Life-cycle management of drug safety issues requires vigilant postmarket monitoring. Increasingly, however, this concept also includes direct management of how drugs are used, to minimize risks and maximize benefits. Legislative proposals from Senators Kennedy and Enzi, as well as plans offered by the Institute of Medicine, are promoting the more widespread adoption of risk-management plans to mitigate a broader range of safety-related issues. These proposals seek to modify physician prescribing patterns to tip risk-benefit balancing in individual prescription decisions. Yet these policies would do nothing to mitigate the drug safety-related issues that have been the source of recent public interest.
In the past three years, increased attention has been paid to the U.S. system for evaluating the safety of drugs, and questions have been raised about whether the Food and Drug Administration (FDA) is striking the right balance between risks and benefits in its approval decisions on new medicines. Many of these current doubts can be traced to public concerns surrounding safety issues that surfaced in relation to certain uses of two widely prescribed drugs: a class of antidepressants, selective serotonin reuptake inhibitors (SSRIs); and a painkiller, the COX-2 inhibitor Vioxx.[1] The FDA, as the chief drug regulatory agency, has been struggling to find the most appropriateway to address these concerns and to balance the risks that all drugs have against the public health benefits they offer. The agency finds itself buffeted by the tremendous confidence and hope people have in medical technology and their worst fears about the risk and uncertainty of disease. It is challenged to strike a careful balance thatweighs these competing desires and reflects the prevailing public mood.
Some argue that as a result of the renewed public focus on drug safety, the agency has grown increasingly risk-averse and reluctant to approve new drugs that have remote but sometimes poorly defined risks. Although the impact of increased FDA caution would be hard to fully quantify, the fact remains that statistics on the rate at which it approves new drug applications or requires additional cycles of review have not changed appreciably in recent years. This would seem to cast doubt on the contention that heightened caution by the agency has led to changes in its decision making, at least once an application reaches the level of an approval decision.[2] Instead, the most immediate and direct impact of the heightened focus on drug safety issues appears to be a growing impetus on the part of federal decisionmakers (including regulators, academicians who serve on the FDA's advisory committees, and legislators) to try to mitigate drugs' risk through restrictions on how pharmacists, physicians, and patients use them.
The FDA struggles with the question of which side effects it must tolerate as a consequence of a product's regular use in a diverse population and which risks it can actively mitigate by imposing parameters on usage. These restrictions are intended to guide prescribing practices toward more-certain outcomes, where benefits are more likely to be maximized and risks avoided. This concept of making approval contingent on sponsors' taking special steps to manage or reduce hazards, broadly referred to as "riskmanagement" and called "RiskMaps" by the FDA, was introduced in its current form almost two decades ago to deal with a several highly effective medicines that also harbored rare but dangerous side effects.[3]
Although the FDA has historically confined its use of these plans to a mostly narrow collection of identifiable risks, proposals offered by the Institute of Medicine (IOM) as well as provisions of legislation introduced by Sen. Edward Kennedy (D-MA) and Sen. Michael Enzi (R-WY) seek to greatly expand the use of these tools tomitigate broad new categories of risk. The proposals would have the FDA more actively regulate the way in which drugs are prescribed. Although well-intentioned, these proposals are flawed by their impracticality and their potential for creating barriers to medical care. Moreover, they fail to directly address the very shortcomings in the U.S. approach to drug safety that were revealed by the episodes related to SSRIs and Vioxx, even though these policy proposals for greater use of risk-management tools are being offered as a direct response to those incidents.
