Drug Safety: Further Actions Needed to Improve FDA's Postmarket Decision-making Process
Published: 2007-05-09T00:00:00

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 were disagreements within FDA about how to address these issues. GAO was asked to testify on FDA's oversight of drug safety. This testimony is based on Drug Safety: Improvement Needed in FDA's Postmarket Decision-making and Oversight Process, GAO-06-402 (Mar. 31, 2006). The report focused on the complex interaction between two offices within FDA that are involved in postmarket drug safety activities: the Office of New Drugs (OND), and the Office of Drug Safety (ODS). OND's primary responsibility is to review new drug applications, but it is also involved in monitoring the safety of marketed drugs. ODS is focused primarily on postmarket drug safety issues. ODS is now called the Office of Surveillance and Epidemiology. For its report, GAO reviewed FDA policies, interviewed FDA staff, and conducted case studies of four drugs with safety issues: Arava, Baycol, Bextra, and Propulsid. To gather information on FDA's initiatives since March 2006 to improve its decision-making process for this testimony, GAO interviewed FDA officials in February and March 2007, and received updated information from FDA in May 2007.
section_title: What GAO Found
paragraphs: In its March 2006 report, GAO found that FDA lacked clear and effective processes for making decisions about, and providing management oversight of, postmarket drug safety issues. There was a lack of clarity about how decisions were made and about organizational roles, insufficient oversight by management, and data constraints. GAO observed that there was a lack of criteria for determining what safety actions to take and when to take them. Insufficient communication between ODS and OND hindered the decision-making process. ODS management did not systematically track information about ongoing postmarket safety issues, including the recommendations that ODS staff made for safety actions. GAO also found that FDA faced data constraints that contributed to the difficulty in making postmarket safety decisions. GAO found that FDA's access to data was constrained by both its limited authority to require drug sponsors to conduct postmarket studies and its limited resources for acquiring data from other external sources. During the course of GAO's work for its March 2006 report, FDA began a variety of initiatives to improve its postmarket drug safety decision-making process, including the establishment of the Drug Safety Oversight Board. FDA also commissioned the Institute of Medicine to examine the drug safety system, including FDA's oversight of postmarket drug safety. GAO recommended in its March 2006 report that FDA take four steps to improve its decision-making process for postmarket safety. GAO recommended that FDA revise and implement its draft policy on the decision-making process for major postmarket safety actions, improve its process to resolve disagreements over safety decisions, clarify ODS's role in scientific advisory committees, and systematically track postmarket drug safety issues. FDA has initiatives underway and under consideration and that, if implemented, could address three of GAO's four recommendations. In the 2006 report GAO also suggested that Congress consider expanding FDA's authority to require drug sponsors to conduct postmarket studies, as needed, to collect additional data on drug safety concerns.

section_title: Letter
paragraphs: I am pleased to be here today as you examine the safety of our nation’s  drug supply. 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. Those cases showed that there were  disagreements and potential delays within FDA about how to address  serious safety problems. My remarks today are based on GAO’s March  2006 report on FDA’s postmarket decision-making process (Drug Safety:  Improvement Needed in FDA’s Postmarket Decision-making and  Oversight Process, GAO-06-402). I will also discuss a number of FDA’s  initiatives to improve its decision-making process, including some that  respond to the recommendations we made in that report.
In carrying out the work for our report between December 2004 and  March 2006, we focused on two offices within FDA’s Center for Drug  Evaluation and Research (CDER) that are involved in postmarket drug  safety activities: the Office of New Drugs (OND) and the Office of Drug  Safety (ODS). While there is some overlap in the activities of OND and  ODS, they have different organizational characteristics and perspectives  on postmarket drug safety. OND is involved in postmarket drug safety  activities as one aspect of its larger responsibility to review new drug  applications, and it has the ultimate responsibility to take regulatory  action concerning the postmarket safety of drugs. ODS is primarily  focused on postmarket drug safety, which includes the review of reports  of adverse reactions to drugs. ODS operates primarily in a consultant  capacity to OND and does not have any independent decision-making  responsibility.
