5
Regulatory Authorities for Drug Safety

Major components of the Food and Drug Administration (FDA) statutory authority have evolved in response to drug-related public health crises and in response to a changing environment. The social and health care environment has changed and continues to evolve—health care providers and patients expect timely access to effective drugs, the user-fee program established in 1992 has increased the pace of drug review and approval, the practice of medicine and the use of drugs have changed, and the information available to the public from advertising and the Internet and from commercial and government or nonprofit sources has transformed consumer knowledge and the patient’s role in health care (see Chapter 1 for more information). In view of those changes, the agency’s regulatory authority must be reconsidered and strengthened to ensure that it is equal to the task. However, the committee cautions against assuming that altering the statute alone will solve all difficulties related to FDA’s regulatory authorities. FDA needs considerable new resources to perform optimally in a fast changing, challenging environment, including resources to support its regulatory activities, such as regulatory oversight of direct-to-consumer (DTC) advertising and staff with training and expertise in drug regulation (see Chapter 7 for more discussion of resources).

This chapter briefly summarizes the history of drug regulation, describes the use of the agency’s authority during the preapproval and postapproval processes, identifies needed changes, and makes recommendations to strengthen or clarify FDA’s authority.



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The Future of Drug Safety: Promoting and Protecting the Health of the Public 5 Regulatory Authorities for Drug Safety Major components of the Food and Drug Administration (FDA) statutory authority have evolved in response to drug-related public health crises and in response to a changing environment. The social and health care environment has changed and continues to evolve—health care providers and patients expect timely access to effective drugs, the user-fee program established in 1992 has increased the pace of drug review and approval, the practice of medicine and the use of drugs have changed, and the information available to the public from advertising and the Internet and from commercial and government or nonprofit sources has transformed consumer knowledge and the patient’s role in health care (see Chapter 1 for more information). In view of those changes, the agency’s regulatory authority must be reconsidered and strengthened to ensure that it is equal to the task. However, the committee cautions against assuming that altering the statute alone will solve all difficulties related to FDA’s regulatory authorities. FDA needs considerable new resources to perform optimally in a fast changing, challenging environment, including resources to support its regulatory activities, such as regulatory oversight of direct-to-consumer (DTC) advertising and staff with training and expertise in drug regulation (see Chapter 7 for more discussion of resources). This chapter briefly summarizes the history of drug regulation, describes the use of the agency’s authority during the preapproval and postapproval processes, identifies needed changes, and makes recommendations to strengthen or clarify FDA’s authority.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public HISTORY OF FDA DRUG REGULATION The foundation of FDA’s regulatory authorities was laid in the 1906 Pure Food and Drug Act, which focused on misbranding and adulteration. In keeping with other consumer product laws, it focused on postmarketing remedies only. That is, if a drug already on the market was proven to be a hazard, it could be seized and further sales halted. In the wake of deaths due to elixir of sulfanilamide in 1937, the 1906 law was replaced with a stronger form of regulation in the Federal Food, Drug, and Cosmetic (FD&C) Act of 1938. The new law changed the emphasis to the period of time before a drug enters the market, and required manufacturers to notify FDA before beginning testing on human subjects and to submit proof of the drug’s safety (though not of its efficacy) (Hutt, 1992). The requirement was a major advance in drug regulation, but it was nonetheless still somewhat weak, as marketing could begin 60 days after submission of the information to the FDA unless the FDA affirmatively found the drug to be unsafe. The statutory scheme for drug regulation went through yet another revision in 1962, after thousands of European children with limb defects were born to mothers who had been administered thalidomide (Kaplan, 1995; FDA, 2006). The Drug Amendments of 1962 shifted the burden of proof from FDA (which previously had to prove harm to keep a drug from being marketed) to manufacturers, who now were required to demonstrate both safety and efficacy prior to receipt of marketing approval (Hutt, 1991). The early 1960s also marked the crystallization of clinical trials into the sequence of phase 1, 2, 3 trials still in use today and described in greater detail in Chapter 2 (DHEW, 1963). The FDA’s ability to form judgments about the safety and efficacy of drugs depends upon the submission of data, usually from drug company sponsors, rather than on the use of data developed independently or on its own initiative. As a result, the statutory scheme governing drug approval in the United States has also included a series of measures to provide an incentive for third parties to develop safety and efficacy data for use by FDA. These incentives include patent extensions (the Drug Price Competition and Patent Term Extension Act of 1984), and periods of market exclusivity in exchange for developing information about new drugs, new indications for old drugs, and new information about the action of old drugs in special populations, such as children (The Orphan Drug Act of 1982; The FDA Modernization Act of 1997 [FDAMA]; the Best Pharmaceuticals for Children Act of 2002). Thus, the statutory scheme is characterized by carrots rather than sticks, in that the development of new information on drug safety and efficacy is achieved more by creating incentives than by issuing mandates. The 1938 FD&C Act, as amended several times, defines FDA’s regula-

