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Report to the Ranking Member, Committee on Finance, U.S. Senate: 

United States Government Accountability Office: 
GAO: 

November 2009: 

Drug Safety: 

FDA Has Begun Efforts to Enhance Postmarket Safety, but Additional 
Actions Are Needed: 

GAO-10-68: 

GAO Highlights: 

Highlights of GAO-10-68, a report to the Ranking Member, Committee on 
Finance, U.S. Senate. 

Why GAO Did This Study: 

There have been long-standing concerns regarding the Food and Drug 
Administration’s (FDA) oversight of postmarket drug safety. In 2006, 
GAO reported that FDA had not clearly defined the roles of two offices 
involved in making decisions about postmarket safety—the Office of New 
Drugs (OND) and the Office of Surveillance and Epidemiology (OSE). GAO 
and others reported additional concerns such as limitations in the data 
FDA relies on to identify postmarket drug safety issues and the systems 
it uses to track such issues. At that time, GAO made recommendations, 
including that FDA improve the independence of its program for 
resolving scientific disputes related to postmarket drug safety. In 
2007, legislation further expanded FDA’s postmarket responsibilities. 
This report examines the steps that FDA is taking to (1) enhance its 
processes for making decisions about the safety of marketed drugs, (2) 
improve access to data that help the agency identify drug safety 
issues, and (3) build its capacity to fulfill its postmarket drug 
safety workload. GAO reviewed FDA policies and planning documents, and 
interviewed FDA officials. 

What GAO Found: 

FDA is beginning to address previously identified weaknesses in its 
oversight of postmarket drug safety issues, but challenges remain. The 
agency is changing its postmarket decision-making process as part of 
its Safety First Initiative, which includes formalizing interactions 
between OND and OSE and providing OSE with added responsibilities. The 
one authority FDA transferred from OND to OSE is a premarket review 
responsibility. FDA officials said the agency plans to transfer 
authority for two postmarket responsibilities for reviewing certain 
types of drug safety studies, but the agency does not have a time frame 
for their transfer. Officials said that OSE must still gain experience 
leading the one transferred responsibility and expand its staff before 
it can assume these additional responsibilities. While most of the OSE 
and OND employees GAO interviewed indicated that OSE’s role in managing 
safety issues has increased since 2006, most OSE employees GAO 
interviewed said that OND’s perspective still carries more weight in 
decision making. OND recently created safety management positions in 
each of its 17 divisions; OSE expanded its similar positions from 9 to 
25, although an employee said turnover has made it difficult for the 
OSE managers to gain experience. FDA is also revising its program for 
resolving scientific disputes, but these changes have not increased its 
independence, as GAO recommended. 

FDA plans to implement new data systems and is increasing access to 
external data to assist with drug safety decisions. FDA plans to 
implement new systems in 2010 to improve the timeliness, quality, and 
analysis of reports of adverse events associated with human drug use. 
FDA has also increased funding for contracts with private companies and 
is in the early stages of forming partnerships with federal data 
holders to access external data. As mandated in the 2007 legislation, 
FDA is developing the Sentinel System, a network of external data 
providers intended to enhance drug safety surveillance, but the agency 
is in the early stages of developing it. 

FDA faces challenges meeting an expanding workload. The agency 
indicated that expanded responsibilities resulting from the 2007 
legislation increased its workload, and both OND and OSE employees 
described difficulties meeting their responsibilities. FDA indicated 
that since fiscal year 2008, OND staff increased from 736 to 928 and 
OSE staff increased from 114 to 193. However, an agency review suggests 
that OSE may still need to more than double its staff of 193 by fiscal 
year 2011 to meet its new responsibilities. Although OSE has increased 
its staff, officials cited hiring challenges, such as competition from 
the private sector, that may make it difficult to hire staff quickly 
enough to meet the increasing workload. FDA also expects to complete a 
growing number of drug safety studies, but technological and staffing 
challenges limit its capacity to conduct these studies. To assist its 
decision making, FDA has increasingly sought advice from members of its 
external drug safety advisory committee. However, the agency has 
encountered difficulty filling several committee vacancies. An official 
said FDA is reviewing candidates with the goal of filling these 
vacancies as soon as possible. 

What GAO Recommends: 

GAO recommends that FDA develop a comprehensive plan to prepare OSE for 
the transfer of additional regulatory authorities from OND. FDA agreed 
with GAO’s recommendation. 

View GAO-10-68 or key components. For more information, contact Marcia 
Crosse at (202) 512-7114 or crossem@gao.gov. 

[End of section] 

Contents: 

Letter: 

Background: 

FDA Has Begun to Formalize Its Postmarket Decision-Making Process and 
Recently Implemented Oversight Initiatives, but Challenges Remain: 

FDA Plans to Implement New Adverse Event Systems and Is Increasing 
Access to External Sources of Drug Safety Data: 

Although Staff Has Recently Increased, FDA Faces Challenges Meeting Its 
Expanding Postmarket Safety Workload: 

Conclusions: 

Recommendation: 

Agency Comments and Our Evaluation: 

Appendix I: Status of FDA Actions Related to Our 2006 Recommendations: 

Appendix II: Comments from the Department of Health and Human Services: 

Appendix III: GAO Contact and Staff Acknowledgments: 

Table: 

Table 1: Selected Data Sources FDA Uses to Inform Its Drug Safety 
Decision Making: 

Figure: 

Figure 1: OSE and OND Funding, Fiscal Years 2004 through 2009: 

Abbreviations: 

AERS: Adverse Event Reporting System: 

CDER: Center for Drug Evaluation and Research: 

CMS: Centers for Medicare & Medicaid Services: 

DARRTS: Document Archiving, Reporting, and Regulatory Tracking System: 

DCI: data collection instrument: 

DOD: Department of Defense: 

DPO: differing professional opinion: 

DSaRM: Drug Safety and Risk Management Advisory Committee: 

ESG: Electronic Submissions Gateway: 

FAERS: FDA Adverse Event Reporting System: 

FDA: Food and Drug Administration: 

FDAAA: Food and Drug Administration Amendments Act of 2007: 

HHS: Department of Health and Human Services: 

IOM: Institute of Medicine: 

MOA: memorandum of agreement: 

OIG: Office of Inspector General: 

OND: Office of New Drugs: 

OSE: Office of Surveillance and Epidemiology: 

PDUFA: Prescription Drug User Fee Act of 1992: 

REMS: Risk Evaluation and Mitigation Strategy: 

VA: Department of Veterans Affairs: 

[End of section] 

United States Government Accountability Office: 
Washington, DC 20548: 

November 9, 2009: 

The Honorable Charles E. Grassley: 
Ranking Member: 
Committee on Finance: 
United States Senate: 

Dear Senator Grassley: 

Concerns about the Food and Drug Administration's (FDA) management of 
safety issues for drugs approved for marketing have been long-standing. 
[Footnote 1] Reviews dating back over 30 years have identified problems 
related to the agency's monitoring of postmarket drug safety.[Footnote 
2] In 2004, high-profile drug safety cases continued to raise concerns 
about FDA's process for evaluating postmarket safety and making 
decisions about what actions to take. For example, FDA was criticized 
for taking too long to inform patients of serious drug risks. There 
were also reports of disagreements within the agency about how to 
address certain safety issues and reports that some FDA scientists were 
discouraged by supervisors from raising questions about the safety of 
certain drugs. FDA's process for making postmarket drug safety 
decisions involves multiple offices, including the Office of New Drugs 
(OND) and the Office of Surveillance and Epidemiology (OSE). OND is 
involved in drug review activities throughout the life cycle of a drug 
(that is, premarket and postmarket). For postmarket safety issues, 
OND's activities include interacting with OSE,[Footnote 3] which 
evaluates and monitors drug risks and promotes the safe use of drugs. 

Since these concerns were raised, we and other organizations have 
conducted reviews of FDA's process for monitoring the safety of 
marketed drugs. In 2006, we reported that FDA had not clearly defined 
the role of OSE in postmarket drug safety and communication problems 
between OND and OSE had hindered the decision-making process.[Footnote 
4] We also found weaknesses in the data that FDA relied on to identify 
postmarket drug safety issues and in the systems it used to track them 
once they were identified. In addition, a 2006 Institute of Medicine 
(IOM) report identified similar weaknesses. IOM also reported that 
FDA's resources for postmarket drug safety were inadequate and that 
this could impede the agency's ability to identify and take actions to 
address drug safety issues.[Footnote 5] More recently, HHS's Office of 
Inspector General (OIG) identified oversight of drug safety as one of 
HHS's top management challenges and earlier this year we added FDA's 
oversight of drugs and other medical products to our list of high-risk 
federal programs.[Footnote 6] 

You raised questions about FDA's postmarket drug safety program and 
asked that we follow up on our 2006 report to examine the role of OND 
and OSE in the postmarket monitoring of drugs. This report examines the 
steps that FDA is taking to (1) enhance its processes for making 
decisions about the safety of marketed drugs, (2) improve access to 
data that help the agency identify drug safety issues, and (3) build 
its capacity to fulfill its postmarket drug safety workload. 

To describe the steps FDA is taking to enhance its processes for making 
decisions about the safety of marketed drugs, we reviewed FDA policies 
and planning documents and interviewed officials to identify specific 
actions being taken by the agency.[Footnote 7] We also interviewed all 
individuals who were members of FDA's drug safety advisory committee of 
external experts, the Drug Safety and Risk Management Advisory 
Committee (DSaRM), as of January 2009. In addition, we examined 
policies related to FDA's program for resolving professional scientific 
disputes and interviewed FDA officials about its utilization by 
employees. To describe steps FDA is taking to improve access to data 
that help the agency identify drug safety issues, we reviewed 
documentation describing the development and implementation of systems 
the agency uses for collecting and monitoring drug safety data. We also 
examined contracts FDA has entered into with external organizations and 
agreements with federal agencies to access information about drug use 
and patient outcomes. To describe the steps that FDA is taking to build 
its capacity to fulfill its postmarket drug safety workload, we 
reviewed staffing data provided by the agency and documents related to 
the agency's efforts to assess workload. We also interviewed FDA 
officials regarding hiring initiatives to meet its postmarket drug 
safety responsibilities. 

In addition, to supplement our work for each of the three objectives, 
we conducted a series of interviews with small groups of OND and OSE 
employees with responsibilities involving postmarket drug safety. Each 
small group interview consisted of a group discussion to capture 
general themes about these activities. At the conclusion of each 
interview, we asked each employee to complete a written data collection 
instrument (DCI) to document their responses to specific questions 
about the agency's postmarket decision-making process. To select 
employees for our small group interviews, we obtained March 2009 
staffing data from FDA and confirmed the accuracy of these data through 
discussions with officials from OND and OSE. We also used our 
discussions with the OND and OSE officials to help us identify 
employees with no management responsibilities and at least 4 years of 
experience in the Center for Drug Evaluation and Research (CDER). We 
selected these employees because they are directly engaged in 
postmarket safety activities and would be in a position to comment on 
changes made by the agency since our 2006 report. 

* For OND, we selected employees from its four divisions with the 
largest number of employees,[Footnote 8] which we identified using the 
March 2009 staffing data. We determined that these data were 
sufficiently reliable for the purpose of our report. For each division, 
we randomly selected to interview five medical reviewers, who are the 
individuals responsible for reviewing data on the safety and efficacy 
of drugs. In one division, we also spoke with a second group of 
reviewers because that division has established separate teams of 
general reviewers and reviewers with specific drug safety 
responsibilities.[Footnote 9] Based on these selection criteria and the 
availability of employees, we conducted five small group interviews of 
four or five employees, each. 

* For OSE, we selected all employees from each of the office's five 
divisions who met our criteria to interview. For one division, we 
divided employees into two interview groups because of the large number 
of employees meeting our selection criteria. Based on these selection 
criteria and the availability of employees, we conducted six small 
group interviews of between three and six employees, each. 

Across all of the small groups, we interviewed a total of 52 employees, 
each of whom completed a DCI. The views expressed by these employees 
cannot be generalized to all employees working within these offices. 

We conducted this performance audit from October 2008 through October 
2009 in accordance with generally accepted government auditing 
standards. Those standards require that we plan and perform the audit 
to obtain sufficient, appropriate evidence to provide a reasonable 
basis for our findings and conclusions based on our audit objectives. 
We believe that the evidence obtained provides a reasonable basis for 
our findings and conclusions based on our audit objectives. 

Background: 

Before a drug can be marketed in the United States, its sponsor must 
demonstrate to FDA that the drug is safe and effective for its intended 
use. FDA approves a drug for marketing when the agency judges that its 
known benefits outweigh its known risks. However, because premarket 
evaluations are limited in their ability to always predict safety and 
efficacy with absolute certainty, FDA continues to assess a drug's 
risks and benefits after it has been marketed. If the agency identifies 
a postmarket safety issue, it makes a decision regarding whether to 
take a regulatory action, such as withdrawing the approval of a drug, 
which it rarely does, or communicating new safety information to the 
public and healthcare providers. 

FDA Organization Related to Postmarket Drug Safety Decision Making: 

The decision-making process for postmarket drug safety is complex, 
multidisciplinary, and relies on an iterative interaction between OND, 
OSE, and other FDA components.[Footnote 10] OND, which primarily 
conducts premarket reviews of drug applications submitted by drug 
sponsors, also has postmarket drug safety as one of its 
responsibilities. Although it interacts with OSE and staff from other 
offices concerning the postmarket safety of drugs, OND has ultimate 
responsibility to decide whether to take regulatory action regarding 
these issues. The office is organized into 17 review divisions that 
generally reflect certain therapeutic areas, such as gastroenterology 
or oncology drugs. The review of safety and efficacy data from drug 
applications is conducted by OND medical reviewers, who typically are 
physicians who have expertise in specific therapeutic areas and are 
skilled in the review of clinical trials. 