For our report, we interviewed ODS, OND, and other CDER managers and  staff, as well as drug safety experts from outside FDA. We also analyzed  documents describing internal FDA policies and procedures. In order to  obtain an in-depth understanding of FDA’s policies and procedures, we  conducted case studies of four drugs—Arava, Baycol, Bextra, and  Propulsid—that help to illustrate the decision-making process. Each of  these drugs presented significant postmarket safety issues that FDA acted  upon in recent years, and they reflect differences in the type of adverse  event or potential safety problem associated with each drug, the safety  actions taken, and the OND and ODS staff involved. To follow up with  FDA about its responses to our recommendations and its initiatives to  improve its postmarket safety decision-making process, we interviewed  four FDA managers, including CDER’s Associate Director for Safety Policy  and Communication, in February and March 2007, and received updated  information from FDA in May 2007. We did not evaluate the effectiveness  of FDA’s efforts to respond to our recommendations. All of our work was  conducted in accordance with generally accepted government auditing  standards.
In summary, we found that FDA lacked a clear and effective process for  making decisions about, and providing management oversight of,  postmarket drug safety issues. There was a lack of clarity about how  decisions were made and about organizational roles, insufficient oversight  by management, and data constraints. We observed that there was a lack  of criteria for determining what safety actions to take and when to take  them, which likely contributed to disagreements over decisions about  postmarket safety. Insufficient communication between ODS and OND’s  divisions was an ongoing concern and hindered the decision-making  process. For example, ODS did not always know how OND had responded  to ODS’s safety analyses and recommendations. ODS management did not  systematically track information about the recommendations its staff  made and OND’s response. This limited the ability of ODS management to  provide effective oversight so that FDA could ensure that safety concerns  were addressed and resolved in a timely manner. FDA has faced data  constraints that contributed to the difficulty in making postmarket safety  decisions. In the absence of specific authority to require drug sponsors to  conduct postmarket studies, FDA has often relied on drug sponsors  voluntarily agreeing to conduct these studies. However, these studies have  not consistently been completed. FDA has also had limited available  resources to obtain data from outside sources.
FDA has undertaken a variety of initiatives to improve its postmarket drug  safety decision-making process. Prior to the completion of our report in  March 2006, FDA commissioned the Institute of Medicine (IOM) to  examine the drug safety system, including FDA’s oversight of postmarket  drug safety. FDA also established the Drug Safety Oversight Board in  CDER and made other internal changes. Since March 2006, FDA has  continued to address its oversight and decision-making shortcomings. In  January 2007, FDA issued a detailed response to IOM’s recommendations.  In our 2006 report, we recommended that FDA revise and implement its  draft policy on the decision-making process for major postmarket safety  actions, improve its process to resolve disagreements over safety  decisions, clarify ODS’s role in scientific advisory committees, and  systematically track postmarket drug safety issues. FDA has since begun  to implement initiatives that we believe could address the goals of three of  the four recommendations in our 2006 report. FDA has made revisions to,  but not finalized, its draft policy on major postmarket drug safety  decisions. FDA has not improved its process to resolve disagreements  over safety decisions, and the agency is developing but has not finalized  guidance to clarify ODS’s role in scientific advisory committees. FDA is in  the process of implementing a tracking system.
subsections: section_title: Background
paragraphs: Because no drug is absolutely safe, FDA approves a drug for marketing  when the agency judges that its known benefits outweigh its known risks.  After a drug is on the market, FDA continues to assess its risks and  benefits. FDA reviews reports of adverse drug reactions (adverse events)  related to the drug and information from clinical studies about the drug  that are conducted by the drug’s sponsor. FDA also reviews adverse events  from studies that follow the use of drugs in ongoing medical care  (observational studies) that are carried out by the drug’s sponsor, FDA, or  other researchers. If FDA has information that a drug on the market may  pose a significant health risk to consumers, it weighs the effect of the  adverse events against the benefit of the drug to determine what actions, if  any, are warranted.