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The Future of Drug Safety: Promoting and Protecting the Health of the Public tory jurisdiction and its enforcement powers. The statute empowers FDA to bring enforcement actions through administrative procedures (warning letters, adverse publicity, recalls, and withdrawals of product approvals) and judicial procedures (seizure, injunction, and prosecution) (Bass, 1997; Levine, 2002). FDA’s enforcement authority is derived by delegation from the secretary of the Department of Health and Human Services (DHHS) to the commissioner of food and drugs (Bass, 1997). Regulations contained in the Code of Federal Regulations empower FDA to enforce the FD&C Act and other statutes, as appropriate. FDA’s ability to regulate is also influenced by Congress and its “oversight jurisdiction” exercised by holding congressional hearings (Hutt, 1991). The judiciary branch also may influence FDA regulation, when FDA’s interpretations of the statute and its development of regulations are successfully challenged in court. AN AGING AND INADEQUATE STATUTORY FRAMEWORK The statutory authority for drug regulation was constructed decades ago, and it remains largely unchanged. The existing regulatory framework is structured around the premarketing testing process; few tools are available for addressing postmarketing safety issues, short of the blunt instruments to respond to clear-cut adulteration and misbranding. As described in Chapter 1, the sciences of drug discovery and development, the practice of medicine and the extent of drug use, and the information environment in which health care providers practice and patients learn about drugs and interact with the health care delivery system have all changed. It is time to reassess and strengthen FDA’s postmarketing authorities and tools in view of these changes. The carefully controlled clinical trials currently conducted premarket under the existing statutory framework consists of study populations that are commonly different in composition and health status from populations that will use the marketed drug. Study populations are chosen for a legitimate reason: to make data from the trials clearer and thus to make safety and efficacy testing more efficient. After approval, drugs are used by larger and more heterogeneous populations, and by people who have comorbidities or are taking multiple prescription and over-the-counter drugs and dietary supplements. Furthermore, the promotion of drugs has moved beyond health care providers, and substantial industry investment goes into directly targeting consumers. It also has become more important to recognize that the assessment of a drug’s risk-benefit profile does not remain static after approval. Every effort must be made to monitor the performance of drugs on the market, to identify safety problems early, and to address them effectively. FDA’s ability to regulate drugs effectively in a rapidly changing context requires reconsideration of the laws and a clarification and strengthening of the agency’s regulatory authority.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public Below, the committee describes main aspects and weaknesses of FDA’s authority before and after approval. FDA Authority Preapproval A primary regulatory activity of the FDA Center for Drug Evaluation and Research (CDER) is shepherding products through phase 1, 2, and 3 trials. If at any point during clinical trials, the agency “does not believe, or cannot confirm, that the study can be conducted without unreasonable risk to the subjects/patients”, the agency has the statutory authority to impose a clinical hold on the trial (CDER et al., 1998). This suspends further progress in the study until the underlying reasons for the hold (e.g., adverse events or other safety questions) are addressed. Center review teams can also ask sponsors to develop and submit for review, when appropriate, plans for postmarketing safety surveillance and study to monitor previously undocumented, unexpected risks, and a risk management program when there are known risks. Other risk management measures and data from epidemiologic studies may be needed if safety signals are identified and confirmed when a drug has been on the market, including label changes, communication to health care providers, restriction of marketing, and public health advisories. In recent years, CDER has developed guidance for industry on preparing and evaluating risk minimization action plans (RiskMAPs), which may include an array of educational and administrative activities to address risks that are known at the time of approval. There appear to be several conditions FDA can impose at the time of approval, for example, requiring distribution limited to a specific medical specialty, distribution with required periodic screening to avoid contraindicated use, and distribution with mandatory enrollment in a registry. Certainly such conditions have been imposed in the past, for example with teratogenic drugs such as thalidomide and isotretinoin. However, varying interpretations by occupants of the general counsel’s office of the FDA’s authority has led to significant variation in the willingness of the FDA to consider using conditions on sale as a condition of approval. And in general, such conditions are even more difficult to put in place after the drug has been approved for marketing, as efforts to impose such conditions nearly always depend upon voluntary compliance by the manufacturer rather than on the threat of withdrawal of the drug from the market as an imminent health hazard. The Prescription Drug User Fee Act of 1992 (PDUFA) complicated FDA’s ability to use its authority before approval. FDA’s existing statute required that drug review be completed in 180 days; in practice, that goal proved largely impossible to achieve (Kaplan, 1995). The desire of patients and the general public for more rapid access to important drugs was among the primary drivers of congressional action to speed up the drug approval

