8
Enhancing Postmarket Regulation and Enforcement

Recommendations on Enhancing Postmarket Regulation and Enforcement from the IOM Report

The Future of Drug Safety: Promoting and Protecting the Health of the Public


Recommendation 5.1 The committee recommends that Congress ensure that the Food and Drug Administration has the ability to require such postmarketing risk assessment and risk management programs as are needed to monitor and ensure safe use of drug products. These conditions may be imposed both before and after approval of a new drug, new indication, or new dosage, as well as after identification of new contraindications or patterns of adverse events. The limitations imposed should match the specific safety concerns and benefits presented by the drug product. The risk assessment and risk management program may include:

  1. Distribution conditioned on compliance with agency-initiated changes in drug labels.

  2. Distribution conditioned on specific warnings to be incorporated into all promotional materials (including broadcast direct-to-consumer [DTC] advertising).

  3. Distribution conditioned on a moratorium on DTC advertising.

  4. Distribution restricted to certain facilities, pharmacists, or physicians with special training or experience.

  5. Distribution conditioned on the performance of specified medical procedures.

  6. Distribution conditioned on the performance of specified additional clinical trials or other studies.

  7. Distribution conditioned on the maintenance of an active adverse event surveillance system.

Recommendation 5.2 The committee recommends that Congress provide oversight and enact any needed legislation to ensure compliance by both the Food and Drug Administration and drug sponsors with the provisions listed above. FDA needs increased enforcement authority and better enforcement tools directed at drug sponsors, which should include fines, injunctions, and withdrawal of drug approval.