The decision-making process for postmarket drug safety is complex,  involving input from a variety of FDA staff and organizational units and  information sources, but the central focus of the process is the iterative  interaction between OND and ODS. OND is a much larger office than ODS.  In fiscal year 2005, OND had 715 staff and expenditures of $110.6 million.  More than half of OND’s expenditures in fiscal year 2005, or $57.2 million,  came from user fees paid by drug sponsors under the Prescription Drug  User Fee Amendments of 2002. ODS had 106 staff in fiscal year 2005 and  expenditures of $26.9 million, with $7.6 million from prescription drug  user fees.
After a drug is on the market, OND staff receive information about safety  issues in several ways. First, OND staff receive notification of adverse  event reports for drugs to which they are assigned and they review the  periodic adverse event reports that are submitted by drug sponsors.  Second, OND staff review safety information that is submitted to FDA  when a sponsor seeks approval for a new use or formulation of a drug, and  monitor completion of postmarket studies. When consulting with OND on  a safety issue, ODS staff search for all relevant case reports of adverse  events and assess them to determine whether or not the drug caused the  adverse event and whether there are any common trends or risk factors.  ODS staff might also use information from observational studies and drug  use analyses to analyze the safety issue. When completed, ODS staff  summarize their analysis in a written consult. According to FDA officials,  OND staff within the review divisions usually decide what regulatory  action should occur, if any, by considering the results of the safety analysis  in the context of other factors such as the availability of other similar  drugs and the severity of the condition the drug is designed to treat. Then,  if necessary, OND staff make a decision about what action should be  taken.
Several CDER staff, including staff from OND and ODS, told us that most  of the time there is agreement within FDA about what safety actions  should be taken. At other times, however, OND and ODS staff disagree  about whether the postmarket data are adequate to establish the existence  of a safety problem or support a recommended regulatory action. In those  cases, OND staff sometimes request additional analyses by ODS and  sometimes there is involvement from other FDA organizations. In some  cases, OND seeks the advice of FDA’s scientific advisory committees,  which are composed of experts and consumer representatives from  outside FDA. In 2002, FDA established the Drug Safety and Risk  Management Advisory Committee, 1 of the 16 human-drug-related  scientific advisory committees, to specifically advise FDA on drug safety  and risk management issues. The recommendations of the advisory  committees do not bind the agency to any decision.
FDA has the authority to withdraw the approval of a drug on the market  for safety-related and other reasons, although it rarely does so. In almost  all cases of drug withdrawals for safety reasons, the drug’s sponsor has  voluntarily removed the drug from the market. For example, in 2001  Baycol’s sponsor voluntarily withdrew the drug from the market after  meeting with FDA to discuss reports of adverse events, including some  reports of fatalities. FDA does not have explicit authority to require that  drug sponsors take other safety actions; however, when FDA identifies a  potential problem, sponsors generally negotiate with FDA to develop a  mutually agreeable remedy to avoid other regulatory action. Negotiations  may result in revised drug labeling or restricted distribution. FDA has  limited authority to require that sponsors conduct postmarket safety  studies.
section_title: FDA Lacked a Clear and Effective Decision-making Process for Postmarket Drug Safety
paragraphs: In our March 2006 report, we found that FDA’s postmarket drug safety  decision-making process was limited by a lack of clarity, insufficient  oversight by management, and data constraints. We observed that there  was a lack of established criteria for determining what safety actions to  take and when, and aspects of ODS’s role in the process were unclear. A  lack of communication between ODS and OND’s review divisions and  limited oversight of postmarket drug safety issues by ODS management  hindered the decision-making process. FDA’s decisions regarding  postmarket drug safety have also been made more difficult by the  constraints it faces in obtaining data.
subsections: section_title: Decision-making Process on Drug Safety Lacked Clarity about Criteria for Action and the Role of ODS
paragraphs: While acknowledging the complexity of the postmarket drug safety  decision-making process, we found through our interviews with OND and  ODS staff and in our case studies that the process lacked clarity about  how drug safety decisions were made and about the role of ODS. If FDA  had established criteria for determining what safety actions to take and  when, then some of the disagreements we observed in our case studies  might have been resolved more quickly. In the absence of established  criteria, several FDA officials told us that decisions about safety actions  were often based on the case-by-case judgments of the individuals  reviewing the data. Our observations were consistent with two previous  internal FDA reports on the agency’s internal deliberations regarding  Propulsid and the diabetes drug Rezulin. In those reviews FDA indicated  that an absence of established criteria for determining what safety actions  to take, and when to take them, posed a challenge for making postmarket  drug safety decisions.