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The Future of Drug Safety: Promoting and Protecting the Health of the Public process. The enactment of PDUFA secured user-fee funds dedicated to enabling FDA drug review divisions to retain the staff and other resources needed to shorten the length of the approval process. PDUFA has clearly expedited agency decision making and has probably led to efficiencies in distinguishing important from less important issues in the final stages of the review process. However, there is concern that the rapid pace of the process needed to meet PDUFA goals (see Chapters 2 and 3) creates an environment that makes it hard or close to impossible for CDER reviewers to pursue safety concerns as carefully as they would in a less frenetic setting (GAO, 2002b; DHHS and OIG, 2003; Levine, 2006; Nickas, 2006; IOM Staff Notes, 2005–2006). Some also have serious concerns that the regulator has been “captured” by industry it regulates, that the agency is less willing to use the regulatory authority at its disposal (see Chapter 3). Patient expectations and misperceptions about drugs, the ever broader array of drugs, the complexity of actual drug use in the real world, and the intense pace of preapproval activities all suggest that FDA needs stronger authority postapproval to conduct adequate surveillance and oversee and enforce safety studies. FDA Authority After Approval The primary expression of FDA’s authority is the threat to withhold or withdraw approval; but because a drug may offer unique benefits to a population in need, the threat of postapproval withdrawal can ring hollow. Authority to Compel Completion of Postmarketing Commitments Many postmarketing study commitments—a key activity requested by the agency to help to narrow the remaining uncertainty about an approved drug’s safety—are not met and many are never undertaken. As described in Chapter 4, postmarketing studies are often planned and designed as an afterthought late in the review process, just before approval, and sometimes the study designs may not be the most useful, necessary, or even practicable (IOM, 2005). That appears to be at least partly a result of the frenetic pace of the review process, but it may also reflect the agency’s awareness of its limited authority after approval. FDA’s statutory authority to require postmarketing studies has been a subject of debate for decades. Although the agency has interpreted FD&C Act section 505(k), which grants it power to require “records and reports” from sponsors as giving it the authority to mandate postmarketing studies, this interpretation has been contested by the industry (Steenburg, 2006). Several commissioners have admitted that the agency’s interpretation of the statute made it vulnerable to court challenges. In 1977, the Review Panel

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The Future of Drug Safety: Promoting and Protecting the Health of the Public on New Drug Regulation also found that the statute did not give FDA that authority. Many of the Panel’s recommendations were incorporated into the 1979 Drug Regulation Reform Act (S. 1075, Kennedy) which passed Senate but failed to garner support in the House (DHEW, 1977; Steenburg, 2006). The panel’s final report asserted that “rather than delay approval of a drug pending additional studies, FDA should have the authority to require a sponsor to conduct additional research as a condition of approval when a drug has been shown to be safe and effective for its intended use, but questions remain, for example, with regard to its long term effects” (DHEW, 1977). The 1979 bill included a provision to allow FDA to require postapproval studies (Dorsen and Miller, 1979). The 1996 Inspector General found that the FDA “tradition” of asking for voluntary postmarketing studies was not supported by statute in most cases (DHHS and OIG, 1996). FDAMA (which included the reauthorization of PDUFA) added a provision to the FD&C Act requiring sponsor submission of annual updates on progress in meeting postmarketing study commitments. However, PDUFA provided no resources or new authorities to enable the agency to enforce that provision. FDA was required to develop and publish a rule on the reporting format and to report annually on sponsor performance in the Federal Register. The 2005 Federal Register notice on sponsor progress in meeting postmarketing study commitments showed that 797 (65 percent) of New Drug Applications (NDAs) and abbreviated NDA-related postmarketing commitments are “pending” (they are neither “ongoing” nor “delayed”) and 47 percent of annual reports on studies that were due were not submitted to FDA. FDA’s limited authority after marketing and its inability to enforce implementation and fulfillment of important and necessary postmarketing commitments have been at the core of many proposals for strengthening FDA’s authority (GAO, 2002b; van der Linden et al., 2003; Ganslaw, 2005; Grassley, 2005; Thaul, 2005). A recent DHHS Office of the Inspector General (OIG) report on FDA’s monitoring of postmarketing commitments noted that FDA has authority to require postmarketing studies only in certain cases (such as accelerated approval) and that 91 percent of postmarketing commitments between 1990 and 2004 were requested by the agency rather than being required by statute or regulation (DHHS and OIG, 2006). The report also found that postmarketing study commitments do not have a high priority in FDA, the agency lacks a system for managing postmarketing study commitments and the existing database of commitments is not consistently populated with information from commitment letters or from annual status reports, one-third of annual status (required by FDAMA) reports on postmarketing commitments are not submitted or are incomplete, and many completed reports lack useful information. The OIG report also concluded that FDA has no recourse when sponsors do not make progress or do not report on their commitments (DHHS and OIG,

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 2006). It is clear that FDA authority to require postmarketing studies (in cases other than accelerated approval, etc.) is at best unclear, and statutory change is needed to enable FDA to require such studies when necessary and appropriate. Authority to Unilaterally Impose Risk-Reducing Remedies, Such as Label Changes and Distribution Restrictions During the drug development process and up to the point of approval, FDA has a great deal of power. Its communications with sponsors at meetings and in written exchanges (including approval and other letters issued while an NDA is under review) carry enormous weight; sponsors are highly motivated to accede to FDA’s requests and demands during this time to avoid any delay in the approval of their product. After approval, however, unless a case meets the statutory definition of fraud or misbranding or the high threshold for proving imminent hazard to the health of the public, FDA’s regulatory and enforcement options generally lie at the ends of the spectrum of regulatory actions: do nothing or precipitate the voluntary withdrawal of the drug.1 FDA relies on firms to withdraw drugs from the market voluntarily when safety issues are revealed. Doing nothing implies not acting on potential threats to the health of the public, and precipitating withdrawal implies taking the drug from patients who need it, so neither is a satisfactory option. Currently, most actions involve softer remedies negotiated with a drug sponsor; FDA cannot unilaterally compel label changes, addition of boxed warnings, or fulfillment of postmarketing study commitments. Nor can it unilaterally restrict marketing, change the content of a package insert (including Medication Guides2), or change the content of other documents intended for the public. The process of negotiation works well in many cases, but for some products the process can be long and have potentially adverse repercussions for safety. The diminished FDA authority after approval is of concern because knowledge of a drug’s risk-benefit profile is never complete at the time of approval. FDA takes several approaches to monitoring postmarketing safety. CDER staff members review Adverse Event Reporting System (AERS) reports using data mining techniques for automated monitoring of the AERS database, conduct retrospective and observational studies using external administrative databases, and track the status of phase 4 studies. CDER 1 Withdrawals are almost always voluntary rather than mandated by FDA. According to its statute, FDA can institute recalls only for devices and baby formula (Adams et al., 1997). 2 Medication Guides, or MedGuides, are patient-specific labeling for prescription drug products determined by FDA to have “serious and significant public health concern requiring distribution of FDA-approved patient information” (21 CFR 208.1, 4-1-05 Edition, p. 114) (CDER, 2006).