Origins of the FDA's RiskMaps
Prior to the creation of the FDA's modern regulatory concept of risk management, the first program to contain many of the features of current RiskMaps was implemented in 1990 for the psychiatric drug clozapine. The highly effective antipsychotic drug carried with it a propensity to cause agranulocytosis, or dangerously low white blood cell counts.[4] The program that the FDA put in place required the drug's sponsor to compel physicians to perform routine blood testing for patients receiving clozapine, an approach dubbed inside the FDA as "no blood, no drug." The program was largely deemed a success in reducing the incidence of major side effects, although the RiskMap itself was not substantially revisited, even after many physicians and patients complained that the frequent and intrusive blood testing could be scaled backwithout creating additional dangers. Eight years later, the next major risk management plan was adopted for the reintroduction of the drug thalidomide, which was approved for leprosy treatment but used at the time to treat AIDS patients. Today the drug is prescribed, with success, for treatment of the blood tumor multiple myeloma.
Growing reliance on RiskMaps. During that time and since, the FDA has put greater reliance on RiskMaps to help it manage approvals. This was partly an outgrowth of its success with these early programs and partly a function of lessons it learned over the intervening years. Many believe that the agency was particularly stung by its seeming inability to influence prescribing behavior as new problems emerged around a handful of new drugs, many launched in the 1990s, including Rezulin, Trovan, Propulsid, and Lotronex. The agency's attempts to mitigate emerging safety concerns through "Dear Doctor" letters and black-box warnings failed, in the agency's view, to stem prescribing patterns that it believed put patients at most risk. One anecdote retold inside the FDA places a senior FDA physician in a regulatory meeting during this time, exclaiming during a discussion of some of these drugs that the agency could no longer trust doctors to "do the right thing" in response to the FDA's warnings. It is hard to argue that this sentiment is not embodied, at least in part, in some of the agency's subsequent approaches to risk mitigation. Under the current approach to RiskMaps, sponsors voluntarily agree to impose certain conditions on the use of drugs that are associated with known and potentially dangerous side effects. To date, the FDA has worked with sponsors to develop risk-management programs for drugs both under its legal authorities that are explained in the regulations on accelerated approval at Subpart H (21 CFR, Part 314, Subpart H) and outside of Subpart H as a part of sponsors' voluntary agreements. Outside of Subpart H, where the FDA lacks clear legal authority to impose postmarketing risk-management plans that include conditions on a product's use and distribution, sponsors are nonetheless often compelled by the FDA to pursue RiskMaps to achieve an appropriate risk-benefit balance that will enable the FDA to approve a drug for marketing.[5]
Elements of RiskMaps. Elements of RiskMaps have included restricted distribution of newly approved drugs to only certain pharmacies or doctors, perhaps in conjunction with intensified adverse-event monitoring or the creation of postmarket registries; mandatory education programs for prescribers, pharmacists, and patients; mandatory physician certification and registration for qualification to prescribe certain products; mandatory informed consent; mandatory blood or urine monitoring; and limiting the initial distribution of drugs to sentinel sites (referred to as primary user facilities). While the definition of what constitutes a RiskMap has been expanded by many to include informational tools such as Medguides and patient labeling, for this paper I confine the discussion of RiskMaps to include only programs that impose direct requirements or interventions on health care providers. These conditions are imposed through contracts or agreements that the drug companies agree to maintain with drug distributors, pharmacies, and even individual prescribing physicians. For example, a drug that is associated with a high risk of severe hypersensitivity or allergic reaction (anaphylaxis) might be approved only if the sponsor agrees to contractually require prescribing doctors to premedicate patients to reduce the risk of allergy or enable special, close monitoring of patients during administration of the medicine.
