Drug Safety: FDA Needs to Further Address Shortcomings in Its Postmarket Decision-making Process
Released: 2007-03-22T00:00:00

Letter

Background

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. 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.

FDA Lacked a Clear and Effective Decision-making Process for Postmarket Drug Safety

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 were also made more difficult by the constraints it faced in obtaining data.

Decision-making Process on Drug Safety Lacked Clarity about Criteria for Action and the Role of ODS

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. For example, in the case of Bextra, ODS and OND staff disagreed about whether the degree of risk for serious skin reactions warranted a boxed warning, the most serious warning placed in the labeling of a prescription medication. Similarly, in the case of Propulsid, some staff, from both OND and ODS, supported proposing a withdrawal of approval because of the cardiovascular side effects of the drug while others believed label modifications were warranted. 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. Although ODS staff presented their postmarket drug safety analyses during some advisory committee meetings, our case study of Arava provided an example of the exclusion of ODS staff. In March 2003, FDA’s 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.

A Lack of Communication and Limited Oversight Hindered the Decision- making Process

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.

Data Constraints Contributed to Difficulty in Making Postmarket Safety Decisions

Data constraints—such as weaknesses in data sources and FDA’s limited ability to require certain studies and obtain additional data—contributed to FDA’s difficulty in making postmarket drug safety decisions. OND and ODS used three different sources of data to make postmarket drug safety decisions. They included adverse event reports, clinical trial studies, and observational studies. While data from each source had weaknesses that contributed to the difficulty in making postmarket drug safety decisions, evidence from more than one source could have helped inform the postmarket decision-making process. The availability of these data sources was 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 were often based on adverse event reports, FDA could not establish the true frequency of adverse events in the population with data from adverse event reports. The inability to calculate the true frequency made it hard to establish the magnitude of a safety problem, and comparisons of risks across similar drugs were difficult. In addition, it would have been difficult to attribute adverse events to particular drugs when there was a relatively high incidence rate in the population for the medical condition. It was 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 constrained 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. For example, in the case of Propulsid, an observational study showed that a 1998 labeling change warning about contraindications did not significantly decrease the percentage of users in one population who should not have been prescribed this drug. Because they are not controlled experiments, however, there is the possibility that the results can be biased or confounded by other factors.

We found that FDA’s access to postmarket clinical trial and observational data was 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 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.

FDA’s Initiatives to Improve Postmarket Drug Safety Decision Making

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 Institute of Medicine (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—including those that involve disagreements—would be discussed by involved OND and ODS managers, beginning at the division level. The draft policy states that decisions about major postmarket safety recommendations would be 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—including the failure to take a drug safety action—that could have a significant negative effect on public health. In that program, the CDER Director would decide whether the process should be initiated, appoint the chair for a panel to review the case, and make the final decision on how the dispute should be resolved. Because the CDER Director is involved in determining whether the process will begin and makes the final decision, the pilot program did not offer employees 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 goals 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 pre-approval and post-approval 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 was fully implemented as of March 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 March 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 March 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. CDER’s Associate Director for Safety Policy and Communication told us that DAARTS would be fully operational by the end of April 2007.

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.

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