Drug Safety: Improvement Needed in FDA's Postmarket Decision-making and Oversight Process
Published: 2006-03-31T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: In 2004, several high-profile drug safety cases raised concerns about the Food and Drug Administration's (FDA) ability to manage postmarket drug safety issues. In some cases there have been disagreements within FDA about how to address safety issues. In this report GAO (1) describes FDA's organizational structure and process for postmarket drug safety decision making, (2) assesses the effectiveness of FDA's postmarket drug safety decision-making process, and (3) assesses the steps FDA is taking to improve postmarket drug safety decision making. GAO conducted an organizational review and case studies of four drugs with safety issues: Arava, Baycol, Bextra, and Propulsid.
section_title: What GAO Found
paragraphs: Two organizationally distinct FDA offices, the Office of New Drugs (OND) and the Office of Drug Safety (ODS), are involved in postmarket drug safety activities. OND, which holds responsibility for approving drugs, is involved in safety activities throughout the life cycle of a drug, and it has the decision-making responsibility to take regulatory actions concerning the postmarket safety of drugs. OND works closely with ODS to help it make postmarket decisions. ODS, with a primary focus on postmarket safety, serves primarily as a consultant to OND and does not have independent decision-making responsibility. ODS has been reorganized several times over the years. There has been high turnover of ODS directors in the past 10 years, with eight different directors of the office and its predecessors. In the four drug case studies GAO examined, GAO observed that the postmarket safety decision-making process was complex and iterative. FDA lacks clear and effective processes for making decisions about, and providing management oversight of, postmarket safety issues. The process has been limited by a lack of clarity about how decisions are made and about organizational roles, insufficient oversight by management, and data constraints. GAO observed that there is a lack of criteria for determining what safety actions to take and when to take them. Certain parts of ODS's role in the process are unclear, including ODS's participation in FDA's scientific advisory committee meetings organized by OND. Insufficient communication between ODS and OND has been an ongoing concern and has hindered the decision-making process. ODS does not track information about ongoing postmarket safety issues, including the recommendations that ODS staff make for safety actions. FDA faces data constraints in making postmarket safety decisions. There are weaknesses in the different types of data available to FDA, and FDA lacks authority to require certain studies and has resource limitations for obtaining data. Some of FDA's initiatives, such as the establishment of a Drug Safety Oversight Board, a draft policy on major postmarket decision making, and the identification of new data sources, may improve the postmarket safety decision-making process, but will not address all gaps. FDA's newly created Drug Safety Oversight Board may help provide oversight of important, high-level safety decisions, but it does not address the lack of systematic tracking of ongoing safety issues. Other initiatives, such as FDA's draft policy on major postmarket decisions and regular meetings between OND divisions and ODS, may help improve the clarity and effectiveness of the process, but they are not fully implemented. FDA has not clarified ODS's role in certain scientific advisory committee meetings. FDA's dispute resolution processes for disagreements about postmarket safety decisions have not been used. FDA is taking steps to identify additional data sources, but data constraints remain.

section_title: Letter
paragraphs: In 2004, several high-profile drug safety cases raised concerns about the  Food and Drug Administration’s (FDA) management of safety issues  concerning drugs that have been approved for marketing. At  congressional hearings in September 2004, FDA was criticized for taking  too long to tell physicians and patients about studies linking the use of  antidepressants among children to an increased risk of suicidal behavior.  Similarly, at a congressional hearing in November 2004, it was alleged that  FDA did not act quickly enough on evidence it obtained in 2001 about the  cardiovascular risks of Vioxx, an anti-inflammatory drug. In these cases  and others there were disagreements within FDA about how to address  safety issues. There were also reports that some FDA scientists were  discouraged by supervisors from raising questions about the safety of  certain drugs.
Problems with FDA’s postmarket drug safety program have been raised  before. There have been numerous reviews by external and internal  groups dating back over 30 years that have identified problems with the  federal government’s postmarket drug surveillance program and that have  made recommendations for improvement. Following passage of the  Prescription Drug User Fee Act of 1992 (PDUFA), additional concerns  were raised about drug safety. Under PDUFA, drug companies  (“sponsors”) began paying fees to FDA, which used the funds to hire more  drug application reviewers and make other changes in order to speed up  the drug review process. As a result, FDA was able to review drug  applications and approve new drugs for marketing more rapidly than  before. However, the increased attention to timely drug approval decisions  led to increased attention to monitoring of postmarket safety as well,  which was reflected in the 2002 reauthorization of PDUFA. The 2002 act  states that FDA should continue to strengthen and improve the review and  monitoring of drug safety, and the PDUFA goals, incorporated by  reference into the act, state that FDA will allocate almost $71 million over  a 5-year period for postmarket drug safety. FDA subsequently increased its  risk management activities, drafted guidance for industry to help drug  companies assess and minimize drug risks, and used PDUFA revenues to  upgrade its system for adverse event reporting and to acquire external  sources of data. In late 2004 and 2005, in response to the safety issues  raised in the case of Vioxx and other drugs, FDA announced plans to  further strengthen its management of postmarket drug safety. These  initiatives, some of which are in an early stage of implementation, include  launching a new Web page to make public information on emerging drug  safety issues while FDA evaluates them, finalizing the risk management  guidance for industry, and making other organizational and policy process  changes.
In light of the recent controversy about drug safety, you asked us to  conduct a review of FDA’s current organizational structure and decision- making process for postmarket drug safety. In this report we (1) describe  FDA’s organizational structure and process for postmarket drug safety  decision making, (2) assess the effectiveness of the postmarket drug safety  decision-making process, and (3) assess steps FDA is taking to improve  postmarket drug safety decision making.
To describe FDA’s organizational structure and process for postmarket  drug safety decision making, we analyzed FDA’s organizational charts and  annual reports, the roles and responsibilities of staff working on drug  safety, documents describing internal FDA policies and procedures, and  other relevant FDA documents. Our review focused on two offices within  FDA’s Center for Drug Evaluation and Research (CDER) that are involved  in postmarket drug safety activities: the Office of New Drugs (OND) and  the Office of Drug Safety (ODS). We interviewed ODS, OND, and other  CDER managers and staff about their roles, responsibilities, workloads,  and the process for postmarket drug safety decision making. We also  interviewed former FDA officials and drug safety experts from outside  FDA. To assess the effectiveness of the postmarket drug safety decision- making process, we analyzed documents describing internal FDA policies  and procedures and interviewed FDA officials. In order to obtain an in- depth understanding of FDA’s policies and procedures, we conducted case  studies of four drugs—Arava, Baycol, Bextra, and Propulsid—that help to  illustrate the current decision-making process. Each of these drugs  presented significant postmarket safety issues that FDA acted upon in  recent years, and they reflect differences in the type of adverse event or  potential safety problem associated with the drug, the safety actions taken,  and the OND and ODS staff involved. For our case studies we reviewed  relevant FDA documents and conducted interviews with OND and ODS  staff and former FDA staff who were directly involved in the cases. We  focused on (1) significant postmarket drug safety regulatory actions;   (2) analyses that ODS conducted on the safety concerns; and (3) internal  FDA meetings, especially those that involved ODS. We did not examine  other elements of the postmarket drug safety decision-making process,  such as internal OND meetings. In some cases there may be gaps in our  description of events because there was no documentation available about  that point in the process. We also did not evaluate the scientific validity of  FDA’s data, methodologies, or decisions in these or other cases. Our cases  cannot be generalized to FDA’s deliberations about postmarket drug safety  issues for other drugs. Finally, to assess FDA’s actions to improve  postmarket drug safety decision making, we reviewed relevant FDA  documents and interviewed FDA officials and outside drug safety experts.  We conducted our review from December 2004 through March 2006 in  accordance with generally accepted government auditing standards.
subsections: section_title: Background
subsections: section_title: Postmarket Drug Safety and FDA’s Role
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.  Because no drug is absolutely safe—there is always some risk of an  adverse reaction—FDA approves a drug for marketing when the agency  judges that its known benefits outweigh its known risks. After a drug is on  the market, FDA continues to assess its risks and benefits. FDA reviews  reports of adverse drug reactions (adverse events) related to the drug and  information from studies about the drug, including clinical trials and  studies following the use of drugs in ongoing medical care (observational  studies), conducted by the drug’s sponsor, FDA, or other researchers. If  FDA has information that a drug on the market may pose a significant  health risk to consumers, it weighs the effect of the adverse events against  the benefit of the drug to determine what actions, if any, are warranted.  This decision-making process is complex and encompasses many factors,  such as the medical importance and utility of the drug, the drug’s extent of  usage, the severity of the disease being treated, the drug’s efficacy in  treating this disease, and the availability of other drugs to treat the same  disorder.
CDER, the largest of FDA’s five centers, is the organizational entity within  FDA that oversees the review of marketing applications for new drugs and  the postmarket monitoring of drugs once they are marketed. Within  CDER there are several key offices involved in activities related to  postmarket drug safety. OND is the largest of the offices with fiscal year  2005 expenditures of $110.6 million and 715 staff. In fiscal year 2005, more  than half of OND’s expenditures, or $57.2 million, came from PDUFA  funds. OND’s staff evaluate new drugs for efficacy and safety to decide if a  drug should be approved for marketing. OND also makes decisions about  actions to take when there are postmarket safety issues with a drug (for  example, revising the label to include adverse event information or having  FDA withdraw approval for marketing). For safety questions, OND  interacts with several FDA offices and divisions, but primarily with ODS.
ODS is currently located within the Office of Pharmacoepidemiology and  Statistical Science (OPaSS), which is organizationally parallel to OND and  also contains the Office of Biostatistics. ODS is a much smaller office  than OND, with fiscal year 2005 expenditures of $26.9 million and 106  staff. In fiscal year 2005, $7.6 million of ODS’s expenditures were from  PDUFA funds. ODS staff evaluate and monitor drug risks and promote the  safe use of drugs. While ODS is involved in both premarket and  postmarket drug safety issues, its primary focus is on postmarket safety.
An important part of the drug approval and postmarket monitoring  process is the advice FDA receives from 16 human-drug-related scientific  advisory committees, composed of experts and consumer representatives  from outside FDA. Considered by FDA as important in helping the agency  accomplish its mission and maintaining public trust, these advisory  committees provide expert advice to the agency on a range of issues,  including safety. The committees are largely organized according to  specialized medical areas or conditions such as cardiovascular disease,  gastrointestinal conditions, or oncology. In 2002, FDA established the  Drug Safety and Risk Management Advisory Committee (DSaRM), 1 of the  16 human-drug-related scientific advisory committees, to specifically  advise FDA on drug safety and risk management issues. The committee is  composed of individuals from outside FDA with experience in the areas of  medication errors, risk communication, risk perception, risk management,  clinical trial methodology, evidence-based medicine, biometrics, and  pharmacoepidemiology. Since it was established, DSaRM has met nine  times, with four of those meetings held jointly with another drug-related  scientific advisory committee. DSaRM members have also been asked to  participate in other scientific advisory committees when safety issues  were discussed. ODS sets the agenda for DSaRM meetings, whereas OND  sets the agenda for the other scientific advisory committee meetings.