The FDA's Current Approach to Risk Mitigation
Five risk categories covered. As the concept behind RiskMaps gained acceptance, however, the definition ofwhat constitutes a "risk-management plan" and the kinds of risks such plans are intended to mitigate have slowly expanded since the original plans were promulgated with some of the first Subpart H drugs. Nonetheless, historically and even today,most of the risk-management plans promulgated by the FDA that impose restrictions directly on the practice environment have been confined to mitigating five general categories of serious drug side effects that are known, preventable, and life-threatening: (1) birth defects: known and serious risk of teratogenicity (capability of producing fetal malformation) that requires special precautions to minimize in utero exposure (examples: thalomide, Accutane, and Tracleer); (2) anaphylaxis: risk of severe hypersensitivity or other immediate lifethreatening reactions that require special monitoring or precautions before administration (examples: Ziagen, Plenaxis, Zevalin, and Bexxar); (3) overdose and diversion: risk of fatal overdose, dangerous diversion, and sudden death that requires special handling with the product (examples: Actiq, OxyContin, and Pallodone; the latter drug was later withdrawn from the market at the FDA's urging); (4) sudden cardiac or central nervous system (CNS) death: risk of unpredictable and serious heart-rhythm or CNS problems requiring special monitoring during drug administration or precautions (examples: Tikosyn and Lindane); and (5) irreversible endorgan destruction: risk of life-threatening--mostly irreversible and often idiosyncratic--end-organ damage that was observed in the clinical program and can be mitigated through monitoring and timely intervention (discontinuation) (examples: Trovan, Lotrenox, and Clozaril).[6]
Lack of plan review. For the most part, the FDA has struggled to resist wider and less judicious adoption of these plans. It has grappled internally with these plans' cumulative impact on an already overburdened health care system, as well as their impact on patient access and drug costs.[7] Complicating the FDA's use of RiskMaps is the fact that few of the risk-management programs have been retrospectively reviewed, so despite the FDA's collective experience with almost two decades of adoption of these programs, the agency has not learned enough about which elements work andwhich do not.Nor does the agency have a vehicle for regularly reviewing these plans after they are imposed to see if they need to be reevaluated and changed after they are put into place. For these reasons, the science of risk management at the FDA is not as well developed as it could be, given the agency's role in overseeing these RiskMaps. These shortcomings, however, are themselves a consequence of staff and budget shortfalls that leave little money to engage in better analysis, and the reauthorization of the Prescription Drug User Fee Act (PDUFA) should provide some limited funds to address this problem. The FDA has struggled with this problem--the call to implement RiskMaps, coupled with an inability to evaluate whether they are working. The refrain inside the agency, however, remains that these plans allow well-intentioned reviewers to approve drugs in cases when serious safety concernsmight otherwise not support a favorable risk-benefit assessment. The existence of the RiskMap sometimes is enough to tilt the balance in favor of approving a drug that has clear benefits for a discrete population when the known risk can be made more manageable. It is clear, however, that RiskMaps are viewed inside the FDA not as a kind of collective panacea to drug safety problems, but as an imperfect response to more systemic problemswith the delivery of medical care.
Final guidance. These sentiments were conveyed in a series of three final guidance documents published by the FDA in March 2005 to address some of its concerns about the correct design of these plans, as well as the proper parameters for determiningwhen risk-management plans should be contemplated by sponsors. One guidance document deals specifically with the development of RiskMaps.[8] Although the guidance documents codified the agency's increasing use of risk-minimization plans as part of certain kinds of product approvals, they also expressed the FDA's deep concerns that these plans be used judiciously,with prudence and science-based precision. The guidance states:
Communication of risks and benefits through product labeling is the cornerstone of risk management efforts for prescription drugs. . . . For most products, routine risk management will be sufficient and a RiskMap need not be considered. There are, however a small number of products for which a RiskMap should be considered (see section III.D of the guidance). FDA recommends that RiskMaps be used judiciously to minimize risks without encumbering drug availability or otherwise interfering with the delivery of the product benefits to patients.[9]
The FDA has recognized that the requirements that are part of the plans themselves can be burdensome on providers and pharmacists. As a result, on the whole, RiskMaps have been historically confined to drugs with serious and known side effects that can be mitigated or avoided with practical measures. These kinds of drugs have certain binary safety problems, revealed during clinical trials, that make them inherently unsafe if not used with appropriate medical supervision. In such cases, the safety problem is often idiosyncratic and is an inherent feature of the drug, generally made manifest apart from the indication for its use. The agency has shown that it can play a role in encouraging conditions for use of drugs with extraordinary risks where special monitoring can reduce harm or save lives. Measures imposed by RiskMaps are geared to mitigating the consequences of the safety problems observed during clinical trials.