We also found that ODS’s role in scientific advisory committee meetings  was unclear. According to the OND Director, OND is responsible for  setting the agenda for the advisory committee meetings, with the  exception of the Drug Safety and Risk Management Advisory Committee.  This includes who is to present and what issues will be discussed by the  advisory committees. For the advisory committees (other than the Drug  Safety and Risk Management Advisory Committee) it was unclear when  ODS staff would participate.
section_title: A Lack of Communication and Limited Oversight Hindered 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  also hindered the decision-making process. ODS and OND staff often  described their relationship with each other as generally collaborative,  with effective communication, but both ODS and OND staff told us that  there had been communication problems on some occasions, and that this  had been an ongoing concern. For example, according to some ODS staff,  OND did not always adequately communicate the key question or point of  interest to ODS when it requested a consult, and as ODS worked on the  consult there was sometimes little interaction between the two offices.  After a consult was completed and sent to OND, ODS staff reported that  OND sometimes did not respond in a timely manner or at all. Several ODS  staff characterized this as consults falling into a “black hole” or “abyss.”  OND’s Director told us that OND staff probably do not “close the loop” in  responding to ODS’s consults, which includes explaining why certain ODS  recommendations were not followed. In some cases CDER managers and  OND staff criticized the methods used in ODS consults and told us that the  consults were too lengthy and academic.
ODS management had not effectively overseen postmarket drug safety  issues, and as a result, it was unclear how FDA could know that important  safety concerns had been addressed and resolved in a timely manner. A  former ODS Director told us that the small size of ODS’s management  team presented a challenge for effective oversight of postmarket drug  safety issues. Another problem was the lack of systematic information on  drug safety issues. According to the ODS Director, ODS maintained a  database of consults that provided some information about the consults  that ODS staff conducted, but it did not include information about whether  ODS staff made recommendations for safety actions and how the safety  issues were handled and resolved, such as whether recommended safety  actions were implemented by OND.
section_title: Data Constraints Have Contributed to Difficulty in Making Postmarket Safety Decisions
paragraphs: Data constraints—such as weaknesses in data sources and FDA’s limited  ability to require certain studies and obtain additional data—have  contributed to FDA’s difficulty in making postmarket drug safety  decisions. OND and ODS have used three different sources of data to  make postmarket drug safety decisions, including adverse event reports,  clinical trial studies, and observational studies. While data from each  source have weaknesses that have contributed 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 has been 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 have often been based on  adverse event reports, FDA cannot establish the true frequency of adverse  events in the population with data from adverse event reports. The  inability to calculate the true frequency makes it hard to establish the  magnitude of a safety problem, and comparisons of risks across similar  drugs are difficult. In addition, it is difficult to attribute adverse events to  particular drugs when there is a relatively high incidence rate in the  population for the medical condition. It is also difficult to attribute adverse  events to the use of particular drugs because data from adverse event  reports may have been confounded by other factors, such as other drug  exposures.
FDA can also use available data from clinical trials and observational  studies to support postmarket drug safety decisions. Although each source  presents weaknesses that constrain the usefulness of the data provided,  having data from more than one source can help improve FDA’s decision- making ability. Clinical trials, in particular randomized clinical trials, are  considered the “gold standard” for assessing evidence about efficacy and  safety because they are considered the strongest method by which one can  determine whether new drugs work. However, clinical trials also have  weaknesses. Clinical trials typically have too few enrolled patients to  detect serious adverse events associated with a drug that occur relatively  infrequently in the population being studied. They are usually carried out  on homogenous populations of patients that often do not reflect the types  of patients who will actually take the drugs. For example, they do not  often include those who have other medical problems or take other  medications. In addition, clinical trials are often too short in duration to  identify adverse events that may occur only after long use of the drug. This  is particularly important for drugs used to treat chronic conditions where  patients are taking the medications for the long term. Observational  studies, which use data obtained from population-based sources, can  provide FDA with information about the population effect and risk  associated with the use of a particular drug.
