FDA's Overall Risk Management Activities
Although the FDA devotes considerable resources to its pre- and postmarketing risk assessment activities, the Agency has in recent years become much more active in other areas of risk management. This part of the report discusses FDA's programs within the current overall risk management system.
Risk assessment includes the estimation and evaluation of a risk. FDA's premarketing risk assessment is intended to identify and quantify risks detected during clinical development and to evaluate how carefully any potential risks were assessed by the manufacturer. In addition, an evaluation of the risk of drug interactions as well as the potential for misadministration is performed. The known risks, along with any deficiencies in safety testing, are then weighed in the approval decision and described in the labeling of approved products. Part 2 of this report describes how the scientific and procedural quality of premarketing review of medical products is ensured.
Postmarketing risk assessment relies primarily on two modes of adverse event reporting to the Agency: spontaneous, voluntary reporting by health professionals and consumers, and mandated reporting by industry based on voluntary reporting to product manufacturers (plus user facilities in the case of medical devices, and physicians regarding specified events with certain vaccines.) As Part 3 of this report details, FDA's postmarketing systems are primarily focused on identifying new, unanticipated adverse effects that were not, or could not be, observed or recognized before marketing or that may arise due to medical use that was not anticipated. The Agency also receives and analyzes reports on medication errors.
In his 1978 book, William W. Lowrance defines something as safe if "its risks are judged to be acceptable." 5 Such a definition emphasizes the relativity of the concept of safety and implies that determining the safety of something requires not only measurement and assessment of its associated risks but also a judgment concerning the acceptability of those risks, in the context of the demonstrated benefits, to the population involved. A risk/benefit analysis is integral to FDA's review process for medical products: approval for marketing follows a determination that a product's benefits outweigh the risks associated with its labeled use for the intended population. The issue of the acceptance of known risks by the affected population is discussed below.
The National Research Council (1989) writes that determining the acceptable level of risk should occur in a larger context.7 This definition implies that social and community values are at least as important as the technical judgments of professionals and should be included in the determination of acceptable risk.
Traditional approaches to risk management assume that science and technology can measure the risks associated with the use of a medical product and quantify their significance. However, science provides only a statistical assessment of risk; it cannot determine its acceptability. Affected communities may differ from regulators in how they value either risks or benefits. They also may judge differently the amount of uncertainty that is tolerable. Advocacy groups for patients with various diseases, most notably AIDS and cancer, have taught us during the past several years that it is impossible to accurately assess the acceptability of risks in light of the potential benefits without the input of the affected community. Although some advocates for patients with life-threatening illnesses are willing to accept a high degree of risk to gain the benefits of new products, other advocacy groups, such as those against mandatory vaccination, feel that no risk is acceptable.
FDA is engaging stakeholders
To obtain community input, FDA has increasingly engaged its stakeholders in the regulatory process and developed partnerships with other Federal and non-Federal agencies when determining the acceptability of product risk. Some of these activities are discussed in the following pages.
Discussion of premarketing applications with FDA advisory committees or device panels involves risk confrontation. The benefits and risks of a product are discussed, and frequently votes from the group are solicited. Not only are patient groups often represented on the committees or panels, but members of the public and interested groups are able to observe the proceedings and speak in the public sessions. The Agency may use these meetings to solicit recommendations on additional risk management approaches such as label warnings. Advisory committee or device panel meetings are sometimes held during the postmarketing period to obtain outside input on new risk information.
Collaboration and partnerships with stakeholders
FDA has developed alliances and collaborative relationships with health professionals, consumer and patient advocacy groups, industry organizations, and Federal and non-Federal agencies to gather information and advice during the assessment of product risks and benefits. Each Agency center that approves human medical products has established relationships or partnerships and developed programs to investigate risks, facilitate risk discussion and communications, and gain feedback about the risk/benefit assessment of medical products. (See examples in Appendix F.)
These risk confrontation activities exemplify some of FDA's best practices in risk confrontation, and they have been very successful. But they represent only a beginning. The Agency has not yet fully engaged stakeholders in the process for managing the risks incurred by using medical products. More community input is needed.
Risk intervention is defined by the National Research Council as "the evaluation of alternative risk control actions, selection among them . . . and their implementation." 8 After the risks of a medical product are identified and assessed, they must be managed or minimized.
