Order Code RL32797 CRS Report for Congress Received through the CRS Web Drug Safety and Effectiveness: Issues and Action Options After FDA Approval March 8, 2005 Susan Thaul Specialist in Social Legislation Domestic Social Policy Division Congressional Research Service ˜ The Library of Congress Drug Safety and Effectiveness: Issues and Action Options After FDA Approval Summary COX-2 inhibitors and SSRIs — the U.S. public has become more familiar with these technical abbreviations for biochemical processes than one might expect from our general level of science knowledge. Safety concerns about these drugs — used primarily to treat pain and depression — have turned a spotlight on the Food and Drug Administration (FDA) and its approach to protecting the public from drug risks that had not been identified before FDA-approval allowed the drugs on the market. Two regulatory frameworks exist for the review of prescription drugs. First, in the pre-market approval process, FDA reviews the safety and effectiveness of new drugs that manufacturers wish to market in the United States. A large part of this review is FDA’s examining the manufacturer-provided data from clinical testing — studies in which humans take the investigational new drug in carefully controlled, and usually randomized, trials — from progressively larger Phases I, II, and III trials. Second, after a manufacturer has sufficiently demonstrated a drug’s safety and effectiveness for a defined population and specified conditions, and the drug is FDAapproved, FDA acts through its postmarket regulatory procedures. Manufacturers must report all serious and unexpected adverse reactions to FDA and clinicians and patients may do so. The law gives FDA authority to take limited action if it finds a drug’s postapproval use presents an increased risk of an adverse event. However, many suggest that not only does FDA need a broader range of enforcement tools, but that FDA also is not taking full advantage of the authority it does have. While critics of FDA differ in their assessment of what is wrong with FDA’s approach to postmarket safety activities, there is broad agreement that it needs significant change. Discussion of the problems and possible solutions revolves around six areas: FDA organization, FDA budget, role of industry, opportunities to use the drug approval process to enhance postmarket activities, insufficient postmarket information, and lack of public access to available data. Some of the proposed changes lie within the power of FDA to implement. Others would require congressional action. This report examines various options for strengthening FDA’s ability to protect the public. It will be updated from time to time to reflect legislative action by Congress. Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 FDA Approval of New Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Legislative History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 The Current System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Investigational New Drug (IND) Application . . . . . . . . . . . . . . . . . . . . 5 Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 New Drug Application (NDA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 FDA Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Funding of the Approval Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 FDA Postmarket Regulation of Approved Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 8 Legislative History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 The Current System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Office of Drug Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Enforcement Authority . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Off-Label Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Funding of Post-Approval Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Safety and Effectiveness Issues and Options Once a Drug Is FDA-Approved . . 11 FDA Organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 FDA Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Put the Office of Drug Safety and the Office of New Drugs under different supervisors . . . . . . . . . . . . . . . . . . . . . . . . . 14 Institute scientific dispute-resolution mechanisms . . . . . . . . . . . 14 Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Move safety oversight to another federal agency . . . . . . . . . . . . . 14 Provide whistleblower protection . . . . . . . . . . . . . . . . . . . . . . . . 15 FDA Budget . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Revise (or repeal) PDUFA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Increase FDA appropriations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Develop alternative funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Industry Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 FDA and Administration Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Fill vacant positions in FDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Reassign conduct of pre-market studies away from manufacturer to government . . . . . . . . . . . . . . . . . . . . . . . . 18 Diminish marketing role in study design . . . . . . . . . . . . . . . . . . . 18 Create transparency in funding of academic research . . . . . . . . . 19 Reduce conflicts of interest in consumer and physician e ducation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Maintain tort claim option . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Opportunities to Use the Drug Approval Process to Enhance Postmarket Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Institute two-phase approval process that includes mandatory reevaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Require specific postmarket surveillance and study commitments for initial approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Require comparative effectiveness trial commitments for initial approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Require commitment to study likely users not considered in pre-approval trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Restrict use of newly approved drugs when first on the market . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Insufficient Postmarket Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 FDA Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Reassess criteria qualifying as a “signal” . . . . . . . . . . . . . . . . . . . 23 Periodically assess the range of off-label use . . . . . . . . . . . . . . . 23 Design and conduct rigorous studies, including clinical trials, to test the safety and effectiveness of drugs used off-label . 24 Use administrative, financial, and clinical databases . . . . . . . . . . 24 Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Mandate more activist surveillance . . . . . . . . . . . . . . . . . . . . . . . 24 Authorize FDA to require postmarket studies of situations that had not been anticipated at the time of approval . . . . . 24 Require comparative effectiveness studies . . . . . . . . . . . . . . . . . 24 Increase funds to FDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Explore alternative systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Existing Information Unavailable to All Groups . . . . . . . . . . . . . . . . . . . . . 25 FDA Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Enhance drug-information dissemination options . . . . . . . . . . . . 27 Transfer current information to prescribers . . . . . . . . . . . . . . . . . 27 Extend collaborative data collection and analysis activities . . . . 27 Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Require that labeling address off-label uses . . . . . . . . . . . . . . . . 28 Remove postmarket study responsibility from both manufacturers and FDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Require clinical trial registration . . . . . . . . . . . . . . . . . . . . . . . . . 28 Make data public . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Give FDA enhanced authority to regulate DTC advertisements . 29 Give FDA ability to institute penalties for misleading ads . . . . . 29 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 List of Tables Table 1. Concerns and Options Raised by Observers . . . . . . . . . . . . . . . . . . . . . 31 Drug Safety and Effectiveness: Issues and Action Options After FDA Approval Introduction On November 18, 2004, the Senate Finance Committee convened to hear testimony sparked by concern over the popular Merck anti-inflammatory drug Vioxx. A few weeks before, Merck had notified the Food and Drug Administration (FDA) that it was withdrawing Vioxx from the market in response to recent study results indicating an increased risk of heart attacks and sudden cardiac deaths among the millions of patients who had been using Vioxx since its introduction in 1999. Senators wanted to find out what had gone wrong and what could be done to prevent it from happening again. This was not the first time that this Congress had reacted to news about dangers posed by drugs that had already reached the market. Just two months earlier, the House Committee on Energy and Commerce’s Subcommittee on Oversight and Investigations had held hearings because of controversy over the safety of antidepressants when prescribed to children. In both cases, Members were worried that neither the public nor FDA were sufficiently informed — or, in the case of FDA, sufficiently forthcoming — about risks occurring after the drugs had been first approved. At the Finance Committee hearing, Dr. David Graham, Associate Director for Science and Medicine in FDA’s Office of Drug Safety, was asked whether these concerns were warranted in the case of Vioxx. He stated, “I would argue that the FDA, as currently configured, is incapable of protecting America against another Vioxx. We are virtually defenseless.”1 Pressed to name other marketed drugs he thought troublesome, Graham named five.2 The furor after Dr. Graham’s testimony reawakened interest in a variety of regulatory issues that have surfaced periodically ever since the storm of protest over 1 Testimony of David J. Graham, M.D., M.P.H., Associate Director for Science, Office of Drug Safety, Center for Drug Evaluation and Research, U.S. Department of Health and Human Services, Food and Drug Administration, Washington, D.C., before the U.S. Senate Committee on Finance hearing, “FDA, Merck and Vioxx: Putting Patient Safety First?” Nov. 18, 2004, at [http://finance.senate.gov/hearings/testimony/2004test/111804dgtest.pdf]. 2 Marc Kaufman, “FDA Officer Suggests Strict Curbs on Five Drugs; Makers Dispute Claims About Health Risks,” Washington Post, Nov. 19, 2004, p. A1. The five drugs named were Accutane (to treat acne), Bextra (a COX-2 inhibitor used to treat pain), Crestor (a statin used to lower cholesterol), Meridia (for weight loss), and Serevent (to treat asthma). CRS-2 “filthy, decomposed or putrid” food and “worthless” medicines resulted in FDA’s creation during Theodore Roosevelt’s presidency.3 The most recent example of intense public and regulatory attention: the meeting of two FDA advisory committees on February 16-18, 2005, coming three months after Dr. Graham’s testimony to the Senate Finance Committee and five months after Merck withdrew Vioxx from the market. After weighing the evidence on the safety and risk-to-benefit of Vioxx and similar drugs, the committees unanimously asserted that the three COX-2 inhibitors currently licensed in the United States — Vioxx, Celebrex, and Bextra — do increase