Drug Safety: FDA Has Begun Efforts to Enhance Postmarket Safety, but Additional Actions Are Needed
Published: 2009-11-09T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: 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.
section_title: What GAO Found
paragraphs: 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.

section_title: Letter
paragraphs: Concerns about the Food and Drug Administration’s (FDA) management  of safety issues for drugs approved for marketing have been long- standing. Reviews dating back over 30 years have identified problems  related to the agency’s monitoring of postmarket drug safety. 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, 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. 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.  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.
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. 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, 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. 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.
subsections: section_title: Background
paragraphs: 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.
subsections: section_title: FDA Organization Related to Postmarket Drug Safety Decision Making
paragraphs: The decision-making process for postmarket drug safety is complex,  multidisciplinary, and relies on an iterative interaction between OND,  OSE, and other FDA components. 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. 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, one division reviews risk management plans submitted  by drug sponsors, 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.
To help it provide oversight of important, high-level safety decisions, FDA  established the Drug Safety Oversight Board in spring 2005. 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.
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. 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. 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. 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.
section_title: Data That Inform FDA’s Postmarket Decision- Making Process
paragraphs: 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. 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, 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.)
section_title: Recent Reviews of FDA’s Postmarket Drug Safety Oversight
paragraphs: 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.
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 app. I for a summary of FDA actions taken in response to these  recommendations.)
section_title: Changes to FDA’s Postmarket Drug Safety Authority and Funding
paragraphs: 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. 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. 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; 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). FDAAA also provided the agency with  authority to impose civil monetary penalties on drug sponsors who violate  these requirements.
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.
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.
FDA is required to use DSaRM to seek input on certain activities, such as  elements of REMS and the analysis of drug safety data.
In addition to increasing FDA’s authorities, FDAAA also reauthorized the  Prescription Drug User Fee Act of 1992 (PDUFA). Originally, PDUFA  authorized FDA to collect user fees 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. 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. 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.
Overall premarket and postmarket funding for OSE and OND increased  since fiscal year 2006. 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.
section_title: FDA Has Begun to Formalize Its Postmarket Decision- Making Process and Recently Implemented Oversight Initiatives, but Challenges Remain
paragraphs: 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.
subsections: section_title: 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
paragraphs: 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. 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.
section_title: FDA Recently Implemented Initiatives to Facilitate Oversight of Postmarket Safety Issues, although There Have Been Implementation Challenges
paragraphs: 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. 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. 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. In 2008,  FDA hired a contractor to monitor and provide support for postmarketing  studies, including the review of these annual status reports. 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.
section_title: FDA Is Revising Its Program for Resolving Scientific Disputes but the Changes Have Not Sufficiently Addressed the Independence of the Process
paragraphs: 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. 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. 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. 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. 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. 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). 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.
section_title: FDA Plans to Implement New Adverse Event Systems and Is Increasing Access to External Sources of Drug Safety Data
paragraphs: 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.
subsections: section_title: FDA Is Developing New Systems to Improve Collection and Analysis of Drug Adverse Event Reports, but Implementation Is Not Expected Until 2010
paragraphs: 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.
subsections: section_title: Adverse Event Collection and Processing
paragraphs: 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. 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. 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).  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, 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, 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. 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, 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. 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. 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.
section_title: Adverse Event Storage and Analysis
paragraphs: 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. 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. 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. 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. 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.
section_title: FDA Increased Funding for External Data Acquisition and Is Beginning to Access Data from Federal Sources
paragraphs: 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. 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 compani in fiscal year 2005, these contracts have yielded five complete d  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  es  changing to a different contract type when these contracts end in 2010.  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. 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. 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. 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.
section_title: FDA Is in the Early Stages of Developing a Network of External Data Providers Intended to Enhance Its Drug Safety Surveillance
paragraphs: 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. 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.
section_title: Although Staff Has Recently Increased, FDA Faces Challenges Meeting Its Expanding Postmarket Safety Workload
paragraphs: 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.
subsections: section_title: FDA Reports That New Postmarket Drug Safety Responsibilities Have Increased Its Workload and That It Is Challenged by Competing Priorities
paragraphs: 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. 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. According to some OND  reviewers, medical reviewers do not have the time to fully analyze these  reports to look for potential safety issues. OSE staff told us that  workload demands prevent them from reviewing these reports. G 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. 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, 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. 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.
section_title: FDA Has Hired Some New Staff, but May Face Obstacles Recruiting Additional Staff to Manage Its Increased Workload
paragraphs: 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. 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. 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. 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.
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.
section_title: FDA Faces Technological and Staffing Challenges That Limit Its Capacity to Conduct a Growing Number of Postmarket Safety Studies
paragraphs: 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. 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. 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. 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. 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.
section_title: FDA Has Encountered Difficulties Filling Vacancies for Its Increasingly Utilized Committee of External Drug Safety Experts
paragraphs: 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. 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.
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.  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. 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.
section_title: Conclusions
paragraphs: 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.
section_title: Recommendation
paragraphs: 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.
section_title: Agency Comments and Our Evaluation
paragraphs: 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 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.
section_title: Appendix I: Status of FDA Actions Related to Our 2006 Recommendations
paragraphs: In our 2006 report, 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  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,  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.
section_title: Appendix II: Comments from the Department of Health and Human Services
section_title: Appendix III: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact
paragraphs: Marcia Crosse, (202) 512-7114, crossem@gao.gov.
section_title: Acknowledgments
paragraphs: 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.