Figure 1 describes the offices and external advisory committees involved  in postmarket drug safety at FDA.
section_title: FDA’s Postmarket Drug Safety Authority
paragraphs: In terms of postmarket drug safety surveillance, FDA has the authority to  require that drug sponsors report adverse events to FDA with different  reporting schedules based on the seriousness of the event and whether the  event has been previously identified and is included in the drug’s label.  Sponsors must report serious, unlabeled adverse events to FDA within 15  days of learning about them. Sponsors are required to report other adverse  events quarterly for 3 years, then annually thereafter in the form of  periodic adverse event reports. In addition, health care providers and  patients can voluntarily submit adverse event reports to FDA through its  MedWatch program. Adverse event reports become part of FDA’s  computerized database known as the Adverse Event Reporting System  (AERS).
FDA has the authority to withdraw the approval of a drug on the market  for safety-related and other reasons, although it rarely does so. Since  2000 there have been 10 drug withdrawals for safety reasons, and in all of  these cases the drug’s sponsor voluntarily removed the drug from the  market. FDA does not have explicit authority to require that drug sponsors  take other safety actions; however, when FDA identifies a potential  problem, sponsors generally negotiate with FDA to develop a mutually  agreeable remedy to avoid other regulatory action. For example, if FDA  determines that an approved drug may produce adverse events not  previously identified, FDA and the sponsor may negotiate on revised  labeling for the drug, and then FDA may issue an accompanying Public  Health Advisory for patients and health care providers that describes the  safety information. FDA may also request that the sponsor restrict the  distribution of the drug in order to minimize a significant risk associated  with the drug.
FDA has limited authority to require that sponsors conduct postmarket  safety studies; it may impose such a requirement during the premarket  phase of drug development in two situations, and in one during the  postmarket phase. In two situations, FDA has the authority to require that  sponsors commit to conducting postmarketing studies as a condition of  approval. First, FDA’s program for accelerated approval of new drugs for  serious or life-threatening illnesses (referred to as “subpart H drugs”)  allows FDA to more quickly approve drugs showing meaningful  therapeutic benefit with the caveat that the sponsor will conduct or finish  studies after the drug is marketed. Such drugs may be made available to  the public sooner but with less complete safety information than the  normal review process requires for approval. Second, in 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. For example, FDA approved a drug in 2003  that is used as a treatment for patients who have been exposed to a  chemical nerve agent called Soman. Evidence of the effectiveness of this  drug was obtained from animals alone because it is unethical to perform  such studies in humans. In either situation, FDA may withdraw approval of  these drugs if, for example, postmarket clinical studies fail to verify  clinical benefits, the sponsor fails to perform postmarketing studies with  due diligence, or postmarketing restrictions (for example, restricted  distribution) are inadequate to assure safe use of the drug. Finally, under  certain conditions, after a drug is approved, FDA can also require that  drug sponsors conduct postmarket studies of marketed drugs when such  studies are needed to provide adequate labeling to ensure the safe and  effective use of these drugs in children.
section_title: Two Distinct FDA Units Involved in Postmarket Drug Safety Activities
paragraphs: Two distinct FDA offices are involved in postmarket drug safety activities.  While there is some overlap in their activities, they have different  organizational characteristics and perspectives on postmarket drug safety.  OND is involved in postmarket drug safety activities as one aspect of its  larger responsibility to review new drug applications, and it has the  decision-making responsibility for postmarket drug safety. ODS has a  primary focus on postmarket drug safety and provides consultation to  OND. ODS has been reorganized several times over the years, and there  has been an absence of stable leadership. FDA’s postmarket drug safety  decision-making process is complex, involving iterative interactions  between OND and ODS.
subsections: section_title: OND Has Decision-making Responsibility for Postmarket Drug Safety
paragraphs: Since OND is responsible for approving or disapproving drug applications,  its staff are involved in safety activities throughout the life cycle of a drug  (that is, premarket and postmarket), and it has the ultimate responsibility  to take regulatory action concerning the postmarket safety of drugs. OND  is organized into six offices that evaluate drugs and drug products, and  within these offices are 17 review divisions organized by medical specialty  (for example, oncology or dermatology). OND’s staff includes physicians,  pharmacologists, toxicologists, and microbiologists. The key decision  makers in OND—division directors and office directors—are physicians.  In general, OND staff take a clinical perspective in their work. According  to the Director of the office, OND’s medical staff have expertise in medical  specialties as well as drug regulation, which he said gave them the ability  to integrate issues related to the disease, available therapy, effectiveness  of the drug, and relative safety. He also told us that OND staff are focused  on meeting patient needs and providing health care practitioners and  patients with a range of drugs for treatment of a specific disease or  condition. Finally, an important characteristic of OND’s organization is  that OND’s work and its pace are driven in part by PDUFA goals to  complete its review of drug applications within certain time frames.
FDA estimates that 51 percent of OND’s work time is devoted to drug  safety, either premarket or postmarket. In the drug development or  premarket phase, OND staff review safety and efficacy data from  sponsors’ animal studies and human clinical trials to decide whether or  not to approve a drug. In some cases OND identifies safety concerns at the  time of approval that it believes can be managed, for example, by  educating patients and providers or restricting distribution to certain  populations. In these cases, OND works with ODS and the sponsor to  develop a risk management plan to outline these strategies. OND may also  request, or in cases where FDA has the authority, require that a sponsor  conduct a postmarketing study as a condition of approval.
After a drug is on the market, OND receives information about safety  issues related to a drug’s use and takes appropriate regulatory action. OND  receives information about safety issues in several ways. First, OND staff  receive notification of adverse event reports for drugs to which they are  assigned and they review the periodic adverse event reports that are  submitted by drug sponsors. Second, OND staff review safety information  that is submitted to FDA when a sponsor seeks approval for a new use or  formulation of a drug, and monitor completion of postmarket studies.  OND also partners with ODS and other CDER offices for information and  analysis to help it make postmarket drug safety decisions. When  considering postmarket drug safety issues, OND staff use evidence found  in clinical trials. For example, one OND manager told us that OND staff  typically review adverse event data related to a drug, obtain a consult from  ODS, and then review any clinical trial data. Then, if necessary, OND  makes a decision about what action should be taken, which may include  negotiating with a sponsor to change a drug’s label, restricting its  distribution, or proposing to withdraw the drug’s approval.
section_title: ODS Serves as a Consultant to OND
paragraphs: ODS serves primarily as a consultant to OND and has an overall goal of  reducing preventable deaths and injuries associated with the use of drugs  with a primary focus on postmarket drug safety. ODS also provides  consultation to OND on premarket safety issues, including risk  management issues. Although FDA’s postmarket drug safety office has  been reorganized several times over the years, the consultant role of the  office has remained consistent. ODS was formed in 2002 when FDA  combined the Office of Postmarketing Drug Risk Assessment with the  MedWatch program (from the Office of Training and Communications)  and with patient labeling and risk communication functions (from the  Division of Drug Marketing, Advertising, and Communications). ODS was  established within the new Office of Pharmacoepidemiology and  Statistical Science (OPaSS). OPaSS was made equivalent to OND within  the CDER organizational structure.
ODS is composed of a small management team and three divisions.  According to the ODS Director, the management team consists of the  director, deputy director, an associate director for regulatory affairs, and  an associate director for science and medicine. ODS’s three divisions are:  the Division of Drug Risk Evaluation (DDRE), the Division of Surveillance,  Research, and Communication Support, and the Division of Medication  Errors and Technical Support. The Division of Surveillance, Research, and  Communication Support is involved with the acquisition and analysis of  data related to drug safety. This division also reviews consumer-oriented  materials for content and patient-friendly language, such as medication  guides, which are dispensed with drugs that have serious safety concerns.  This division also disseminates safety information to the medical  community and general public through the MedWatch Web site. The  Division of Medication Errors and Technical Support is responsible for  conducting premarketing reviews of all proprietary names and labels of  drugs in order to minimize medication errors due to similar names or  confusion related to the labeling and packaging of drugs. This division also  provides postmarketing review and analysis of medication errors.
ODS’s DDRE is the primary unit responsible for postmarket drug safety  surveillance. Its staff of 47 include safety evaluators, who are generally  pharmacists, and epidemiologists, with many having either a Ph.D. in  epidemiology or an M.D. with epidemiologic training. The division’s safety  evaluators are assigned to cover specific groups or classes of marketed  drugs. They primarily review reports of individual adverse events from  AERS in order to detect safety signals. The division’s epidemiologists work  collaboratively with the safety evaluators, using population-level data to  analyze potential safety signals and put them into context. They also  review the published literature and conduct research through the use of  contracts and other agreements with researchers outside of government,  health care utilization databases, and surveillance systems. Finally, safety  evaluators and epidemiologists interact with international colleagues on  drug safety issues.
ODS operates primarily in a consultant capacity to OND and does not have  any independent decision-making responsibility. When there is a safety  concern, ODS staff conduct an analysis and produce a written report for  OND called a consult. Safety consults conducted by DDRE staff include  analyses of adverse event reports and assessments of postmarket study  designs and risk management plans. In fiscal year 2004, DDRE completed  approximately 600 safety consults. A majority of DDRE’s consults are  requested by OND. In fiscal year 2004, 71 percent of DDRE’s consults were  requested by OND; 22 percent were requested by other sources; and   7 percent were self-initiated by DDRE. Over time, the proportion of DDRE- initiated consults has declined while the proportion of OND-requested  consults has increased.
In general, ODS staff take a population-based perspective in their work,  which ODS staff we spoke with contrasted with the clinical perspective of  OND. They look at how a drug is being used in the general population and  its side effects, and they base their safety analyses on adverse event  reports, observational studies, and other population-based data sources.  ODS staff do not typically use clinical trial data for their safety analyses  and conclusions. In their postmarket work, ODS staff also do not operate  under PDUFA drug review goals and therefore do not face the same kinds  of deadlines that OND staff face. Furthermore, ODS staff have sometimes  taken an academic research approach to safety work, for example,  publishing case reports about adverse events or safety analyses in peer- reviewed journals.
There has been high turnover of ODS directors—there have been eight  different directors of the office and its various predecessors—in the past  10 years. Four of the directors have been “acting” directors, not permanent  ones. From February to September 2002 and again from October 2003 to  January 2005, the Director of OPaSS also served as the Acting Director of  ODS. The Director of CDER, as well as staff within and outside of ODS,  told us that the lack of consistent leadership of ODS has had a negative  effect on the work and morale of staff. One ODS staff member told us that  since drug safety issues often take a fair amount of time to resolve, it is  important to have consistency in leadership so that the leaders are  knowledgeable of ongoing issues. In October 2005 FDA appointed a  permanent director of ODS from within the organization, the first  permanent director since October 2003.
section_title: Postmarket Drug Safety Decision Making Is Complex and Iterative
paragraphs: The decision-making process for postmarket drug safety is complex,  involving input from a variety of FDA staff and organizational units and  information sources, but the central focus of the process is the iterative  interaction between OND and ODS. As we have described, ODS safety  consults can be initiated within ODS or requested by OND, but typically  OND requests them. OND often requests an analysis because of  information it receives from the drug’s sponsor about a safety concern.  ODS safety evaluators then search AERS for all relevant cases and develop  a summary of individual cases from the reports. The safety evaluators  assess the cases to determine whether the adverse events are drug-related  and whether there are any common trends or risk factors. ODS  epidemiologists sometimes collaborate with the safety evaluators by  estimating how frequently an adverse event occurs among the population  exposed to a particular drug, and they compare this estimate with how  frequently the same event occurs in a population not treated by the drug.  The epidemiologists also might use information from observational studies  and drug use analyses to analyze the safety issue. When completed, ODS  staff summarize their analysis in a written consult. The ODS division  director of the staff who worked on the consult typically reviews the  consult and either signs it, indicating agreement, or writes a memorandum  explaining what part he or she disagrees with and why. According to FDA  officials, OND staff within the review divisions usually decide what  regulatory action should occur, if any, by considering the results of the  safety analysis in the context of other factors such as the availability of  other similar drugs and the severity of the condition the drug is designed  to treat. Several CDER staff, including OND and ODS staff, that we  interviewed told us that most of the time there is agreement within FDA  about what safety actions should be taken. At other times, however, OND  and ODS disagree about whether the postmarket data are adequate to  establish the existence of a safety problem or support a recommended  regulatory action. In those cases, sometimes OND requests additional  analyses by ODS and sometimes there is involvement from other FDA  organizations. In some cases, OND seeks the advice of FDA’s scientific  advisory committees, including DSaRM, for decisions about postmarket  drug safety. The recommendations of the advisory committees do not bind  the agency to any decision. According to FDA officials, if a decision is  made by OND that a safety action is warranted, then OND staff generally  work with the drug’s sponsor to implement it.