the risk of heart attack and stroke. Illustrating the complexity of decisions that FDA faces, a majority of the committee members recommended to FDA that the benefits of the drugs outweigh the risks for certain groups of people and that FDA should, therefore, permit their sale — with, however, several severe limitations on advertising and strong warnings in consumer and clinician labeling about cardiovascular risk that is likely associated with dose and duration of use.4 Concerns about regulatory agencies’ abilities to protect the public are not unique to FDA or public health.5 The life-and-death issues of medicine, however, strike most closely to home for many Americans. There has not been a decade since FDA’s creation without a highly publicized incident involving drug safety that has led to legislation expanding and strengthening FDA’s authority to protect the public. Examples include the scores of children killed by an untested antibiotic (elixir of sulfanilamide) marketed by a company in Tennessee in 1937; the mistakes at a plant manufacturing polio vaccine in 1954 that actually caused 260 cases of polio and 11 deaths; and, in 1962, thalidomide, the sleeping pill that eventually resulted in the birth of at least 8,000 severely deformed babies and thousands of prenatal deaths, mostly in Europe.6 In some of these episodes, FDA scientists have emerged as heros: thalidomide would have caused many more birth defects had it not been for FDA researcher Dr. Frances Kelsey, who refused to approve the manufacturer’s application to market the drug in the United States. But in doing so, Kelsey had to fight both company threats and the inaction of FDA’s commissioner. 3 Philip J. Hilts, Protecting America’s Health: The FDA, Business, and One Hundred Years of Regulation (New York: Alfred A. Knopf, 2003), pp. xi and 54. (Hereafter cited as Hilts, 2003.) 4 FDA, Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee, Gaithersburg, Md., Feb. 16-18, 2005, Agenda, at [http://www.fda.gov/oc/advisory/accalendar/2005/cder12532ddd0216171805.html], and Discussion Points, at [http://www.fda.gov/ohrms/dockets/ac/05/questions/2005-4090Q1 _Final.pdf]; and Marc Kaufman, FDA Panel Opens Door for Return of Vioxx, Washington Post, Feb. 19, 2005, p. A1. 5 Robert B. Reich, “A Suitable Remedy: When the FDA Is Weak,” Washington Post, Jan. 9, 2005, p. B5. (Hereafter cited as Reich, Jan. 9, 2005.) 6 Hilts, 2003, p. 158; and FDA, “Milestones in U.S. Food and Drug Law History,” FDA Backgrounder, May 3, 1999, updated Aug. 5, 2002, at [http://www.fda.gov/opacom/ backgrounders/miles.html], visited Feb. 7, 2005. CRS-3 In FY2005, FDA operates on a budget of $1.8 billion ($1.45 billion from tax revenue and $350 million from user fees),7 almost $6 per U.S. citizen. With that money, FDA is expected to oversee about $1 trillion of goods, which make up about one-quarter of all U.S. consumer spending. Each month, FDA receives about 33,000 reports of threats to the public from possibly unsafe drugs.8 Congressional funding for FDA has increased at about half the rate as that of industry user fees, established by Congress as a way to defray costs of new resources to allow quicker progression through the approval process. Even though the user fees account for somewhat less than 20% of the FDA total, their proportion within FDA’s Center for Drug Evaluation and Research (CDER) is both larger and increasing more rapidly: in 1992, user fees accounted for 53% of the CDER budget; they now make up almost 80% of that budget.9 Two regulatory frameworks exist for the review of prescription drugs. First, FDA reviews the safety and effectiveness of new drugs that manufacturers wish to market in the United States; this process is called pre-market approval or preapproval review. Once a drug has passed that threshold and is FDA-approved, FDA acts through its postmarket or post-approval regulatory procedures. Concerns about postmarket safety involve many drugs. The Vioxx situation, however, has uniquely sparked congressional and public attention because of the sheer numbers of prescriptions filled — 93 million by some estimates. Dr. Graham’s analysis led him to see a “7-fold increase in heart attack risk” resulting in, he calculated, between 88,000 and 139,000 Americans who suffered heart attack or stroke from the drug. In addition, there have been a wide variety of recent books, editorials, and polls on industry and FDA responsibilities for action, offering criticisms similar to those Graham made in November. Both Senate and House leaders have made it clear that the 109th Congress will see both hearings and legislation dealing with the safety and effectiveness of drugs. This report examines issues related to drug safety, specifically in the context of the regulatory process that Congress and the FDA have established for ensuring that drugs are safe and effective. It includes a primer on drug approval: how drugs are approved and come to market, including FDA’s role in that process. It also describes FDA and industry roles once drugs are on the pharmacy shelves, the postmarket or post-approval period. It moves on to a discussion of the problems in identifying and resolving postmarketing safety and effectiveness issues that are raised most frequently in the debate. It outlines actions that a variety of analysts have suggested to improve the situation, both ones that FDA could adopt on its own and others for which legislation would be necessary. 7 HHS, Budget in Brief, Fiscal Year 2006, FDA table, p. 12. 8 FDA, Protecting Consumers, Promoting Public Health, at [http://www.fda.gov/oc/ opacom/fda101/fda101text.html], visited Jan. 7, 2005. 