OSE's primary focus is on postmarket safety, although it is also 
involved in certain premarket drug safety issues. OSE has traditionally 
operated primarily in a consultant capacity to OND and has not had any 
independent decision-making responsibility. When a safety issue is 
identified, OSE staff may conduct an analysis and produce a written 
report called a "consult" to assist OND. Safety consults could include 
analyses of adverse event reports and assessments of postmarket study 
designs.[Footnote 11] In contrast to OND's organization by therapeutic 
area, OSE is organized into five divisions that each reflect different 
areas of its drug safety responsibilities. Two divisions analyze 
adverse event reports, one division reviews epidemiologic studies 
completed by drug sponsors and conducts its own studies,[Footnote 12] 
one division reviews risk management plans submitted by drug sponsors, 
[Footnote 13] and one division reviews proposed proprietary drug names 
submitted by drug sponsors for their new products and postmarket 
studies of medication errors completed by drug sponsors and others. 
[Footnote 14] 

To help it provide oversight of important, high-level safety decisions, 
FDA established the Drug Safety Oversight Board in spring 2005. 
[Footnote 15] The board is comprised primarily of FDA staff, including 
OND and OSE officials, but also includes officials from other federal 
agencies, such as the National Institutes of Health. It was established 
with the goal of providing independent oversight and making 
recommendations to the CDER Director about the management of important 
drug safety issues.[Footnote 16] 

An important part of the drug approval and postmarket monitoring 
process is the advice the agency receives from CDER's 16 drug-related 
scientific advisory committees composed of external experts.[Footnote 
17] The committees are generally organized into specific therapeutic 
areas, such as gastrointestinal drugs or oncologic drugs. In 2002, FDA 
established DSaRM, which is one of the 16 committees. In contrast to 
the committees focused on a specific therapeutic area, DSaRM was 
established to advise FDA on drug safety and risk management issues 
across therapeutic areas. The committee's charter states that DSaRM is 
to be composed of 14 members--13 voting members with drug safety 
expertise and 1 nonvoting member to represent the drug industry. DSaRM 
members can also be asked to participate in other scientific advisory 
committee meetings when safety issues are discussed. OSE sets the 
agenda for DSaRM meetings, whereas OND sets the agenda for meetings of 
the other 15 committees. Advisory committees may make recommendations 
to FDA that are not binding on the agency's decision making. 

If individuals within CDER have differences of professional opinion or 
scientific disputes regarding a decision taken by the agency, they are 
generally expected to try to resolve them through their supervisory 
chain. If staff cannot resolve the dispute through this process, they 
can access CDER's differing professional opinion (DPO) 
program.[Footnote 18] First implemented as a pilot program in November 
2004, it provides a process through which individuals can protest 
agency actions or inaction when they believe there is a risk of a 
significant negative impact on public health. Under this process, a 
dispute filed by a CDER employee could be reviewed by an ad hoc panel 
of three to four employees.[Footnote 19] The panel chair, who is 
appointed by the CDER Director, appoints the additional members, one of 
whom is nominated by the employee initiating the dispute. The panel 
would make a recommendation for resolving the dispute to the CDER 
Director. Several elements of this process are overseen by the CDER 
Ombudsman's Office, in consultation with the CDER Director.[Footnote 
20] 

Data That Inform FDA's Postmarket Decision-Making Process: 

FDA uses evidence from multiple data sources to inform its postmarket 
decision-making process, each of which has certain strengths and 
weaknesses. FDA uses randomized clinical trial data to assess drug 
safety prior to approval. However, these data have inherent weaknesses. 
Therefore, the agency uses other data to continue to assess drug safety 
once drugs are on the market. One method of assessing postmarket drug 
safety is through the collection and analysis of reports of adverse 
events associated with drug use. FDA requires drug sponsors to submit 
adverse event reports for the drugs they market.[Footnote 21] In 
addition, healthcare providers and patients may voluntarily submit 
adverse event reports to FDA's Medwatch program by telephone, by 
mailing or faxing a paper form, or through a Web-based application on 
the Medwatch Web site. In 1997, CDER implemented the Adverse Event 
Reporting System (AERS), which it uses to store reports of adverse 
events. Adverse events are often a basis for postmarket safety actions; 
however, adverse event reporting has limitations that make it hard to 
establish the magnitude of a safety problem or to compare risks across 
similar drugs. Therefore, once a "safety signal" is identified for a 
marketed drug,[Footnote 22] FDA may use data from observational 
epidemiologic studies to further examine relationships between a drug's 
use and reported adverse events. To conduct these studies, the agency 
seeks data from large, external databases of electronic health 
information--including claims data collected by health insurance 
companies and electronic medical records of care provided through large 
healthcare systems. (See table 1 for a description of these data 
sources used to inform drug safety decision making before and after 
approval.) 

Table 1: Selected Data Sources FDA Uses to Inform Its Drug Safety 
Decision Making: 

Data source: Description; 
Market status: Premarket: approval: Studies that randomly assign 
patients to either a treatment group that receives a drug or a control 
group that does not receive that drug; 
Market status: Postmarket: signal generation: Reports of adverse events 
received from patients, healthcare providers, and drug manufacturers 
once a drug is on the market; 
Market status: Postmarket: signal confirmation: Studies in which 
patients are not assigned to groups, but are studied as they receive 
treatment, such as, epidemiologic studies using data from large 
databases of electronic health information (insurance or medical 
records). 

Data source: Use; 
Market status: Premarket: approval: To assess drug safety and efficacy; 
Market status: Postmarket: signal generation: To generate "safety 
signals," which are potential relationships between use of a drug and 
an adverse event; 
Market status: Postmarket: signal confirmation: To confirm safety 
signals by further investigation of the relationship between the drug 
and the adverse event. 

Data source: Strengths; 
Market status: Premarket: approval: Randomization minimizes differences 
between the groups at the outset, which typically allows outcome 
differences to be attributed to the treatment; 
Market status: Postmarket: signal generation: Provides valuable 
information on rare, unexpected adverse events, including events that 
occur in patients other than those tested in clinical trials; 
Market status: Postmarket: signal confirmation: May involve larger 
groups of typical patients over longer periods of time, in more "real 
world" settings. 

Data source: Weaknesses; 
Market status: Premarket: approval: 
* Generally involve a small group of patients relative to the 
population that will ultimately use the drug; 
* Patients typically receive the drug over a short duration; 
* Elderly persons, pregnant women, and patients who have other medical 
problems may be excluded, thus enrolled patients may not reflect the 
patients who will take the drug; 
Market status: Postmarket: signal generation: 
* Not effective for attributing common events, such as heart attack, to 
drug use; 
* Adverse events are underreported and, for some drugs, FDA may not 
have access to the total number of people exposed, which makes 
estimating the magnitude of a safety problem difficult; 
Market status: Postmarket: signal confirmation: 
* There could be systematic differences between the treatment and 
control groups at the outset that account for outcome differences; 
* Concomitant use of other products, such as over-the-counter drugs or 
herbal supplements, may not be recorded in the databases, which could 
affect study results. 

Source: GAO. 

Note: This table presents examples of data sources that FDA may consult 
during the life cycle of a drug. FDA may use multiple data sources to 
evaluate a safety issue at any given time. For example, although 
clinical trial data are used to evaluate premarket safety, FDA also 
uses clinical trial data to evaluate postmarket drug safety. 

[End of table] 

Recent Reviews of FDA's Postmarket Drug Safety Oversight: 

In 2006, we reported that FDA's process for overseeing postmarket drug 
safety was limited by a lack of clarity about OSE's role in decision 
making. For example, while OSE often made recommendations to OND in the 
consults that it completed, the agency had no policy explicitly stating 
whether this was part of OSE's role. OSE staff also reported that these 
consults sometimes fell into a "black hole" or "abyss" and OSE staff 
would not be informed of the results of their recommendations. Also in 
2006, IOM noted that an imbalance in authority, formal role, and 
resources between OND and OSE constituted a major obstacle to a healthy 
organizational culture in CDER. Furthermore, IOM reported that FDA's 
challenges are reflective of how premarket and postmarket functions 
have been divided historically. OSE generally takes a population-based 
perspective in their drug safety work by utilizing adverse event 
reporting and observational studies, while OND generally takes a 
clinical perspective that focuses primarily on randomized clinical 
trials. They reported that OND staff often view the observational data 
used by OSE as "soft" and unconvincing, while OSE staff view these data 
as informative and carrying great weight. IOM noted that the imbalance 
in roles and responsibilities denoted a subservience of the safety 
function and a devaluation of OSE's discipline and approach by agency 
management. 

We also identified several specific limitations to FDA's postmarket 
decision-making process. Several years prior to the release of our 2006 
report, FDA started drafting a policy intended to clarify the role of 
staff, including those from OSE, in the decision-making process. 
However, the policy had not been finalized and implemented by the time 
our 2006 report was issued. In addition, we reported that the role of 
OSE staff in planning for and participating in advisory committee 
meetings, other than those involving DSaRM, was not clear. We also 
found that the DPO program had not been used and may not have been 
viewed as sufficiently independent because it did not offer employees a 
forum for resolving disputes that was independent of the CDER Director. 
We reported, for example, that the CDER Director would help decide 
whether a dispute warranted review and would also make the final 
decision about how the dispute would be resolved. 

We also found that OSE management had not effectively overseen 
postmarket drug safety and lacked systematic information on this 
process. Specifically, although OSE maintained a database of consult 
requests it received from OND, the database did not include information 
about whether OSE staff had made recommendations to OND regarding 
safety actions. It also did not include information on how the safety 
issues were resolved, including whether OSE's recommended safety 
actions were implemented by OND. In addition, in 2006, OIG found 
weaknesses in the extent to which FDA tracked another element of 
postmarket drug safety, the progression of postmarketing studies that 
FDA had requested drug sponsors to complete. OIG found that FDA could 
not readily identify whether or how timely these studies were 
progressing toward completion.[Footnote 23] 

We also found in 2006 that FDA faced constraints in its access to data 
that allow it to monitor the safety of marketed drugs. For example, FDA 
staff and external drug safety experts told us that OSE did not have 
enough funding to support the purchase of data for postmarket drug 
surveillance. Similarly, IOM found that funding for purchasing data was 
severely limited and had changed little in over 20 years. IOM also 
found that FDA devoted limited resources for staff training and 
supportive technology that was needed to fully utilize purchased data. 
Furthermore, IOM concluded that AERS was outdated and inefficient and 
the agency had given little attention to using systematic methods for 
screening AERS for adverse events. 

We made multiple recommendations to FDA in 2006 that were intended to 
improve its oversight of postmarket drug safety. We recommended that 
FDA: 

* revise and implement its draft policy on major postmarket drug safety 
decisions, 

* clarify OSE's role in FDA's scientific advisory committee meetings 
involving postmarket drug safety issues, 

* improve CDER's dispute resolution process by revising the DPO program 
to increase its independence, and: 

* establish a mechanism for systematically tracking OSE's 
recommendations and subsequent safety actions. 

(See appendix I for a summary of FDA actions taken in response to these 
recommendations.) 

Changes to FDA's Postmarket Drug Safety Authority and Funding: 

The Food and Drug Administration Amendments Act of 2007 (FDAAA) 
provided the agency with additional responsibilities intended to 
improve its oversight of postmarket drug safety.[Footnote 24] For 
example, FDAAA provided FDA with new authority to require drug sponsors 
to complete postmarketing studies to identify a serious risk or assess 
a known serious risk.[Footnote 25] Prior to the enactment of FDAAA, FDA 
only had the authority in limited circumstances to require drug 
sponsors to conduct a postmarket drug safety study;[Footnote 26] 
outside of these circumstances, the agency could request that drug 
sponsors voluntarily agree to conduct such studies. FDAAA also provided 
FDA with new authority to require drug sponsors to complete risk 
management plans. Previously, FDA issued guidance to drug sponsors to 
assist in the development of voluntary risk management plans. FDA may 
now require drug sponsors to implement a risk management plan through 
specific approaches, known as a Risk Evaluation and Mitigation Strategy 
(REMS).[Footnote 27] FDAAA also provided the agency with authority to 
impose civil monetary penalties on drug sponsors who violate these 
requirements.[Footnote 28] 

FDAAA also requires FDA to conduct several other postmarket drug safety 
activities. For example: 

* FDA must, in collaboration with public, academic, and private 
entities, develop a postmarket risk identification and analysis system 
that can be used to analyze safety data from multiple sources.[Footnote 
29] 

* FDA is required to screen AERS biweekly and publish quarterly reports 
of new safety information or potential signals of serious risks 
associated with the use of a drug.[Footnote 30] 

* FDA is required to use DSaRM to seek input on certain activities, 
such as elements of REMS and the analysis of drug safety data.[Footnote 
31] 

In addition to increasing FDA's authorities, FDAAA also reauthorized 
the Prescription Drug User Fee Act of 1992 (PDUFA).[Footnote 32] 
Originally, PDUFA authorized FDA to collect user fees[Footnote 33] from 
drug sponsors in order to support the review of drug applications and 
it established performance goals, such as time frames for the review of 
applications. The increase in attention to timely drug approval 
decisions led to greater awareness of the need for FDA to strengthen 
its monitoring of postmarket drug safety, which was reflected in the 
2002 reauthorization of PDUFA.[Footnote 34] The most recent 
authorization of PDUFA, in September 2007 as part of FDAAA, expanded 
the postmarket drug safety activities for which FDA is authorized to 
apply user fees.[Footnote 35] For example, the law identified the 
development of adverse event data collection systems as an activity 
that could be funded through user fees. In addition to amounts 
authorized to be used for all user fee activities, both premarket and 
postmarket, the PDUFA reauthorization identified specific annual fee 
revenues to be used for postmarket drug safety activities. In total, 
FDA reported that it plans to increase its allocation of annual user 
fees to support postmarket drug safety from about $54 million in fiscal 
year 2008 to about $102 million in fiscal year 2012.[Footnote 36] 

Overall premarket and postmarket funding for OSE and OND increased 
since fiscal year 2006.[Footnote 37] From fiscal year 2006 through 
fiscal year 2008, OSE funding increased from about $31 million to about 
$71 million. During that same period, OND funding increased from about 
$115 million to $144 million. For both OSE and OND, much of the 
increase occurred in fiscal year 2008 and can be attributed to 
increased user fees. (See fig. 1.) Additionally, across all of CDER, 
funding for postmarket drug safety increased from about $54 million in 
fiscal year 2006 to $139 million in fiscal year 2008. Of the $139 
million in fiscal year 2008, about $84 million was from fiscal year 
appropriations and $55 million was from user fees. 

