Drug Safety
FDA Has Begun Efforts to Enhance Postmarket Safety, but Additional Actions Are Needed Gao ID: GAO-10-68 November 9, 2009There 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.
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.
RecommendationsOur recommendations from this work are listed below with a Contact for more information. Status will change from "In process" to "Open," "Closed - implemented," or "Closed - not implemented" based on our follow up work.
Director: Team: Phone:GAO-10-68, Drug Safety: FDA Has Begun Efforts to Enhance Postmarket Safety, but Additional Actions Are Needed
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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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