FDA makes the marketing decision
During the premarketing period, FDA is responsible for the ultimate action for managing risk: the marketing approval decision. If FDA decides that a product's risks outweigh its benefits, the Agency can prevent those risks by denying the product entry to the marketplace. Alternatively, if the Agency determines that a product's benefits exceed its associated risks, it grants marketing approval. After marketing, if new information changes the risk/benefit equation unfavorably, FDA can take a number of actions, including even initiating a product's withdrawal from the market.
FDA regulates product labeling
Another central FDA risk intervention activity is regulating the information in the product's labeling. The Agency must approve the original labeling, and review and approve most labeling changes. In addition, FDA regulates the advertising and promotion of marketed products. Promotional materials must not be false (i.e., must conform to the label and be substantiated), and they must not be misleading (i.e., they must be balanced and include the material facts). In great part, this means that benefits should not be exaggerated and that risks should be presented clearly. Regulation of labeling, promotion, and advertising is intended to ensure that healthcare providers and consumers are adequately informed of the potential risks and benefits of the product, so that they can make decisions appropriate for each patient. Once aware of medication error reports, FDA, in some cases, has compelled the manufacturer to withdraw, repackage, or relabel the product. (See Appendix E.)
FDA engages in a number of other risk management activities
For products with specific risks, FDA may engage in a number of other risk management activities, such as mandating education for product users or limiting product distribution. Following are risk management activities currently undertaken by the FDA to manage risk associated with the use of medical products.
Additional restrictions on use
Occasionally, FDA may take special steps to limit risk directly. Restrictions on distribution (e.g., to specific hospitals or specialists) or requirements for practitioner qualifications or training may be imposed, or other restrictions on a specific product may be required. An example of such an intervention is the unprecedented effort the Agency took in restricting the use of thalidomide due to the product's potential to cause birth defects. Following extensive discussion of the sponsor's proposal for a fetal exposure prevention program, FDA approved thalidomide for the treatment of complications of leprosy and invoked regulatory authority to tightly control its U.S. marketing. The sponsor was required to develop a comprehensive oversight plan for the prescribing, dispensing, and use of thalidomide for physicians, pharmacists, and patients. (See Appendix F.)
Another example of restriction on use is demonstrated in the approval of a surgical transmyocardial revascularization device for the treatment of angina pectoris. In this case, the device was approved, but restricted to patients with severe symptoms who also provided written informed consent. For several other devices, including injectable collagen used to support the bladder in women with urinary incontinence, and excimer lasers for vision correction, FDA mandated that the products be provided only to practitioners specifically trained in their use. (For more examples of restrictions on use, see Appendix G.)
Postmarketing study requirements
Postmarketing studies can be used as risk management tools. Under the accelerated approval regulations, FDA requires postapproval clinical studies after marketing to support continued product approval. In addition, FDA has the authority to require postmarketing studies as a condition of approval for high-risk devices. Although the Modernization Act repealed a mandatory postmarketing surveillance program for some high-risk devices, it gave the Center for Devices discretion to order a manufacturer to conduct postmarketing surveillance for any class II or class III device under certain conditions. 9 (See Appendix G.)
For drugs or biologics, FDA may obtain commitments from sponsors to conduct postmarketing studies if it determines further delineation of risks is necessary. For example, if there are concerns about how the safety findings in the clinical trials will relate to safety when marketed, the sponsor of the product may agree to conduct additional clinical investigations or epidemiological studies of the drugs in actual use (typically, phase-4 studies). Changes in the Modernization Act that require sponsors who have made postmarketing study commitments to report annually on the progress of the study should encourage the completion of these phase-4 study studies.
FDA licensing of a vaccine for the prevention of chickenpox provides an example of such a phase-4 commitment. In this case, there were considerable concerns about the duration of immunity. In a commitment prior to licensing, the manufacturer agreed to conduct several postmarketing studies, including one 10-year study and two 15-year studies, to assess long-term immunity. (For more examples of commitments to additional studies, see Appendix G.)
Only the Secretary of the U.S. Department of Health and Human Services (HHS) may suspend the approval of a new drug application if there is an imminent hazard to the public health. This provision of the FD&C Act is cumbersome for use in an emergency and has been invoked only once. The only other route for nonvoluntary withdrawal of a drug product is quite time-consuming, requiring formal notices and an opportunity for a hearing. Therefore, the primary mechanism for removing risky medical products from the market requires FDA to obtain voluntary agreement from the manufacturer. The FD&C and PHS Acts and Agency regulations provide a framework for manufacturers and distributors to follow when voluntary removal of marketed products is necessary. (See Appendix G.)