9 Gardiner Harris, “At FDA, Strong Drug Ties and Less Monitoring,” New York Times, Dec. 6, 2004. (Hereafter cited as Harris, Dec. 6, 2004.) CRS-4 FDA Approval of New Drugs Legislative History Derived from the Dutch word meaning to boast (quacken), “quack” was the word Americans commonly used to describe charlatans in medicine. Quacks peddled adulterated and mislabeled medicines throughout the United States without penalty, until 1906, when Congress passed the Food and Drugs Act, outlawing the practice. It was the first of a series of laws intended to assure Americans that the medicines they used did no harm and actually worked — that they are, in other words, safe and effective. Over the next half-century, Congress passed two major pieces of legislation expanding FDA authority in pursuit of those goals. It passed the Federal Food, Drug, and Cosmetic Act (FFDCA)10 in 1938, requiring that drugs be proven safe before they could be sold in interstate commerce. Then, in 1962, in the wake of the thalidomide tragedy, Congress amended the law to require that drugmakers prove the effectiveness of their products as well.11 The process has not remained the same since 1962. The 1983 Orphan Drug Act began a series of additional laws passed by Congress in recent decades to boost pharmaceutical research and development, speed the approval of new medicines, or, in some cases, both. The Orphan Drug Act provided incentives for pharmaceutical manufacturers to develop drugs, biotechnology products, and medical devices for the treatment of rare diseases and conditions. Other laws include the 1984 HatchWaxman Act, the landmark compromise balancing greater patent protection of manufacturers with quicker public access to lower-priced generic drugs; the 1992 Prescription Drug User Fee Act (PDUFA), which ushered in user fees and performance goals for faster drug approvals; and the 1997 FDA Modernization Act (FDAMA), which relaxed clinical testing requirements, eased access to experimental therapies, and awarded drugmakers six more months of marketing protection for testing drugs in pediatric patients. The 107th Congress reauthorized the FDAMA pediatric testing provision within the 2002 Best Pharmaceuticals for Children Act, and extended the drug user fee law for five more years under the Public Health Security and Bioterrorism Preparedness and Response Act.12 All six pieces of legislation inform the U.S. drug approval process, which is supervised by FDA in accordance with the laws from 1938 and 1962. In the following section, we describe the drug approval process as it functions now. 10 The Federal Food, Drug, and Cosmetic Act, P.L. 75-717, 1938. 11 Kefauver-Harris Drug Amendments to the FFDCA, P.L. 87-781, 1962. 12 The Orphan Drug Act (P.L. 97-414), the Hatch-Waxman Act (the Drug Price Competition and Patent Term Restoration Act of 1984, P.L. 98-417), PDUFA (P.L. 102-571), FDAMA (P.L. 105-115), the Best Pharmaceuticals for Children Act (107-109), and the Public Health Security and Bioterrorism Preparedness Act (P.L. 107-188). CRS-5 The Current System A drug cannot be marketed in the United States until three things occur: the manufacturer demonstrates the drug’s safety and effectiveness to FDA’s satisfaction, sees its manufacturing plant pass FDA inspection, and obtains FDA approval for the drug’s labeling — a generic term for all written and electronic material about the drug, including packaging, prescribing information for physicians, and patient brochures.13 There are five steps leading to FDA approval of a drug for marketing in the United States:14 Investigational New Drug (IND) Application. Before testing in humans — referred to as clinical testing — the drug’s sponsor (usually its manufacturer) must file an IND application with FDA. It includes information about the proposed study protocol, completed animal test data, the lead investigator’s qualifications, and the written approval of an Institutional Review Board based on its determination that the study participants will be made aware of the drug’s investigative status and that any risk of harm will be explained, minimized, and necessary. The manufacturer will meet with FDA to discuss whether the clinical study design has sufficient statistical power to enable the manufacturer to draw conclusions about the safety and effectiveness of the drug.15 The application must include an Indication for Use section that describes what the drug does and the clinical condition and population for which drug use is intended. Trial subjects should be representative of those who would receive the drug if it is approved. The FDA has 30 days to review an IND. If there is no objection, a manufacturer may begin clinical testing after that time. Clinical Trials. With IND status, researchers proceed to test in a small number of human volunteers the safety they had demonstrated in animals. These trials, called Phase I clinical trials, “try to determine dosing, document how a drug is metabolized and excreted, and identify acute side effects.” If the product still 13 Labeling has become the focal point for much of the controversy involving safety and effectiveness. Some contend that changes in prescribing information are not enough to protect the public’s health because, as recent questions from consumers and Members of Congress demonstrate, the labeling language, clear to those in the drug approval business, can confuse lay readers. For example, “Effectiveness in children has not been demonstrated” represents a different state of knowledge than “Studies in children have not demonstrated effectiveness.” In the second sentence, we learn that researchers have looked to see whether it was effective and were unable to find that evidence — although, the drug still could be effective in children but the study design or analysis did not see that. The first sentence, however, does not make clear whether any study had been