There was sometimes a lack of consensus in our drug case studies, and we  observed that ODS often performed a series of related analyses about the  same safety concerns for OND over a significant period of time. As an  illustration of this iterative decision-making process, OND requested in  2002 that ODS analyze cases of serious skin reactions associated with the  pain reliever Bextra after the drug’s sponsor had communicated with OND  about this potential risk. ODS staff searched the AERS database and found  several related cases for review. They estimated the occurrence of  reported cases of serious skin reactions among Bextra users by using the  cases and drug utilization data. On the basis of their analysis, ODS  recommended that Bextra’s label be updated to include this risk, and OND  followed the recommendation by working with the sponsor to update the  label in 2002. Between 2002 and 2004, ODS staff conducted five other  analyses of the occurrence of serious skin reactions associated with  Bextra, including two that were requested by OND. In March 2004, ODS  staff recommended that Bextra carry a boxed warning about its risks of  serious skin reactions. The ODS staff based their recommendation on their  finding that Bextra’s risk for serious skin reactions was 8 to 13 times  higher than that for other similar drugs and 20 times higher than the  incidence rate in the population. The ODS Division Directors who  reviewed the analysis and recommendation agreed, but the OND review  division responsible for Bextra did not initially agree. About 5 months  later, the OND review division decided a boxed warning was warranted,  after ODS performed another analysis requested by OND, comparing  Bextra’s risk with several other similar drugs, including Mobic. ODS  found no reported cases of serious skin reactions associated with Mobic.  In 2005, a joint meeting of FDA’s Arthritis Advisory Committee and DSaRM  was held to discuss the postmarket safety of several anti-inflammatory  drugs including Bextra, with a focus on their cardiovascular risks. The  committees recommended, after presentations by FDA staff and others,  that Bextra should remain on the market. A few months later, FDA asked  the sponsor to withdraw the drug from the market because, in part, its risk  for serious skin reactions appeared to be greater than for other similar  anti-inflammatory drugs.
section_title: FDA Lacks a Clear and Effective Decision-making Process for Postmarket Drug Safety
paragraphs: FDA’s postmarket drug safety decision-making process has been limited  by a lack of clarity, insufficient oversight by management, and data  constraints. We observed that there is a lack of established criteria for  determining what safety actions to take and when. Aspects of ODS’s role  in the process are unclear, including its role in participating in scientific  advisory committee meetings organized by OND. A lack of communication  between ODS and OND’s review divisions and limited oversight of  postmarket drug safety issues by ODS management has hindered the  decision-making process. FDA relies primarily on three types of data  sources—adverse event reports, clinical trial studies, and observational  studies—in its postmarket decision making. Each data source has  weaknesses, however. FDA also faces constraints in requiring certain  studies and obtaining data.
subsections: section_title: Decision-making Process on Drug Safety Lacks Clarity about Criteria for Action and the Role of ODS
paragraphs: While acknowledging the complexity of the postmarket drug safety  decision-making process, we observed in our interviews with OND and  ODS staff and in our case studies that the process lacked clarity about  how drug safety decisions are made and about the role of ODS. If FDA had  established criteria for certain postmarket drug safety decisions, then  some of the disagreements we observed in our case studies could have  possibly been resolved more quickly. For example, in the case of Bextra,  as described earlier, ODS and OND staff disagreed about whether the  degree of risk warranted a boxed warning, the most serious warning  placed in the labeling of a prescription medication. As another example,  there were differing opinions over taking stronger actions against  Propulsid, the nighttime heartburn medication which was associated with  cardiovascular side effects, or whether to modify the label. Between 1995  and 1997, Propulsid’s label had been modified, including the addition of a  boxed warning, to warn consumers and professionals about the  cardiovascular side effects of the drug. In June 1997 a task force within  FDA, including OND and ODS staff, was convened to further evaluate the  efficacy and safety of Propulsid. FDA staff, including task force members,  later met to discuss several regulatory options, including proposing further  label modifications, presenting the agency’s concerns to an advisory  committee, and proposing to withdraw approval of Propulsid. According  to a former OND manager, as a result of this meeting, FDA decided to seek  further label modifications. Some staff, from both OND and ODS, however,  supported stronger actions at this time, including proceeding with  proposing a withdrawal of approval. According to several FDA officials,  in the absence of established criteria, decisions about safety actions are  often based on the case-by-case judgments of the individuals reviewing the  data.
Our observations are consistent with previous FDA reviews. In 2000, two  internal CDER reports based on interviews that FDA conducted with staff  indicated that an absence of established criteria for determining what  safety actions to take, and when, posed a challenge for making postmarket  drug safety decisions. The reports recognized the need to establish criteria  to help guide such decisions. In a review of the safety issues concerning  Propulsid, CDER staff recommended that a standardized approach to  postmarket drug safety issues be established, by addressing various issues  such as how to determine when to incorporate safety issues into labeling  and when stronger actions should supersede further labeling changes.  According to the report, several staff noted frustration with the numerous  changes made to Propulsid’s label that were mostly ineffective in reducing  the number of cardiovascular adverse events. Similarly, after the diabetes  drug Rezulin was removed from the market in 2000 because of its risk for  liver toxicity, a CDER report focused on Rezulin also recommended that a  consistent approach to postmarket drug safety be developed, including  what regulatory actions should occur to address postmarket drug safety  concerns, and when they should occur.
In addition to a lack of criteria for safety actions, we observed a lack of  clarity related to ODS’s recommendations. In practice, ODS often makes  written recommendations about safety actions to OND but there is some  confusion over this role, according to several ODS managers, and there is  no policy that explicitly states whether ODS’s role includes this  responsibility. The case of Arava illustrates this confusion. In 2002, the  OND review division responsible for Arava, a drug used to treat  rheumatoid arthritis, requested that ODS review postmarket data for cases  of serious liver toxicity associated with its use. The ODS staff who worked  on this analysis recommended that Arava be withdrawn from the market  because they concluded that the risk for serious liver toxicity exceeded its  benefits. The OND Division Director responsible for Arava felt that ODS  should not have included a recommendation in its consult because he  argued that this was the responsibility of OND, not ODS. Some of the  confusion may be the result of ODS’s evolving role in postmarket drug  safety. A current and a former ODS manager told us that in the past, ODS’s  safety consults were technical documents summarizing adverse events  with minimal data analysis and few recommendations. Over time the  consults have become more detailed with sophisticated data analyses and  more recommendations about what safety action is needed (for example,  label change, medication guide, drug withdrawal).
ODS’s role in scientific advisory committee meetings is also unclear.  According to the OND Director, OND is responsible for setting the agenda  for the advisory committee meetings, with the exception of DSaRM. This  includes who is to present and what issues will be discussed by the  advisory committees. For the advisory committees (other than DSaRM) it  is unclear when ODS staff will participate. While ODS staff have presented  their postmarket drug safety analyses during some advisory committee  meetings, our case study of Arava, and another case involving  antidepressant drugs, provide examples of the exclusion of ODS staff. For  example, in March 2003, the Arthritis Advisory Committee met to review  the efficacy of Arava, and its safety in the context of all available drugs to  treat rheumatoid arthritis. The OND review division responsible for Arava  presented its own analysis of postmarket drug safety data at the meeting,  but did not allow the ODS staff—who had recommended that Arava be  removed from the market—to present their analysis because it felt that  ODS’s review did not have scientific merit. Specifically, the OND review  division felt that some of the cases in the ODS review did not meet the  definition of acute liver failure, the safety issue on which the review was  focused. The OND division also believed that in some of the cases ODS  staff inappropriately concluded that liver failure resulted from exposure to  Arava. After the meeting, ODS epidemiologists and safety evaluators  asked the ODS and OPaSS Directors to clarify ODS’s role involving  postmarket drug safety issues, including its role at advisory committee  meetings. According to an FDA official, there was no written response to  this request.
As another example of ODS’s unclear role in scientific advisory  committees, in February 2004 an ODS epidemiologist was not allowed to  present his analysis of safety data at a joint meeting of the  Psychopharmacologic Drugs Advisory Committee and the Pediatric  Subcommittee of the Anti-Infective Drugs Advisory Committee that was  held to discuss reports of suicidal thoughts and actions in children with  major depressive disorder during clinical trials for various antidepressant  drugs. According to statements by FDA officials at a congressional  hearing, OND believed that the ODS staff member’s analysis, which  showed a relationship between the use of antidepressants and suicidal  thoughts and behaviors in children, was too preliminary to be presented in  detail. The analysis was based on pediatric clinical trial data that FDA  requested from the sponsors of several antidepressant drugs. FDA had  asked the sponsors to identify suicide-related events using specific  methods, and then ODS was asked to analyze all of the submitted data.  OND later decided that the sponsors may have been inconsistent in their  classification approaches and asked outside experts to perform additional  reviews of all the cases by rating whether particular events could be  classified as suicidal. The staff member who performed the ODS review,  however, believed that the available data were sufficient to conclude a  relationship between the use of antidepressants and suicidal thoughts and  behaviors in pediatrics and to recommend further safety actions. In his  consult, the ODS staff member also concluded that while additional  analyses would yield valuable information, they would also take several  more months to complete. In light of this delay, he recommended an  interim plan to discourage the use of all but one antidepressant in the  treatment of pediatric major depressive disorders. In December 2004,  ODS epidemiologists communicated to the CDER Director their position  that ODS’s role should include the responsibility of presenting all relevant  ODS data at advisory committee meetings. According to an FDA official,  there was no written response to this request. However, in our interviews,  the Directors of CDER and OND told us that in retrospect they felt it was a  mistake for FDA to have restricted the ODS epidemiologist from  presenting his safety information at the meeting.