For devices, FDA has authority to mandate a recall if it concludes that there is a reasonable probability that a device intended for human use would cause serious adverse health consequences or death. Biological products are subject to mandatory recall provisions if a substantial or imminent hazard exists. FDA also has the authority to suspend or revoke a biological license.
The accelerated approval regulations (21 CFR 314.500-.560 and 601.40-.46) establish procedures for streamlining the medical product development and review processes for critically needed products without sacrificing good science and rigorous FDA oversight. FDA can approve a drug or biological product based on surrogate endpoints or markers. 10 Although these products can be approved more quickly, they must still meet legal safety and effectiveness standards. The regulation also establishes a streamlined withdrawal process if the postmarketing studies do not verify the product's clinical benefit, if there is new evidence that the product is not safe and effective, or if other specified circumstances arise. To date, this withdrawal portion of the regulation has not been invoked.
These examples illustrate some of FDA's risk management activities. Because they have been successful, some critics have encouraged the Agency to become more proactive in risk intervention, more involved in the overall risk management system. Some critics have asked if the Agency shouldn't implement additional interventions.
Risk communication is a key component in risk managment
Risk communication is an interactive process of exchanging information related to risk. Effective risk communication facilitates the exchange of information and helps affected parties make more informed decisions.
Within the historical framework of healthcare delivery, FDA's strategy for communicating risk information about approved prescription medical products has been to target the risk managers, that is, the physicians and other healthcare professionals. The primary communication tool has been the approved package labeling. Any risk-related information reported to the FDA subsequent to approval has traditionally been communicated primarily to healthcare providers through changes in a product's labeling information. However, in recent years FDA has sought more direct routes of communication and increased its communication with consumers and patients. Although FDA's current communication strategy, as described below, primarily consists of direct dissemination of information to the healthcare community and consumers, FDA is increasing those activities that promote a two-way exchange of information.
The product labeling, including the package insert, is revised and updated periodically by the manufacturer as new risk information becomes available. Healthcare professionals rely on the package insert for information on a product's known risks, benefits, and dosing information (or information for use) for the specific indications studied during clinical trials. In a recent FDA survey about how physicians use the product package insert, physicians responded that the Dosing and Administration, Contraindications, Warnings, Adverse Reactions, and Precautions sections of the package insert were most important. 11
In 1979, FDA issued regulations extensively revising the organization of labeling, resulting in the eventual revision of the majority of product labeling. These changes included the addition and expansion of the Clinical Pharmacology section, a more structured organization of information on using the drug during pregnancy, and expanded information about adverse events. Since that time, FDA has continued to expand the content of the product package insert and provide more comprehensive information. For example, the presentation of adverse event information has become more extensive due to improvements in detecting and collecting adverse events data during development. The insert also contains more descriptions and data from clinical trials that support the product's indications. More recently, information about using the product in pediatric and geriatric populations has been added.
Efforts are underway at the Agency to redesign the prescription drug and biological product package inserts so that healthcare professionals can access key prescribing information more readily. The design will be made available for public comment through a proposed rule.
When important new information emerges during the postmarketing period, methods in addition to package labeling revisions are used to communicate risks, primarily targeting the healthcare community. More recently, FDA has recognized the importance of communicating risk information about medical products directly to the public in a manner that is easy to understand. In some circumstances, information is communicated through the media or the Internet. For some pharmaceutical products, FDA requires the manufacturer to provide important patient counseling information in the Precautions section of the approved product labeling and encourages manufacturers to voluntarily provide patient package inserts that contain product risk information in consumer-friendly language. FDA has also asked manufacturers to provide patient package inserts for device products (e.g., for home use parenteral products).
Risk information for patients
Because communicating risk information to patients is important, FDA has tried for many years to ensure that patients receive patient labeling when they pick up their prescriptions. In August 1995, FDA proposed an increase in the dissemination of useful written prescription drug information for patients who receive prescription drugs on an outpatient basis. The next year, Congress passed a law requiring that the private sector be given the opportunity to develop a plan to reach the goals specified in the proposal. In January 1997, the Secretary of HHS accepted the plan. FDA continues to assess progress toward the year-2000 goal of at least 75 percent of people receiving useful written information with new prescriptions. By the year 2006, the goal is for at least 95 percent of people to receive such information.