done. 14 More detail on the drug approval process is in CRS Report RL30989, The U.S. Drug Approval Process: A Primer, by Blanchard Randall IV. 15 A trial result may be considered positive if it demonstrates that the new drug has a statistically significant benefit over a placebo or comparative drug. Accordingly, a result could be called negative if, despite sufficient statistical power to demonstrate that the new drug offers a benefit over placebo or comparative drug, the trial does not show a benefit. A trial with insufficient statistical power to draw a conclusion regarding effectiveness, most often due to inadequate sample size, that does not find an association is considered inconclusive. CRS-6 seems viable, the sponsor continues with Phase II and Phase III trials to gather evidence of the drug’s efficacy and effectiveness in larger groups of individuals with the particular characteristic, condition, or disease of interest, while continuing to monitor safety.16 New Drug Application (NDA). Once the clinical trials are completed, the sponsor submits an NDA to FDA’s Center for Drug Evaluation and Research (CDER), containing not only the clinical trial results, but also information about the manufacturing process and facilities, including quality control and assurance procedures. During the review, CDER officials evaluate the drug’s safety and effectiveness data, analyze samples, inspect the facilities where the finished product will be made, and check the proposed labeling for accuracy. FDA Review. The law requires “substantial evidence” of drug safety and effectiveness. FDA has interpreted legislative intent to mean at least two adequate, well-controlled, and convincing studies, although the agency exercises flexibility.17 As its regulations describe in detail, FDA can assess safety and effectiveness in a variety of ways, relying on combinations of studies by the manufacturer and reports of other studies in the medical literature.18 FDA has 180 days to review an NDA. If it finds deficiencies, such as missing information, the clock stops until the manufacturer submits the additional information. If the manufacturer cannot respond to FDA’s request (i.e., if a required study had not been done, making it impossible to evaluate safety or effectiveness), the manufacturer may voluntarily withdraw the application. If and when the manufacturer is able to provide the information, the clock resumes and FDA continues the review. For many NDAs, FDA convenes advisory panels of experts to review the clinical data. While not bound by an advisory panel’s recommendation regarding approval, FDA usually accepts it. FDA makes the final determination: “approved,” 16 Safety tests, often referred to as toxicity testing, seek to determine the highest tolerable dose or the optimal dose of the drug needed to achieve the desired benefit. Studies that look at safety also seek to identify any potential adverse effects that may result from exposure to the drug. Efficacy refers to whether a drug demonstrates a health benefit over a placebo or other intervention when tested in an ideal situation, such as a tightly controlled clinical trial. Effectiveness describes how the drug works in a real-world situation. Effectiveness is often lower than efficacy because of interactions with other medications or health conditions of the patient, sufficient dose or duration of use not prescribed by the physician or followed by the patient, or use for a off-label condition that had not been tested. Also, see Carol Rados, “Inside Clinical Trials: Testing Medical Products in People,” FDA Consumer, Sept.Oct. 2003, at [http://www.fda.gov/fdac/features/2003/503_trial.html]; and CRS Report RL32478, Genetic Testing: Scientific Background and Nondiscrimination Legislation, by Michele Schoonmaker and Erin Williams. 17 See FDA, “[DRAFT] Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products,” CDER and CBER, May 1998, at [http://www.fda.gov/cder/guidance/1397fnl.pdf]. 18 The requirements for adequate and well-controlled studies are enumerated in 21 C.F.R. § 314.126. CRS-7 “approvable” (if certain changes, such as more testing, are made), or “unapprovable.” FDA can reject an NDA on two grounds: if the manufacturer failed to perform adequate tests to demonstrate safety and effectiveness for its proposed use, or if the clinical data were not sufficient to show a favorable benefit-to-risk profile. A manufacturer may appeal FDA’s decision by filing a complaint with CDER’s Ombudsman. Finally, once drugs are marketed, manufacturers and FDA monitor their overall safety using MedWatch, the agency’s postmarketing surveillance system [described later in this report], and any Phase IV clinical trials that FDA required as a condition of approval or for which the sponsor otherwise agreed with FDA and committed to undertake. Funding of the Approval Process FDA funds its new drug approval reviews with appropriations provided by Congress and fees paid by industry. The current funding arrangement grew out of the long-standing tension between FDA and both industry and consumer groups over how long the FDA reviews took. In 1993, median review times for priority drugs averaged 16.3 months,19 a figure FDA acknowledged could be lower with more FDA staff. The pressure for quicker approvals came from two directions. First, manufacturers wanted it. Because the 20year patent protection begins with NDA submission, manufacturers see the time from NDA submission to FDA approval decision as lost income. The Pharmaceutical Research and Manufacturers of America (PhRMA) argues that because of the long approval process and the Hatch-Waxman Act, encouraging generics, “the average effective patent life for prescription medicines ... is 11-12 years, compared to an average of 18.5 