Several ODS managers that we interviewed told us that there is also a lack  of clarity regarding the role of the epidemiologist in postmarket drug  safety work. Despite the fact that ODS’s epidemiologists have some  defined responsibilities, there appears to be some confusion about the  scope of their activities and a lack of understanding on the part of OND  about their role and capabilities. A prior review of postmarket drug safety  identified similar issues. For example, in that review some  epidemiologists indicated that they should be able to maintain an  independent approach to their research and the publication of their  research. However, some OND review division directors indicated that the  work of the epidemiologists should be considered within the context of  CDER’s overall regulatory mission. Further, the epidemiologists’ research  conclusions do not necessarily reflect the conclusions of FDA but may be  perceived as such by the medical community. ODS managers indicated  that a current challenge for FDA is to determine how it should use its  epidemiologists and what their work products should be. According to the  current ODS Director, efforts are needed to help OND better understand  what epidemiologists can do. The epidemiologists themselves have asked  for greater clarity about their role and a stronger voice in decision making.
section_title: A Lack of Communication and Limited Oversight Hinders the Decision- making Process
paragraphs: A lack of communication between ODS and OND’s review divisions and  limited oversight of postmarket drug safety issues by ODS management  have also hindered the decision-making process. The frequency and extent  of communication between ODS and OND’s divisions on postmarket drug  safety vary. ODS and OND staff often described their relationship with  each other as generally collaborative, with effective communication. But  both ODS and OND staff said sometimes there were communication  problems, and this has been an ongoing concern. For example, according  to some current and former ODS staff, OND does not always adequately  communicate the key question or point of interest to ODS when it requests  a consult, and as ODS works on the consult there is sometimes little  interaction between the two offices. After a consult is completed and sent  to OND, ODS staff reported that OND sometimes does not respond in a  timely manner or at all. Several ODS staff characterized this as consults  falling into a “black hole” or “abyss.” OND’s Director told us that OND staff  probably do not “close the loop” in responding to ODS’s consults, which  includes explaining why certain ODS recommendations are not followed.  In some cases CDER managers and OND staff criticized the methods used  in ODS consults and told us that the consults were too lengthy and  academic.
ODS management has not effectively overseen postmarket drug safety  issues, and as a result, it is unclear how FDA can know that important  safety concerns have been addressed and resolved in a timely manner.  According to a former ODS Director, the small size of ODS’s management  team has presented a challenge for effective oversight of postmarket drug  safety issues. Another problem is the lack of systematic information on  drug safety issues. According to the ODS Director, ODS currently  maintains a database of consults that can provide certain types of  information such as the total count, the types of consults that ODS staff  conducted, and the ODS staff that wrote the consults. But it does not  include information about whether ODS staff have made  recommendations for safety actions and how the safety issues were  handled and resolved, including whether recommended safety actions  were implemented by OND. For example, ODS was unable to provide us  with a summary of the recommendations for safety actions that its staff  made in 2004 because it was not tracking such information.
section_title: Data Constraints Contribute to Difficulty in Making Postmarket Safety Decisions
paragraphs: Data constraints—such as weaknesses in data sources and limitations in  requiring certain studies and obtaining data—contribute to FDA’s  difficulty in making postmarket drug safety decisions. OND and ODS use  three different sources of data to make postmarket drug safety decisions.  They include adverse event reports, clinical trial studies, and observational  studies. While data from each source have weaknesses that contribute to  the difficulty in making postmarket drug safety decisions, evidence from  more than one source can help inform the postmarket decision-making  process. The availability of these data sources is constrained, however,  because of FDA’s limited authority to require drug sponsors to conduct  postmarket studies and its resources.
While decisions about postmarket drug safety are often based on adverse  event reports, FDA cannot establish the true frequency of adverse events  in the population with AERS data. The inability to calculate the true  frequency makes it hard to establish the magnitude of a safety problem,  and it makes comparisons of risks across similar drugs difficult. In  addition, it can be difficult to attribute adverse events to particular drugs  when there is a relatively high incidence rate in the population for the  medical condition. For example, ODS staff analyzed adverse event  reports of serious cardiovascular events among users of the anti- inflammatory drug Vioxx in a 2001 consult. However, because Vioxx was  used to treat arthritis, which occurs more frequently among older adults,  and because of the relatively high rate of cardiovascular events among the  elderly, ODS staff concluded that the postmarket data available at that  time were not sufficient to establish that Vioxx was causally related to  serious cardiovascular adverse events. With AERS data it is also difficult  to attribute adverse events to the use of particular drugs because the  AERS reports may be confounded by other factors, such as other drug  exposures. For example, one AERS report described a patient who  developed cardiac arrest after he was given the drug hyaluronidase with  two local anesthetics in preparation for cataract surgery. Because local  anesthetics can lead to cardiac events, the ODS safety evaluator who  reviewed this case concluded that the causal role of hyaluronidase alone  could not be established.
FDA may also use data from clinical trials and observational studies to  support postmarket drug safety decisions, but each source has  weaknesses that constrain the usefulness of the data provided. Clinical  trials, in particular randomized clinical trials, are considered the “gold  standard” for assessing evidence about efficacy and safety because they  are considered the strongest method by which one can determine whether  new drugs work. However, clinical trials also have weaknesses. Clinical  trials typically have too few enrolled patients to detect serious adverse  events associated with a drug that occur relatively infrequently in the  population being studied. They are usually carried out on homogenous  populations of patients that often do not reflect the types of patients who  will actually take the drugs, including those who have other medical  problems or take other medications. In addition, clinical trials are often  too short in duration to identify adverse events that may occur only after  long use of the drug. This is particularly important for drugs used to treat  chronic conditions where patients are taking the medications for the long  term. Observational studies, which use data obtained from population- based sources, can provide FDA with information about the population  effect and risk associated with the use of a particular drug. Because they  are not controlled experiments, however, there is the possibility that the  results can be biased or confounded by other factors.
Despite the weaknesses of clinical trials and observational studies,  evidence from both types of studies helps inform FDA’s postmarket drug  safety decision-making process. For example, clinical trials conducted by  drug sponsors for their own purposes sometimes provide information for  FDA’s evaluation of postmarket drug safety issues. For instance, drug  sponsors sometimes conduct clinical trials for drugs already marketed in  order to seek approval for a new or expanded use. These studies may  also be conducted to support claims about the additional benefits of a  drug, and their results sometimes reveal safety information about a  marketed drug. For example, to support the addition of a claim for the  lower risk of gastrointestinal outcomes (such as ulcers and bleeding),  Vioxx’s sponsor conducted a clinical trial that found a greater number of  heart attacks in patients taking Vioxx compared with another anti- inflammatory drug, naproxen. This safety information was later added to  Vioxx’s labeling. In addition to relying on sponsors, ODS partners with  researchers outside of FDA to conduct postmarket observational studies  through cooperative agreements and contracts. For example, several  cooperative agreements supported a study of Propulsid using population- based databases from two managed care organizations and one state  Medicaid program, before and after warnings on contraindications were  added to the drug’s label in 1998. The cooperative agreement researchers,  which included ODS staff, measured the prevalence of contraindicated use  of Propulsid, and found that a 1998 labeling change warning about the  contraindication did not significantly decrease the percentage of users  who should not have been prescribed this drug.
FDA’s access to postmarket clinical trial and observational data, however,  is limited by its authority and available resources. As described previously,  FDA does not have broad authority to require that a drug sponsor conduct  an observational study or clinical trial for the purpose of investigating a  specific postmarket safety concern. One senior FDA official and several  outside drug safety experts told us that FDA needs greater authority to  require such studies. Long-term clinical trials may be needed to answer  safety questions about risks associated with the long-term use of drugs,  such as those that are widely used to treat chronic conditions. For  example, during a February 2005 scientific advisory committee meeting,  some FDA staff and members of the Arthritis Advisory Committee and  DSaRM indicated that there was a need for better information on the long- term use of anti-inflammatory drugs and discussed how a long-term trial  might be designed to study the cardiovascular risks associated with the  use of these drugs. As another example, FDA approved Protopic and  Elidel, both eczema creams, in December 2000 and December 2001,  respectively. Since their approval, FDA has received reports of lymphoma  and skin cancer in children and adults treated with these creams. In March  2005, FDA announced that it would require label changes for the creams,  including a boxed warning about the potential cancer risk. An ODS  epidemiologist told us that FDA has been trying for several years to get the  sponsor to do long-term studies of these drugs, but that it has been  difficult to negotiate.
In the absence of specific authority, FDA often relies on drug sponsors  voluntarily agreeing to conduct such postmarket studies. But the  postmarket studies that drug sponsors agree to conduct have not  consistently been completed. For example, one study estimated that the  completion rate of postmarket studies, including those that sponsors have  voluntarily agreed to conduct, rose from 17 percent in the mid-1980s to   24 percent between 1991 and 2003. FDA has little leverage to ensure that  these studies are carried out, for example, by imposing administrative  penalties.
In terms of resource limitations, several FDA staff (including CDER  managers) and outside drug safety experts told us that in the past ODS has  not had enough resources for cooperative agreements to support its  postmarket drug surveillance program. Annual funding for this program  was less than $1 million from fiscal year 2002 through fiscal year 2005. In  October 2005 FDA awarded four contracts to replace the cooperative  agreements, and FDA announced that these contracts would allow FDA to  more quickly access population-level data and a wider range of data  sources. The total amount of the contracts, awarded from 2005 to 2010, is  about $5.4 million, which averages about $1.1 million per year, a slight  increase from fiscal year 2005 funding. The new contracts will provide  access to data from a variety of health care settings including health  maintenance organizations, preferred provider organizations, and state  Medicaid programs.
According to an FDA official, FDA does not conduct its own clinical trials  because of the high cost associated with carrying out such studies and  because FDA does not have the infrastructure needed to conduct them. It  was recently estimated that clinical trials designed to study long-term drug  safety could cost between $3 million and $7 million per trial. The  estimated cost of just one such trial would exceed the amount FDA has  currently allocated ($1.1 million) for its contracts with researchers outside  of FDA.
section_title: FDA Initiatives Are an Improvement, but Will Not Address All Gaps
paragraphs: FDA has undertaken several initiatives to improve the postmarket drug  safety decision-making process, but these are unlikely to address all the  gaps. FDA’s newly created Drug Safety Oversight Board (DSB) may help  provide oversight of important, high-level safety decisions, but it does not  address the need for systematic tracking of ongoing safety issues. Other  initiatives, such as FDA’s draft policy on major postmarket drug safety  decisions and communication initiatives may help improve the clarity and  effectiveness of the process, but they have not been fully implemented.  FDA’s dispute resolution processes to help resolve disagreements over  safety decisions have not been used and may not be viewed as sufficiently  independent. FDA is taking steps to identify additional data sources for  postmarket drug safety studies, and expects to use additional funds for  this purpose, but FDA still faces data constraints.
subsections: section_title: DSB May Provide Broad Oversight, but Systematic Tracking Is Still Needed
paragraphs: FDA’s DSB, created in the spring of 2005, may help provide oversight of  important, high-level safety decisions within CDER; however, there is still  a need for systematic tracking of ongoing safety issues. FDA established  the DSB to help provide independent oversight and advice to the CDER  Director on the management of important safety issues. The DSB reports  directly to the head of CDER and consists primarily of FDA officials from  within CDER and other FDA centers. According to an FDA policy  document, the DSB includes 11 voting members from CDER, with   3 representatives from ODS and 3 from OND. Currently the OND and ODS  Directors are voting members. It also includes representatives from other  federal agencies. DSB members who conducted the primary preapproval  review of the drug or who were involved with a drug’s approval or  postmarket safety review will not be allowed to vote on issues concerning  that drug. As of February 2006, the DSB was meeting regularly and an FDA  official told us that it is expected to meet monthly. The meetings are not  open to the public, but FDA posts abbreviated summaries of the meeting  minutes on its Web site.
According to an FDA policy document, the DSB will identify, track, and  oversee the management of important drug safety issues. Important drug  safety issues include serious side effects identified after a drug’s approval  that have the potential to significantly alter the drug’s benefit-to-risk  analysis or significantly affect physicians’ prescribing decisions. According  to an FDA official, ODS and OND submit monthly reports of safety issues  for discussion by the DSB to be used in setting the agenda for the  meetings. In addition, at any time individuals within and outside of FDA  can submit issues to be considered by contacting a DSB member or the  executive director. The FDA official said that the DSB will not be involved  in the ongoing process of postmarket surveillance and decision making  about drug safety issues, but rather will be involved with ensuring that  broader safety issues—such as ongoing delays in changing a label—are  effectively resolved. The DSB may also develop standards for certain kinds  of safety-related actions, such as when a drug warrants a boxed warning  or a medication guide. The FDA official acknowledged that safety-related  decisions are still based on individual judgments and lack consistency. The  DSB has plans to form subcommittees to look at policy development in  this and other areas.