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The Future of Drug Safety: Promoting and Protecting the Health of the Public staff also evaluate and oversee sponsor-designed efforts to manage known risks, such as developing and implementing RiskMAPs for specific products, and negotiate with sponsors on actions needed to confirm and address just-identified risks. Such actions may include additional study, label changes, and risk communication including Dear Health Professional letters. If safety problems are identified, FDA can ask the sponsor to propose label language but cannot require specific language to describe the newly identified risks. Often, companies argue strongly against label changes, limitation of marketing, boxed warnings, and so on. Regulatory Oversight of Sponsor Promotional Activities Pharmaceutical companies engage in various activities to promote their products to the public and to health care providers. Historically, health care professionals have been the primary target of such promotional activities; even at the time of this writing, more than 80 percent of promotional budgets are spent on reaching prescribers through such activities as “detailing” (in-person promotion by sales representatives in the health care setting) and sponsorship of professional educational opportunities (Rosenthal et al., 2002). An increasing proportion of promotional funds goes toward DTC advertising, which is an increasingly contentious area of drug regulation (GAO, 2002a). In 2006, the United States and New Zealand were the only nations that permitted DTC advertising of prescription drugs. However, the European Medicines Agency has for some time considered allowing DTC advertising for three disease categories (HIV/AIDS, diabetes, and asthma and other respiratory conditions). (See Box 5-1 for a history of FDA DTCA regulation.) Around the turn of the 20th century, some analysts became concerned that regulation of DTC advertising was not keeping pace with the rapid evolution in advertising, and the debate that began with the introduction of DTC advertising became multifaceted (Hunt, 1998). Consumer groups, insurers, providers, and others have identified several interrelated concerns about DTC advertising, such as its influence on drug pricing, patient behavior, and prescriber behavior. A 2002 report from the Government Accountability Office concluded that DTC advertising appears to increase spending on prescription drugs and drug utilization (GAO, 2002a). One concern is that advertising may lead to more rapid uptake of a new drug, which, in cases where the drug in question is later found to present greater risks than older drugs in the same class, could potentially dramatically increase the exposure to that particular drug, even among patients who are not good candidates for it. That exemplifies the continuing tension between safety concerns and benefits that outweigh the risks for certain patients. Also, DTC advertising may distort use patterns within classes of drugs, often driving

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The Future of Drug Safety: Promoting and Protecting the Health of the Public use of more costly but no more effective therapies at the expense of older, cheaper options (e.g., generics). As a communication or educational tool, DTC advertising appears to have mixed effects. There is evidence that advertisements have raised awareness about certain health conditions and led people to visit their health care provider and in some cases, receive needed diagnosis and treatment (Ostrove, 2000; Calfee, 2002; Aikin, 2003; Almasi et al., 2006) (see Box 5-2 for a sample of public opinion of DTC advertising). Advertisements about drugs may increase consumer familiarity with products available to treat their particular condition(s), perhaps empowering them to initiate discussion about therapy with their health care provider, and in some cases, to alert a less well-informed provider to a particular therapy (Wilkes et al., 2000; Lyles, 2002; Almasi et al., 2006). On a potentially more negative note, viewers of television prescription drug advertisements may learn more about the benefits than about the risks. Also, DTC advertising has been shown to have an effect on physician prescribing patterns (Aikin, 2003; Mintzes et al., 2003; Aikin et al., 2005; Weissman et al., 2004; Spence et al., 2005). FDA’s authority to regulate prescription drug advertisements is found in Section 502(n) of the FD&C Act, and Title 21 of the Code of Federal Regulations (CFR) section 202.1 is the source of the implementing regulations that describe the content required in such advertisements (Behrman, 2005). Specifically, regulations require that print advertisements must disclose every risk listed in the FDA-approved label as part of a brief summary, but broadcast advertisements may either contain a brief summary of side effects and contraindications or make “adequate provision” for conveying the product’s complete labeling information, that is, a toll-free telephone number or Web site. FDA can regulate advertising that is false or misleading, but its regulatory actions must harmonize with First Amendment protections of truthful commercial speech. FDA does not have the authority to approve drug advertisements or require that advertising materials be reviewed prior to their use. The agency can require and enforce corrective action only after a drug advertisement has been broadcast (Woodcock et al., 2003). To avoid having to issue a correction after beginning a marketing activity, a majority of sponsors submit advertising materials for comment to the CDER Division of Drug Marketing and Communication (DDMAC) before airing them (Woodcock et al., 2003) (see Box 5-3). The history of court challenges to restrictions on DTC advertising is lengthy and instructive. Attempts to ban DTC advertising have foundered due in part to uncertainty as to whether such a prohibition is constitutional. Drug advertising has been held to be commercial speech deserving First Amendment protection (Virginia State Board of Pharmacy v. Virginia Citizens Consumer Council, Inc., 425 U.S. 748, 762 [1976]). In Central