Figure 1: OSE and OND Funding, Fiscal Years 2004 through 2009: 

[Refer to PDF for image: 2 line graphs] 

OSE Funding: 

Fiscal year: 2004; 
Fiscal year appropriations: $20.7 million; 
User fees: $6.3 million. 

Fiscal year: 2005; 
Fiscal year appropriations: $17 million; 
User fees: $7.6 million. 

Fiscal year: 2006; 
Fiscal year appropriations: $22 million; 
User fees: $8.9 million. 

Fiscal year: 2007; 
Fiscal year appropriations: $24.2 million; 
User fees: $9.6 million. 

Fiscal year: 2008; 
Fiscal year appropriations: $37.3 million; 
User fees: $33.2 million. 

Fiscal year: 2009 estimate; 
Fiscal year appropriations: $38.9 million; 
User fees: $38.6 million. 

OND Funding: 

Fiscal year: 2004; 
Fiscal year appropriations: $46.4 million; 
User fees: $51.7 million. 

Fiscal year: 2005; 
Fiscal year appropriations: $49.3 million; 
User fees: $56.8 million. 

Fiscal year: 2006; 
Fiscal year appropriations: $51.4 million; 
User fees: $63.7 million. 

Fiscal year: 2007; 
Fiscal year appropriations: $50.7 million; 
User fees: $73 million. 

Fiscal year: 2008; 
Fiscal year appropriations: $56.6 million; 
User fees: $87.4 million. 

Fiscal year: 2009 estimate; 
Fiscal year appropriations: $57.2 million; 
User fees: $107.3 million. 

Source: GAO analysis of FDA data. 

Note: Under PDUFA, FDA receives user fees from the pharmaceutical 
industry as part of its annual appropriation for salaries and expenses. 
We use the terms "user fee funding" to describe amounts derived from 
user fee collections and "fiscal year appropriations" to describe 
amounts derived from the General Fund of the Treasury to delineate the 
source of the appropriated funds. Both user fee funding and fiscal year 
appropriations are made available through the annual appropriations 
process. 

[End of figure] 

FDA Has Begun to Formalize Its Postmarket Decision-Making Process and 
Recently Implemented Oversight Initiatives, but Challenges Remain: 

FDA has begun to implement a new process and initiatives intended to 
clarify roles related to postmarket safety decision making, but faces a 
variety of challenges. Several initiatives have not been fully 
implemented and the agency has not increased the independence of its 
dispute resolution program. 

FDA Has Begun to Formalize OND and OSE's Decision-Making Process for 
Postmarket Drug Safety, but a Time Frame for Implementing Key Elements 
Has Yet to Be Established: 

To enhance postmarket drug safety, FDA has begun to formalize 
interactions between OND and OSE, although some key elements of this 
new process have not been implemented. In the past, FDA has not 
afforded the same focus and attention to postmarket drug safety as it 
has to the drug approval process. For example, an agency official said 
that, unlike for the premarket process, roles and responsibilities for 
the postmarket process have not been clearly defined. Therefore, in 
January 2008, the agency began to establish a new framework for drug 
safety--which it calls the Safety First Initiative--that is intended to 
provide this structure. Under the initiative, the agency has adopted a 
multidisciplinary approach based on the principles the agency refers to 
as Equal Voice, which are intended to ensure that all necessary parties 
contribute to decision making. In addition, OSE and OND signed a 
memorandum of agreement (MOA) in June 2008 that states FDA's intent for 
the two offices to contribute equally in determining regulatory actions 
related to drug safety.[Footnote 38] However, in most cases, OND 
retains the authority to decide whether to take regulatory action. 
According to FDA, OND retains these authorities because, for most 
decisions related to postmarket drug safety, OND staff have the 
broadest expertise in evaluating and managing clinical risks and 
benefits of drugs. 

However, as part of the MOA, FDA has transferred authority for one 
regulatory responsibility related to premarket drug safety from OND to 
OSE and plans to transfer authority for two postmarket 
responsibilities, but has not set a time frame for doing so. The MOA 
describes the agency's intent to transfer to OSE the authority to make 
final decisions for those activities in which the office has expertise. 
Initially, these include three drug safety activities that reside with 
OND: (1) review of proprietary drug names submitted by sponsors, (2) 
review of protocols and findings of observational epidemiologic 
studies, and (3) review of protocols and studies that assess medication 
error risks. In April 2009, OSE was transferred authority for the first 
regulatory responsibility, the premarket review of proprietary drug 
names, which gives OSE final decision-making authority for the activity 
and allows the office to communicate directly with the drug sponsor and 
issue letters approving or rejecting drug names. An OND official said 
that the transfer of authority for this responsibility has been 
beneficial because proprietary name review was not an area in which OND 
had much expertise. An OSE official said that, since the transfer, 
decisions have been more consistent and the decision letters issued to 
drug sponsors have been more transparent. Agency officials said they 
selected proprietary name reviews as the first authority to transfer to 
OSE because the process is well defined and self contained, and it will 
give OSE experience leading a significant drug safety activity while 
building its expertise to assume authority for the additional 
responsibilities named in the MOA. Officials said the agency intends to 
transfer authority for the two postmarket drug safety responsibilities 
to OSE, but it has not set a time frame for doing so. Agency officials 
added that coordinating some elements of the remaining responsibilities 
will be more complex and OSE still needs to increase its staff to 
assume these additional responsibilities. 

FDA has established multiple opportunities for staff from different 
disciplines to discuss drug safety issues. As part of the MOA, 
postmarket safety issues would be managed by an interdisciplinary team 
process that is similar to FDA's process for managing drug approvals. 
FDA issued an interim policy describing these safety issue teams in May 
2009. Teams would be created as needed and include the OSE, OND, and 
other staff necessary to evaluate a given safety issue and make a 
decision about any needed regulatory actions. As part of this process, 
the teams would establish target dates for evaluating the safety issue 
and later monitor the implementation of any regulatory actions. FDA 
officials said that teams have been formed in the past to discuss 
safety issues, but this new policy formalizes existing team-based 
review practices to provide consistency in resolving safety issues. 
Officials said that they began training staff on the new policy in July 
2009, but they could not provide an estimate of the number of teams 
that have been formed. In addition, FDA established routine joint 
safety meetings between OND divisions and their OSE counterparts. In 
contrast to the safety issue teams, which are established to manage a 
specific issue, the joint safety meetings focus on broader scientific 
matters and status updates of joint interest to both OND and OSE. The 
agency also continues to hold meetings of its Drug Safety Oversight 
Board. FDA indicated that the board serves as a forum to discuss 
emerging and often controversial drug safety issues. The board recently 
expanded its membership to include representatives from additional 
federal agencies, including the Department of Defense and HHS's Indian 
Health Service. According to FDA, board members from other federal 
agencies allow FDA to hear perspectives on how its drug safety 
decisions affect federal healthcare systems. 

OSE and OND employees in our small group interviews generally 
identified positive outcomes from FDA's initiatives, although most OSE 
employees indicated that OND still has more authority in the postmarket 
decision-making process. Many of the OND and OSE employees who 
participated in our small group interviews told us that the more 
formalized process for managing safety issues has helped improve 
interactions between the two offices since our last report. For 
example, several OSE employees said that they now consistently receive 
a response from OND about their consults and recommendations, even if 
they are not always followed, and these reports no longer fall into a 
"black hole," as we reported in 2006. Employees also described 
increased communication between the two offices, which some said 
improved tracking of safety issues but others said slowed the decision- 
making process. With regard to OSE's influence in the postmarket 
decision-making process, 75 percent (39 of 52) of OND and OSE employees 
who completed our DCI indicated that OSE's influence has increased 
since 2006. However, OND and OSE employees differed in whether they 
thought OSE currently serves as an equal partner in decision making. Of 
the OND employees who completed our DCI, 64 percent (14 of 22) 
indicated that OSE now serves as an equal partner. In contrast, 57 
percent (17 of 30) of OSE employees indicated that OND's perspective 
still carries more weight, although 60 percent (18 of 30) indicated 
that they thought OSE would serve as an equal partner once the new 
initiatives were fully implemented. 

Despite changes to FDA's postmarket decision-making process, OND and 
OSE employees report that differences still exist in how the two 
offices view information used to make decisions. For example, one OSE 
employee said that OND staff trust the results of randomized clinical 
trials over the epidemiologic data used by OSE, and another OSE 
employee said that OND is generally more resistant to accepting drug 
safety recommendations based on epidemiologic data. Some OND employees 
also said that physicians are better at identifying the direct clinical 
impact of a drug than other types of staff, such as epidemiologists, 
who may be more skilled in data analysis. OSE is taking steps to 
address these differences. For example, an official said that OSE has 
provided training to OND staff on the methods it uses to do its work. 
In addition, officials told us that OSE plans to increase clinical 
expertise by hiring additional medical reviewers to assist it with the 
review of adverse event reports. 

FDA Recently Implemented Initiatives to Facilitate Oversight of 
Postmarket Safety Issues, although There Have Been Implementation 
Challenges: 

FDA implemented both staffing and tracking initiatives intended to 
improve oversight of postmarket drug safety issues. In January 2008, 
OND created two new safety management positions within each of its 17 
review divisions to reduce variability in how the divisions oversee 
postmarket drug safety.[Footnote 39] In addition to coordinating 
interactions between the offices, employees in these new management 
positions are to provide leadership and to ensure that adequate OND 
resources and attention are focused on safety issues. They also track 
postmarket safety activities which may reduce the burden on individual 
medical reviewers, who are also responsible for reviewing and 
recommending whether to approve drug applications. Several OND medical 
reviewers indicated during the small group interviews that the OND 
safety management positions have helped to track and coordinate 
management of postmarket safety issues. For example, one medical 
reviewer noted that medical reviewers have competing premarket 
deadlines related to PDUFA and it is helpful to have safety staff who 
do not have these deadlines and can focus on postmarket drug safety. 

In addition, OSE reorganized its existing safety project manager 
positions into a single group in October 2006 to oversee the management 
of safety issues across OSE divisions. These safety project manager 
positions serve as OSE counterparts to the OND management positions and 
are responsible for, among other things, coordinating meetings with OND 
and monitoring OSE activities. These project manager positions were 
each previously assigned to a specific OSE division. An OSE official 
said this reorganization was intended to provide OND staff with a 
single point of contact within OSE, rather than having separate 
contacts for each OSE division. Since the reorganization, the total 
number of safety project manager positions in this group has expanded 
from 9 to 25. However, several OSE employees in our small group 
interviews cited challenges related to their interactions with those 
holding these OSE safety project manager positions. Some said 
individuals in these positions still seem to be learning their new 
roles and responsibilities. An employee also said that turnover among 
the safety project manager positions has made it difficult for the 
individuals holding those positions to gain experience. As of July 
2009, 20 of the 25 OSE safety project manager positions were filled, 
but an official stated that turnover has been a problem and only one of 
the individuals has been in that position since October 2006. The 
official said that the expansion of responsibilities resulting from the 
reorganization was challenging for some of the individuals and noted 
that a lack of training and clear policies and procedures for these new 
positions may have contributed to the high turnover. The official said 
OSE is hoping to improve retention by implementing training and other 
support systems for these staff. 

FDA is also implementing a new tracking system to assist OSE and OND 
staff in overseeing identified safety issues, although the system has 
limitations. In January 2007, in response to our 2006 recommendation, 
FDA began to incorporate a safety module within its Document Archiving, 
Reporting, and Regulatory Tracking System (DARRTS) to track the 
agency's management of and response to significant safety issues 
identified with the use of marketed drugs.[Footnote 40] FDA requires 
that each significant safety issue identified by OND and OSE be tracked 
within DARRTS by creating a "tracked safety issue" file. As of July 14, 
2009, there were 394 active issues. DARRTS is used, among other things, 
to generate a workplan and assign responsibilities for managing these 
issues, as well as to provide updates on the status of these issues. 
Officials told us that while the system contains documents describing 
specific recommendations and safety actions, it does not, as we 
recommended, allow FDA to systematically track how issues were resolved 
and whether OSE's recommendations were implemented. For example, an FDA 
official told us that DARRTS cannot provide the agency with a summary 
of the recommendations for safety actions that OSE has made to OND or 
how the safety issues were ultimately resolved. FDA indicated that, due 
to limited resources, it does not plan to incorporate this capability 
into DARRTS in the next year or two. In addition, FDA has identified 
certain limitations with the system, such as problems of completeness 
and accuracy and the need for a mechanism to notify relevant staff when 
a new tracked safety issue is created. According to FDA, some of the 
identified problems have been corrected while others will be addressed 
at a later date. An official said that the agency expects that future 
problems will be minimized by improved preimplementation testing. For 
example, the official noted that the July 2009 update of DARRTS, which 
allows the system to be used for monitoring both postmarket studies and 
risk management plans, was more rigorously tested by users prior to its 
implementation. 