The DSB may help provide high-level oversight of safety issues, but it does  not address the problem of the lack of systematic tracking of safety issues  and their resolution. Information about the resolution of safety issues  identified by ODS staff is still not available to ODS management nor to the  DSB.
section_title: Other Process and Organizational Initiatives Are Promising, but Not Fully Implemented
paragraphs: FDA’s draft policy on major postmarket drug safety decision making and  other process and organizational initiatives may make the process clearer  and more effective, but these efforts have not been fully implemented.  Several years ago, FDA drafted a policy entitled “Process for Decision- Making Regarding Major Postmarketing Safety-Related Actions” that could  help improve the decision-making process, but as of February 2006, this  policy has not been finalized and implemented. The draft policy was  designed to ensure that all major postmarket safety recommendations,  such as the market withdrawal of a drug, would be discussed by involved  CDER managers, starting at the division level. The draft policy states that  CDER staff, including ODS staff, are to write a detailed memorandum  describing their recommendation for a major safety action. If the  immediate supervisor disagrees, he or she prepares a memorandum  explaining the nature of the differences, and then the division director  prepares a memorandum indicating how the issue should be resolved. In  some cases the supervisor and division director may be the same person.  A Division Consensus Meeting is to be convened for every  recommendation regardless of whether there is initial agreement between  the staff member making the recommendation and the supervisor and  division director. The process stops at the division level if a decision is  reached that a major safety action is not needed. Otherwise, the  recommendation is discussed at higher levels of management in CDER. An  Office Action Meeting would then be held to recommend a course of  action to the CDER director, although it is possible that there still could be  disagreement at the office level. A final meeting, called the Decisional  Meeting, would then be held to decide a course of action, and would  include the CDER director as well as office- and division- level staff. It is  not clear how the new DSB will be integrated into the draft policy on  major postmarket drug safety decision making, and FDA officials told us  they are still trying to determine how to do this.
Other initiatives may improve the decision-making process, but these  efforts have not been fully implemented. For example, ODS has  established a Process Improvement Team to assess the safety consult  process, including how OND asks questions about postmarket safety  concerns and how ODS should answer the questions. OND has established  a similar team to assess the overall process for reviewing postmarket  safety information, including the consult process. Both teams plan to make  recommendations; for example, the OND representative chairing the OND  team told us the OND team plans to recommend which office (OND or  ODS) should have responsibility for certain postmarket tasks, such as  reviewing periodic adverse event reports. According to the OND chair, the  OND team expects to finalize its recommendations by the end of March  2006. According to the ODS Director, the ODS team’s work was still in  progress as of January 2006 and would not be completed for about   6 months. In February 2006, ODS established a new Process Improvement  Team to identify best practices for safety evaluators in order to make sure  there is standardization of their work (for example, reviewing of adverse  event reports). The ODS Director estimated that the work of this team  would be completed in 3 to 4 months.
FDA officials told us that they have proposed reorganizing CDER to  dissolve OPaSS and have the director of ODS report to the CDER director.  FDA plans to implement this reorganization in May 2006. In the meantime,  ODS has taken some other steps to improve communication and oversight  of safety issues. According to the ODS Director, the DDRE Director  recently instituted regular meetings between the safety evaluators in his  division and the OND review divisions in order to discuss drug safety  issues, including ongoing consults, issues that DDRE staff have not yet  provided consultation on, and how safety issues have been resolved.  According to the DDRE Director, over half of OND’s review divisions have  participated in these regular meetings to date. The Director of ODS also  acknowledged that ODS needs to have a better way to track safety issues  as they are emerging. He told us that ODS is developing a tracking system  that is currently being tested and is expected to become operational in  2006. The Director also said he had plans to build up the immediate office  of ODS by adding an associate director of operations and staff responsible  for working on relationships with other federal agencies (for example,  National Institutes of Health) and contractors. He has decided to hold  regular meetings with the ODS deputy director and division directors for  the specific purpose of discussing the status of drug safety problems.
Despite the efforts that FDA has made to improve its postmarket drug  safety decision-making process, the role of ODS in advisory committee  meetings (other than DSaRM) has not been clarified. The role of ODS in  scientific advisory committee meetings is not discussed in the draft policy  on major postmarket drug safety decisions or in other policy documents.  In addition, according to the ODS Director, the role of epidemiologists in  ODS requires further clarification. A Process Improvement Team that was  formed to address this issue was suspended, and the ODS Director said  that other ways to approach this issue are being evaluated.
section_title: Dispute Resolution Processes Have Not Been Used
paragraphs: The DSB and a pilot program have not been used as of February 2006 to  help resolve organizational and individual disagreements that occur within  CDER over safety decisions and may not be viewed as sufficiently  independent. According to an FDA policy document, the DSB will resolve  organizational disputes over approaches to drug safety. According to an  FDA official, as of February 2006, however, the DSB had not handled any  such formal disputes. An FDA official told us that, as an example, ODS  might believe that a drug should come off the market but OND does not  agree, and resolving this matter could be handled by the DSB. Although  DSB members who were involved with a drug product’s approval or safety  review will be recused from the DSB’s decision-making process  concerning that drug, the current DSB membership includes CDER  managers who oversee the drug approval and safety review processes,  which may limit the ability of the DSB to provide neutral, independent  advice in the handling of organizational disputes. In addition, decisions  made by the DSB will serve as recommendations to the CDER director,  who is the final decision maker. This reporting chain may further limit the  independence of the DSB since the CDER director manages the overall  drug approval and safety review processes.
In addition to the DSB, a pilot program for dispute resolution procedures  has not been used by CDER staff as of February 2006. In November 2004  FDA implemented a pilot program for dispute resolution that is designed  for individual CDER staff to have their views heard when they disagree  with a decision that could have a significant negative effect on public  health, such as a proposed safety action or the failure to take a safety  action. Any CDER employee can initiate the process, but the CDER  ombudsman, in consultation with the CDER director, determines  whether a dispute warrants formal review. If the CDER director and  ombudsman decide to proceed, the CDER director would establish a panel  of three or four members, one of which the CDER employee initiating the  process would nominate. The panel would review the case and make a  recommendation to the CDER director, who would then decide how the  dispute should be resolved. Like the DSB, the pilot program also does not  offer employees an independent forum for resolving disputes. The CDER  director decides whether the process should be initiated, appoints the  chair of the panel, and is the final adjudicator.
section_title: FDA Is Taking Steps to Identify Additional Data Sources, but Constraints Remain
paragraphs: FDA is taking steps to identify additional data sources that it may obtain  with its current authority and resources. In fiscal year 2006, FDA expects  to use $10 million for this purpose consistent with direction in the  Conference Report accompanying FDA’s fiscal year 2006 appropriation.  The Conference Report specified that a $10 million increase over the prior  year was provided for drug safety activities, including $5 million for ODS  and $5 million for drug safety activities within CDER. The conferees  intended for the increases to be used for FDA’s highest-priority drug safety  needs that were not funded in fiscal year 2005, such as acquiring access to  additional databases beyond those that will be accessed through its new  contracts. The ODS Director told us that ODS plans to use the $5 million  to hire staff, specifically safety evaluators and technical support staff. The  other $5 million is to be used for postmarket drug safety work throughout  CDER and those plans had not been finalized as of February 2006. The  Director of ODS said that given the high cost of planning and conducting  observational studies, only one or two studies can be funded each year.
According to the ODS Director, FDA has started to work with the Centers  for Medicare & Medicaid Services to obtain access to data on Medicare  beneficiaries’ experience with prescription drugs covered under the new  prescription drug benefit, which began in 2006. This data source may  provide information about drug utilization for a very large population of  Medicare recipients and can potentially be linked to claims data, providing  information about patients’ medical outcomes. According to the ODS  Director, a team of ODS staff has been working with the Centers for  Medicare & Medicaid Services to determine what data elements ODS  would seek to access; however, it is uncertain how useful the data will be  because there are potential data reliability issues. For example, it is  unclear whether ODS will be able to do medical chart reviews to verify  medical outcomes. Additionally, in April 2005 FDA requested information  from other organizations about their active surveillance programs in the  United States for identifying serious adverse events. In its request, FDA  noted that it was seeking information related to these programs because  active surveillance would strengthen and complement the tools it  currently has to monitor postmarket drug safety. As an example, FDA  noted interest in learning about systems that can identify specific acute  outcomes for which a drug is frequently considered as a potential cause,  such as acute liver failure and serious skin reactions. According to the  ODS Director, a working group within ODS is currently evaluating the  responses to the request for information; however, it is unlikely that they  will fund any of these active surveillance systems in 2006 because FDA  needs to ensure that such systems are able to identify drug safety concerns  earlier compared to other data sources before the agency invests in them.
The working group’s review of the request for information was still  ongoing as of March 2006.
section_title: Conclusions
paragraphs: Postmarket drug safety decision making at FDA is a complex process that  sometimes results in disagreements, as observed in our case studies.  Scientific disagreements may be expected in a large regulatory agency,  especially given the different professional orientations of the key players,  OND and ODS, and the inherent limitations of the available data. However,  because of the potential public health consequences of FDA’s decisions  about postmarket drug safety issues, it is important to come to a decision  quickly. In our review, we observed opportunities for improving the clarity  and oversight of the process and strengthening the information used for  decision making. FDA has recently made some important organizational  and policy changes, but more could be done to improve management  oversight of postmarket drug safety issues, to improve the dispute  resolution process, and to strengthen the collaboration between OND and  ODS. In order to address the serious limitations of the data, FDA will need  to continue its efforts to develop useful observational studies and to  access and use additional healthcare databases. However, even if FDA is  successful in expanding its data sources for postmarket drug safety  surveillance, it would still benefit from information from long-term clinical  trials of certain drugs and the additional authority to require that these  studies be carried out.
section_title: Matter for Congressional Consideration
paragraphs: To improve the decision-making process for postmarket drug safety, the  Congress should consider expanding FDA’s authority to require drug  sponsors to conduct postmarket studies, such as clinical trials or  observational studies, as needed, to collect additional data on drug safety  concerns.
section_title: Recommendations for Executive Action
paragraphs: To improve the postmarket drug safety decision-making process, we  recommend that the Commissioner of FDA take the following four actions:    establish a mechanism for systematically tracking ODS’s  recommendations and subsequent safety actions;    with input from the DSB and the Process Improvement Teams, revise and  implement the draft policy on major postmarket drug safety decisions;  improve CDER’s dispute resolution process by revising the pilot program  to increase its independence; and    clarify ODS’s role in FDA’s scientific advisory committee meetings  involving postmarket drug safety issues.
section_title: Agency Comments and Our Evaluation
paragraphs: FDA reviewed a draft of this report and provided comments, which are  reprinted in appendix V. FDA also provided technical comments, which  we incorporated as appropriate.