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Challenges for the FDA: The Future of Drug Safety - Workshop Summary 8 Enhancing Postmarket Regulation and Enforcement Recommendations on Enhancing Postmarket Regulation and Enforcement from the IOM Report The Future of Drug Safety: Promoting and Protecting the Health of the Public Recommendation 5.1 The committee recommends that Congress ensure that the Food and Drug Administration has the ability to require such postmarketing risk assessment and risk management programs as are needed to monitor and ensure safe use of drug products. These conditions may be imposed both before and after approval of a new drug, new indication, or new dosage, as well as after identification of new contraindications or patterns of adverse events. The limitations imposed should match the specific safety concerns and benefits presented by the drug product. The risk assessment and risk management program may include: Distribution conditioned on compliance with agency-initiated changes in drug labels. Distribution conditioned on specific warnings to be incorporated into all promotional materials (including broadcast direct-to-consumer [DTC] advertising). Distribution conditioned on a moratorium on DTC advertising. Distribution restricted to certain facilities, pharmacists, or physicians with special training or experience. Distribution conditioned on the performance of specified medical procedures. Distribution conditioned on the performance of specified additional clinical trials or other studies. Distribution conditioned on the maintenance of an active adverse event surveillance system. Recommendation 5.2 The committee recommends that Congress provide oversight and enact any needed legislation to ensure compliance by both the Food and Drug Administration and drug sponsors with the provisions listed above. FDA needs increased enforcement authority and better enforcement tools directed at drug sponsors, which should include fines, injunctions, and withdrawal of drug approval.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Recommendation 5.3 The committee recommends that Congress amend theFood, Drug and Cosmetic Act to require that product labels carry a special symbolsuch as the black triangle used in the UK or an equivalent symbol for new drugs,new combinations of active substances, and new systems of delivery of existingdrugs. The Food and Drug Administration should restrict direct-to-consumer advertising during the period of time the special symbol is in effect. Once a drug has been approved by the FDA for marketing, the agency’s regulatory authority over the drug and the manufacturer changes markedly. Prior to approval, the FDA has complete control over decisions about how and by whom the drug can be used and how it is manufactured. More important, the potential for rejection of the application gives the FDA strong leverage in dealings with the company, including, for example, requests for data and negotiation of postmarket commitments. After approval, if the FDA finds problems in the way a product is manufactured or marketed or if it becomes aware of safety concerns, it has two principal options: withdraw approval of the drug, or try to persuade the manufacturer to comply with the agency’s requests. Panel moderator Alta Charo, Warren P. Knowles Professor of Law and Bioethics, University of Wisconsin–Madison, explained that the FDA’s current authority is grounded largely in its mandate to prevent the sale of adulterated or misbranded drugs, and that it is differing interpretations of the phrase “adulterated or misbranded” that lead to inconsistent application of the agency’s authority from one administration to the next. This variation in the application of the FDA’s authority led to the call in the IOM report for clarifying and strengthening the agency’s existing authority to regulate marketed drugs, and for giving the FDA sufficient enforcement tools to ensure that regulatory requirements imposed at or after approval are fulfilled (see the recommendations listed above). In his presentation, Peter Hutt, Senior Counsel, Covington & Burling LLP, argued that the FDA needs resources, not new legal authorities. This assertion prompted many comments by subsequent speakers and led to debate about the potentially beneficial versus harmful consequences of legally altering the FDA’s authority or enforcement mechanisms.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary THE FDA’S REGULATORY AUTHORITY1 Mr. Schroeder echoed Ms. Charo’s comments about the inconsistent interpretation of the FDA’s authority, “under which it has expanded under one chief counsel, only to shrink again under another.” He further described the FDA’s authority as not sufficiently nuanced to give the agency the flexibility required to implement a life-cycle approach to benefit–risk profiling. Currently, the agency either exercises its leverage or takes a withdrawal action, both of which involve prolonged negotiations with the manufacturer. Mr. Schroeder emphasized that, although resource limitations are more important than the issue of regulatory authority, the authors of the IOM report concluded that some revision of the FDA’s statutory authority