FDA is also utilizing contractors to improve oversight of specific new 
authorities created by FDAAA. We and others have identified problems in 
the agency's tracking of required and requested postmarketing studies, 
such as OND reviewers not meeting their goals for reviewing in a timely 
manner the annual status reports submitted by drug sponsors.[Footnote 
41] In 2008, FDA hired a contractor to monitor and provide support for 
postmarketing studies, including the review of these annual status 
reports.[Footnote 42] FDA officials said that this contract has been 
very productive because it allows the review of the annual status 
reports to be completed, which is very time consuming, while allowing 
the agency to move ahead in its oversight of the new postmarketing 
studies it is requiring under its FDAAA authority. The agency is also 
hiring a contractor to help oversee the required risk management plans. 

FDA Is Revising Its Program for Resolving Scientific Disputes but the 
Changes Have Not Sufficiently Addressed the Independence of the 
Process: 

FDA is revising CDER's program for resolving scientific disputes raised 
by individual employees, but the changes do not sufficiently address 
our prior recommendation for improving the independence of the process. 
Beginning in 2007, FDA conducted a review of each of its centers' 
dispute resolution processes, including CDER's DPO program.[Footnote 
43] As a result of this review, FDA developed a list of mandatory 
elements for all centers to implement during fiscal year 2008 and a 
list of voluntary best practices for scientific dispute resolution 
activities. For example, FDA now requires that employees of each center 
who file a DPO have the option to appeal to FDA's Office of the 
Commissioner for a review to determine if the center followed its own 
dispute resolution process correctly.[Footnote 44] CDER indicated that 
its DPO policy is being revised to reflect this "process review" and 
other new agencywide requirements, but noted that CDER plans to make 
few other changes. As of October 2009, the revised policy had not been 
finalized. 

While CDER continues to make changes to its DPO policy, the planned 
changes do not address a weakness we identified in our 2006 report-- 
that the program it established to resolve scientific disputes may not 
be viewed as independent as a result of the CDER Director's extensive 
involvement. According to a July 2009 draft of the revised policy, as 
was the case in 2006, the Ombudsman, whom the policy designates as the 
focal point for overseeing the resolution of disputes, would consult 
with the CDER Director before deciding whether a dispute warrants 
review. An agency official told us that this consultation is important 
because the Ombudsman does not have the same scientific expertise as 
the CDER Director. The official acknowledged that, while the Ombudsman 
is included as a way to improve the independence of the DPO program, 
this position does not meet the standards of independence established 
by the Coalition of Federal Ombudsmen.[Footnote 45] In addition, 
according to the draft DPO policy, the CDER Director would still 
appoint the chair of the ad hoc review panel and decide how the dispute 
should be resolved, in consideration of the panel's recommendation. The 
draft DPO policy includes the required option of a process review by 
the Office of the Commissioner, which would not involve the center 
director or other center staff in decision making. However, this review 
is limited to determining whether CDER followed its own processes 
correctly, and it does not consider the scientific merits of the 
dispute. As a result, CDER's revised DPO program still may not be 
viewed as sufficiently independent for resolving disputes. 

As of July 2009, CDER's DPO program had not been used to resolve a 
difference of opinion. The Ombudsman attributed the lack of use to the 
CDER Ombudsman's Office's management of disputes so that they never 
reach the level of a formal DPO.[Footnote 46] FDA also indicated that 
the DPO program is narrowly focused on individual disagreements that 
employees have been unable to resolve within their supervisory chain; 
if agreement has not been reached between scientific disciplines, the 
principles of Equal Voice are intended to help different disciplines 
express differences of opinion. OND and OSE employees who completed our 
DCI reported a variety of reasons for why they chose not to file a 
formal DPO. Of the 52 OND and OSE employees who completed our DCI, 36 
indicated that they had not had a difference of opinion that would have 
qualified for filing a dispute. However, 13 of the employees did report 
having a difference of opinion where they thought that FDA's action or 
lack of action had the potential to have a significant negative impact 
on public health.[Footnote 47] When asked why they did not use CDER's 
program to resolve this difference, these employees most frequently 
indicated that they preferred to express the opinion in written 
documentation (7) or were not aware of the program (6).[Footnote 48] In 
addition, 3 of these 13 employees noted concerns about the fairness of 
the DPO program as one reason for why they did not utilize it. None of 
the 13 employees indicated that they preferred the option of discussing 
the differing opinion informally with the Ombudsman.[Footnote 49] 

FDA Plans to Implement New Adverse Event Systems and Is Increasing 
Access to External Sources of Drug Safety Data: 

FDA plans to improve its identification of drug safety issues by 
developing new adverse event systems to collect and store adverse event 
reports and by increasing access to external sources of data. However, 
the adverse event systems and a new network of external data providers 
have not yet been implemented. 

FDA Is Developing New Systems to Improve Collection and Analysis of 
Drug Adverse Event Reports, but Implementation Is Not Expected Until 
2010: 

FDA is developing two new adverse event systems to help it identify 
drug safety problems--one to improve the collection and processing of 
adverse event reports and another to store reports and provide FDA 
staff with improved tools for analyzing them. FDA's complete adverse 
event system for human drugs will not be implemented until the end of 
2010. 

Adverse Event Collection and Processing: 

The new adverse event report collection and processing system, 
MedWatchPlus, is intended to increase the accuracy and timeliness of 
reports accessible to FDA staff and is scheduled to be implemented for 
human drugs by summer 2010.[Footnote 50] The current MedWatch Web site 
collects adverse event reports about prescription drugs by providing 
forms that patients and healthcare providers can submit online or 
download and send to FDA in paper form.[Footnote 51] Drug manufacturers 
may also use this system to download forms, although they may elect to 
submit electronically through an alternative system, the Electronic 
Submissions Gateway (ESG).[Footnote 52] Although reports submitted 
through ESG go directly into CDER's database of adverse events, AERS, 
paper reports, and reports submitted using the MedWatch online form 
must be processed and manually entered into AERS before they are 
available to FDA staff. FDA estimates that reports submitted on paper 
may take from 2 weeks to 2 months from the time of receipt to be 
entered into AERS where they can be analyzed by FDA staff. The new 
MedWatchPlus system will allow online reports to be processed 
automatically and transferred directly into the agency's adverse event 
system,[Footnote 53] reducing the need to process and enter reports 
manually. According to FDA, automatic processing will cut down on 
errors related to data entry and should allow for more timely 
availability of reports for analysis. FDA estimates that electronic 
submissions are generally available in AERS within 2 days of their 
receipt. 

FDA expects that MedWatchPlus will enable the agency to increase the 
electronic submission rate of reports, increase the number of reports 
accessible to FDA staff for analysis, and improve report quality. In 
fiscal year 2008, 61 percent of reports from manufacturers were 
submitted electronically. In August 2009, FDA issued notice of a 
proposed rule that would require manufacturers to submit adverse event 
reports electronically,[Footnote 54] which would mean that 
manufacturers who do not currently submit reports electronically would 
either use ESG or would need to use the MedWatchPlus online form. 
[Footnote 55] Increasing the electronic submission rate should allow 
for more reports to be available to FDA staff. Currently, FDA does not 
routinely enter all paper reports from manufacturers into AERS, 
[Footnote 56] which an official said is because of the cost to the 
agency. However, all reports from manufacturers submitted 
electronically through MedWatchPlus will be automatically entered into 
AERS, which should reduce costs and allow for more reports to be 
available for analysis.[Footnote 57] FDA also expects to increase the 
number of electronic submissions from patients and healthcare providers 
by making the system easier to use. As part of MedWatchPlus, FDA will 
use an interactive questionnaire that will guide submitters through a 
series of questions, which FDA expects will increase the accuracy and 
completeness of reports. For example, submitter errors, such as 
inaccurate drug names, create a burden for FDA.[Footnote 58] Through 
MedWatchPlus, the submitter will be provided with a menu of choices for 
the name of the drug. The questionnaire will also audit the information 
received and prompt for missing information. 

Adverse Event Storage and Analysis: 

FDA is also developing a new database to store adverse event reports 
once they have been submitted that should offer integrated data 
analysis features to facilitate the identification of safety issues. 
The new database, the FDA Adverse Event Reporting System (FAERS), is 
expected to receive reports from MedWatchPlus and other FDA 
applications for all FDA-regulated products and store them in a single 
location.[Footnote 59] In addition to avoiding redundancy among the 
center databases, FDA has stated that a consolidated database would 
benefit drug safety, for example, by facilitating the sharing of 
adverse event reports across centers for combination products.[Footnote 
60] FAERS will replace AERS and is intended to address some current 
AERS limitations that affect how OSE staff do their work. FDA officials 
told us that OSE staff view the current version of AERS as a giant 
"filing cabinet," which lacks integrated software for data mining and 
signal management that could help them to monitor drug safety more 
effectively.[Footnote 61] FDA officials said that, currently, to use 
the software, staff have to periodically extract the data from AERS and 
transfer them to another system for analysis, which means that analyses 
cannot be conducted in real time. In contrast, FDA plans to include 
integrated signal management and data mining software in FAERS, which 
will make these features easier to use and allow for analyses of safety 
signals closer to real time. 

FDA officials said that the agency plans to address other adverse event 
report quality problems by including new features in FAERS. For 
example, an adverse event reviewer told us that AERS lacks a dedicated 
data field (such as a checkbox) to indicate whether a female patient 
described in an adverse event report is pregnant. As a result, 
reviewers must manually review the narrative of reports for women aged 
15 to 45 to determine whether the patient was pregnant. FDA officials 
said that FDA plans to include a dedicated data field to indicate 
whether a report identified the patient as pregnant in FAERS. An 
adverse event reviewer also identified the lack of a link between an 
adverse event report and FDA-approved label information as a problem 
because it hinders staff in determining whether the adverse event is 
new or has already been identified and included in the drug's label. 
FDA officials said that linkage to label information is a goal for 
inclusion in FAERS, but it is complex and the agency does not have a 
time frame for its inclusion. 

FAERS development has experienced delays, but FDA expects that it will 
be partially implemented by the end of 2010. FDA began developing an 
update to AERS in 2004. However, according to a 2006 report by an FDA 
contractor, deficiencies in FDA's procurement practices and the 
agency's decision to expand the project's scope to develop an 
agencywide database for all FDA-regulated products resulted in delays. 
[Footnote 62] The contractor reported that these obstacles in 
development resulted in a 4-to 5-year delay and an estimated $25 
million in additional development costs. Currently, FDA indicated that 
it is prioritizing FAERS requirements to determine what features and 
capabilities are possible for the first version of FAERS. FDA plans to 
complete the first version of FAERS, for drugs and biologics, by the 
end of 2010. However, this version will not include fully integrated 
data mining and signal management software. FDA does not have an 
estimated time frame for when these features will be fully integrated. 

FDA Increased Funding for External Data Acquisition and Is Beginning to 
Access Data from Federal Sources: 

FDA increased funding for acquiring the external data that it uses to 
examine drug safety issues from about $5 million in fiscal year 2007, 
to about $28 million in fiscal year 2008.[Footnote 63] FDA recently 
added additional funds to existing contracts with four private 
companies that conduct drug safety studies using their own databases of 
electronic health information. Since FDA initially awarded about $5.4 
million in total to these companies in fiscal year 2005, these 
contracts have yielded five completed epidemiologic studies on drug 
safety, including a study on how antidepressant use in pregnancy 
affects the health of newborns. In fiscal year 2008, FDA added about $9 
million in total to the four contracts. However, FDA officials said 
that under the current contracts it is difficult to expand funding in 
response to the agency's needs and they will be changing to a different 
contract type when these contracts end in 2010.[Footnote 64] They said 
the new contract type will make it easier to add funds as the need 
arises for additional epidemiologic studies to examine previously 
unknown drug safety issues. 

FDA has also used the increased data acquisition funds for contracts 
with private companies that allow FDA staff direct access to data that 
can be used to conduct drug safety studies internally. These contracts 
provide the agency with access to drug utilization data, which are 
useful to FDA for, among other things, providing an estimate of how 
many people have been exposed to a drug, which provides context for 
adverse event analyses. These contracts allow FDA to download the data 
onto the agency's servers where staff can access the data to conduct 
drug safety studies. In 2008, FDA awarded contracts valued collectively 
at over $14 million for a base year and 3 option years.[Footnote 65] 
The three new contracts replaced an existing contract with a single 
vendor and, according to an FDA official, represent an approximate 
tripling of funding for access to drug utilization data. The official 
also said that contracts with three vendors allow shortcomings in one 
data set to be compensated by information from another. For example, 
one contractor has mail order pharmacy claims data, which are not 
available from the other two contractors. 