FDA commented that our conclusions were reasonable and consistent  with actions that it has already begun or planned. FDA did not comment  on our recommendations. In addition, FDA made six comments about  specific aspects of our draft report. First, concerning our description of  the complexity of the postmarket decision-making process, FDA stated  that the draft report implied the process is too complex and that FDA  should not be criticized for its difficult task of weighing the risks and  benefits associated with drugs with the data available to the agency. We  agree with FDA that postmarket drug safety issues are inherently complex.  For that reason, we believe that FDA needs to have greater clarity about  how decisions are made and to establish more effective oversight of the  decision-making process. Furthermore, we believe that our report fairly  characterizes the limitations of the data that FDA relies on in this complex  process. Because of the data limitations, we believe that FDA needs  greater authority to access certain kinds of postmarket safety data.  Second, FDA noted that factors other than PDUFA goals influence OND’s  work and its pace. FDA also stated that ODS plays a role in certain  premarket safety activities and that PDUFA goals also apply to these  activities. We clarified these points in the report. Third, FDA stated that  referring to ODS as a consultant to OND understates the role of ODS in  drug safety and that CDER considers ODS and OND to be equal partners in  the identification and timely resolution of drug safety issues. As we stated  in the draft report, we found that the central focus of the process is the  iterative interaction between OND and ODS. Nonetheless, ODS does not  have any independent decision-making responsibility while OND has the  ultimate responsibility to make decisions about regulatory actions  concerning the postmarket safety of drugs. Further, both OND and ODS  refer to ODS reports on drug safety as consults. For these reasons, we  believe that our description of ODS as a consultant to OND is accurate.
Fourth, FDA agreed with our statements about the role of the DSB and  indicated that the DSB has reviewed current mechanisms for identifying  safety issues and discussed ways to enhance the tracking of those issues.  Fifth, FDA commented that our examples of ODS staff being excluded  from advisory committee meetings imply that such disagreements occur  frequently. FDA stated that this is not the case, and that OND and ODS  work cooperatively in the vast majority of cases. However, our work  demonstrates a need for further clarification of ODS’s role. Finally, FDA  commented that our case study chronology for Arava was incomplete  because it did not describe two meetings. We provided additional  clarification in the report about the meetings in the chronology for Arava.
As we agreed with your offices, unless you publicly announce the contents  of this report earlier, we plan no further distribution of it until 30 days  from the date of this letter. We will then send copies to others who are  interested and make copies available to others who request them.
If you or your staffs have any questions about this report, please contact  me at (202) 512-7119 or crossem@gao.gov. Contact points for our Offices  of Congressional Relations and Public Affairs may be found on the last  page of this report. GAO staff who made major contributions to this report  are listed in appendix VI.
section_title: Appendix I: Regulatory History and FDA Decision-making Process for Arava
subsections: section_title: Background and Summary
paragraphs: Arava was approved for marketing in 1998. Arava is indicated in adults for  the treatment of active rheumatoid arthritis to reduce the signs and  symptoms of the disease, slow down damage to joints, and improve  physical function. Arava has been associated with cases of serious liver  injury, some of which have been fatal.
In this case, the Office of Drug Safety (ODS) identified a serious safety  signal—hepatic failure and fatal hepatitis—associated with Arava in March  2001. A citizen’s petition in 2002 spurred further inquiry into the issue. An  ODS analysis of adverse event reports concluded that Arava was  associated with a substantial increased risk of liver failure and  recommended removal from the market, but the Office of New Drugs  (OND) disagreed. OND established an internal panel of senior staff and  hired outside consultants to further review the reports of liver failure, and  both the panel and outside consultants concluded that in most cases Arava  was not causally related to liver failure. In 2003 a Food and Drug  Administration (FDA) advisory committee meeting was held to discuss  Arava and ODS staff were not allowed to present their analysis. FDA  approved revised labeling of Arava in 2003 that strengthened the drug’s  warnings, and it remained on the market as of February 2006.
section_title: Chronology
subsections: section_title: September 1998
paragraphs: FDA approved Arava for marketing. At approval there was a known risk of  liver toxicity (hepatotoxicity); in clinical trials Arava was associated with  elevated liver enzymes in a significant number of patients. This  information was included in the original label.
section_title: March 2001
paragraphs: During routine surveillance of incoming adverse event reports, an ODS  safety evaluator had identified 11 cases of hepatic failure and fatal  hepatitis associated with the use of Arava. The safety evaluator  recommended that Arava’s label mention more extensive liver damage,  such as liver-related fatalities. The ODS Division Director who reviewed  the consult concurred with the findings and recommendation, but the  OND Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug  Products did not. OND did not agree with the findings or recommendation  because officials were uncertain about the causal relationship between  Arava and liver damage in the case reports and they believed that the  current label was adequate for communicating risk about hepatotoxicity.
section_title: March 2002
paragraphs: Public Citizen, a national nonprofit public interest organization, filed a  petition requesting that FDA immediately remove Arava from the U.S.  market. Public Citizen said that a significantly higher number of serious  adverse events, including fatal liver toxicity, had been associated with  Arava, compared with another drug used to treat patients with rheumatoid  arthritis. In response to the petition, OND requested that ODS review  postmarket data for serious hepatic events and liver failure since the  approval of Arava.
section_title: August 2002
paragraphs: ODS and OND staff met to discuss ODS’s preliminary work in response to  the Public Citizen request. ODS’s preliminary review concluded that Arava  was associated with a substantially increased risk for acute liver failure  and recommended removal from the market. OND disagreed with the  review.
section_title: October 2002
paragraphs: Because of the disagreements about causality, OND established a panel of  senior-level Center for Drug Evaluation and Research (CDER) staff, which  included managers from OND and ODS. The panel met twice to review  U.S. postmarket reports of 16 cases of acute liver failure and to vote on the  probability that Arava caused the liver injury. The majority of panel  members voted that Arava was likely to be causally related to liver failure  in only 2 of the cases.
section_title: November 2002
paragraphs: ODS staff finalized their review on Arava and sent the consult to OND. The  report included the recommendation to remove Arava from the market  because the authors believed that the risks of Arava greatly exceeded its  benefits and because the available risk management strategies (for  example, label changes and periodic liver enzyme monitoring) had been  shown to be ineffective in minimizing risk for other drugs. The ODS  Division Director who reviewed the consult concurred with the findings  and recommendation. The ODS Director and the Office of  Pharmacoepidemiology and Statistical Science (OPaSS) Director also  reviewed the consult. Both disagreed with the findings and  recommendation.
section_title: December 2002
paragraphs: At the request of OND, an ODS safety evaluator reviewed adverse event  reports of liver injury associated with Arava from outside the United  States. The ODS safety evaluator, who did not work on the prior analysis  of the U.S. cases, analyzed 13 cases of liver failure and concluded that  there was a possible association between the use of Arava and the  development of liver failure. The safety evaluator also concluded that  these findings were consistent with the earlier ODS findings in the 16 U.S.  liver failure cases. The ODS Division Director who reviewed the consult  concurred with the findings.
Because of the disagreement on Arava’s safety, OND had hired outside  consultants, including two hepatologists, to further review Arava’s safety  profile. The hepatology consultants completed their analysis, which  included a review of the U.S. reports of acute liver failure, by mid- December 2002. They identified no definite cases of Arava-induced liver  failure, but found some cases to be possibly related to Arava.
section_title: March 2003
paragraphs: FDA’s Arthritis Advisory Committee met to review Arava’s benefit-to-risk  profile and ways to improve risk management, and to discuss whether  Arava should be approved for a claim of improvement in physical function.  OND presented its own analysis of the postmarket safety data, and did not  allow ODS staff to present their analysis of postmarket safety data. A  former OND manager told us that OND believed that the ODS analysis did  not have scientific merit.
FDA’s Advisory Committee voted unanimously that Arava’s benefits in  rheumatoid arthritis outweighed its potential risks and that its risks were  no greater than other similar drugs. The committee also voted that Arava  should be approved for a claim of improvement in physical function.
ODS’s epidemiologists and safety evaluators submitted a letter to the ODS  and OPaSS Directors, expressing their concerns with the Arthritis  Advisory Committee meeting. They recommended that ODS staff should  present postmarket safety data at advisory committee meetings and that  there should be a policy that defines the role of ODS at all advisory  committee meetings involving postmarket safety issues.
CDER’s Director and Deputy Director sent a memo about ODS’s  November 2002 consult to the ODS Director, an ODS Division Director,  and the OPaSS Director. The memo criticized the quality of ODS’s consult  and stated that ODS had analyzed postmarket data on Arava with a “bias  toward concluding that the risk is as large as possible.” The memo also  included the general expectations for an ODS consult. For example, it  stated that consults should include a summary of the strengths and  weaknesses of the analytic approach used to evaluate postmarket data.
section_title: June 2003
paragraphs: FDA approved revised labeling of Arava to support the claim of improved  physical function. The revised labeling also stated that rare cases of severe  liver injury, including cases with fatal outcomes, had been reported in  Arava users. OND decided that although the liver toxicity risk was very  rare, the accumulated evidence provided support for strengthening the  warnings on the label.
OND asked the sponsor to submit liver-related adverse events within   15 days rather than annually, on the basis of an ODS request.
section_title: October 2003
paragraphs: The sponsor issued a Dear Healthcare Professional letter explaining the  labeling changes approved in June 2003.
section_title: March 2004
paragraphs: Information was added to Arava’s label about the use of Arava in pediatric  populations, including instances of liver-related adverse reactions from  pediatric study reports.
FDA sent a letter to Public Citizen denying its request to remove Arava  from the U.S. market.
section_title: Appendix II: Regulatory History and FDA Decision-making Process for Baycol
subsections: section_title: Background and Summary
paragraphs: Baycol was approved for marketing in 1997. Baycol is a member of the  class of drugs known as statins that lower cholesterol levels in the body.  Baycol was associated with rhabdomyolysis, a severe adverse reaction  involving the breakdown of muscle fibers, which can lead to death.
In this case, the Office of Drug Safety (ODS) and the Office of New Drugs  (OND) agreed from the outset (spring 2001) that adverse event reports  received for high-dose Baycol were alarming. At the request of OND, ODS  conducted an analysis that verified the increased safety risk associated  with Baycol, but it did not make specific recommendations for action.  Shortly thereafter, OND and ODS met with the sponsor and the Food and  Drug Administration (FDA) communicated to the sponsor that it was  considering withdrawing the high-dose Baycol from the market. In August  2001 the sponsor voluntarily withdrew all doses of Baycol.
section_title: Chronology
subsections: section_title: June 1997
paragraphs: FDA approved Baycol for marketing (doses up to 0.3 mg). The original  label stated that rhabdomyolysis had been reported with the use of other  statins.
section_title: January 1999
paragraphs: FDA approved a change in the warnings section of Baycol’s label to  indicate that rare cases of rhabdomyolysis had been reported with Baycol  and other drugs in the class. FDA also approved adding a new  subsection—postmarketing adverse event reports (including  rhabdomyolysis)—to the label.
section_title: May 1999
paragraphs: FDA approved the 0.4 mg dose of Baycol.
section_title: December 1999
paragraphs: FDA approved a change in Baycol’s label, requested by the sponsor, to  include a contraindication with gemfibrozil (a member of a class of drugs  called fibrates, which also lower cholesterol). The combined use of Baycol  and gemfibrozil was contraindicated because of the risk for  rhabdomyolysis. The sponsor issued a Dear Healthcare Professional letter  shortly thereafter, explaining the labeling changes.