would be consistent with and help reinforce the agency’s ability to fully implement a life-cycle approach to benefit–risk profiling. While the FDA may be able to carry out many of its responsibilities in the postmarket environment under its existing mandates, there are some actions it cannot take. The growing complexity of drug therapies and widespread patient misperceptions about drugs reinforce the argument for strengthening the FDA’s regulatory authority. Mr. Schroeder suggested that the FDA needs more explicit postmarket authority to conduct adequate surveillance and to oversee and enforce safety studies. Preapproval trials frequently will not detect drug risks that are the result of drug interactions or variations in risk across the general population. The IOM report argued that enhanced postmarket authority would take some of the pressure off the preapproval process. Mr. Schroeder noted, however, that while the FDA will always be inclined to take advantage of its leverage in the preapproval period, approval is only one of many milestones at which the benefit–risk profile of a drug should be assessed. Having clearer postmarket authority would minimize the agency’s incentive to make last-minute decisions prior to approval. Strengthening postmarket regulatory authority may take some pressure off the preapproval process, but it is unlikely to compensate for failures earlier in the evaluation process. Moreover, Mr. Schroeder argued that once a certain level of comprehensiveness has been achieved (meaning that information has been acquired, and hypotheses have been generated, tested, and converted into actionable knowledge), the importance of strengthened authority is modest. However, the rationale for providing the FDA with a more flexible array of enforcement options is that if the agency does decide it needs to take action, it can do so swiftly. 1 This section is based on the presentation of Chris Schroeder, Professor of Law and Public Policy Studies, Duke University School of Law.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary THE FDA’S STATUTORY AUTHORITY2 Mr. Hutt asserted that the FDA has no need for additional regulatory authority. With respect to legal authority, he described the 1906 Food, Drug and Cosmetic Act, which was revised in 1938 and has since been amended more than 100 times, as an “old-fashioned statute” written in broad, sweeping terms, not addressing the minutiae dealt with by many modern statutes. Pointing to the definition of safety (“a drug must be proved safe by all tests reasonably applicable to show safety”), he observed that it is not an operational rule. He noted that since 1962, there has not been a single case of an FDA safety decision’s having been overturned in court. According to Mr. Hutt, a larger issue is the lack of scientific information and the reality that there are many questions about drug safety for which there are no answers. While FDA reviewers occasionally fail to take all the action that could be taken (and by doing so, leave an unsafe drug on the market), taking strenuous and immediate action can in many cases be more harmful than waiting for more information (by preventing a safe drug from reaching the market). These decisions are often difficult to make. Mr. Hutt reiterated that the agency already has the strong legal enforcement mechanisms it needs. Formal mechanisms include seizure, injunction, and criminal action, the latter representing one of only two statutes in U.S. history that imposes criminal liability on corporate officials regardless of whether they had knowledge of or intent to commit a crime. More important are the FDA’s informal actions—publicity and negotiations with industry. Mr. Hutt pointed to phenylpropanolamine and ephedra as two examples of the power of publicity. With regard to negotiating with industry, he noted that in most negotiations, both sides have relatively balanced power, either side can walk away, and therefore a balanced agreement must be forged. A company coming to the FDA with an Investigational New Drug (IND) application or a New Drug Application (NDA), by contrast, cannot walk away from the negotiations, a fact that gives the FDA the final word. Mr. Hutt concluded by stating his view, noted above, that what the FDA needs is the resources to address the issues discussed during the symposium. Although these are not new issues—indeed, they have been discussed for more than 35 years—the technological tools needed to strengthen postmarket approval and surveillance now exist. The money to pay for these tools, however, is lacking. 2 This section is based on the presentations of Mr. Hutt; Mary Pendergast, President, Pendergast Consulting; and Eve Slater, former Assistant Secretary for Health, U.S. Department of Health and Human Services, and Director, Vertex Pharmaceuticals and Theravance, Inc.