In addition to funding contracts with private companies, FDA is in the 
early stages of forming partnerships with the Department of Veterans 
Affairs (VA), the Department of Defense (DOD), and the Centers for 
Medicare & Medicaid Services (CMS) to access their databases of 
electronic health information for drug safety research. FDA signed 
memoranda of understanding with VA and DOD in 2007 to enable these 
agencies to share information necessary to evaluate drug safety with 
FDA. FDA allocated about $3.6 million to fund these agreements in 2008, 
which among other things, provided funding for research projects, such 
as a study of the relationship between the use of smoking cessation 
drugs and suicidal behavior, and funding for staff to support such 
studies.[Footnote 66] In addition, FDA signed an interagency agreement 
with CMS in August 2008 to access both Medicaid and Medicare data. As 
part of this agreement, FDA transferred $1 million to CMS in part to 
fund a project to create a Medicaid database amenable to research on 
drug safety.[Footnote 67] FDA is also working on several pilot projects 
using Medicare prescription drug data. These data on Medicare 
beneficiaries provide the agency with access to new information on the 
elderly and disabled--groups that are generally underrepresented in 
traditional clinical trials that FDA uses to assess safety prior to 
approval. FDA officials said that partnering with federal agencies is 
beneficial because they have large databases of electronic health 
information that may be accessed more cheaply than contracting with 
private entities. 

FDA Is in the Early Stages of Developing a Network of External Data 
Providers Intended to Enhance Its Drug Safety Surveillance: 

FDA is also taking steps to improve identification of safety issues by 
creating a network of external drug safety data providers, but the 
agency is in the early stages of developing it. The FDAAA-mandated 
surveillance system, known as the Sentinel System, will be a network of 
databases of electronic health information that can be utilized for 
safety signal evaluation for drugs and other marketed medical products. 
FDA officials said one of the purposes of the Sentinel System will be 
to provide the agency with an active surveillance tool that will be 
capable of generating safety signals that are not identifiable through 
AERS. For example, AERS relies on patients and doctors to submit 
adverse event reports, but if they do not recognize an event as being 
potentially drug-related, they may not file an adverse event report. In 
addition, FDA expects that the Sentinel System will build on the 
current data contracts the agency uses to conduct formal epidemiologic 
studies, which are generally used to confirm safety signals after they 
have been identified, by allowing researchers to specify potential 
safety problems in advance and monitor for these problems in near real 
time. The Sentinel System is in the early stages of development and as 
of June 2009 there were no established milestones.[Footnote 68] Thus 
far, FDA has established a senior management team, conducted a series 
of meetings with stakeholders, and created a working group of federal 
agencies that are developing complimentary initiatives. FDA officials 
said they have not finalized funding or staffing plans for the system. 
In addition, many other key decisions have yet to be made, including: 
sources of data, an information technology infrastructure, and methods 
of analysis. In 2008, FDA awarded eight contracts to investigate these 
and other issues. Seven of the reports from these contracts have been 
completed and FDA expects that the remaining report will be completed 
by the end of 2009. 

Although Staff Has Recently Increased, FDA Faces Challenges Meeting Its 
Expanding Postmarket Safety Workload: 

FDA's workload related to postmarket drug safety has increased as a 
result of new authorities and other factors. While the agency received 
increased funding and is hiring staff to conduct postmarket drug safety 
activities, it faces difficulties in recruiting the additional staff 
and external experts needed to meet its increasing responsibilities. 

FDA Reports That New Postmarket Drug Safety Responsibilities Have 
Increased Its Workload and That It Is Challenged by Competing 
Priorities: 

FDA reports that new postmarket drug safety responsibilities and other 
factors have led to an increased workload for which FDA has identified 
a need for increased staff.[Footnote 69] Of the OSE and OND staff that 
completed our DCI, 77 percent (40 of 52) indicated that their workload 
had increased or greatly increased since 2006. In addition, 60 percent 
(31 of 52) of the employees said that they either were not able to meet 
their postmarket drug safety responsibilities during an average 
workweek or were only able to meet these responsibilities by working 
overtime. Many employees told us during our small group interviews that 
one source of this increased workload has been the new postmarket drug 
safety responsibilities added by FDAAA. FDA officials said that 
requiring a drug sponsor to conduct postmarketing studies is more time 
consuming for FDA staff than the past process of requesting such 
studies. For example, to require a study, officials said the agency 
needs to document its rationale in a legally enforceable contract with 
a sponsor that may describe specific elements of the study design. The 
agency also works with sponsors to establish milestones for the 
completion of these studies. In addition, officials said the process of 
overseeing the development and implementation of a drug sponsor's 
required risk management plan has led to additional meetings between 
OND and OSE, as well as additional interactions with drug sponsors to 
review the proposal and discuss even minor modifications to it. FDA 
officials said that the new FDAAA authorities are especially time 
consuming because the agency is still developing processes for how to 
conduct this new work. Officials said that proposals for requiring 
postmarketing studies and REMS are being reviewed by others within FDA 
to ensure consistency in the application of the authorities. FDA 
officials expect that some of this additional workload will decrease as 
the process becomes more routine. 

OND medical reviewers described challenges meeting their premarket and 
postmarket responsibilities. Several reviewers noted that their primary 
focus is on completing premarket work within PDUFA time frames, and 
issues related to postmarket safety receive lesser priority. Two 
medical reviewers said that important identified safety issues would 
take priority over meeting PDUFA deadlines, but other reviewers told us 
that their workload prevents them from conducting reviews that would 
allow them to identify new postmarket safety issues. For example, 
reviewers said they are unable to fully review the Periodic Safety 
Update Reports submitted by drug sponsors, which are comprehensive 
reports containing information on serious and nonserious adverse 
events.[Footnote 70] According to some OND reviewers, medical reviewers 
do not have the time to fully analyze these reports to look for 
potential safety issues.[Footnote 71] OSE staff told us that workload 
demands prevent them from reviewing these reports. Given that 
nonserious adverse events may not be entered into AERS, failure to 
fully review Periodic Safety Update Reports may result in FDA missing 
safety signals for nonserious adverse events. 

OSE also reported that competing demands impact its ability to meet its 
postmarket responsibilities, such as its new premarket responsibilities 
for reviewing proposed proprietary drug names within PDUFA deadlines 
and communicating its decisions to drug sponsors. The staff involved in 
these reviews estimated that approximately 90 percent of their time is 
spent on such premarket activities, which leaves little time to spend 
on their other postmarket drug safety responsibilities, such as 
analyzing reports of medication errors. For example, an FDA employee 
told us that they do monitor AERS to identify safety signals, but they 
do not have time to complete follow-up reviews of these signals. 
Although employees agreed that the most important safety issues do get 
resolved, one employee said that follow-up reviews are often lower 
priority than fulfilling premarket responsibilities.[Footnote 72] In 
addition, other OSE staff identified competing demands that hampered 
their ability to conduct postmarket safety work. For example, OSE 
adverse event reviewers told us that consult requests from OND consumed 
the majority of their time, leaving them less time to conduct self- 
initiated safety analyses of adverse event data. According to FDA, each 
OSE adverse event reviewer receives an average of about 44 adverse 
events reports per day,[Footnote 73] and reviewers told us that given 
competing priorities, they are not able to review them all. 

A contractor reviewing OSE's increasing workload found that additional 
staff will be needed in order to fulfill the new responsibilities 
related to FDAAA and the MOA. According to the contractor's December 
2008 report, OSE would need an estimated total of 453 full-time 
equivalent employees by 2011 to meet its increased workload, more than 
double OSE's current staffing.[Footnote 74] While the contractor 
identified workload increases throughout OSE, it found that the 
greatest increases would be related to the review of risk management 
plans and postmarket safety data, such as adverse events. 

FDA Has Hired Some New Staff, but May Face Obstacles Recruiting 
Additional Staff to Manage Its Increased Workload: 

OSE and OND officials described fiscal year 2008 as a very successful 
hiring year, due in part to specific hiring initiatives. FDA indicated 
that since the start of fiscal year 2008, OND increased its staff from 
736 to 928 and OSE increased its staff from 114 to 193.[Footnote 75] 
The staff hired included OND medical reviewers who conduct premarket 
and postmarket reviews and OSE staff with postmarket drug safety 
responsibilities, such as epidemiologists and risk management experts. 
Agency officials attributed this success to specific hiring 
initiatives. For example, officials told us that both OSE and OND used 
a summer 2008 job fair and direct-hire authority to hire staff more 
quickly.[Footnote 76] While the agency has had direct-hire authority 
for medical reviewers since 2003, FDA indicated that it temporarily 
obtained direct-hire authority from April 2008 through September 2008 
for epidemiologists. The OSE and OND Directors said that they hired 
candidates within weeks under the authority, rather than the 3 to 6 
months it can typically take to announce positions, screen 
applications, conduct interviews, and hire individuals. The OSE 
Director told us that without the authority, interested candidates have 
sometimes accepted employment offers elsewhere before FDA could extend 
its own offer.[Footnote 77] In addition, an official said that CDER's 
ability to offer hiring bonuses, relocation reimbursement, and student 
loan repayment contributed to its hiring success during fiscal year 
2008.[Footnote 78] 

Although OSE significantly increased its staff in fiscal year 2008, 
hiring and staffing challenges could make it difficult for the office 
to meet the workload generated by its new postmarket drug safety 
responsibilities. While the contractor estimated that OSE would need 
453 full-time equivalent employees by 2011, the OSE Director did not 
know if the agency planned to increase OSE's fiscal year 2009 staff 
ceiling of 211 in fiscal year 2010. However, officials said that 
recruiting the right people with the desired drug safety expertise is 
difficult. For example, an OSE official said that it is hard to find 
candidates who have experience with the specific epidemiologic 
activities conducted by FDA, and the agency therefore looks for 
candidates with epidemiologic skills who can then be trained by the 
agency once they are hired. Officials indicated that while the new 
hires can bring up-to-date skills, their lack of experience means that 
it can take up to 3 years before newly hired employees can work 
independently. In addition, an official said it is difficult for OSE to 
compete with drug companies, who can offer higher compensation, for the 
same pool of talent. Given the estimated workload increases identified 
in the FDA contractor's December 2008 review, OSE may be challenged to 
hire staff quickly enough to meet its increasing workload. 

FDA Faces Technological and Staffing Challenges That Limit Its Capacity 
to Conduct a Growing Number of Postmarket Safety Studies: 

FDA officials said that they lack adequate computational capacity and 
enough staff to make full use of external sources of data for drug 
safety studies, and FDA expects the number of such studies to grow. OSE 
has increased funding for acquiring external data and a recent workload 
planning report prepared by an FDA contractor indicates that OSE 
intends to triple the number of epidemiological studies it conducts 
using such data from 13 in 2008 to 39 in 2011. An OSE official told us 
that currently, most of the epidemiologic studies are conducted by 
contractors, but that OSE would like to conduct more studies 
internally. The official said that internal studies afford FDA more 
control over the analyses, as well as provide increased professional 
opportunities to OSE staff, which may lead to greater staff retention. 
However, the official said that conducting more internal studies would 
require greater computational capacity and more staff.[Footnote 79] OSE 
officials told us, for example, that the current technological 
infrastructure limits staff to running a single analysis at a time and 
that the computer servers in CDER "routinely crash" when dealing with 
large data sets. OSE officials also said that they lack programmers who 
are needed to extract data from databases and prepare data sets for 
analysis. OSE officials said that the office has faced difficulties 
hiring programmers because the position descriptions that it would use 
to hire these programmers are currently only available to the agency's 
Office of Information Management, which has meant that such staff may 
not be hired by OSE.[Footnote 80] They indicated that, without enough 
programmers, this work is shifted to epidemiologists, who must then 
spend more time on each study and have less time to devote to 
developing and carrying out additional studies. 

CDER is developing a computational science center that is intended to 
address some of these challenges, but this center is in the early 
stages of development. FDA indicated that the center is intended to 
support both pre-and postmarket quantitative analyses of the safety, 
efficacy, and quality of drugs.[Footnote 81] FDA officials said it 
should address current problems by providing increased computational 
capacity and more staff, including programmers and data managers that 
can be utilized by OSE. However, they said that the center is currently 
in the developmental stages, and that there is no time frame for its 
completion.[Footnote 82] In the interim, OSE is using short-term fixes, 
such as increasing the memory capacity of existing servers. OSE 
officials noted that OSE may also contract out some programming work, 
although they described challenges associated with contracting out this 
type of work. The officials said that each drug safety study can take 1 
to 2 years to complete and receiving programming support on a task-by- 
task basis requires OSE to spend time reeducating new programmers each 
time there is a new task. In contrast, an OSE official said that having 
programmers within CDER could allow them to gain expertise on the kind 
of work OSE does. 