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The Future of Drug Safety: Promoting and Protecting the Health of the Public BOX 5-1 History of FDA’s DTC Advertising Regulation As a variety of social changes began to transform the passive patient into an empowered seeker and contributor of knowledge and information, the patient-provider relationship and other interactions and spheres of influence around it changed as well. As early as 1968, FDA developed the first patient package insert in recognition of the need to instruct patients on the use of a drug, the inhalational product isoproterenol (Pines, 1999). In the 1970s and 1980s, more health-related information was made available to the general public (such as the Physician’s Desk Reference), cable television experimented with physician-oriented channels, and pharmaceutical companies began to advertise in print to patients. As FDA and the industry reoriented some of their communication activities to target patients, the agency worked in two different directions: furthering its own role in communicating to patients through patient package inserts (see Chapter 6) and making determinations about how to regulate and ascertain the public health implications of emerging industry promotional efforts directed at consumers (Pines, 1999; DHHS et al., 2005). FDA’s authority in that respect originates in the FD&C Act, which gave FDA authority over drug labeling and gave the Federal Trade Commission (FTC) authority over advertising (Kaplan, 1995). Current statutes give FDA and FTC overlapping and concurrent authority over the labeling of FDA-regulated products and over advertising of prescription drugs and devices. FTC is responsible for regulating false or deceptive claims about products other than prescription drugs and FDA has primary jurisdiction over false and misleading labeling of all jointly regulated products and, on the basis of the definition of advertising as an extension of labeling, over DTC advertising (Adams et al., 1997; Pines, 1999; Palumbo and Mullins, 2002). In 1983, FDA requested a voluntary moratorium on all drug advertising to Hudson Gas & Electric Corp. v. Public Service Commission (447 U.S. 557 (1980)), the Court stated that a governmental restriction upon commercial speech is lawful only if the asserted governmental interest in the restriction is substantial, that the speech restriction directly advances the governmental interest asserted, and that the speech restriction is not more extensive than is necessary to serve the asserted governmental interest. If the government cannot demonstrate that it meets all three prongs of the Central Hudson test, the speech restriction is unlawful. In Thompson v. Western States Medical Center, 535 U.S. 357 (2002), the Supreme Court applied the Central Hudson test and ruled that the statutory ban on advertising of compounded drugs

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The Future of Drug Safety: Promoting and Protecting the Health of the Public allow the agency to determine where there were adequate statutory protections for consumers (Palumbo and Mullins, 2002). After its internal decision making and discussion with academic, consumer, health care, and other communities, the agency concluded in the Federal Register (1985-Notice 50 FR 36677) that “current regulations governing prescription drug advertising provide sufficient safeguards to protect consumers.” The notice also stated that DTC advertising must meet the same requirements as advertising to physicians, including the “brief summary” of risk information required by statute (21 CFR 202.1). In the 1990s, as DTC advertising progressed from print to television, pharmaceutical companies found they could not make product claims in advertisements, because that required presenting the statutorily “brief summary” of safety and contraindications information. The television equivalent of the page of minuscule print on the back of magazine advertisements “would take a minute or more at a barely readable scrolling rate” (Woodcock et al., 2003). For this reason, DTC advertisements did not make product claims and generally consisted of “help-seeking” and “reminder” advertisements. The former described an identifiable condition and urged viewers to “see your doctor,” while the latter mentioned the name of a product without the indication. Advertisements that talked about the disease, but not the drug, or about the drug without mentioning the indication left viewers confused and led FDA to reconsider the entire subject of DTC advertising (Pines, 1999). In 1997, FDA produced the draft Guidance for Industry: Consumer-Directed Broadcast Advertisements. That document, issued in final form in 1999, allowed television product claim advertisements, finding that they could meet the statutory requirement and make “adequate provision” for the information contained in the brief summary by providing a toll-free number or Web site where consumers could receive the complete information contained in the drug’s label. violated commercial speech rights. How the court would react to restrictions short of outright ban on DTC advertisements is unclear, but it is worth noting that in the western states decision the court was unsympathetic to the argument that DTC advertisements of compounded drugs might affect physician prescribing practices, to the detriment of their patients. The same court cases are relevant to whether FDA can require prior approval of the advertisements. If courts were to conclude that this amounts to a “prior restraint” on First Amendment protected speech, FDA would have to show a compelling government purpose for such a policy. FDA’s regulation of promotional activities was challenged in court by