Distinguishing between Different Types of Risk
This is an important distinction from cases in which safety problems are not well defined in clinical trials or when the severity of the safety problem, or the willingness of regulators to tolerate it, exists on a continuum that is tied, in part, to the drug's proposed use. RiskMaps are increasingly being called for by outside parties in each of these latter kinds of scenarios. Themost problematic is the use of RiskMaps to confine prescribing to indications for which regulators believe the side-effect profile justifies the proven benefits. In these cases, the RiskMaps are called upon to oblige doctors to stick to the labeled use of a drug.
Life-threatening risks versus known side effects. There remains an important distinction between drugs that have extraordinary, life-threatening risks such as the risk of anaphylaxis or teratogenicity and drugs that have certain recognized side effects that are a known feature of the drug's use. One the one hand, a drug that causes severe allergic reactions in a small but unpredictable group of patients is randomly dangerous. This is distinct from a drug such as warfarin that is known to cause a risk of bleeding as a consequence of its mechanism of action, where there is often a smoothly changing risk-benefit ratio as uses move from the core label indications to some off-label uses, where the benefits might not be as clearly defined. It is one thing to require special monitoring for a drug that can cause specific rare and catastrophic side effects. It is quite another to limit prescribing of a drug that has certain uncommon side effects simply because those adverse events are not deemed to outweigh the benefits of the drug for the full range of problems for which physicians might be inclined to prescribe a medicine.
In the latter scenario, the FDA would clearly be taking on the role of making medical practice decisions or engaging in efforts to limit off-label prescribing. The agency is ill equipped to engage in the kinds of careful balancing that lead physicians to prescribe medicines outside of labeled indications. This is especially true in fast-moving fields of medicine, where FDA-approved labels are sometimes two years or more behind the state of the medical literature. In these fields, off-label prescribing is an important bridge between reports in the medical literature of emerging science and the FDA review process. In fact, there is typically a six-to-twelve-month delay between the receipt of medical information by the FDA and its inclusion in drug labeling, evenwhere there is clear evidence that a new indication for a drug is effective. The delay can be even longer, since it often takes a drug company months and maybe even years to prepare clinical data for submission to the agency. It can also be argued that the ratio of risk to benefit for off-label uses probably gets better as often as it gets worse, given that patients studied in clinical trials, from which labeled indications emanate, are often sicker than a lot of patients prescribed a medicine off-label.
Symlin example. One recent example that overstepped the traditional use of RiskMaps was the risk-management plan promulgated with the approval of the diabetes drug Symlin (pramlintide acetate). This RiskMap was perhaps more aptly described by the trade publication Pink Sheet as a "restricted marketing plan."[11] The Symlin RiskMap is instructive because it is a potential harbinger for where we may be heading if current legislative proposals and ideas offered by the IOM take hold. The Symlin RiskMap was prompted by major concerns about that drug's propensity to, in some cases, induce dangerously low blood sugar or hypoglycemia on its own or in combination with other diabetes medications. As a result of this risk, Symlin carries a black-box warning in its product labeling. To ensure that it is used appropriately, the product labeling highlights patients who are not candidates for treatment, including those who with poor compliance and those who have no awareness of hypoglycemia.