FDA Has Encountered Difficulties Filling Vacancies for Its Increasingly 
Utilized Committee of External Drug Safety Experts: 

FDA increasingly utilized external drug safety experts serving on DSaRM 
to participate in advisory committee meetings to discuss identified 
safety issues of specific products, but the agency faces challenges 
recruiting new members. From 2002 through 2006, DSaRM met 9 times in 5 
years--5 times on its own as a committee and 4 times as part of joint 
meetings with other advisory committees. DSaRM met more frequently from 
January 2007 through December 2008, meeting 9 times--once on its own 
and 8 times as part of joint meetings. Most DSaRM meetings, and all 9 
of the meetings in 2007 and 2008, have been held to discuss drug- 
specific issues. In addition to attending joint advisory committee 
meetings, individual DSaRM members served temporarily to supplement 
expertise during 12 meetings of other CDER advisory committees that 
occurred from 2007 through 2008.[Footnote 83] While several DSaRM 
members acknowledged the important expertise in drug safety that they 
can bring to discussions with other advisory committees, some members 
told us that the small number of meetings involving only DSaRM has 
resulted in a lack of cohesion among committee members. In addition, 
some members noted that meeting as a single committee would allow them 
to discuss broad principles of drug safety, rather than specific drug 
products, and to examine lessons learned across meetings. One member 
noted that without meeting as a single group on broad safety issues, 
the committee is unable to take advantage of the cumulative learning 
that comes with a coherent process. An FDA official said that the 
agency recognizes that temporarily serving on other advisory committees 
has been a burden for DSaRM members. The official said that, therefore, 
the agency has been expanding a pool of consultants that can instead 
provide temporary drug safety expertise at these other advisory 
committee meetings.[Footnote 84] 

Despite the increased demand for DSaRM's drug safety expertise, the 
agency has been challenged to fill all of the committee's vacancies. 
For the past few years DSaRM has had between 6 and 9 of its 14 slots 
vacant. In contrast, from 2003 through 2006, DSaRM had no more than one 
vacancy.[Footnote 85] A few of the DSaRM members that we interviewed 
told us that additional members are needed to reduce the existing 
members' workload. The OSE Director said that a more intensive effort 
to recruit members to the committee began in 2008, but it has been 
difficult to find qualified individuals who have no financial conflicts 
of interest.[Footnote 86] Recruiting new members will be especially 
important because 3 members' terms expired on May 31, 2009. An official 
said that the agency appointed 3 new members to the committee on July 
1, 2009. While this gives the committee a total of 8 members, 3 of 
these members' terms expire on May 31, 2010. An official said the 
agency is reviewing approximately 43 candidates for potential conflicts 
of interest, with the goal of filling the DSaRM vacancies as soon as 
possible. 

The number of vacancies may present challenges to FDA's implementation 
of new FDAAA requirements for seeking advice from DSaRM on risk 
management plans and the analysis of drug safety data. FDA indicated 
that it plans to convene DSaRM in accordance with the FDAAA 
requirements, although officials said that the agency has not yet done 
so and the requirements will result in FDA using DSaRM differently than 
in the past. An official said that the agency is therefore in the 
process of determining how to best involve the committee in these new 
activities. Some of the DSaRM members with whom we spoke noted that the 
FDAAA provisions appear to relate to broader drug safety issues than 
the committee has generally considered. One member noted that the 
committee would not be able to fulfill the new FDAAA requirements at 
product-specific meetings; rather, the complete committee would 
probably have to meet on its own. If the agency continues to have a 
large number of vacancies with DSaRM, it could be difficult for the 
committee to fulfill these additional duties while also participating 
in discussions of specific drug products. 

Conclusions: 

FDA's oversight of postmarket drug safety has been a long-standing 
concern, with various groups reporting problems for more than 30 years. 
Our 2006 report on this topic cited the need for FDA to improve its 
decision-making process for postmarket drug safety. To enhance this 
process, FDA has recently begun to take steps that respond to our 
concerns, as well as those expressed by others. However, many of its 
initiatives are new and are in the early stages of development and 
implementation. For example, the agency's efforts to begin formalizing 
its decision-making process, hire more staff, and establish dedicated 
safety positions within OND are an encouraging start. As FDA has gone 
about planning to improve its postmarket oversight, it has also needed 
to respond to changes brought about by FDAAA, which resulted in 
increased responsibilities for postmarket drug safety. FDA employees 
have since cited several instances in which increases in their workload 
and competing premarket demands and other priorities have prevented 
them from fully carrying out their postmarket drug safety 
responsibilities. We recognize that with a growing workload, come 
additional challenges. The agency's initiatives will require time and 
resources before they can make a significant impact on previously 
identified problems. While we view FDA's plans as positive, it is not 
yet clear if or when FDA's decision-making process will be 
substantially improved as a result of its efforts. 

As one of its efforts to enhance postmarket decision making, the agency 
plans to transfer additional authorities from OND to OSE. Transferring 
these authorities could help FDA better align decision-making 
responsibilities with the division of expertise between the two 
offices. However, the agency has set no time frames for their transfer 
and has stated that OSE needs increased experience and resources before 
the office is able to assume the new authorities. FDAAA provided the 
agency with greater flexibility to allocate funds to postmarket drug 
safety. Therefore, as FDA considers this transfer, it is important that 
it take advantage of this flexibility to align its resources in such a 
way that it strike an appropriate balance between its competing 
premarket and postmarket priorities and ensure postmarket safety 
receives sufficient attention. Establishing a time frame for this 
transfer and adequately preparing OSE to assume these authorities are 
important next steps to ensuring appropriate oversight of postmarket 
drug safety. 

Recommendation: 

To address weaknesses in FDA's oversight of postmarket drug safety, we 
recommend that the Commissioner of FDA develop a comprehensive plan for 
transferring the additional regulatory authorities from OND to OSE that 
includes time frames for the transfer and steps to ensure resources are 
properly aligned to allow OSE to assume these responsibilities. 

Agency Comments and Our Evaluation: 

We provided a draft of this report to HHS for review. HHS provided 
comments from FDA, which agreed with our recommendation. FDA's comments 
are reprinted in appendix II. FDA also provided technical comments, 
which we incorporated as appropriate. 

Regarding our recommendation, FDA agreed that developing a 
comprehensive plan to prepare OSE for the transfer of additional 
regulatory authorities is desirable. However, it noted that the details 
of such a plan, including time lines, remain dependent upon available 
funding and the agency's ability to recruit and retain the necessary 
staff to assume additional responsibilities. While we agree that both 
funding and staff are important to the successful transfer of these 
regulatory authorities, we believe that FDA has the flexibility to 
align its resources in such a way as to ensure that postmarket drug 
safety receives appropriate attention. Furthermore, we believe that the 
development of a comprehensive plan and time line is an important step 
towards ensuring that necessary funding levels and staffing needs are 
identified and secured. 

In addition to commenting on our recommendation, FDA addressed several 
other issues. First, it emphasized that, since our 2006 report was 
issued, it has undertaken a comprehensive set of activities to improve 
its postmarket drug safety program. We agree that FDA has begun to take 
some important steps to improve its decision-making process, but as we 
noted earlier, we believe that it is too early to judge the 
effectiveness of these steps. Second, FDA stressed that postmarket drug 
safety decisions are often complex and frequently require the 
involvement of staff from a number of scientific disciplines. The 
agency noted that for each of the many regulatory decisions that need 
to be made, a decision maker must have the delegated responsibility and 
authority to make these decisions. It indicated, for example, that in 
most cases OND has the broadest expertise to make decisions about 
postmarket drug safety. We understand that, while multiple areas of 
expertise are brought to bear in assessing safety issues, there may 
need to be a single office responsible for making final decisions. We 
added language in the report to clarify FDA's position on OND expertise 
in postmarket decision making. Third, it also noted that we implied 
that OND and OSE are the only significant participants in drug safety 
decision making. We understand that, depending on the safety issue, a 
variety of FDA offices and scientific disciplines may be involved in 
decision making and our draft report acknowledged this. However, our 
work appropriately focused on OND and OSE because of the key roles they 
play in postmarket decision making and because of the concerns that 
were raised about the relationship between these two offices in our 
2006 report. Finally, FDA said that our report omitted the contribution 
its Drug Safety Oversight Board has made to postmarket decision making. 
We recognize that this board plays a role in postmarket safety, as 
discussed in our 2006 report. The focus of our current report was to 
describe new initiatives underway at FDA. However, we have added 
information about the board to our report in response to FDA's 
comments. 

As agreed with your office, unless you publicly announce the contents 
of this report earlier, we plan no further distribution until 30 days 
from the report date. At that time, we will send copies to the 
Commissioner of FDA and appropriate congressional committees. The 
report also will be available at no charge on the GAO Web site at 
[hyperlink, http://www.gao.gov]. If you or your staff have any 
questions about this report, please contact me at (202) 512-7114 or 
crossem@gao.gov. Contact points for our Offices of Congressional 
Relations and Public Affairs may be found on the last page of this 
report. GAO staff who made major contributions to this report are 
listed in appendix III. 

Sincerely yours, 

Signed by: 

Marcia Crosse: 
Director, Health Care: 

[End of section] 

Appendix I: Status of FDA Actions Related to Our 2006 Recommendations: 

In our 2006 report,[Footnote 87] we made recommendations to the Food 
and Drug Administration (FDA) that were intended to improve its 
oversight of the postmarket drug safety decision-making process. 
Specifically, we recommended that FDA: 

1. revise and implement its draft policy on major postmarket drug 
safety decisions, 

2. clarify the Office of Surveillance and Epidemiology's (OSE) role in 
FDA's scientific advisory committee meetings involving postmarket drug 
safety issues, 

3. improve the Center for Drug Evaluation and Research's (CDER) dispute 
resolution process by revising the pilot program for resolving 
differing professional opinions (DPO) to increase its independence, 
[Footnote 88] and: 

4. establish a mechanism for systematically tracking OSE's 
recommendations and subsequent safety actions. 

Regarding the draft policy on major postmarket drug safety decision 
making, according to FDA, the agency no longer plans to complete it. 
This policy was intended to ensure that all major postmarket safety 
recommendations be discussed by the relevant officials and present a 
process for making recommendations and resolving disagreements. An 
official said that, in light of the multidisciplinary approach it has 
established through the Safety First Initiative and principles of Equal 
Voice, FDA's postmarket decision-making process has changed, and as a 
result, the process described in the draft policy was no longer 
relevant. The official said that the agency determined that it was not 
necessary to issue a separate policy on major postmarket drug safety 
decision making. 

Regarding the clarification of OSE's role at scientific advisory 
committee meetings, an FDA official told us that instead of developing 
such a policy, the agency added language to the manual for the agency 
staff responsible for managing the advisory committees. The manual 
instructs these staff to ask the OND division coordinating an advisory 
committee meeting involving drug safety issues whether OSE should be 
involved in the meeting. This manual does not specifically address the 
role of presentations by OSE staff in those advisory committee 
meetings. However, an FDA official we spoke with was not aware of any 
recent instances in which OSE employees were excluded from presenting 
at an advisory committee meeting. Of the 30 OSE employees who completed 
our data collection instrument, 15 indicated that they had no opinion 
about the extent to which CDER has become more or less accepting of 
employees expressing dissenting views at advisory committee meetings. 
However, of the remaining 15 employees, 10 indicated that CDER has been 
more accepting of such presentations since 2006. 

Regarding CDER's DPO program, FDA initiated an agencywide review of its 
dispute resolution process that instituted new requirements for each 
center to follow. CDER indicated that it is making few changes to its 
DPO policy, which an official told us already incorporated most of the 
new elements resulting from the agencywide review. However, according 
to a July 2009 draft of that policy, the planned changes do not address 
our recommendation to increase the program's independence. A CDER 
official indicated that, under the revised policy, the Ombudsman would 
still consult with the CDER Director before deciding whether a dispute 
warrants formal review. In addition, the CDER Director is still the 
final decision maker regarding how the dispute should be resolved. 

Regarding the implementation of a mechanism for systematically tracking 
OSE's recommendations and subsequent safety actions, FDA is in the 
process of implementing the Document Archiving, Reporting, and 
Regulatory Tracking System (DARRTS). In January 2007, in response to 
our 2006 recommendation, FDA began to incorporate a safety module 
within DARRTS to track the agency's response to significant safety 
issues identified with the use of marketed drugs. For each significant 
safety issue, FDA creates a "tracked safety issue" within DARRTS that 
allows staff, among other things, to generate a workplan and assign 
responsibilities for managing these issues, as well as update their 
status. While the system contains documents describing specific 
recommendations and safety actions, an official told us that it does 
not, as we recommended, allow FDA to systematically track how issues 
were resolved and whether OSE's recommendations were implemented. 

[End of section] 

Appendix II: Comments from the Department of Health and Human Services: 

Department Of Health & Human Services: 
Office Of The Secretary: 
Assistant Secretary for Legislation: 
Washington, DC 20201: 

October 19, 2009: 

Marcia Crosse: 
Director, Health Care: 
U.S. Government Accountability Office: 
441 G Street N.W. 
Washington, DC 20548: 

Dear Ms. Cross: 

Enclosed are comments on the U.S. Government Accountability Office's 
(GAO) report entitled: Drug Safety: FDA Has Begun Efforts to Enhance 
Postmarket Safety but Additional Actions Are Needed (GAO-10-68). 

The Department appreciates the opportunity to review this report before 
its publication. 

Sincerely, 

Signed by: 

Andrea Palm: 
Acting Assistant Secretary for Legislation: 

Enclosure: 

[End of letter] 

Department Of Health And Human Services: 
Food and Drug Administration: 
Silver Spring, MD 20993: 

Date: October 19, 2009: 

To: Acting Assistant Secretary for Legislation: 

From: Principal Deputy Commissioner of Food and Drugs: 

Subject: FDA's General Comments to GAO's Draft Report Entitled, Drug 
Safety: FDA Has Begun Efforts to Enhance Postmarket Safety but 
Additional Actions Are Needed (GAO-10-68): 

FDA is providing the attached general comments to the U.S. Government 
Accountability Office's draft report entitled, Drug Safety: FDA Has 
Begun Efforts to Enhance Postmarket Safety but Additional Actions Are 
Needed (GA0-10-68). 

FDA appreciates the opportunity to review and comment on this draft 
report before it is published. 

Signed by: 

Joshua	Sharfstein, M.D. 
Principal Deputy Commissioner of Food and Drugs: 

Attachment: 

[End of letter] 

FDA's General Comments to the United States Government Accountability 
Office's Draft Report Entitled, Drug Safety: FDA Has Begun Efforts to 
Enhance Postmarket Safety but Additional Actions are Needed (GAO-10-
68): 

The Food and Drug Administration (FDA) welcomes the opportunity to 
comment on the Government Accountability Office's (GAO) findings in the 
draft report and respond to the single recommendation made by GAO to 
FDA. 

