, DAARTS will track ODS's safety recommendations and the 
responses to them. CDER's Associate Director for Safety Policy and 
Communication told us that DAARTS would be fully operational by the end 
of April 2007. 

We also suggested in our report that Congress consider expanding FDA's 
authority to require drug sponsors to conduct postmarket studies in 
order to ensure that the agency has the necessary information, such as 
clinical trial and observational data, to make postmarket decisions. 

Mr. Chairman, this concludes my prepared remarks. I would be pleased to 
respond to any questions that you or other members of the Subcommittee 
may have. 

For further information regarding this testimony, please contact Marcia 
Crosse at (202) 512-7119 or crossem@gao.gov. Contact points for our 
Offices of Congressional Relations and Public Affairs may be found on 
the last page of this testimony. Martin T. Gahart, Assistant Director; 
Pamela Dooley; and Cathleen Hamann made key contributions to this 
statement. 

FOOTNOTES 

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

[2] ODS was renamed the Office of Surveillance and Epidemiology in May 
2006. For the purposes of this testimony, we are referring to this 
office by its former name. 

[3] FDA approved Arava to treat arthritis; Baycol to treat high 
cholesterol; Propulsid to treat nighttime heartburn; and Bextra to 
relieve pain. Baycol, Bextra, and Propulsid have since been withdrawn 
from the market (in August 2001, April 2005, and March 2000, 
respectively), and the warnings on Arava's label were strengthened. 

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

[5] Observational studies can provide information about the association 
between certain drug exposures and adverse events. In observational 
studies, the investigator does not control the therapy, but observes 
and evaluates ongoing medical care. In contrast, in clinical trials the 
investigator controls the therapy to be received by participants and 
can test for causal relationships. 

[6] Health care providers and patients can voluntarily submit adverse 
event reports to FDA. Adverse event reports become part of FDA's 
computerized database known as the Adverse Event Reporting System. 

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

[8] 21 U.S.C. ß 355(e). FDA may propose withdrawal when, for example, 
it determines through experience, tests, or other data that a drug is 
unsafe under the conditions of use approved in its application, there 
is a lack of substantial evidence that the drug will have the effect 
that it purports to have or that is suggested in its labeling, or 
required patent information is not timely filed. Prior to withdrawal, 
FDA would need to notify the affected parties and provide an 
opportunity for a hearing. Approval may be suspended immediately, prior 
to a hearing, if the Secretary of Health and Human Services finds that 
continued marketing of a particular drug constitutes an imminent hazard 
to the public health. 

[9] At this meeting FDA communicated to the sponsor that it was 
considering proceeding with a withdrawal of the highest dose of Baycol 
because of its increased risk for a severe adverse event involving the 
breakdown of muscle fibers. 

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

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

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

[13] The committee was asked to consider whether the data presented by 
the drug's sponsor supported improvement in physical function and 
whether the drug's labeling needed to be updated to add any additional 
warning about liver toxicity. Ultimately, the label was strengthened in 
2003 to state that rare cases of severe liver injury, including cases 
of fatal outcomes, had been reported in Arava users. 

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

[15] This is due, in part, to the underreporting of adverse events and 
inconsistency in how those reporting define cases. These limitations 
have been reported elsewhere. See, for example, D.J. Graham, P.C. 
Waller, and X. Kurz, "A View from Regulatory Agencies," in 
Pharmacoepidemiology, ed. Brian L. Strom (Chichester: John Wiley & 
Sons, Ltd., 2000), pp. 109-124. 

[16] In these trials, patients are randomly assigned to either receive 
the drug or a different treatment, and differences in results between 
the two groups can typically be attributed to the drug. 

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

[18] Postmarket studies for approved drugs and biologics are included 
in the percent calculations. See: Tufts Center for the Study of Drug 
Development (Kenneth I. Kaitin, ed.), "FDA Requested Postmarketing 
Studies in 73% of Recent New Drug Approvals," Impact Report: Analysis 
and Insight into Critical Drug Development Issues, vol. 6, no. 4 
(2004). 

[19] Institute of Medicine of the National Academies, Committee on the 
Assessment of the U.S. Drug Safety System, Editors A. Baciu, K. 
Stratton, and S.P. Burke, The Future of Drug Safety: Promoting and 
Protecting the Health of the Public (Washington, DC: Sept. 22, 2006). 

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

[21] In October 2006, the Centers for Medicare & Medicaid Services 
published a proposed rule that would, when finalized, facilitate access 
by FDA and others to information about prescription drugs covered by 
Medicare. See 71 Fed. Reg. 61445 (Oct. 18, 2006). 

[22] HHS, FDA, The Future of Drug Safety--Promoting and Protecting the 
Health of the Public: FDA's Response to the Institute of Medicine's 
2006 Report (Rockville, Md.: January 2007). 

[23] The original draft policy included the market withdrawal of a 
drug, restrictions on a drug's distribution, and boxed warnings as 
major postmarket drug safety decisions. 

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