years for other products.”20 Meanwhile, consumer groups also wanted quicker approvals to speed their access to promising drugs. Congress reacted by looking for legislative ways to speed up the drug review process without lowering approval standards, especially those that might compromise patient safety. In 1992, it passed the Prescription Drug User Fee Act (PDUFA) and five years later, in 1997, the Food and Drug Administration Modernization Act (FDAMA). These laws created a system in which congressional appropriations only partially fund new drug review; those monies are supplemented with “user fees” paid by pharmaceutical companies.21 A third of the user fee money comes from an application fee; the remaining two-thirds is unlinked to the application process, based 19 FDA, Approval Times for Priority and Standard NDAs; Calendar Years 1993-2003, at [http://www.fda.gov/cder/rdmt/NDAapps93-03.htm], visited Jan. 29, 2005. 20 PhRMA, Fact Sheet: Pharmaceutical Patent Incentives, at [http://www.phrma.org/publications/publications/17.06.2003.746.cfm], visited Jan. 29, 2005. Also, CRS Report RL30756, Patent Law and Its Application to the Pharmaceutical Industry: An Examination of the Drug Price Competition and Patent Term Restoration Act of 1984 (‘The Hatch-Waxman Act’), by Wendy H. Schacht and John R. Thomas. 21 See CRS Report RL31453, The Prescription Drug User Fee Act: Structure and Reauthorization Issues, by Donna U. Vogt and Blanchard Randall IV. CRS-8 instead on the type of manufacturing facility and product submitted for review. User fees are paid at the start of the fiscal year. Following the introduction of user fees, FDA quickly reduced its median approval time for priority new drugs from the 16.3 months of 1993. By 1995, it had fallen to six months, where it generally remained until 2002 when it jumped to 13.8 months, coming down to 7.7 months in 2003.22 FDA has established and maintained detailed records tracking the PDUFA fees collected. FDA Postmarket Regulation of Approved Drugs We now turn to a discussion of FDA’s role after a drug appears on the market. First, we describe the current system. Then we present what critics have identified as problems — and the solutions they propose. Legislative History The Federal Food, Drug, and Cosmetic Act gives the Secretary of Health and Human Services (HHS) the authority to withdraw marketing approval of a drug.23 FDA-issued regulations regarding new drug approval require postmarketing reports of adverse drug experiences and of other information produced or acquired by the sponsor.24 The Current System Office of Drug Safety. The webpage of FDA’s Office of Drug Safety (ODS) describes its duties to include using reports of adverse events that consumers, clinicians, or manufacturers believe might be drug-related to “identify drug safety concerns and recommend actions to improve product safety and protect the public health. Activities include updating drug labeling, providing more information to the community, implementing or revising a risk management program, and, on rare occasions, reevaluating approval or marketing decisions.”25 22 FDA, Approval Times for Priority and Standard NDAs; Calendar Years 1993-2003, at [http://www.fda.gov/cder/rdmt/NDAapps93-03.htm], visited Jan. 29, 2005. 23 Section 505 of the FFDCA (21 U.S.C. § 355: New drugs.). In particular, 21 U.S.C. § 355(e): Withdrawal of approval; grounds; immediate suspension upon finding imminent hazard to public health. 24 At 21 C.F.R. § 314. Applications for FDA approval to market a new drug, see, in particular, Section 314.80. Postmarketing reporting of adverse drug experiences, Section 314.81. Other postmarketing reports, Section 314.150. Withdrawal of approval of an application or abbreviated application, Section 314.200. Notice of opportunity for hearing; notice of participation and request for hearing; grant or denial of hearing, and Section 314.126. Adequate and well-controlled studies. 25 FDA, Organizational Components: Office of Drug Safety, CDER, at [http://ww.fda.gov/ cder/Offices/ODS/default.htm], visited Feb. 9, 2005. CRS-9 ODS, itself part of the Office of Pharmacoepidemiology and Statistical Science,26 has three divisions. Staff in the Division of Drug Risk Evaluation works to detect and evaluate safety data and published literature, and assess manufacturerprovided plans for epidemiologic studies and surveillance tools. The Division of Medication Errors and Technical Support assesses specific drug labeling questions. The Division of Surveillance, Research, and Communication Support manages risk communication activities that include research and patient materials, and MedWatch and other epidemiologic data resources.27 A Drug Safety and Risk Management Advisory Committee was established in 2002. Another FDA webpage, The Enforcement Story: Fiscal Year 2003, presents the range of FDA-wide legal and other enforcement activities.28 Reporting. Once FDA approves a drug, it monitors safety. Manufacturers must report all serious and unexpected adverse reactions within 15 days of becoming aware of them (21 C.F.R. § 310.305) to FDA’s Adverse Events Reporting System (AERS). Health professionals or patients may report adverse reactions to FDA’s MedWatch reporting system at any time. FDA can approve a drug even when it still has questions about the drug’s longer- term effects; in such cases, FDA can require formal postmarket studies and summary reports as conditions of approval. These mechanisms of postmarket study are particularly important when it comes to identifying rare adverse events. Often, these become clear only after many people have taken the drug. Some adverse events warrant regulatory actions such as labeling changes, letters to health professionals, or, once in a great while, withdrawal from the market. FDA does not need proof that a drug causes harm before ordering a labeling change. The regulations require the company to make the label change as soon as there is reasonable evidence of an association with serious hazard.29 The art and science of these judgments result, at times, in different decisions by different reviewers. A current example appeared on FDA’s website February 9, 2005, regarding Adderall, a stimulant medication used to treat attention deficit disorder. On the basis of data from U.S. reporting systems, Canadian authorities chose to stop sales, whereas U.S. authorities chose to alert the public yet not restrict sales at this time.30 26 The Office of Pharmacoepidemiology and Statistical Science is parallel organizationally to the Office of New Drugs. 