But as an added measure to ensure appropriate use of Symlin, the manufacturer agreed to follow a RiskMap that includes no direct-to-consumer advertising of Symlin, no journal advertising for one year after launch, limiting promotion to physicians who specialize in diabetes management and are supported by certified diabetes educators, and gradual introduction of Symlin into the marketplace accompanied by concomitant evaluation of usage patterns by both targeted and nontargeted health care providers with semiannual submission of the data to the FDA. The FDA believes that more highly trained clinicianswho are accustomed to dealing with advanced diabetics will be better able to manage the drug's narrow therapeutic margins and that they will not prescribe it for nonlabeled indications for which the FDA has not formally opined on the drug's risk-benefit profile. One problem with these assumptions is that in many cases, patients with serious diabetes--especially those who receive care in busy clinics or urban or rural settings--lack access to this kind of specialty care.
This use of risk-management tools is inconsistent with the original concept underlying the creation of this policy tool. The aim of using RiskMaps to influence what are judged to be more marginal prescribing decisions directly challenges the sovereignty of medical practice and puts the FDA squarely in the role of dictating medical practice standards and promoting specific clinical behavior.
New Proposals That Would Expand the Use of RiskMaps
Proposals offered by the IOM, as well as provisions of the legislation offered by Senators Kennedy and Enzi, would accelerate the trend toward using risk management to constrain medical decision making. Both seek to expand the concept of risk management in a way that could limit off-label prescribing to ensure that a drug is used solely for purposes where the known and suspected risks have already been deemed by FDA-approved labeling to be reasonable relative to the known benefits. The FDA has historically reserved these kinds of more restrictive measures mostly for only a handful of high-risk drugs; however, current IOM and legislative proposals would inevitably extend the use of these plans to encompass a wider range of drugs and to solve a broader range of medical challenges.[12]
Kennedy-Enzi proposals. Title I of the legislation cosponsored by Senators Kennedy and Enzi would amend the federal Food, Drug, and Cosmetic Act (FDCA) to require that new drug and biologic sponsors develop and complywith potentially extensive new Risk Evaluation and Mitigation Strategies (REMS) to obtain and maintain FDA approval of their drugs. The REMS for any prescription drug would include at least four elements. Two of these elements are now required for every drug: The FDA now approves a drug with its professional labeling, and regulations require the sponsor of every drug to submit adverse-event reports on the drug. These current requirements would not change. The bill adds two additional requirements for every drug: (1) a pharmacovigilance statement that is intended to explain and justify whether standard adverse-event reporting is adequate to assess the drug's known serious risks and to identify any unexpected serious risks, or whether andwhat additional studies or clinical trials are needed to assess those risks, and (2) a timetable for implementation of the risk-mitigation plan.
In addition, the REMS might also include restrictions on distribution or use for a drug "when the restrictions are needed to assure safe use of the drug." This provision contemplates restrictions similar to kinds of requirements that the FDA has imposed on the about thirty drugs that now have risk-minimization plans associated with their use, including limits on distribution, marketing, and prescribing conditions. The new provision codifies in statute the legal authority for the FDA to require such restrictionswhen a drug is approved. It also extends this authority from current practice by allowing new restrictions to be imposed after approval.