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Ms. Pendergast seconded Mr. Hutt’s point about the FDA’s power in negotiations with industry, noting that in her 20 years with the FDA, she could not recall a single case in which she did not ultimately attain what the agency wanted from the negotiating process. According to Ms. Charo, on the other hand, it could sometimes be said that the process took too long. Ms. Pendergast responded that, to people at the FDA, this translates to their not having pressed hard enough. Even with Vioxx, she asserted, it was unclear whether the problem was a failure of information or a failure of will on the part of the FDA. Dr. Califf suggested that the battle is unfair: an FDA employee with a myriad of other things to do and no administrative support is up against a large number of people who are highly paid, technically gifted, well supported, and highly focused on selling a product. He expressed the view that, although an extremely diligent FDA employee who stays on the case, sometimes to the detriment of other responsibilities, may be able to make things happen, in many cases the company’s promise and initial effort to conduct a study are considered enough. Thus the remedy may not be legal, but a matter of resources. Mr. Hutt concurred with Ms. Pendergast that the will to press hard must exist, and he agreed with Dr. Califf that the problem is one of resources. Disagreeing with the preceding speakers, Dr. Slater asserted that new, carefully considered regulations are necessary because the current system is failing. While this failure has been attributed to faster drug approvals, she argued that the Prescription Drug User Fee Act (PDUFA) did not accelerate review and approval as much as it redressed unwarranted delays. Furthermore, modern drugs intervene via much more complex pathogenetic and biochemical mechanisms than do older drugs and with multiple consequences that are difficult to determine. Dr. Slater cited other reasons for failure of the system, including alleged malfeasance by sponsors and within the FDA, which may or may not be the case, and well-documented deficiencies in the current safety surveillance system and its associated enforcement capabilities. PHASE IV COMMITMENTS3 One area of particular concern cited in the IOM report was the FDA’s lack of authority to enforce Phase IV commitments. At the time of approval, the FDA often negotiates hurriedly with a company to design a Phase IV 3 This section is based on the presentations of Mr. Schroeder, Mr. Hutt, Dr. Califf, and Ms. Pendergast.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary study.4 While the company may have agreed to conduct the study prior to approval, the FDA has few options for ensuring that it actually meets that commitment once the drug is on the market. Because these studies may be negotiated quickly at the last moment, they can be poorly designed. As a result, a company may have difficulty gaining approval for such a study from an institutional review board (IRB) or enrolling subjects, or may conduct the study but end up with meaningless results. Mr. Schroeder supported the recommendation of the IOM report that the FDA be given the authority, both before and after approval of a new drug, to require such postmarket studies if needed to monitor and ensure the safe use of drug products (Recommendation 5.1). In response to this recommendation, Mr. Hutt argued that the FDA does not need statutory authority to regulate Phase IV studies. Rather, he suggested that there be a mechanism for reviewing postmarket Phase IV commitments to ensure that studies are well designed and executable, either before or after approval, and that the FDA follow up with a later review in the event a company claims it cannot gain IRB approval or enroll enough patients. Dr. Califf commented that it is easy to design a study that sponsors know is not going to succeed in enrolling enough patients, to which Mr. Hutt responded that identifying and penalizing those sponsors would be an effective way of resolving the issue, and something the FDA has the ability to do. It was suggested that instead of penalties, incentives could be used— for example, rewards for shorter negotiation times or prompter actions. Dr. Califf mentioned a recent article on the Pediatric Rule describing how such an approach can work (Li et al., 2007). Another incentive suggested was that the guaranteed market exclusivity that usually comes with approval of a new drug could be contingent on completion of reasonably determined requirements for postmarket surveillance trials. Ms. Pendergast responded by noting the difficulty of differentiating good and bad excuses for not finishing a trial, and she suggested that every drug needs to be dealt with on a case-by-case basis. She added that the dialogue between companies and the FDA about postmarket studies should occur earlier in the FDA review process instead of at the time of approval. She proposed that a reasoned discussion of postmarket commitments take place perhaps 6 weeks before approval instead of during the last 24 hours. While the FDA may not need more formal authority, Mr. Schroeder asked whether a statute enabling the FDA to order a Phase IV study after 4 Phase IV studies are conducted once a drug has been approved and is on the market. There are many reasons for conducting Phase IV studies, for example, to monitor potential safety signals observed in premarket clinical studies, to look for interactions with other drugs, or to study particular populations (e.g., pediatric patients or pregnant women).