27 FDA, Organizational Components: Office of Drug Safety, CDER, at [http://ww.fda.gov/ cder/Offices/ODS/default.htm], visited Feb. 9, 2005. 28 FDA, The Enforcement Story: Fiscal Year 2003, at [http://www.fda.gov/ ora/about/enf_story/]. One section offers statistics concerning agency actions including civil money penalty, prosecution, seizures, injunctions, recalls, and warning letters, not all relating to postmarketed drugs (at [http://www.fda.gov/ora/about/enf_story/ ch10/stats_charts.htm#1], visited Jan. 29, 2005). 29 30 21 C.F.R. § 201.57(e). FDA, Statement on Adderall, FDA Statement, Feb. 9, 2005, at [http://www.fda.gov/ bbs/topics/news/2005/NEW01156.html], visited Feb. 9, 2005. CRS-10 For certain categories of new drug approvals (those applications approved under rules for accelerated approval, the animal efficacy rule, or the Pediatric Research Equity Act), the manufacturer and FDA negotiate time-frames and study-topics of required postmarket studies at the time of drug approval. Although not required for an application that falls outside of those categories, postmarket study agreements between manufacturer and FDA can be set at the time of approval.31 FDA can institute label changes on the basis of information it gathers from mandatory industry reports to AERS and committed postmarket studies and from voluntary adverse event reports from clinicians and patients. A manufacturer itself can instigate a label change to support a new marketing claim. When it believes data from original or published studies support a new use for a drug, a manufacturer may submit a supplement to the original NDA including the new data, and request that FDA allow it to modify the labeling. FDA must then review these supplemental applications. Enforcement Authority. At many recent congressional hearings, Members have asked FDA officials about the agency’s enforcement authority. The responses have not included the specificity for which the questioners were looking; this seems to be unclear territory, and FDA’s authority is limited. The law authorizes FDA to withdraw a drug’s approval. To get label changes and other most other actions, FDA must couch its concerns as requests to the manufacturer. Off-Label Use. The law prohibits manufacturers’ promoting or advertising their drugs for any use not listed on the FDA-approved label: those claims for which FDA has reviewed safety and effectiveness evidence. However, the FFDCA does not give FDA authority to regulate the practice of medicine; that responsibility lies with the states and medical professional associations. Once a drug is approved, a licensed physician may prescribe it without restriction. A prescription to an individual whose demographic or medical characteristics differ from those indicated in a drug’s FDAapproved labeling is called off-label use and is accepted medical practice. A drug that was tested in an eight-week trial may be prescribed for long-term use; if it was tested at one dose it may be used at higher or lower doses; one tested in adults may be prescribed to children; and a drug tested for the treatment of one disease may be prescribed in an attempt to prevent another. Using drugs in these new ways (for which researchers have not yet demonstrated safety and effectiveness) can create problems that premarket studies did not address. Off-label use also presents an evaluation problem to FDA safety reviewers. Manufacturers rarely design studies to establish the safety and effectiveness of their drugs in off-label uses. 31 FDA, Draft Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER), May 2004, at [http://www.fda.gov/cder/guidance/5767dft.pdf]; and FDA, Draft Guidance for Industry: Reports on the Status of Postmarketing Studies — Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997, CDER and CBER, Apr. 2001, at [http://www.fda.gov/cber/gdlns/post040401.pdf]. CRS-11 Funding of Post-Approval Activities The FY2005 program level budget for the Office of Drug Safety is $26.9 million, up from $15.4 million in FY2002. The FY2006 request is $33.4 million. The growth comes primarily from the addition of PDUFA user fees beginning in FY2003 following amendments known as PDUFA III in 2002.32 Staff full-time equivalent (FTE) levels went from 77 in FY2002 to 109 in FY2005. The FY2006 budget request includes an additional 20 FTEs.33 Safety and Effectiveness Issues and Options Once a Drug Is FDA-Approved While critics of FDA differ in their assessment of what is wrong with FDA’s approach to postmarket safety activities, there is broad agreement that it needs significant change.34 The overall problem of postmarketing surveillance is similar to a house with many windows. Consider, for example, the imbalance perceived by some between FDA resources for new drug approval and postmarket activities: 80% to 20%. Do we look at it through the window of Organization? Yes, if the solution is to add more postmarket-review staff because that would change the FDA organizational chart. And, yes, if the plan is to establish a separate entity with the aim of a more independent staff. But to do those would require more or redirected money, which means looking at it through the window of Budget. 