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The Future of Drug Safety: Promoting and Protecting the Health of the Public Approval Should Not Be the “Last Call” for Realistic Regulatory Action on Safety In acknowledgement of the complexity of regulatory decision-making, the multiple conflicting interests involved, and the undesirability of delaying the approval of important drugs, the committee has sought to recommend tools that will allow FDA greater regulatory flexibility postapproval and throughout a drug’s lifecycle. Establishing an interval for reviewing all accumulated information about new molecular entities (NMEs) will provide FDA with the authority to take necessary regulatory action when appropriate. For most drugs, the review of the drug’s performance for renewal of approval will be a relatively simple process. For others, the review of postapproval data will give FDA an opportunity to reconsider the drug’s risk-benefit profile and respond to safety issues. Over the years, patient groups and industry representatives have expressed concern that regulatory actions that are too risk-averse could stifle innovation in drug development. Longer and larger preapproval trials to improve certainty about a drug’s risk and benefit at the time of approval are often not possible, because the extremely broad-based testing in complex populations needed to get a better picture of postapproval use and risks would slow drug development unacceptably in many disease settings. Many scientists agree that CDER needs better resources for research and surveillance and better regulatory tools to manage risk-benefit uncertainty after approval (Deyo, 2004; Avorn, 2006; Ray and Stein, 2006). In earlier chapters, the committee described an organizational culture and a scientific milieu that encourage thinking about and preparing to address postmarketing safety issues much earlier in the development and review process. In this chapter, the committee calls for strengthening FDA’s authority so that the point of approval would no longer be the “last call” for major regulatory action. The committee finds that FDA’s authority is built on an aging regulatory framework, that FDA’s largely all-or-nothing regulatory tools limit its ability to regulate effectively after approval, and that strengthened agency authority would greatly mitigate the concern that fast review and approval may sacrifice safety. Current enforcement options limit FDA’s ability to regulate in a manner that matches the agency’s mission—protecting and advancing the health of the public. FDA’s strongest tools are largely all-or-nothing, and these are unrealistic options in light of patients’ needs for given drugs. The agency needs a more nuanced set of tools to respond to uncertainty, to reduce advertising that drives rapid uptake of new drugs, or to compel additional studies in the actual patient populations who take the drug after its approval.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public STRENGTHENING FDA’S REGULATORY AUTHORITIES The committee has examined five areas of regulation in which it believes that FDA’s authority requires strengthening. The committee reasserts the importance of a regulatory system that is dynamic and flexible; a key aspect is that most NDAs and approvals pose few issues of concern and little or no need for unusual postapproval monitoring and risk management. For most drugs, the existing interaction between regulator and sponsor is adequate—incoming safety information does not reveal extremely serious unlabeled adverse events (AEs), and regulatory re-examination (for new indications and labeling changes) is more or less routine. The committee’s recommendations for regulatory change apply mainly to what may be a smaller proportion of drugs—which cannot always be identified beforehand—that have complex risk-benefit assessments and both lingering and emergent safety concerns. Possible examples may be found among drugs that are similar to those with a poor safety record, NMEs with unique modes of action, drugs for which preclinical testing revealed a potential for clinical safety problems, and so on. First, clarification or strengthening of existing authority for use postapproval is needed to take important regulatory action out of the realm of negotiation and the bully pulpit. Second, FDA needs a new way to address DTC advertising that has provoked great interest and debate in recent years. Third, FDA needs sufficient enforcement tools to ensure that regulatory requirements imposed at or after approval are fulfilled. Fourth, FDA needs to develop a major strategy to improve public and health care provider awareness that approval is not the end of uncertainty and that as new drugs enter the market, more information about their benefits and risks is likely to become available. Fifth, regulation of drugs in the United States would be greatly strengthened by requiring a milestone in each drug’s lifecycle that triggers a comprehensive review of consolidated safety and efficacy data and of the status of postmarketing conditions and commitments. Conditions and Restrictions on Distribution Throughout the Drug Lifecycle The committee has found that FDA has some ability to ask for and negotiate with sponsors about various risk management and other actions. For example, marketing of isotretinoin is conditioned on a four-step RiskMAP (iPLEDGE) that consists of: registration of and an educational program for patients, pharmacies, prescribers, and distributors; implementation of an education program for the four groups just listed; implementation of a reporting and data collection system for serious AEs in compliance with statutory requirements and as pertaining to the sale and dispensing of isotretinoin outside the iPLEDGE program; and implementation of a