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary approval would relieve the pressure of the hurried negotiations that take place within the 24-hour period prior to approval. If everyone involved understood that there would be time after approval to discuss whether a postapproval study was necessary, this might eliminate some of the poorly conceived studies for which commitments are now made.5 Mr. Hutt agreed with this concept, but asserted that it could be implemented without a new statute. One panelist pointed to the Best Pharmaceuticals for Children Act (Public Law 107-109), a mandated safety review for products that receive exclusivity, as an example of how legislation has helped the FDA in establishing its priorities. All stakeholders know up front what is going to happen and when, and the system has worked. Mr. Hutt responded that while the new statute requires the FDA to act accordingly, the agency could have implemented this process without further statutory authority—as is the case for many of the safety initiatives described during the symposium. As with an earlier comment about the possibility of enacting legislation authorizing the FDA to undertake the combining of databases around the country, he stressed that the impediment is not a lack of authority, but insufficient resources. Ms. Charo asked Mr. Hutt whether, given the varying interpretations of the FDA’s authority over the years, as discussed earlier, and the apparent effect of a lack of clarity on the agency’s internal behavior, there would be any harm in explicitly acknowledging the authority Mr. Hutt claimed the agency clearly has. She noted that IOM Recommendation 5.1 suggested not that the FDA consider a Phase IV study as a requirement for approval, but that it be permitted to impose new postmarket or Phase IV commitments at any time if it felt doing so was necessary. The IOM committee anticipated that this would not happen very often. Mr. Hutt disagreed. He argued that the number of Phase IV requirements would rise “exponentially” because those with the authority to impose such requirements would use it in any situation where they believed they or the FDA could be faulted in the future for not having done so. RESOURCES FOR ENHANCED ENFORCEMENT6 Throughout the above discussion, Mr. Hutt, Ms. Pendergast, and Dr. Califf all cited a lack of resources as one of the major roadblocks to the FDA’s postmarket regulatory enforcement. Ms. Pendergast stressed the 5 In the FDA’s 2006 report to Congress, there were 1,632 open postmarket commitments (1,259 NDAs or Abbreviated New Drug Applications [ANDAs], and 373 Biological License Applications [BLAs]). 6 This section is based on the presentation of Ms. Pendergast.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary importance of realizing what implementation of some of the IOM report’s recommendations addressing postmarket compliance will cost in terms of both resources and time. An example is the amount of effort required to address the current backlog of postmarket commitments. The number of commitments is rising every year, but many of these trials never even get under way. Between 1991 and 2000, there were on average 1.5 postmarket commitments per drug; by 2003 and 2004, that number had risen to 5 per drug (with some companies having none and one company having as many as 26). In fiscal year 2006, there were 1,632 postmarket commitments, 63 percent of which had not been initiated (Table 8-1). Ms. Pendergast gave an example to demonstrate how resource-intensive implementation of this recommendation would be. She explained that, to determine why a postmarket commitment had not begun, a first step would be to assign an FDA investigator, likely a clinical expert, to the case and identify the specific problem causing the delay. For example, the sponsor might be slow to undertake the study. The investigator would need to look into communications between the sponsor and the FDA division responsible for overseeing the product, and determine whether the commitment was a last-minute one just prior to approval or involved a meaningful dialogue about the trial and its design. The investigator would also need to interview company personnel, look through records, and perhaps investigate the IRB in an effort to learn from the company its reasons for the delay. Or maybe the investigator would determine that the problem lay with the clinical researchers or the study design. For example, the trial might be one that would never get published; it might require computer-assisted tomography (CAT) scans and magnetic resonance imaging (MRI) or other procedures that would be disruptive to a medical practice; or the subjects might not be highly motivated. In such cases, the company might not be at fault for the trial’s not starting in a timely manner. The investigator would need to examine a multitude of factors before the FDA could make an enforcement decision as to whether a particular trial was just slow getting off the ground or the company was culpable. Ms. Pendergast also noted that the same questions could be asked of a company that failed to complete a trial. Moreover, once the FDA had finished its investigation and deliberations and decided to pursue an enforcement action, it would have to convince the Department of Justice to join in taking action against the company. That itself would be a challenge because of the Department of Justice’s own priorities and resource constraints.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary TABLE 8-1 Summary of Postmarket Study Commitments (Numbers as of September 30, 2006)   New Drug Applications (NDAs)/Abbreviated New Drug Applications (ANDAs) (% of Total) Biological License Applications (BLAs)a (% of Total) Number of Applicants with Open Postmarket Commitments 127 45 Number of Open Postmarket Commitments 1,259 373 Status of Open Postmarket Commitments     Pending 899 (71%) 127 (34%) Ongoing 184 (15%) 90 (24%) Delayed 31 (3%) 78 (21%) Terminated 1 (<1%) 2 (1%) Submitted 144 (11%) 76 (20%) Concluded Studies (October 1, 2005, through September 30, 2006) 194 38 Commitment Met 160 (83%) 33 (87%) Commitment Not Met 10 (5%) 0 Study No Longer 24 (12%) 5 (13%) Needed or Feasible     Applications with Open Postmarket Commitments with Annual Reports Due, but Not Submitted Within 60 Days of the Anniversary Date of U.S. Approval 133 (37%)b 33 (47%) aOn October 1, 2003, the FDA completed a consolidation of responsibility for certain products formerly regulated by the Center for Biologics Evaluation and Research (CBER) into the Center for Drug Evaluation and Research (CDER). The previous association of BLA reviews only with CBER is no longer valid; BLAs are now received by both CBER and CDER. Fiscal year statistics for CDER BLA postmarket study commitments are counted under BLA totals in this table. bNote that this statistic counts all annual reports submitted more than 60 days after the anniversary date of U.S. approval as overdue, including reports that may have been submitted on a modified reporting schedule in accordance with prior FDA agreement. Of the applications categorized as having overdue annual reports using this definition, annual reports were subsequently submitted in fiscal year 2006 for 133/133 (100%) of NDAs/ANDAs and 15/33 (45%) of BLAs. SOURCE: Federal Register, 2007.