The safety of drugs throughout their lifecycle has always been a key 
focus of FDA's mission to protect and promote the public health. Since 
the GAO issued its last report on postmarket drug safety in 2006, the 
FDA has undertaken a comprehensive set of activities to improve our 
postmarket drug safety program, and much progress has been made. These 
efforts are now incorporated into the Safety First initiative. 

One major area of focus for FDA since the previous GAO report study has 
been enhancing the processes for decision-making in the Center for Drug 
Evaluation and Research (CDER), including making decisions about the 
safety of marketed drugs, as examined in this report. While the GAO 
report has noted FDA's progress in this area, it seems to focus on two 
Offices in CDER, the Office of New Drugs (OND) and the Office of 
Surveillance and Epidemiology (OSE), as the only two significant 
participants in postmarket drug safety decision-making. Postmarket drug 
safety decisions are often very complex and frequently require much 
broader involvement than described by GAO, including substantial input 
from a number of scientific disciplines working closely together as a 
multidisciplinary team. 

Ensuring the continued availability of drugs for which the benefits 
continue to outweigh the risks demands that CDER reach institutional 
decisions efficiently within legislative, regulatory and practical time 
limits. For each of the many regulatory decisions that must be made, 
someone must be designated as the decision-maker, having the delegated 
responsibility and authority to make the decision. In many cases, this 
is the signatory authority. For most decisions related to new drug 
approvals and postmarket drug safety, the delegated authority rests 
with OND, where staff with the broadest expertise and experience in 
evaluating and managing the clinical risks and benefits for drug 
products resides. For other types of regulatory decisions, the 
authority resides in other organizational units where the most 
expertise about the issues exists. For example, as mentioned in the 
report, authority for regulatory decision-making for proprietary names 
was transferred to OSE because most of the expertise for issues related 
to regulation of proprietary name exists in that organization. Similar 
transfer of regulatory authority occurred some years ago, when 
signatory authority for manufacturing supplements was moved from OND to 
the Office of New Drug Quality Assessment. 

The GAO report emphasizes which organizational unit within the Center 
is assigned regulatory (or signatory) authority for postmarket 
decisions. Under its Equal Voice initiative, the focus of CDER's 
efforts over the past two years has been to assure that, regardless of 
where the signatory authority resides, regulatory decisions are made 
only after all appropriate expertise is brought to bear. 

Within this framework, the Center forms multidisciplinary teams to best 
inform the ultimate decisions. Within those teams, each discipline is 
expected to have an "equal voice" in representing the expertise they 
bring to bear on the issue. The designated decision-maker is expected 
to carefully consider the input of all relevant disciplines before 
reaching what he/she considers to be the best decision based on law, 
the regulations, the science, the precedents, and public health 
concerns. If one of the disciplines believes an action to be taken is 
so flawed (i.e., having a significant adverse impact on public health 
and safety, to be counter to law or regulation, or to be counter to 
existing precedent without adequate justification for deviation) that 
the action must be revisited, that discipline can elevate the decision 
through the management ranks to the Center Director. 

One notable omission from the GAO's report is the contribution of the 
Drug Safety Oversight Board (DSB) to postmarket decision-making. FDA 
established the DSB in 2005 to strengthen its internal management of 
complex drug safety issues and to provide a forum to discuss these 
issues as well as emerging, and often controversial, drug safety 
issues. The DSB provides advice and recommendations to the CDER 
Director on how CDER should handle these important drug safety issues. 
In 2009, the DSB continued to provide an ongoing forum for healthy 
debate within CDER, to anticipate and embrace new methods for 
evaluating drug safety, and to incorporate the best ideas from its 
Federal partners. Over the past year, the Board has added additional 
members and now has representation from five agencies within the 
Department of Health and Human Services (AHRQ, CDC, FDA, NIH, IHS), as 
well as representatives from the Department of Veteran Affairs and the 
Department of Defense. In addition, the Board routinely invites guest 
experts to participate in the meetings to help sort through complex 
drug safety issues. 

Response to GAO's Recommendation: 

GAO recommended that FDA develop a comprehensive plan to prepare OSE 
for the transfer of regulatory authorities from OND. 

FDA has acknowledged and explicitly stated in the Memorandum of 
Agreement between OSE and OND that additional transfer of regulatory 
authorities and responsibilities would occur once OSE has the resources 
and experience to accept such transfer. FDA agrees that developing a 
comprehensive plan to prepare OSE for the transfer of additional 
regulatory authorities is desirable. The details of such a plan, 
including timelines, remain dependent upon available appropriated and 
PDUFA funding as well as the Agency's ability to recruit and retain the 
necessary staff to assume additional responsibilities. 

[End of section] 

Appendix III: GAO Contact and Staff Acknowledgments: 

GAO Contact: 

Marcia Crosse, (202) 512-7114, crossem@gao.gov. 

Acknowledgments: 

In addition to the contact named above, Geraldine Redican-Bigott, 
Assistant Director; William Hadley; Cathleen Hamann; Rebecca 
Hendrickson; Hannah Sypher Locke; Lisa Motley; Coy J. Nesbitt; and 
Suzanne Worth made key contributions to this report. 

[End of section] 

Footnotes: 

[1] FDA is an agency within the Department of Health and Human Services 
(HHS). Within FDA, the Center for Drug Evaluation and Research (CDER) 
is responsible for overseeing the safety and effectiveness of drugs. 

[2] See, for example, National Research Council, Report of the 
International Conference of Adverse Reactions Reporting Systems 
(Washington, D.C.: National Academies of Science, 1971); FDA, Program 
Review of the Division of Epidemiology and Surveillance (DES) in the 
Office of Epidemiology and Biometrics (OEB) (Washington, D.C.: 1993); 
and HHS, Office of Inspector General, Review of the Food and Drug 
Administration's Handling of Adverse Drug Reaction Reports (Washington, 
D.C.: December 1999). 

[3] OSE was formerly known as the Office of Drug Safety. The office was 
renamed in May 2006. In this report, we refer to the office by its 
current name. 

[4] GAO, Drug Safety: Improvement Needed in FDA's Postmarket Decision- 
making and Oversight Process, GAO-06-402 (Washington, D.C.: Mar. 31, 
2006). 

[5] 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). 

[6] HHS, Fiscal Year 2008 Agency Financial Report (November 2008), 
[hyperlink, http://www.hhs.gov/afr/](accessed Dec. 17, 2008); and GAO, 
High-Risk Series: An Update, [hyperlink, 
http://www.gao.gov/products/GAO-09-271] (Washington, D.C.: January 
2009). 

[7] Our work is focused on human drugs regulated by CDER and not on 
biologics. Biologics are materials, such as vaccines, derived from 
living sources such as humans, animals, and microorganisms. Some 
biologics are regulated by CDER and such products are included in the 
scope of our work. 

[8] OND has a total of 17 review divisions. We selected individuals 
from the Divisions of Anesthesia, Analgesia, and Rheumatology Products; 
Drug Oncology Products; Gastroenterology Products; and Neurology 
Products. 

[9] The Division of Neurology Products has medical reviewers who 
fulfill traditional review duties and those who are members of a safety 
review team. Therefore, we conducted separate interviews with each of 
these groups of medical reviewers. 

[10] FDA indicated that, in addition to OND and OSE, other FDA offices 
and divisions, such as the Office of Compliance, the Office of Clinical 
Pharmacology, and the Office of Biotechnology Products, are routinely 
involved in postmarket decision making. 

[11] The term "adverse event" is used by FDA to indicate any untoward 
medical event that is associated with the use of a drug, whether 
causally related to the drug or not. 

[12] Epidemiologic studies are intended to provide information about 
the association between drug use and adverse events by allowing 
observation of care delivered in the population. 

[13] Risk management plans are submitted by drug sponsors and document 
plans for developing and implementing tools to minimize a drug's risks 
while preserving its benefits. 

[14] OSE provides premarketing reviews of proprietary drug names to 
minimize any potential conflicts with names of drugs already being 
marketed that could lead to a healthcare provider misprescribing or 
misinterpreting the correct name, and dispensing or administering the 
wrong product, or dispensing it incorrectly. The office also reviews 
drug labeling and packaging in order to reduce the potential for a 
medication error. 

[15] The Drug Safety Oversight Board has since been mandated by law. 
See 21 U.S.C. § 355-1(j). 

[16] The Drug Safety Oversight Board also has responsibility to, among 
other things, manage the dissemination of certain safety information 
through FDA's Web site to healthcare professionals and patients; 
establish policies regarding management of drug safety issues in CDER; 
and track important emerging safety issues and ensure that they are 
resolved in a timely manner. 

[17] In addition, the Pediatric Review Committee, an FDA-wide 
committee, also focuses on postmarket safety for drugs and biologics. 
FDA advisory committee members can be medical professionals, 
scientists, researchers, industry leaders, consumers, or patients. 

[18] In our prior report, we referred to multiple FDA processes for 
resolving scientific disputes as "dispute resolution processes," 
including what FDA terms as its DPO program. See GAO-06-402. For the 
purposes of this report, we use the term "dispute resolution" to refer 
to the broad category of processes involved in resolving scientific 
disputes, including the review of the dispute by the supervisory chain 
and DPO program. 

[19] When appropriate and feasible, a member with relevant technical 
expertise who is external to the agency could also be chosen. 

[20] In addition to these duties, CDER's Ombudsman receives inquiries 
and investigates complaints from the drug industry, consumers, and 
healthcare professionals and provides general information on product 
development and regulation. In 2008, 94 percent of the contacts 
received by the Ombudsman were from the drug industry and consumers and 
6 percent were from FDA employees. 

[21] See 21 C.F.R. §§ 310.305, 314.80, 314.98, 600.80 (2009). 

[22] Safety signals, which are potential relationships between drug use 
and adverse events, are sometimes the first indicator of a potential 
drug safety problem. 

[23] HHS Office of Inspector General, FDA's Monitoring of Postmarketing 
Study Commitments (June 2006), downloaded from [hyperlink, 
http://www.oig.hhs.gov/oei/reports/oei-01-04-00390.pdf] (accessed Aug. 
6, 2008). 

[24] Pub. L. No. 110-85, 121 Stat. 823. 

[25] 21 U.S.C. § 355(o). 

[26] Prior to FDAAA, FDA had the authority in limited situations to 
require that sponsors commit to conducting postmarketing studies as a 
condition of approval. See 21 U.S.C. § 356(b)(2). For example, in 
certain cases where human efficacy studies of a drug may not be ethical 
or feasible, FDA may rely on animal studies alone to approve the use of 
a drug and require postmarket studies as a condition of approval when 
studies on humans become feasible and ethical. 21 C.F.R. § 
314.610(b)(1)(2009). 

[27] 21 U.S.C. § 355-1. 

[28] 21 U.S.C. § 333(f)(4). 

[29] 21 U.S.C. § 355(k)(3). 

[30] 21 U.S.C. § 355(k)(5). 

[31] 21 U.S.C. § 355-1(f)(5). 

[32] See Pub. L. No. 110-85, §§ 101-109, 121 Stat. 823, 825-42. 

[33] Under PDUFA, FDA receives user fees from the pharmaceutical 
industry as part of its annual appropriation for salaries and expenses. 
To delineate the source of the appropriated funds in this report, we 
use the terms "user fee funding" to describe amounts derived from user 
fee collections, and "fiscal year appropriations" to describe amounts 
derived from the General Fund of the Treasury. Both user fee funding 
and fiscal year appropriations are made available through the annual 
appropriations process. 

[34] See Pub. L. No. 107-188, §§ 501-509, 116 Stat. 594, 687-94. 

[35] See 21 U.S.C. § 379g(6)(F). 

[36] FDA, Prescription Drug User Fee Act (PDUFA) IV Drug Safety Five- 
Year Plan, December 2008, [hyperlink, 
http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFe
e/UCM119244.pdf], (accessed July 16, 2009). According to FDA, these 
user fee funds were allocated to CDER, the Center for Biologics 
Evaluation and Research, and other components of the agency. 

[37] FDA was not able to provide OSE and OND funding specifically for 
postmarket drug safety. However, based on a fiscal year 2004 study, it 
estimated that OSE devoted about 91 percent of its work time to 
postmarket drug safety, while OND devoted about 11 percent. 

[38] The MOA expired in June 2009 and a new agreement is in effect 
through June 2010. FDA officials said the agency plans to reevaluate 
the MOA each year to determine if it is still necessary. 

[39] Each OND division now has a Deputy Director for Safety and a 
Safety Regulatory Project Manager; one division has two Safety 
Regulatory Project Managers. As of July 2009, 3 of the 17 Deputy 
Director for Safety positions and 11 of 18 Safety Regulatory Project 
Manager positions were filled in an acting capacity; the remaining 
positions had permanent staff. OND has also created an Associate 
Director for Safety that has responsibility for coordinating the 
activities of the safety positions across review divisions. 

[40] DARRTS is intended to help CDER staff manage the drug review 
process by serving as a central repository for information and allowing 
staff to upload communications and other documentation, generate 
reports, and create status updates. The agency is releasing DARRTS in 
stages. The first version was released in January 2006. 

[41] GAO, New Drug Approval: FDA Needs to Enhance Its Oversight of 
Drugs Approved on the Basis of Surrogate Endpoints, GAO-09-866 
(Washington, D.C.: Sept. 23, 2009). See also, Booz Allen Hamilton, 
Postmarketing Commitments Study Final Report, a report prepared at the 
request of FDA, January 2008, [hyperlink, 
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm11985
6.htm] (accessed July 23, 2009). 