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The Future of Drug Safety: Promoting and Protecting the Health of the Public plan to monitor and minimize drug exposure during pregnancy through a pregnancy registry (Houn, 2006). It must be noted here that the iPLEDGE program has drawn criticism from providers and patients who find its requirements onerous and the administration of the program inadequate (Ritter, 2006). In another example, FDA issued a public health advisory pertaining to the multiple sclerosis drug natalizumab after an unexpected serious AE surfaced. The sponsor later withdrew natalizumab from the market and began working with CDER staff to develop a risk management program (including restricted distribution through certified infusion centers and so on). FDA convened the appropriate advisory committee to review the sponsor’s proposed risk management program and CDER’s evaluation of it. The advisory committee recommended that natalizumab be returned to the market with the necessary safeguards; after additional FDA consideration, Tysabri was returned to the market in July 2006. Another important example is clozapine, an antipsychotic whose use was conditioned on regular blood work showing that agranulocytosis, a potentially fatal side effect of the drug, was not emerging. Even more recently, FDA suggested 5-year followup of patients on the HIV drug class of CCR5 antagonists, which target a novel pathway and pose a serious risk of worsening the disease. The committee believes that although FDA is able to negotiate for label changes (including warnings), and to impose restrictions or conditions on distribution at approval, it exercises those options inconsistently and lacks both the ability to require sponsor agreement with label changes and compliance with conditions imposed after approval and enforcement threats short of withdrawal. The conditions on the distribution of isotretinoin were implemented at the conclusion of an extremely long process. Label change negotiations for some drugs with emergent safety problems (such as cisapride, rofecoxib) have been unreasonably drawn out, and sponsors have made great effort to soften the language preferred by FDA (Harris and Koli, 2005). Such delays and barriers to timely action are problematic given the seriousness of the AEs which such label changes and similar measures are intended to warn about and to prevent (Kweder, 2004). FDA’s regulatory authorities do not give the agency sufficient flexibility to address safety concerns quickly during a drug’s lifecycle and as consistent with the agency’s public health mission. No drug is thoroughly understood at the time of approval, but most drugs perform effectively and without major safety concerns once they are on the market. FDA needs more a consistent approach and more nuanced range of enforcement measures to act when an approved drug’s risk-benefit profile is in question and when safety concerns arise after marketing. FDA needs new authority or a clarification of existing authority to apply restrictions and conditions on distribution from the regulatory “tool kit” described below. Some of the regulatory options described have already

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The Future of Drug Safety: Promoting and Protecting the Health of the Public been used in some cases, but are often exercised at the point of approval. In general, even if FDA is successful in placing a condition or restriction at the time of approval, doing so after marketing is substantially more challenging. For example, FDA’s authority over labels is limited to approving the contents of a label prepared by the sponsor, after a sometimes lengthy process of negotiation about the language. Although FDA may disagree with the sponsor and request certain changes, it is the committee’s understanding that the agency cannot compel the sponsor to make changes. 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. As with any grant of regulatory authority, FDA authority to revise labels, require conditions on distribution, and to impose penalties must be accompanied by administrative procedures that protect the due process rights of affected parties. These procedures, as generally used throughout federal law, include adequate notice, opportunity for response, and avenues of appeal within the agency and, typically, with the courts. In this fashion, statutory authority to impose restrictions and remedies is neither dictato-

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The Future of Drug Safety: Promoting and Protecting the Health of the Public rial nor unlimited. It does, however, provide the FDA with a wider range of remedies and a stronger base from which to negotiate voluntary actions, while still providing affected parties an avenue of relief from what they may perceive as unwarranted or overly burdensome actions. The committee also finds that FDA needs enforcement tools to ensure that the regulatory requirements described above are applied and met. Specifically, FDA does not have the set of flexible regulatory actions that it needs to enforce necessary and important postmarketing commitments effectively. 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. The agency’s timely performance of the required postmarketing safety reviews could be listed as one of the goals associated with PDUFA and reported on in the goals letter to Congress (see Chapter 3). A Symbol to Denote Limited Knowledge About New Drugs A recurring theme in this report is the committee’s concern that the public and even health care providers may base their choices and behaviors related to prescription drugs on inaccurate assumptions. For example, there may be a lack of general awareness that FDA approval does not represent a lifetime guarantee of safety or the end of uncertainty, that the understanding of a drug’s risk-benefit profile evolves over the drug’s lifecycle, and that new drugs are approved on the basis of carefully controlled limited testing in relatively small populations and under circumstances that may differ greatly from a drug’s use after marketing. The committee believes that a symbol or icon could be added to the labels and all materials associated with new drugs, new combinations of active substances, and new delivery systems to alert patients and the general public that such products are new and that the knowledge available about their performance is often incomplete. In the United Kingdom, a black triangle marks every newly marketed drug approved by the Medicines and Health products Regulatory Agency (MHRA). The black triangle signifies that a pharmaceutical product is under intense scrutiny of regulatory authorities, and the symbol is placed next to the product name in the British National Formulary and in the British pharmaceutical industry’s compendium of