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary THE FDA’S REGULATORY AUTHORITY OVER DRUG LABELING7 Panelists discussed whether the FDA has the authority to force labeling changes once a product is on the market. One panelist questioned why, if the agency has that authority, it is not used, and FDA leaders instead refer to the process as one of negotiation. Mr. Hutt responded that the FDA does have the authority, but the problem is, first, a matter of priorities—the FDA cannot always grant an immediate meeting with a company—and, second, a consequence of the reality that the agency does not know everything about a drug, and should therefore negotiate and engage in discussion with a company about labeling. While negotiating is necessary, however, it need not be prolonged. Dr. Slater observed that, although limited resources are a hindrance in dealing with labeling issues, in reality no amount of money is going to fix the problem unless a well-developed infrastructure is in place to support the volume and complexity of the work involved—one that might enable a labeling meeting within 30 days instead of, say, 75. Indeed, one of the reasons the drug industry can mobilize its resources more quickly than can the FDA is because it is a regulated industry and over the years has had to invest a great deal in infrastructure. According to Dr. Slater, the FDA has the will but not the funding to do the same. Advertising or marketing of a drug falls within the purview of drug labeling; therefore, the FDA’s mandate does not include approving advertising and promotional materials beyond the labeling negotiations that occur prior to approval. While advertising materials must be submitted to the FDA at the time of use, they need not be approved by the agency before being used. The IOM report recommended that the FDA restrict direct-to-consumer (DTC) advertising of all new drugs for a period to be determined by the agency (Recommendation 5.3). Dr. Slater cautioned against moving quickly to place a moratorium on DTC because it has the potential to become a much more effective method of communicating drug information to the public. Rather, she suggested that a revised concept of DTC could serve as a valuable tool for providing information to both prescribers and patients, and eventually could replace drug detailing. Considering that there is no way to impede the flow of information to patients (with information being posted on blogs and elsewhere on the Internet), it would be just as well to lend as much FDA expertise and authority to the process as possible. 7 This section is based on the presentations of Mr. Hutt and Dr. Slater.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary PATIENT SAFETY AND ACCESS8 The IOM report cautioned against assuming that simply altering the statute governing the FDA’s regulatory authority will resolve the difficulties related to that authority. Several additional challenges will need to be addressed: New legislation will take time. Because enforcement through litigation is time-consuming, most of the benefits of enhanced enforcement are realized only post hoc. Even if the FDA gained increased funding, execution of the recommendations would require a well-structured and -supported infrastructure. Many of the enhancements proposed in the IOM report (e.g., extensive risk management plans) would cost money and time, which would likely translate into higher drug prices. If restrictions were placed on DTC advertising, the flow of information about new drugs to practitioners and patients could suffer. Enhanced enforcement could unintentionally drain critical resources from areas of more urgent need (e.g., study of the science of drug safety). Restricted use of a drug in the name of safety could limit access to the drug by those who need it. In addition, as discussed in Chapter 3, the science of safety needs to be strengthened, a new cohort of drug safety professionals needs to be trained, practitioner and patient education needs to be enhanced, and the public needs to be engaged. INDUSTRY PERSPECTIVE9 Dr. Haffner remarked that drug safety is not the responsibility of a single group, but the collective responsibility of patients, providers, regulators, and industry, all of whom have vested interests in optimizing the benefit–risk balance of therapeutic molecules. Moreover, the responsibility for drug safety does not end at approval, but demands continuing assessment and improvement of the benefit–risk profile throughout a product’s lifetime. Effective continuing assessment, in turn, requires partnerships across the health care spectrum. To be effective, those partnerships require governance, transparency, and clarity about the roles and responsibilities of each partner. With respect to the IOM report’s Recommendation 5.2 (that the FDA should have increased enforcement 8 This section is based on the presentation of Dr. Slater. 9 This section is based on the presentation of Marlene Haffner, Executive Director, Global Regulatory and Intelligence Policy, Amgen, Inc.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary authority and better enforcement tools, including fines, injunctions, and withdrawals), Dr. Haffner suggested that if the FDA is given more authority, there must be a clear description of that authority, how it is to be exercised, and how it can and should be exercised with input from other stakeholders. Moreover, that authority should be used only outside the political arena. While industry benefits from a strong and scientifically based FDA, and while the FDA should have the authority to withdraw a product, Dr. Haffner emphasized that this must be done with care and only under rare circumstances. The IOM report recommended that the FDA have increased authority to restrict drug distribution (Recommendation 5.1). With respect to Recommendation 5.1.a—conditional distribution based on agency-initiated changes in drug labels—Dr. Haffner argued that imposition of this condition (1) must include dialogue with industry, (2) should be a transparent process involving communication of risk to patients, and (3) should involve only thoughtful changes that meet the perceived safety need. With respect to Recommendation 5.1.d—distribution restricted to certain facilities, pharmacists, or physicians with special training or experience—Dr. Haffner noted that to some extent, the FDA already has this authority and uses it. Once again, however, she emphasized that such restrictions should be used only in the appropriate circumstances, that patient access should be taken into account, and that patients should be properly accommodated when necessary.