Under the legislation, these restrictions are to be reserved for "serious risks" with the concept of serious risk based on existing definitions of serious adverse events from the FDA's drug regulations. But the FDA's definition of serious adverse event under 21 CFR 314.80 is broad enough to include a range of drug safety risks that are not contemplated by the FDA's existing RiskMaps. For example, under the FDA's current definition, a serious adverse event could include side effects that may require medical intervention to avert hospitalization. That broad definition could fit a wide range of even more common safety-related issues. Indeed, given the broad nature of that definition, sponsors who are required to submit serious adverse events to the FDA usually err on the side of caution and submit reports of even common side effects. The legislation also contemplates a full range of tools to manage the distribution and use of a drug that meets the threshold. In an accompanying white paper summarizing the legislation, it is stated:
Whatever is required for a drug that needs such restrictions depends entirely on the serious risk with the drug that needs to be managed. That said, the restrictions can impose rigorous requirements on health care practitioners and patients, and should be designed so as not to be unduly burdensome on patient access, nor should they differ for drugs with similar risks, so as to minimize the burden on the health care system.[13]
IOM proposals. The IOM recommends similar provisions, suggesting that the FDA pursue more policies and procedures to put direct requirements, and restrictions, on how products are used. Both the IOM and the Enzi-Kennedy legislation proposed specific new legal authorities to give the FDA the ability to require that sponsors impose these requirements on the medical practice environment and on drug distribution channels and for the FDA to take steps to ensure compliance. The IOM report calls for requirements for "new authority or a clarification of existing authority to apply restrictions and conditions on distribution from the regulatory 'tool kit'." The IOMproposes that the tool kit include moratoriums on direct-to-consumer advertising, restricted distribution (referred to by the FDA as Performance Linked Access Systems, or PLAS) by facility or practitioner with requirements for special training and dispensing within field of expertise, distribution conditioned on the performance of specified medical procedures, or specified clinical trials or data collection. The FDA would have at its disposal fines and injunctions as tools to force compliance by sponsors. Sponsors, in turn,would be on the hook for enforcing compliance by drug distributors, pharmacists, and clinicians.[14]
Legislative Proposals: The Wrong Solution to the Wrong Problem
Drug companies cannot be expected to enforce these requirements on a sundry pharmaceutical supply chain and on a diverse provider community merely through contracts. The only effective tool available to them is the ability to deny access to a drug. Drug companies already have very little leverage over secondary wholesalers in the pharmaceutical supply chain and even less leverage over physicians. To ensure and document compliance with distribution restrictions, they would have to create entire audit and compliance departments devoted to policing doctors and pharmacies, and the FDA would have to watch the watchers, which would require it to regulate the medical practice environment and drug distribution channel. Even if drug companies could maintain tight control over the distribution of certain drugs by dispensing them directly or supplying them only through certain pharmacies and by monitoring how doctors prescribe them, such measures would inevitably limit access to drugs and increase the cost of acquiring them by forcing more medicines to be distributed through expensive specialty pharmacies or specialist physicians. The Enzi-Kennedy bill imposes civil money penalties for intentional violations of a REMS requirement. Imposition of these penalties will require the FDA to maintain a compliance operation charged with inspecting applicants and reviewing their records. Although the FDA has not estimated the cost of such a program, it could be substantial.
Risk-management plans are flawed. It also needs to be recognized that by their complexity, risk-management plans do not necessarily cause the patient to get the best therapy. Decisions aremade on compliance issues in busy offices. What is of even greater concern, the broader use of risk-management plans could end up creating obstacles to accessing modern drugs for patients who already face major problems obtaining innovative, high-quality health care. For example, some riskmanagement plans could push complicated primary care drugs into the hands of specialists, putting patients who do not have ready access to such specialists at a real disadvantage. These are sometimes the very same patients who already face obstacles to obtaining higher-level medical care because they live in environments, or hail from social circumstances,where gaining access to specialist care is already difficult. Moreover, access restrictions on a new drug might drive physicians to prescribe an older drug that is less effective or has more serious adverse effects. Finally, geographic diversity can make the implementation of RiskMaps especially challenging. From a vantage point of Washington, D.C., for example, it might seem reasonable to limit distribution to prequalified pharmacies, but this might effectively put a drug out of reach to a patient in Wyoming or New Mexico,who might have to drive hundreds of miles to get it.