We have found that FDA’s access to postmarket clinical trial and  observational data is limited by its authority and available resources. FDA  does not have broad authority to require that a drug sponsor conduct an  observational study or clinical trial for the purpose of investigating a  specific postmarket safety concern. One senior FDA official and several  outside drug safety experts told us that FDA needs greater authority to  require such studies. Long-term clinical trials may be needed to answer  safety questions about risks associated with the long-term use of drugs.  For example, during a February 2005 scientific advisory committee  meeting, some FDA staff and committee members indicated that there was  a need for better information on the long-term use of anti-inflammatory  drugs and discussed how a long-term trial might be designed to study the  cardiovascular risks associated with the use of these drugs.
Lacking specific authority to require drug sponsors to conduct postmarket  studies, FDA has often relied on drug sponsors voluntarily agreeing to  conduct these studies. But the postmarket studies that drug sponsors have  agreed to conduct have not consistently been completed. One study  estimated that the completion rate of postmarket studies, including those  that sponsors had voluntarily agreed to conduct, rose from 17 percent in  the mid-1980s to 24 percent between 1991 and 2003. FDA has little  leverage to ensure that these studies are carried out.
In terms of resource limitations, several FDA staff (including CDER  managers) and outside drug safety experts told us that in the past ODS has  not had enough resources for cooperative agreements to support its  postmarket drug surveillance program. Under the cooperative agreement  program, FDA collaborated with outside researchers in order to access a  wide range of population-based data and conduct research on drug safety.  Annual funding for this program was less than $1 million from fiscal year  2002 through fiscal year 2005. In 2006, FDA awarded four contracts for a  total cost of $1.6 million per year to replace the cooperative agreements.
section_title: FDA’s Initiatives to Improve Postmarket Drug Safety Decision Making
paragraphs: Prior to the completion of our March 2006 report, FDA began several  initiatives to improve its postmarket drug safety decision-making process.  Most prominently, FDA commissioned the IOM to convene a committee of  experts to assess the current system for evaluating postmarket drug  safety, including FDA’s oversight of postmarket safety and its processes.  IOM issued its report in September 2006. FDA also had underway several  organizational changes that we discussed in our 2006 report. For example,  FDA established the Drug Safety Oversight Board to help provide  oversight and advice to the CDER Director on the management of  important safety issues. The board is involved with ensuring that broader  safety issues, such as ongoing delays in changing a label, are effectively  resolved. FDA also drafted a policy that was designed to ensure that all  major postmarket safety recommendations would be discussed by  involved OND and ODS managers, beginning at the division level, and  documented. FDA implemented a pilot program for dispute resolution  that is designed for individual CDER staff to have their views heard when  they disagree with a decision that could have a significant negative effect  on public health. Because the CDER Director is involved in determining  whether the process will be initiated, appoints a panel chair to review the  case, and makes the final decision on how the dispute should be resolved,  we found that the pilot program does not offer CDER staff an independent  forum for resolving disputes. FDA also began to explore ways to access  additional data sources that it can obtain under its current authority, such  as data on Medicare beneficiaries’ experience with prescription drugs  covered under the prescription drug benefit.
Since our report, FDA has made efforts to improve its postmarket safety  decision-making and oversight process. In its written response to the IOM  recommendations, FDA agreed with the goal of many of the  recommendations made by GAO and IOM. In that response, FDA stated  that it would take steps to improve the “culture of safety” in CDER, reduce  tension between preapproval and postapproval staff, clarify the roles and  responsibilities of pre- and postmarket staff, and improve methods for  resolving scientific disagreements.
FDA has also begun several initiatives since our March 2006 report that we  believe could address three of our four recommendations. Because none  of these initiatives were fully implemented as of May 2007, it was too early  to evaluate their effectiveness.