section_title: June 2000
paragraphs: At the request of OND’s Division of Endocrine and Metabolic Drug  Products, ODS completed a postmarketing safety review of  rhabdomyolysis resulting from the combined use of statins and fibrates.  OND requested the review because sponsors of other statins (not Baycol)  were seeking over-the-counter status for their drugs. ODS safety  evaluators and an epidemiologist analyzed reports from the Adverse Event  Reporting System (AERS) and calculated reporting rates of  rhabdomyolysis for Baycol and other statins when taken alone, and in  combination with gemfibrozil. The reporting rate for Baycol combined  with gemfibrozil was higher than that of other statins combined with  gemfibrozil. But the reporting rate for Baycol alone was only slightly  higher compared with the other statins. On the basis of their findings and  the severity of rhabdomyolysis as a clinical diagnosis, the ODS staff  recommended that the statins not be granted over-the-counter designation.  The ODS Division Director who reviewed the consult concurred. In  agreement with ODS’s position, OND decided to discuss with the sponsor  sending stronger messages to healthcare professionals about the adverse  reaction.
section_title: July 2000
paragraphs: FDA approved the 0.8 mg dose of Baycol.
section_title: November 2000
paragraphs: FDA approved the addition of a patient package insert for Baycol.
section_title: April 2001
paragraphs: An ODS safety evaluator contacted the OND medical officer responsible  for Baycol about reports of fatal rhabdomyolysis associated with Baycol,  especially at the 0.8 mg dose, since ODS’s last consult in 2000. The medical  officer agreed the data were alarming and asked for more analysis. At  about the same time, the sponsor notified OND about a dose-related  occurrence of adverse events.
section_title: May 2001
paragraphs: FDA approved several revisions to labeling for Baycol, including an  emphasis that the correct starting dose of Baycol should be 0.4 mg  because of the increased risk of rhabdomyolysis at higher doses. The  sponsor issued a Dear Healthcare Professional letter explaining the  changes.
section_title: July 2001
paragraphs: OND and ODS staff met with the sponsor to discuss concerns over the  safety of Baycol. An ODS epidemiologist presented an analysis of fatal  cases of rhabdomyolysis associated with the 0.8 mg dose of Baycol  compared with Lipitor, another statin, and compared with the 0.4 mg dose  of Baycol. ODS found that the risk of fatal rhabdomyolysis was higher for  Baycol than for Lipitor. ODS also found that the risk appeared to be dose- related, with twice as many of the fatalities among patients taking the  highest daily dose—0.8 mg—of Baycol (without concomitant gemfibrozil)  compared with the lower dose—0.4 mg.
At the meeting, FDA communicated to the sponsor that it was considering  several safety actions to address its concerns about Baycol, including the  withdrawal of the 0.8 mg dose, and a boxed warning with information  about not exceeding a dosage of 0.4 mg daily and a contraindication with  gemfibrozil.
section_title: August 2001
paragraphs: OND and ODS staff met with the sponsor again to discuss their ongoing  concerns over the safety of Baycol, particularly concerns about the risk of  rhabdomyolysis at higher doses or in combination with gemfibrozil. The  sponsor proposed to (1) voluntarily withdraw the 0.8 mg dose in the  United States, (2) add a boxed warning on the label about not exceeding a  dose of 0.4 mg daily, and (3) add a boxed warning on the label for  contraindicated use of Baycol and gemfibrozil. FDA asked the sponsor for  a comprehensive analysis of the 0.4 mg dose.
A week later, FDA announced that the sponsor voluntarily withdrew all  doses of Baycol from the United States market and the sponsor issued a  Dear Healthcare Professional letter explaining its decision.
section_title: Appendix III: Regulatory History and FDA Decision-making Process for Bextra
subsections: section_title: Background and Summary
paragraphs: Bextra was approved for marketing in 2001. Bextra was part of the class of  drugs known as the COX-2 selective nonsteroidal anti-inflammatory drugs  (NSAID). Bextra was approved to relieve the symptoms of osteoarthritis  and rheumatoid arthritis in adults, and to relieve painful menstrual cycles.  Bextra was associated with serious, potentially fatal skin reactions,  including Stevens-Johnson Syndrome and toxic epidermal necrolysis.  Bextra was also later associated with an increased risk of serious  cardiovascular events, similar to the other approved COX-2 drugs.
In this case, after the Office of Drug Safety (ODS) did an analysis of  serious skin reactions associated with Bextra in 2002, Bextra’s label was  modified. ODS continued to do a series of analyses of adverse events  associated with Bextra from 2003 to 2004, recommending in 2004 that  there be a boxed warning, the most serious warning, on the label, but the  Office of New Drugs (OND) disagreed. OND changed its position after  ODS did a comparison, at OND’s request, of Bextra’s rate of serious skin  reactions with the reporting rates of other similar drugs. A boxed warning  was added to Bextra’s label in late 2004. In February 2005, two scientific  advisory committees that met primarily about the cardiovascular risks  associated with the COX-2 NSAIDs voted that Bextra’s overall risk-to- benefit profile supported continued marketing. But a few months later the  Food and Drug Administration (FDA) came to a different conclusion and  announced that the overall risk-to-benefit profile of Bextra was not  favorable, and as a result requested that it be withdrawn from the market,  which it was in April 2005.
section_title: Chronology
subsections: section_title: November 2001
paragraphs: FDA approved Bextra for marketing.
section_title: September 2002
paragraphs: The sponsor had identified the occurrence of serious skin reactions,  proposed adding information about this risk to the label, and proposed  issuing a Dear Healthcare Professional letter. At the request of OND’s  Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products,  ODS staff reviewed reports of serious skin reactions in the Adverse Event  Reporting System (AERS) for Bextra. They compared Bextra’s reporting  rate of serious skin reactions with rates for Vioxx and Celebrex (other  COX-2 NSAIDs), and the incidence in the general population. The ODS  staff agreed that the label should be changed and that a Dear Healthcare  Professional letter should be issued because the rates for Bextra were  higher than those for Vioxx, Celebrex, and the general population. The  ODS Division Director that reviewed the consult and OND concurred with  the findings.
section_title: November 2002
paragraphs: FDA announced an updated label describing the risk for serious skin  reactions associated with Bextra and that Bextra was contraindicated in  patients with histories of allergic reactions to sulfa, a substance that  Bextra contains. The sponsor issued a Dear Healthcare Professional letter  explaining the updated label.
section_title: April 2003
paragraphs: The Division of Pediatrics and Therapeutics had asked ODS for a  recommendation on whether Bextra should be studied in pediatric  populations for the treatment of acute pain, as proposed by the sponsor.  ODS staff recommended that Bextra not be studied in pediatric  populations because of its risk of serious skin reactions in the adult  population. In addition, ODS staff analyzed data from the National Center  for Health Statistics and found that serious skin reactions generally occur  more commonly in children than adults. The ODS Acting Division Director  that reviewed the consult agreed with the analysis and recommendation as  did the Division of Pediatrics and Therapeutics. However, OND disagreed  with the recommendation and supported the study of Bextra in pediatric  populations because staff in OND felt this drug could have value in certain  pediatric populations, such as patients who cannot tolerate other NSAIDs.  Ultimately, Bextra was not studied in children in part because, according  to a former OND manager, OND deferred to ODS’s judgment on this  recommendation.
section_title: July 2003
paragraphs: ODS staff updated their original analysis and concluded that the reporting  rates for serious skin reactions associated with Bextra remained markedly  elevated above the incidence in the general population and above the rates  for Celebrex and Vioxx. ODS staff recommended adding another skin  reaction to the warnings in the label and the ODS Acting Division Director  that reviewed the consult concurred. Although OND did not respond to the  consult, a former OND manager told us that it would not have been  important to add this skin reaction to the label since the label already  included the most severe forms of skin reactions.
section_title: March 2004
paragraphs: ODS staff updated their assessment of the risks of serious skin reactions  associated with Bextra, on the basis of additional AERS reports, and  commented on a risk management plan submitted by the sponsor. They  recommended to OND several stronger safety actions, including a boxed  warning and a medication guide, because the risk remained elevated  compared with the incidence in the general population and relative to  Celebrex and Vioxx (for example, 13-fold relative to Vioxx). The ODS staff  stated that very little was known about the risk factors for serious skin  reactions, making them difficult to avoid. In addition, they recommended  that OND consider the clinical circumstances in which Bextra had a  favorable benefit-to-risk profile relative to other treatment alternatives.  Two ODS Division Directors that reviewed the consult concurred, but  OND did not agree that Bextra needed stronger safety actions at this time.
section_title: April 2004
paragraphs: Bextra’s label was changed to include the statement that fatalities due to  serious skin reaction had been reported.
section_title: June 2004
paragraphs: At the request of OND, ODS staff compared Bextra’s reporting rate of  serious skin reactions with an antibiotic drug’s reporting rate because  both Bextra and the antibiotic contained sulfa and both drugs were  contraindicated in patients with known allergies to sulfa. ODS staff  compared the reporting rates, but indicated in their consult that it was  inappropriate to compare an antibiotic marketed for more than 30 years  and was used for acute, potentially life-threatening illnesses with a  recently marketed pain reliever that was generally used for a chronic non- life-threatening illness. The ODS Division Director that reviewed the  consult concurred. However, the OND medical officer involved in the case  maintained it was an appropriate comparison. ODS staff found a higher  reporting rate for serious skin reactions associated with Bextra when  compared with the rate for the antibiotic drug.
section_title: August 2004
paragraphs: At the request of OND, ODS staff compared Bextra’s rate of serious skin  reactions with the reporting rates of Celebrex, Vioxx, and Mobic, anti- inflammatory drugs that are used to treat arthritis. ODS staff concluded  that Bextra’s reporting rate continued to be elevated compared with the  other drugs, including Mobic, which had no reported cases of serious skin  reactions. As a result of this analysis, and the reports of death (at least  four deaths have been associated with Bextra), OND asked Bextra’s  sponsor for a boxed warning about this risk, which it previously did not  support.
section_title: October 2004
paragraphs: The sponsor issued a Dear Healthcare Professional letter summarizing the  serious skin reactions associated with Bextra and stated that it had  proposed an updated label to FDA to expand previous warnings about the  skin reactions.
section_title: December 2004
paragraphs: FDA announced that Bextra would carry a boxed warning for serious skin  reactions. The sponsor also issued a Dear Healthcare Professional letter  explaining these changes.
section_title: February 2005
paragraphs: A joint meeting of FDA’s Arthritis Advisory Committee and the Drug  Safety and Risk Management Advisory Committee was held. The meeting  was focused primarily on the cardiovascular risks of the COX-2 selective  NSAIDs, including Bextra. The advisory committees voted (17 yes, 13 no,   2 abstentions) that Bextra’s overall risk-to-benefit profile supported  continued marketing.
section_title: April 2005
paragraphs: After reviewing information from multiple sources, which included  specific votes and recommendations that the advisory committees made in  February 2005, FDA announced its conclusion that Bextra’s overall risk-to- benefit profile was not favorable and, as a result, requested that the  sponsor voluntarily withdraw Bextra from the market. FDA concluded  that in addition to its cardiovascular risk (similar to the other COX-2  drugs), Bextra already carried a boxed warning for serious skin reactions.  While the other COX-2 drugs also had a risk for these serious skin  reactions, the reporting rate appeared to be greater for Bextra. In addition,  the occurrence of the skin reactions was unpredictable, for example,  occurring after both short- and long-term use, making attempts to manage  this risk difficult. Also, there were no data supporting a unique therapeutic  benefit for Bextra over other available NSAIDs, which could have offset  the increased risk of serious skin reactions.