Patients knowingly take on risks. All of these proposals arewell-intentioned efforts to try to reduce the number of people harmed by drug-related side effects. Most side effects, however, are not the result of unknown problems with drugs. Rather, they usually result from patients' and providers' consciously accepting certain risks in the course of medical practice. Moreover, the fact remains as well that the expanded risk-management tools would have done little or nothing to mitigate the problems that eventually surfaced with the SSRIs and the COX-2 inhibitor Vioxx. Yet it was these drug safety issues that first inspired our most recent public discussion on drug safety, aswell as the recommendations of the IOM and the legislative proposals offered by Senators Kennedy and Enzi. In the case of the SSRIs and Vioxx, the problem was not an inability to produce a safety signal or to inspire physicians to heed new warnings on these drugs. Rather, it was an inability to definitively determine--even years after the safety signals were first identified--that these drugs had certain subtle side effects associated with them. Our inability to fully adjudicate the kinds of safety signals that emerged with the COX-2s and the SSRIs were related to a fragmented system for health information thatmakes the accumulation and evaluation of practical knowledge in the postmarket environment exceedingly hard. In both of these cases, the protracted safety problems were a consequence not of the drugs' misuse given the available information but of the failure to reveal that information more quickly and inform physicians and patients.
What we need. Ultimately, we need a more robust system for the more rapid accumulation of postmarket information that encourages collaboration among providers, payers, and product developers around issues of drug safety. The expansion of risk-management tools is an imprecise solution to the wrong problem. When it comes to improving on drug safety, our challenge is not to directly manage the way drugs are used but to seek out better tools for how they are evaluated. We need better systems for detecting rare side effects sooner, for fully evaluating these signals, and better vehicles for communicating this information to providers and patients so that people can make informed choices. This includes better systems for engaging in more proactive, real-time surveillance for potential drug safety issues, similar to the system that is in place inside the FDA's medical device center or the system for vaccine adverse-event monitoring that is maintained by the Centers for Disease Control and Prevention (CDC) and the FDA. Once these signals are detected, the FDA needs better tools and resources for marshalling evaluations of the signals to discern if they are real. This is especially true when it comes to evaluating class effects, which are typically outside the scope of any one sponsor to adequately assess, or evaluating whether or not there is an increased incidence of some subtle safety signals that is already occurring at a background rate inside the normal population, which can require large and expensive prospective, randomized trials. These latter two challenges were both features of the problems that were eventually revealed in association with SSRIs and COX-2s. Finally, the agency and the medical practice environment can benefit from a more comprehensive, collaborative approach to risk communication. Questions remain about the ability of patients to contemplate low-probability risks, given the way information is communicated, and the ability of physicians to explain them.
Role for the medical community. Once this information is made available and promulgated to patients and providers, putting it into practical use in medical practice cannot be the responsibility of the FDA alone through imposition of RiskMaps. The medical community must take responsibility for making sure that physicians responsibly integrate new risk information into their practice environments. The increasing reliance on risk-minimization plans is, in fact, a direct result of the failure of organized medicine, including the medical journals, hospitals, licensing boards, and specialty medical societies, to fulfill their professional obligation to promulgate and more uniformly enforce good practice standards for the discrete number of drugs with more obvious risks. Medical journals, in particular, are in a unique position to help pursue risk-communication effortswhen it comes to informing physicians. The medical community is inviting government curbs on its autonomy by failing to address obvious safety issues. The FDA is pressured to react because when patients are harmed by medicines that are prescribed under uncertain circumstances or for the wrong conditions, the media, Congress, and others place the blame for these bad outcomes solely on the FDA, even if the medical community has done nothing to discourage bad practice patterns. Since the FDA alone faces the blame for these bad outcomes, it is little wonder that it believes that it alone must act to meet the challenge of policing medicine, even if this impulse represents an expansion of the agency's authority into areas it has previously avoided.
Self-governance is a fundamental principle that defines a profession. Although it might be in dispute whether or not the federal government has the authority to regulate aspects of the practice of medicine, there can be no dispute that traditionally the regulation of practice conditions has been delegated to the states, which in turn relied on a degree of self-governance from the profession.[15] If the profession does not take a more active role in addressing issues of risk associated with the growing benefits and increasing complexity of the medical products, then the pressure for ever-increasing federal intrusion into medical decision making will be relentless. In the end, there is an inherent fallacy in the belief that federal authorities can reduce medical side effects by promulgating rules and requirements that create very prescriptive scenarios on how drugs get prescribed. It is unrealistic to think that these kinds of conditions can be imposed as a provision of the routine use of common drugs on an already burdened health care system without bringing along with them negative consequences for patients.