To make the postmarket safety decision-making process clearer and more  effective, we recommended that FDA revise and implement its draft policy  on major postmarket drug safety decisions. CDER has made revisions to  the draft policy, but has not yet finalized and implemented it. CDER’s  Associate Director for Safety Policy and Communication told us that the  draft policy provides guidance for making major postmarket safety  decisions, including identifying the decision-making officials for safety  actions and ensuring that the views of involved FDA staff are documented.  According to the Associate Director, the revised draft does not now  discuss decisions for more limited safety actions, such as adding a boxed  warning to a drug’s label. As a result, fewer postmarket safety  recommendations would be required to be discussed by involved OND and  ODS managers than envisioned in the draft policy we reviewed for our  2006 report. Separately, FDA has instituted some procedures that are  consistent with the goals of the draft policy. For example ODS staff now  participate in regular, bimonthly safety meetings with each of the review  divisions in OND.
To help resolve disagreements over safety decisions, we recommended  that FDA improve CDER’s dispute resolution process by revising the pilot  program to increase its independence. FDA had not revised its pilot  dispute resolution program as of May 2007, and FDA officials told us that  the existing program had not been used by any CDER staff member.
To make the postmarket safety decision-making process clearer, we  recommended that FDA clarify ODS’s role in FDA’s scientific advisory  committee meetings involving postmarket drug safety issues. According to  an FDA official, the agency intends to, but had not yet, drafted a policy  that will describe what safety information should be presented and how  such information should be presented at scientific advisory committee  meetings. The policy is also expected to clarify ODS’s role in planning for,  and participating in, meetings of FDA’s scientific advisory committees.
To help ensure that safety concerns were addressed and resolved in a  timely manner, we recommended that FDA establish a mechanism for  systematically tracking ODS’s recommendations and subsequent safety  actions. As of May 2007, FDA was in the process of implementing the  Document Archiving, Reporting and Regulatory Tracking System  (DARRTS) to track such information on postmarket drug safety issues.  Among many other uses, DAARTS will track ODS’s safety  recommendations and the responses to them.
We also suggested in our report that Congress consider expanding FDA’s  authority to require drug sponsors to conduct postmarket studies in order  to ensure that the agency has the necessary information, such as clinical  trial and observational data, to make postmarket decisions.
Mr. Chairman, this concludes my prepared remarks. I would be pleased to  respond to any questions that you or other members of the subcommittee  may have.
For further information regarding this testimony, please contact Marcia  Crosse at (202) 512-7119 or crossem@gao.gov. Contact points for our  Offices of Congressional Relations and Public Affairs may be found on the  last page of this testimony. Martin T. Gahart, Assistant Director; Pamela  Dooley; and Cathleen Hamann made key contributions to this statement.
section_title: Related GAO Products
paragraphs: Drug Safety: FDA Needs to Further Address Shortcomings in Its  Postmarket Decision-making Process. GAO-07-599T. Washington, D.C.:  March 22, 2007.
Pediatric Drug Research: Studies Conducted under Best  Pharmaceuticals for Children Act. GAO-07-557. Washington, D.C.:   March 22, 2007.
Prescription Drugs: Improvements Needed in FDA’s Oversight of Direct- to-Consumer Advertising. GAO-07-54. Washington, D.C.: November 16,  2006.
Internet Pharmacies: Some Pose Safety Risks for Consumers and Are  Unreliable in Their Business Practices. GAO-04-888T. Washington, D.C.:  June 17, 2004.
Internet Pharmacies: Some Pose Safety Risks for Consumers.   GAO-04-820. Washington, D.C.: June 17, 2004.
Antibiotic Resistance: Federal Agencies Need to Better Focus Efforts to  Address Risk to Humans from Antibiotic Use in Animals. GAO-04-490.  Washington, D.C.: April 22, 2004.
Pediatric Drug Research: Food and Drug Administration Should More  Efficiently Monitor Inclusion of Minority Children. GAO-03-950.  Washington, D.C.: September 26, 2003.
Women’s Health: Women Sufficiently Represented in New Drug Testing,  but FDA Oversight Needs Improvement. GAO-01-754. Washington, D.C.:  July 6, 2001.
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