[42] The contractor is annually reviewing the annual status reports 
associated with postmarketing studies that were requested prior to the 
enactment of FDAAA--what the agency defines as its "backlog." The 
review of these reports is required by FDAAA. Pub. L. No. 110-85, § 
921, 121 Stat. 823, 962 (codified at 21 U.S.C. § 355(k)(5)). The 
contractor is also reviewing the annual reports submitted by drug 
sponsors for those postmarket studies that have been required or 
requested since FDAAA. See, for example, Booz Allen Hamilton, 
Deliverable 2-8: Final Report on the PMR/PMC Backlog Review, a report 
prepared at the request of FDA, April 10, 2009, [hyperlink, 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-
marketingPhaseIVCommitments/ucm180982.htm] (accessed Oct. 20, 2009). 

[43] FDA has five centers: CDER, the Center for Biologics Evaluation 
and Research, the Center for Devices and Radiological Health, the 
Center for Food Safety and Applied Nutrition, and the Center for 
Veterinary Medicine. 

[44] The process review would also include an assessment of whether the 
center considered all relevant evidence bearing on the scientific 
question at issue and whether the initiator of the dispute was provided 
an opportunity to express his or her concerns at all appropriate 
levels. As examples of other requirements, FDA requires center dispute 
resolution policies to include antiretaliation language and an 'opt-up' 
to the center director if a dispute is of sufficient immediacy and 
scale of impact to public health. 

[45] The standards state that several factors are important to 
assessing independence, such as whether anyone affected by the 
ombudsman's actions can control or limit the ombudsman's performance or 
reduce the ombudsman's budget or resources. Coalition of Federal 
Ombudsmen (CFO) and Federal Interagency ADR Working Group Steering 
Committee, A Guide For Federal Employee Ombuds: A Supplement to and 
Annotation of the Standards For The Establishment And Operations Of 
Ombuds Offices Issued By The American Bar Association, May 9, 2006, 
[hyperlink, http://www.adr.gov/pdf/final_ombuds.pdf], (accessed July 
27, 2009). 

[46] An agency official told us that CDER asked staff in 2007 for input 
on why the program had not been used, but only a few staff responded. 
The official said that CDER interpreted the low response rate to mean 
that staff did not feel strongly about the program, so, at that time, 
no changes were made to the program. 

[47] The remaining 3 employees out of the 52 who completed the DCI 
indicated that they had no opinion about the issue (2) or did not 
provide an answer (1). 

[48] Under 21 C.F.R. § 10.70, an agency employee working on a matter 
may record individual views on that matter in a written memorandum, 
which is to be placed in the file. 

[49] Employees completing the DCI were able to select more than one 
reason why they did not use CDER's program to resolve differences of 
opinion. 

[50] MedWatchPlus will be implemented in stages. The first version is 
scheduled to be complete by fall 2009, but will only be able to accept 
adverse event reports for food and veterinary drugs. In spring 2011, 
FDA plans to release a version that will be able to accept adverse 
event reports for medical devices and other remaining products. 

[51] FDA also provides a toll-free telephone number that can be used to 
submit adverse event reports. 

[52] ESG is an FDA system that enables the electronic submission of 
regulatory information, such as adverse event reports, for review. 
Manufacturers that choose not to utilize ESG must submit paper forms, 
which may be obtained through MedWatch. 

[53] MedWatchPlus will process each report by assigning a unique 
identifier, translating the report into accepted medical terminology 
using standard medical dictionaries, prioritizing the report based on 
factors such as the seriousness of the adverse event, and routing the 
report to the correct center within FDA. 

[54] See 74 Fed. Reg. 42,184 (Aug. 21, 2009). This proposed rule amends 
previous requirements for the submission of postmarket safety reports, 
see 21 C.F.R. §§ 310.305, 314.80, 314.98, and 600.80 (2009). The rule 
will be available for comment until November 19, 2009, after which FDA 
may issue the final rule. FDA has proposed that the new requirements 
would go into effect 1 year after the publication of the final rule. 

[55] According to FDA, it is mostly larger manufacturers that have 
invested in the data exchange systems needed to use ESG. The agency 
expects that MedWatchPlus will provide smaller manufacturers with a 
more cost effective means of reporting adverse events electronically. 

[56] FDA enters all adverse event reports sent directly to it from 
patients and healthcare providers. The agency also enters all 
electronic reports from manufacturers, as well as all paper reports 
from manufacturers concerning new molecular entities for the first 3 
years after approval. New molecular entities are potentially innovative 
drugs containing active chemical substances that have never been 
approved for marketing in the United States in any form. For all other 
paper reports from manufacturers, FDA only enters reports for serious 
adverse events. In fiscal year 2008, 93,085 paper reports from 
manufacturers of adverse events not classified as serious, which 
comprised almost 18 percent of all reports received by FDA, were not 
entered into AERS. 

[57] According to FDA, paper reports cost approximately $35 per report 
to process, whereas electronic submissions cost approximately $12 per 
report to process. 

[58] In a 2008 report, IOM noted that submitters may use multiple 
different names for the same drug due to the use of the trade name 
rather than the generic name, inclusion of dosage information in the 
drug name, or misspellings. IOM reported that a manual review of the 
AERS database identified 300,000 different drug names that reviewers 
determined actually represented only about 3,000 standard generic 
names. S. Robinson, R. Pool, and R. Giffin, Institute of Medicine of 
the National Academies, Forum on Drug Discovery, Development, and 
Translation, Emerging Safety Science: Workshop Summary (Washington, 
D.C.: National Academies Press, Apr. 9, 2008). 

[59] Currently, FDA maintains multiple databases for storing adverse 
event data. For example, AERS is used by CDER to store drug reports, 
while another center uses a separate database to store medical device 
reports. 

[60] Combination products are comprised of two or more regulated 
components, for example, a drug-device combination product. According 
to FDA, sharing information about such products is currently difficult 
to do in a timely manner. 

[61] Data mining software allows OSE staff to more easily identify 
patterns in the reports to find new safety signals. Signal management 
software allows OSE staff to monitor safety signals over time and 
create alerts. 

[62] Breckenridge Institute, Independent Verification and Validation of 
AERS II Requirements Process (Breckenridge, Colo.: 2006). 

[63] Most of the increase, about $22 million, came from user fee 
funding resulting from the reauthorization of PDUFA. 

[64] The new contracts will be indefinite delivery contracts, which do 
not procure or specify a firm quantity of services (other than a 
minimum or maximum quantity) and which provide for the issuance of 
orders for the performance of tasks during the period of the contract. 

[65] FDA officials explained that the contracts are structured with 
multiple option years so that FDA has adequate time to learn to use the 
databases, but can choose to switch vendors as new technologies emerge. 

[66] FDA allocated an additional $4.3 million for VA and DOD in fiscal 
year 2009. 

[67] Currently, each state Medicaid program stores its data files in 
separate state databases, which makes it difficult to conduct drug 
safety studies. This project will combine these databases into a 
single, unified Medicaid database. An FDA official said the agency 
planned to continue funding this project in 2009 and has allocated an 
additional $1 million. 

[68] In June 2009, we recommended that FDA develop a plan for 
completing Sentinel, including the establishment of milestones. We also 
recommended that FDA implement appropriate security and privacy 
safeguards as Sentinel is developed. GAO, Privacy and Security: Food 
and Drug Administration Faces Challenges in Establishing Protections 
for Its Postmarket Risk Analysis System, GAO-09-355 (Washington, D.C.: 
June 1, 2009). 

[69] Similarly, in June 2009, we reported that FDA's workload had grown 
due to an increase in the agency's statutory responsibilities and a 
growing number of medical products subject to FDA oversight. We also 
reported that an increased reliance on user fee funding has limited the 
agency's ability to fulfill its oversight responsibilities in some 
other areas. GAO, Food and Drug Administration: FDA Faces Challenges 
Meeting Its Growing Medical Product Responsibilities and Should Develop 
Complete Estimates of Its Resource Needs, GAO-09-581 (Washington, D.C.: 
June 19, 2009). 

[70] FDA defines adverse events as serious when they result in death, 
are life-threatening, require inpatient hospitalization or prolongation 
of hospitalization, cause significant disability/incapacity, or cause a 
birth defect. Other events may also qualify as serious if they require 
medical or surgical intervention to prevent one of these outcomes from 
occurring. See 21 C.F.R. § 314.80(a) (2009). FDA defines nonserious 
adverse events as any events that do not qualify as serious. However, 
an FDA medical reviewer advised us that events categorized as 
nonserious may include events that would constitute an important safety 
signal. For example, the reviewer said that a medical event that is 
significant enough to send a patient to the emergency room may not be 
considered serious in the regulatory sense, if the patient is treated 
and released without being admitted to the hospital. FDA officials said 
that, as a result, staff need to consider both serious and nonserious 
adverse event reports when monitoring the safety of drugs. 

[71] OND is officially responsible for reviewing these reports. OND 
medical reviewers described several other challenges that impeded their 
review, including a lack of sufficient epidemiologic expertise and 
available guidance. They also said that these reports are of poor 
quality and do not provide the total numbers of adverse events reported 
by the sponsor since the drug was approved, which limits their 
usefulness in identifying potential trends in the data. 

[72] One employee said that there are safety issues identified in 2006 
for which they still have not been able to complete follow-up reviews. 

[73] Adverse event reviewers told us that the number of reports they 
receive varies considerably based on the drugs in each adverse event 
reviewer's portfolio, and can be as high as 200 reports per day. 

[74] Leadership Performance Solutions, Office of Surveillance and 
Epidemiology Workload Analysis Report, a report prepared at the request 
of FDA (Silver Spring, Md.: December 2008). The contractor acknowledged 
that its estimates were not statistically valid because it used agency 
estimates to analyze OSE's future workload. The contractor noted that 
OSE did not have a consistent, systematic process for collecting 
workload data and recommended that the office implement an ongoing 
process for estimating staffing needs. In a 2009 report, we also found 
that FDA lacks reliable data on workload and accomplishments, and we 
recommended that FDA develop an evidence-based estimate of the 
resources need to fulfill all of its responsibilities. GAO-09-581. 

[75] FDA provided staff counts as of September 22, 2009. According to 
FDA officials, the fiscal year 2009 staffing ceiling for OND was 930, 
while for OSE it was 211. 

[76] Direct-hire authority, given by the Office of Personnel 
Management, allows agencies to expedite the hiring of qualified 
applicants for critically needed positions by eliminating the need to 
comply with certain elements of the federal hiring process. See 5 
C.F.R. §§ 337.201-337.206 (2009). 

[77] According to FDA, the agency no longer plans to request new direct-
hire authority for epidemiologists from the Office of Personnel 
Management. 

[78] The official said the incentives it offered new hires were made 
available by FDA from savings realized from unfilled vacancies. These 
incentives are no longer available. 

[79] According to FDA, studies completed by external contractors also 
consume agency resources. An FDA official said that each external 
epidemiologic study conducted by a contractor should have an OSE lead 
epidemiologist assigned to it to help plan the study, as well as a 
programmer to extract the data from the contractor's database. 

[80] Agency officials said that OSE could still hire staff with 
programming expertise under the office's existing position 
descriptions. While OSE officials said that they have managed to hire 
an employee with programming expertise to support ongoing drug safety 
studies under the epidemiologist position description, they said that 
it is extremely rare to find a programmer who meets all of the 
qualification requirements for an epidemiologist position. 

[81] According to FDA, the center will be a virtual organization that 
draws on expertise from across CDER and it will not be housed in a 
single location or set of offices. 

[82] According to FDA, a contractor has developed a strategic plan for 
the completion of the center for activities to be taken through the end 
of fiscal year 2013. 

[83] In a January 2007 response to IOM's drug safety report, FDA 
indicated that it would increase involvement of epidemiology expertise 
in advisory committee meetings, including by utilizing DSaRM members. 
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, 
January 2007, [hyperlink, 
http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInform
ationforPatientsandProviders/UCM171627.pdf] (accessed July 22, 2009). 

[84] Consultant pools are lists of individuals who FDA has determined 
have expertise that may be needed in the future for a specific advisory 
committee meeting. FDA officials also told us that consultants may be 
former FDA advisory committee members. GAO, FDA Advisory Committees: 
Process for Recruiting Members and Evaluating Potential Conflicts of 
Interest, [hyperlink, http://www.gao.gov/products/GAO-08-640] 
(Washington, D.C.: Sept. 30, 2008). 

[85] Although DSaRM was created in 2002 and held one meeting in that 
year, members were not appointed to the committee until 2003. The 2002 
meeting was attended by nine temporary members, most of whom would be 
appointed as full members in 2003. 

[86] See 5 U.S.C. app. 2 § 5(b)(2). FDA advisory committees are subject 
to the Federal Advisory Committee Act, which requires that committee 
memberships also be fairly balanced in terms of views presented and the 
functions to be performed by the advisory committee. FDA is also 
experiencing similar recruitment difficulties for recruiting members of 
other committees as well. See GAO-08-640. 

[87] GAO, Drug Safety: Improvement Needed in FDA's Postmarket Decision- 
making and Oversight Process, [hyperlink, 
http://www.gao.gov/products/GAO-06-402] (Washington, D.C.: Mar. 31, 
2006). 

[88] In our prior report, we referred to multiple FDA processes for 
resolving scientific disputes as "dispute resolution processes," 
including what FDA terms as its DPO program. See GAO-06-402. For the 
purposes of this report, we use the term "dispute resolution" to refer 
to the broad category of processes involved in resolving scientific 
disputes, including the review of the dispute by the supervisory chain 
and DPO program. 

[End of section] 

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