Scott Gottlieb, M.D., is a resident fellow at AEI.
1. B. Meier, "Dispute Puts a Medical Journal under Fire," New York Times, 17 January 2005; and A. Berenson, "Trial Lawyers NowTake Aimat DrugMakers," New York Times, 18 May 2003.
2. "First-Cycle Approvals May Rise for Second Consecutive Year--Parexel Report," FDC Reports (Pink Sheet), 19 June 2006, 21; "CDER's 2005 Performance by the Numbers," FDC Reports (Pink Sheet), 28 August 2006, 4; "Pharmaceutical ApprovalsMonthly: Total NDA/BLA, New Use Approvals Recovered s NMEs Slowed--CDER," FDA Reports, 15 September 2006; G. Chacko, P. Tufano, and G. Verter, "Taking Risk Management Theory Seriously," NBER Working Paper no. 7748 (Cambridge, Mass.: National Bureau of Economic Research, June 2000); and E.M. Perfetto et al., "Evidence-Based Risk Management: How CanWe Succeed? Deliberations from a Risk Management Advisory Council," Drug Information Journal 37 (2003): 127-134.
3. K. Uhl and P. Honig, "Risk Management of Marketed Drugs: FDA and the Interface with the Practice of Medicine," Pharmacoepidemiology and Drug Safety 10, no. 3 (2001): 205-208; and D.J. Graham et al., "Liver Enzyme Monitoring in Patients Treated with Troglitazone," Journal of the American Medical Association 286, no. 7 (2001): 831-833.
4. J.M. Alvir et al., "Clozapine-Induced Agranulocytosis: Incidence and Risk Factors in the United States," New England Journal of Medicine 329, no. 3 (1993): 162-167.
5. G. Steidle and S.E. Hodges, "The United States Food and Drug Administration's Risk Management Framework," Drug Information Journal 36 (2002): 333-341; Scott Gottlieb, deputy commissioner for medical and scientific affairs, Food and Drug Administration, speech at the American Medical Association Annual Meeting, Chicago, Illinois, 12 June 2006; and FDA, "Guidance for Industry: Development and Use of Risk Minimization Action Plans," March 2005, http://www.fda.gov/cber/gdlns/riskminim.pdf (accessed 23 February 2007).
6. FDA, "Guidance for Industry."
7. Gottlieb, speech before AMA Annual Meeting.
8. FDA, "FDA Issues Final Risk Minimization Guidances," Press Release, 24 March 2005, http://www.fda.gov/bbs/topics/news/2005/NEW01169.html (accessed 23 February 2007).
9. FDA, "Guidance for Industry."
10. Ibid.
11. "FDA's Risk Communication Committee Puts Promotion in Center of NDA Review," FDC Reports (Pink Sheet), 12 February 2007, 5-7.
12. A. Baciu, K. Stratton, and S.P. Burke, eds., The Future of Drug Safety: Promoting and Protecting the Health of the Public (Washington: National Academies Press, 2006); and Enhancing Drug Safety and Innovation Act of 2006, introduced by Sen. Mike Enzi and Sen. Edward M. Kennedy 3 August 2006. The bill contains four titles: drug safety; establishment of the Reagan-Udall Institute for Applied Biomedical Research; clinical trials registry and results databases; and reform of conflicts of interest on FDA advisory committees.
13. Enhancing Drug Safety and Innovation Act of 2007, S. 484, sponsored by senators Enzi and Kennedy, introduced 1 February 2007 (bill summary released by Senator Kennedy's office).
14. Baciu et al., eds., The Future of Drug Safety, Section 5.1.
15. L. Noah, "Ambivalent Commitments to Federalism in Controlling the Practice of Medicine" (Unpublished paper, University of Florida, 3 August 2003).