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The Future of Drug Safety: Promoting and Protecting the Health of the Public drugs approved for marketing (MHRA, 2006). The black triangle program has an additional purpose of alerting National Health Service providers to report all adverse reactions (rather than only serious ones) associated with drugs labeled with the symbol. Study of reporting patterns indicates that despite the request for both serious event and non-serious event reporting, providers are five times more likely to report a serious than a non-serious adverse drug reaction (Heeley et al., 2001). Therefore, it is not clear whether the black triangle program in the United Kingdom was successful in increasing provider reporting. However, the black triangle was not intended as a tool to inform or educate consumers, so evidence from the United Kingdom would not necessarily be informative in the case of a somewhat different use for such a symbol. The committee believes that marking the label and all promotional material for newly approved drugs or indications with a special symbol and communicating its meaning to patients and consumers may help to increase awareness of the nature of newly approved therapies, for example, the incompleteness of information on safety. 5.3: The committee recommends that Congress amend the FD&C Act to require that product labels carry a special symbol such as the black triangle used in the United Kingdom or an equivalent symbol for new drugs, new combinations of active substances, and new systems of delivery of existing drugs. The FDA should restrict direct-to-consumer advertising during the period of time the special symbol is in effect. The symbol should remain on the drug label and related materials for 2 years unless FDA chooses to shorten or extend the period on a case-by-case basis. The committee believes that companies should refrain from DTC advertising during the black triangle period, and would favor imposition of a formal moratorium on such advertising. Such restraints may be necessary because DTC advertising has the ability to dramatically increase the uptake of a newly approved drug. In some cases, that may expose larger numbers of people (compared with a lower-key market introduction) to a new drug with not-yet-documented safety concerns. Recognizing the legal uncertainties surrounding such an imposition, the committee suggests that at the very least any DTC advertising during this period should include explicit notice that the data related to risks and benefits associated with the product are less extensive than those related to alternative products that have been in use for a longer period and should include a caution to speak to one’s health care provider about alternatives. If a moratorium on DTC advertising for the time that the special symbol is in effect is deemed to be inconsistent with First Amendment protections of commercial speech, the committee believes

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The Future of Drug Safety: Promoting and Protecting the Health of the Public that it is necessary to require placement of the symbol on all promotional materials, patient or consumer information, and all DTC advertising while the special symbol is in effect. Products carrying the special notation also would be subject to heightened postmarketing scrutiny, with measures that include: Prompt review of individual 15-day reports of AEs (sponsors are required to report serious, unexpected AEs to the agency within 15 calendar days)3 in addition to review of regular tabulations of such reports. Followup of these reports as needed to obtain additional information, such as that on related health factors and resolution of AEs, that may be helpful in assessing role of product and overall impact of AEs. Scheduling of regular meetings of postmarketing and premarket reviewers at which summaries of recent reports of AEs related to newly approved products prepared by the postmarketing reviewers would be discussed. Preparation of annual summaries of reports received on new products to be posted on the FDA Web site—not simply a list or tabulation, but a thoughtful interpretation of the reported experiences and what they mean for continued use of the drug. The committee believes that a broad-based discussion of the most appropriate symbol for a US audience would be desirable before the program is launched, and an evaluation of the effect of such a program on public awareness and knowledge would be important. Periodic Review of Data on New Molecular Entities In 1977, the Review Panel on New Drug Regulation found that “FDA even lacks a basis for judging whether the approved drug and the approved labeling are still correct, since there is no comprehensive system for gathering and utilizing data on an approved drug’s performance and effect” (Department of Health Review Panel on New Drug Regulation, 1977:91). This continues to be the case. The committee finds that a lifecycle approach to risk and benefit would be facilitated by establishing a milestone in a drug’s lifecycle for a comprehensive review of consolidated safety and efficacy data and the status of postmarketing conditions and commitments (see Chapter 4 for discussion of the assessment of risks and benefits). There is no systematic CDER review of 3 Refer to the Code of Federal Regulations, 21 CFR 314.80.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public accumulated knowledge about a drug a year or more after its approval for marketing. In 2005, the European Medicines Agency enacted a new statute requiring that prescription drug marketing authorizations in the European Union be reviewed and, if appropriate, renewed at 5 years after initial approval (EMEA, 2005).4 5.4: The committee recommends that FDA evaluate all new data on new molecular entities no later than 5 years after approval. Sponsors will submit a report of accumulated data relevant to drug safety and efficacy, including any additional data published in a peer-reviewed journal, and will report on the status of any applicable conditions imposed on the distribution of the drug called for at or after the time of approval. As described above, such conditions on distribution may include a moratorium on DTC advertising, postmarketing studies, monitoring (such as registries, active surveillance, and so on), and restricted distribution. The 5-year report would include results of postmarketing studies, outcomes of monitoring, and, where applicable, the extent of DTC advertising (examples of all advertisements and total expenditure) during the first 5 years. For most drugs, the committee expects the 5-year “review” process to entail nothing more than a one-page FDA letter agreeing with the sponsor’s summary of all accumulated (or consolidated) safety and efficacy information. On rare occasions, as a consequence of the review, regulatory action including suspension or withdrawal of approval (for example, if evidence of imminent public health hazard emerged in the course of the review) would be a possibility. This recommendation is not intended to preclude any regulatory action, and it does not constitute a request for new authority for FDA, rather, for the creation of a milestone moment in a drug’s lifecycle that would allow FDA to review what has been learned during a drug’s first 5 years on the market. REFERENCES Adams DG, Cooper RM, Kahan JS, Eds. 1997. Fundamentals of Law and Regulation: An In-Depth Look at Therapeutic Products. Vol. 2. Washington, DC: FDLI. 4 Product safety specialists from the Center for Biologics Evaluation and Research routinely develop reviews of the postmarket safety experience with a new vaccine within 2–3 years of the time the vaccine is licensed. These reviews are published in journals and are available on the FDA Web site’s Vaccine Adverse Event System page.

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