The sponsor agreed to withdraw the drug in the United States.
section_title: Appendix IV: Regulatory History and FDA Decision-making Process for Propulsid
subsections: section_title: Background and Summary
paragraphs: Propulsid was approved for marketing in 1993. Propulsid was indicated for  use in adults for the symptomatic relief of nighttime heartburn due to  gastroesophageal reflux disease. Propulsid was associated with serious  cardiac arrhythmias, including reports of death, and most of these adverse  events occurred in patients who were taking other medications or  suffering from underlying conditions known to increase the risk of cardiac  arrhythmia.
In this case there was general agreement about the safety concern  between the Office of New Drugs (OND) and the Office of Drug Safety  (ODS), but differing opinions within the Food and Drug Administration  (FDA) over what safety actions should be taken regarding the drug. In  1997 FDA decided to continue to work with the sponsor to make changes  to the drug’s label, which included a boxed warning, but some staff felt  stronger actions were needed. An FDA-supported study later found that  the boxed warning did not significantly deter use of the drug with  contraindicated drugs or medical conditions. During this case, a task force  within FDA was formed to help evaluate Propulsid’s safety and efficacy,  and ODS staff conducted numerous analyses and made multiple  recommendations for stronger safety actions, including a market  withdrawal. The sponsor voluntarily removed the drug from the market in  2000. Propulsid is currently available through a limited-access program to  ensure that only certain patients receive the medication.
section_title: Chronology
subsections: section_title: July 1993
paragraphs: FDA approved Propulsid for marketing in tablet form.
section_title: January 1995
paragraphs: The sponsor submitted information to the Center for Drug Evaluation and  Research (CDER) about reports of cardiac arrhythmias associated with  the use of Propulsid. Subsequently, an ODS safety evaluator identified and  reviewed 12 reports of torsade de pointes in FDA’s MedWatch  Spontaneous Reporting System (SRS) and identified potential risk factors,  including cardiac history and the concomitant use of several other drugs.
OND’s Division of Gastrointestinal and Coagulation Drug Products agreed  with ODS that this was a safety concern.
section_title: February 1995
paragraphs: Propulsid’s label was revised to state that it was contraindicated with  certain other drugs which, when taken with Propulsid, can increase the  concentration of Propulsid and lead to arrhythmias. A clinical study  conducted by the sponsor provided this evidence. The label was also  revised to include information about other risk factors, including a history  of cardiac disease. The sponsor issued a Dear Healthcare Professional  letter with similar information.
section_title: September 1995
paragraphs: FDA approved Propulsid for marketing in liquid form.
A boxed warning was added to Propulsid’s label, specifying its  contraindication with other drugs. The boxed warning also included the  statement that some of the reported adverse events had resulted in death.  The sponsor issued a Dear Healthcare Professional letter in October with  similar information.
section_title: January 1996
paragraphs: An ODS epidemiologist identified and analyzed 46 adverse event reports of  patients who developed serious cardiac arrhythmias while using  Propulsid, from July 1993 through early October 1995, and concluded that  many patients who developed arrhythmias had histories of cardiac and  renal conditions. Most patients who developed arrhythmias were not  taking contraindicated medications; as a result, the epidemiologist  concluded that Propulsid may itself cause arrhythmias. The  epidemiologist recommended that risk factors, such as histories of  significant cardiac and renal disease, should be displayed in the label’s  warning with the same emphasis as the contraindicated drugs. The ODS  Division Director concurred with the consult.
section_title: August 1996
paragraphs: At the request of OND, an ODS safety evaluator searched SRS for all  adverse event reports associated with Propulsid in children aged 19 years  and younger. Although Propulsid was not approved for use in children, it  had been prescribed to children (for example, in newborn infants for  feeding problems such as reflux). Six children were reported to have had  cardiac arrhythmias with the use of Propulsid and several other children  had other cardiovascular events. The safety evaluator also reported that  the estimated usage of Propulsid in children was increasing steadily.
FDA rejected the sponsor’s application for a pediatric indication for  Propulsid.
section_title: June 1997
paragraphs: OND established a task force within FDA to evaluate the safety and  efficacy of Propulsid. The task force included members from OND and  ODS. At its initial meeting, the task force decided to gather information  from several sources, including the reviews done by ODS, in order to  accurately assess the safety of Propulsid.
section_title: August 1997
paragraphs: As agreed in the June 1997 Propulsid task force meeting, an ODS  epidemiologist reviewed adverse event reports of Propulsid users with  serious arrhythmias. The epidemiologist found that in about half of the  cases, patients had taken contraindicated drugs with Propulsid and that a  high proportion of the remaining cases had medical problems that may  have predisposed them to arrhythmias. The epidemiologist recommended  that the risk factors, such as predisposing medical problems, should be  displayed in the label’s warning with the same emphasis as the  contraindicated drugs and that the recommended dosage should not be  exceeded. The ODS Division Director who reviewed the consult  concurred.
section_title: September 1997
paragraphs: The task force on Propulsid met for the second time. The group discussed  information that was gathered on the safety of Propulsid. An ODS  epidemiologist summarized her August 1997 consult, including her  recommendation that predisposing medical problems should be displayed  in the label’s warnings similar to the contraindicated drugs and that the  recommended dosage should not be exceeded. She also noted that  Propulsid was primarily being prescribed for off-label use. Other relevant  studies were discussed, including a clinical trial study where 3 out of 32  healthy elderly volunteers had abnormal electrocardiogram results after  exposure to Propulsid alone.
section_title: October 1997
paragraphs: An ODS safety evaluator reported that there were additional cases of  serious, cardiovascular adverse events among children who were  prescribed Propulsid.
section_title: November 1997
paragraphs: FDA approved a rapidly disintegrating tablet form of Propulsid for  marketing.
The task force on Propulsid met and decided to seek further input from a  CDER-wide group about pursuing the following regulatory actions: adding  the risk for cardiac arrhythmias with the use of Propulsid alone (for  example, without taking contraindicated drugs) to the label; holding an  advisory committee meeting; and withdrawing approval of all Propulsid  formulations.
section_title: December 1997
paragraphs: OND’s Division of Gastrointestinal and Coagulation Drug Products  consulted another OND division that was responsible for the drug Seldane  to find out what information would be required to withdraw the approval  of a drug since FDA had initiated proceedings to withdraw its approval of  Seldane in 1996 for a similar cardiovascular side effect. That division  recommended that data be gathered to support the assertion that  Propulsid was still being coprescribed with contraindicated drugs despite  the boxed warning and Dear Healthcare Professional letters.
At the request of OND, an ODS epidemiologist evaluated the sponsor’s  epidemiological study on risk of serious cardiac arrhythmias among  Propulsid users. In this study the researchers concluded that serious  cardiac arrhythmias were not associated with Propulsid. The ODS  epidemiologist outlined several major limitations with the study, including  the potential for the misclassification of arrhythmia in patients not  diagnosed by an electrocardiogram.
A meeting was held in CDER to discuss FDA’s regulatory options for  Propulsid. This meeting included some senior-level managers in CDER and  an FDA attorney. The OND medical officer responsible for Propulsid  presented his concerns, including his conclusion that Propulsid should be  removed from the market. Proceeding with a withdrawal from the market  was discussed at the meeting. FDA continued to work with the sponsor to  change Propulsid’s label. Some staff believed that stronger safety actions  were needed.
section_title: May 1998
paragraphs: An ODS epidemiologist summarized reports of 186 patients who developed  serious cardiac disorders and arrhythmias (including deaths) with and  without contraindicated drugs from July 1993 through early May 1998. The  ODS epidemiologist recommended to OND that the boxed warning should  state that serious arrhythmias had occurred in Propulsid users who had  not been taking contraindicated drugs, and that an accompanying Dear  Healthcare Professional letter should be issued.
The ODS epidemiologist also recommended that Propulsid’s labeling  should state that the safety and effectiveness of Propulsid had not been  demonstrated in pediatric patients for any indication.
section_title: June 1998
paragraphs: FDA announced revisions to the boxed warning that strengthened its  warnings and precautions, and the sponsor issued a Dear Healthcare  Professional letter explaining the revisions. The changes included the  statement that Propulsid was contraindicated in patients with medical  problems known to predispose them to arrhythmias, such as heart disease.  The revision also stated that other therapies for heartburn should be used  before Propulsid, and that the safety and effectiveness in pediatric patients  had not been established. Also, the revised boxed warning included the  statement that cardiac adverse events, including sudden death, had  occurred among Propulsid users who were not taking contraindicated  drugs.
section_title: July 1998
paragraphs: An ODS epidemiologist summarized cardiac adverse event reports from  the beginning of Propulsid’s marketing (July 1993) through May 1998.  There were 187 reports, including 38 deaths.
section_title: November 1998
paragraphs: FDA implemented a medication guide and unit-dose packaging for  Propulsid.
section_title: May 1999
paragraphs: An ODS epidemiologist worked on a study to evaluate labeling compliance  among Propulsid users, which was carried out through ODS’s cooperative  agreement program. The study ultimately found that the boxed warning  did not significantly deter the use of Propulsid with contraindicated drugs  or medical conditions.
section_title: June 1999
paragraphs: The sponsor issued a Dear Healthcare Professional letter with information  about revisions to the boxed warning. The revisions included two new  contraindications and a new drug interaction. Similar revisions were  incorporated into the medication guide.
An ODS epidemiologist analyzed and summarized the reports of Propulsid  users who developed cardiovascular problems, including deaths, in four  separate consults. The reports included adult and pediatric patients who  took Propulsid with and without contraindicated drugs and medical  conditions. The ODS epidemiologist recommended to OND that other  contraindications should be added to the label, including one for patients  with structural heart defects.
The ODS epidemiologist recommended that OND consider several safety  actions, including asking the sponsor to conduct a clinical or  epidemiological study on the association between Propulsid and cardiac  adverse events in its users, and removing Propulsid from the market.
section_title: November 1999
paragraphs: ODS and OND staff and the CDER Director met to discuss further options  for regulatory actions. It was decided that FDA would hold a public  advisory committee meeting to discuss ways to reduce the occurrence of  adverse events with Propulsid. The preliminary results of the cooperative  agreement study were going to be presented at the advisory committee  meeting.
section_title: January 2000
paragraphs: FDA announced further revisions to the boxed warning and that a public  advisory committee meeting was scheduled for April. The label revision  included new recommendations for performing diagnostic tests and a new  contraindication for patients with electrolyte disorders. Similar revisions  were incorporated into the medication guide. The sponsor issued a Dear  Healthcare Professional letter explaining these revisions.
section_title: March 2000
paragraphs: FDA announced that the sponsor would withdraw Propulsid from the U.S.  market as of July 14, 2000. FDA also announced that its scheduled public  advisory committee meeting was cancelled.
section_title: April 2000
paragraphs: The sponsor announced that it would make Propulsid available to certain  patients through an investigational limited-access program, approved by  FDA.
section_title: March 2002
paragraphs: An ODS epidemiologist summarized reports of adverse events, including  cardiovascular events, among patients enrolled in the limited-access  program. The epidemiologist recommended that the availability of  Propulsid should not be expanded from the limited-access program to a  restricted distribution. The ODS Division Director who reviewed the  consult agreed. The drug’s availability was not expanded.
section_title: Appendix V: Comments from the Food and Drug Administration
section_title: Appendix VI: GAO Contact and Staff Acknowledgments
subsections: section_title: Acknowledgments
paragraphs: In addition to the contact named above, Martin T. Gahart, Assistant  Director; Anne Dievler; Pamela Dooley; Cathleen Hamann; and Julian  Klazkin made key contributions to this report.