FDA recently published a regulation that requires FDA-approved patient labeling (Medication Guides) for drug and biological products that pose a serious and significant public health concern. 12 This regulation is expected to be invoked for a relatively small number of products (on average, between five and ten annually). (See Appendix G.)
FDA ensures that promotional materials comply with regulations and include a balanced presentation of product benefits and risks (fair balance). For direct-to-consumer (DTC) promotional materials - through broadcast media, such as television, radio, or telephone - the risk information must be presented in a manner that is easily understood by consumers. DTC print advertisements are also required to have a summary of the risk information in the approved package insert (brief summary). These brief summaries appear on the back of advertisements in journals or consumer magazines. For DTC ads, FDA encourages manufacturers to present brief summaries in consumer-friendly language.
Ensuring the widest possible distribution of new risk information is a major goal of FDA outreach. Historically, notifications produced by the Agency have included press releases, talk papers, meeting announcements, Safety Alerts, Public Health Advisories, articles, brochures, and Medical Bulletins. FDA staff members have also made numerous presentations on medical product safety at conferences and meetings in a variety of settings.
With advances in information technology, the Agency has begun using new avenues to reach target audiences. Websites maintained by FDA centers and offices contain general and specific information for designated constituencies. This information includes product approval letters, package insert text, patient package inserts (when available), Dear Healthcare Professional letters, and information on product withdrawals and recalls. For example, FDA regularly posts notices of recalls and withdrawals of plasma-derivative products. At the urging of the National Hemophilia Foundation and other patient representative groups, FDA also began providing automated patient notification of these regulatory actions via e-mail.
When a significant safety-related regulatory action is taken, some notifications are sent automatically. Facsimiles (sent on the day information is issued) and periodic mailings of Agency documents are sent to major health organizations, healthcare agencies in other countries, congressional contacts, and consumer and patient advocacy groups. Over 140 health professional and industry organizations participate in the MEDWATCH Partners program, with each organization immediately notified (by listserv e-mail or fax) of new material posted on the MEDWATCH website, a site specifically devoted to medical product safety. Each MEDWATCH partner disseminates this safety information to constituents, ensuring to the greatest degree possible that healthcare professionals and consumers have the latest risk information. A second MEDWATCH e-mail service, open to anyone who wishes to subscribe, provides immediate e-mail notification of new safety information.
The Agency is taking a proactive stance in getting information to those concerned, working directly with manufacturers on drafting Dear Healthcare Professional letters that they can disseminate. In certain circumstances (such as the issuance of a new boxed warning for a drug or a product recall involving a direct hazard to health), the Agency may arrange a conference call to appropriate health professional and consumer groups to inform them and solicit their input. In addition, supplementary question-and-answer sheets (Q & As) may be drafted and distributed.
FDA continues to look for ways to provide risk information about medical products as part of its ongoing effort to protect the public health. However, it is difficult to measure whether the information is effectively communicated (i.e., does the right information target the right audience at the right time). One specific improvement FDA will explore is the feasibility of identifying important communications consistently across the centers. Although healthcare professionals, consumers, and patient groups have all stated that they want additional information and are encouraged by the Agency's efforts, the effectiveness of these communications in managing risk has never been systematically evaluated.
Today's environment of performance measurement demands that any system include an evaluation phase to monitor and ensure effectiveness. During the postmarketing phase, risk information is received and assessed by the FDA. This information is used to develop and implement risk management strategies and to formulate risk communication messages.
The Agency also uses this information to evaluate the effectiveness of some of its risk communications by, for example, monitoring changes in physician prescribing habits related to a product's adverse event rates. Communications about risk information (e.g., Dear Healthcare Professional letters and public safety alerts) can be effective in decreasing the number of prescriptions written, and often the rate of injury, as reflected by the frequency of such reports to the Agency. The Center for Devices routinely sends out a questionnaire concerning the safety alert/advisory to a random sample of recipients to evaluate its effectiveness.
However, even frequent communications may not always succeed in managing known, preventable risks. For example, until it was withdrawn from the market, physicians continued to prescribe, and pharmacists to dispense, terfenadine (Seldane) concomitantly with interacting medications, despite multiple warnings about potentially lethal interactions when using the drug with some other medications. 13 Overall, because of the lack of complete data on the causes and incidences of adverse events, evaluation of the effectiveness of some FDA interventions is difficult. (See Appendix I.)