32 PDUFA III is the popular name for Subtitle A of Title V of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, P.L. 107-188. According to data from the FDA Budget and Evaluation Office (FPC Spreadsheets/ODS figures FY96 to FY2005, dated Jan. 31, 2004), FY2002: $15.4 million (BA only); FY2003: $20.2 million total ($13.4 million BA, $6.6 million user fees); FY2004: $23.8 million total ($15.8 million BA, $8.0 million user fees); FY2005 estimate: $26.9 million total ($17.9 million BA, $9.0 million user fees); and FY2006 estimate: $33.4 million total ($22.9 million BA, $10.5 million user fees). 33 FDA, FY 2006 Budget Summary and Budget in Brief, at [http://www.fda.gov/oc/oms/ofm/ budget/2006/PDFs/Summary/Pages28thru31.pdf]. 34 In the last two years, several extremely reputable authors — historians, clinicians, and editors — have published serious, popular books about what they see as problems with government and industry’s handling of drug safety issues. These include: Marcia Angell, The Truth About Drug Companies: How They Deceive Us and What to Do About It (New York: Random House, 2004) (Hereafter cited as Angell, 2004, p. 124.); Jerry Avorn, Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs (New York: Alfred A. Knopf, 2004; and Philip J. Hilts, Protecting America’s Health: The FDA, Business, and One Hundred Years of Regulation (New York: Alfred A. Knopf, 2003). Also, an FDA task force proposed sweeping changes in its report Creating A Risk Management Framework: Report to the FDA Commissioner from the Task Force on Risk Management, May 1999, at [http://www.fda.gov/oc/tfrm/riskmanagement.pdf], visited Jan. 29, 2005. CRS-12 Or maybe we should peer in through the window of Industry Role. After all, PDUFA fees, among other factors, contribute to the perceived imbalance. Or, because the goal of these organizational and budget shifts would be to obtain more information about postmarket dangers, maybe we should look at it through the window of Information. Which window to choose depends on one’s perspective and ability to influence the process. Someone skeptical of industry might want to repeal PDUFA and increase federal appropriations for FDA. Someone unwilling to enlarge the budget might preserve PDUFA but use it differently while keeping appropriations flat. To make this paper useful to legislators, we organize this paper around the six areas — windows, if you will — through which most analysts view the problems in postmarketing surveillance, study, and regulatory action. We do this knowing that the options we list in one section might not be possible without those from other sections — especially Budget. Most difficult to categorize is the influence of industry. To make the discussion manageable, we limit the options listed under Industry Role to those that would diminish what some analysts consider inappropriate industry behavior. The options aimed at increasing postmarket information, many of which involve expanding industry role, we put in the other procedure-defined sections. That said, we turn to a discussion of the six areas around which most recommendations revolve: ! ! ! ! ! ! FDA organization FDA budget Role of industry Opportunities to use the drug approval process to enhance postmarket activities Insufficient postmarket information Lack of public access to available data Some of the proposed changes lie within the power of FDA to implement. Others would require congressional action. As an appendix, we provide a list of concerns, FDA options, and congressional options. FDA Organization Some critics argue that FDA’s Office of Drug Safety (ODS) cannot be effective because it has so much less influence than the Office of New Drugs (OND) in regard to safety and effectiveness decisions. The FDA organization chart shows ODS as one administrative level lower on the Center for Drug Evaluation and Research (CDER) organizational chart, part of the Office of Pharmacoepidemiology and Statistical Science, which is parallel to OND, both reporting directly to the CDER director.35 35 FDA, CDER [Center for Drug Evaluation and Research] Organization Charts and (continued...) CRS-13 In his November 18th testimony,36 Dr. Graham put it this way: The organizational structure within CDER is entirely geared towards the review and approval of new drugs. The same group that approved the drug is also responsible for taking regulatory action against it postmarketing. This is an inherent conflict of interest. At the same time, the Office of Drug Safety has no regulatory power and must first convince the new drug reviewing division that a problem exists before anything ... can be done. Often, the new drug reviewing division is the single greatest obstacle to effectively protecting the public ... A close second in my opinion is an ODS management that sees its mission as pleasing the Office of New Drugs. Dr. Graham is not alone in his belief. A related issue surfaced recently with the revelation of an HHS Inspector General-conducted survey of FDA scientists. Completed in 2002, the survey found that almost one-fifth of FDA scientists sometimes felt pressured to ignore their safety reservations.37 A recent commentary in the British medical journal The Lancet raises a more general point. It asks whether bureaucratic or other constraints inhibit ODS from finding fault with a drug that its sibling office, OND, had approved for marketing as safe and effective.38 Critics have recommended actions that address both whether ODS scientists feel political pressure or are inhibited by a bureaucratic reluctance to restrict a drug that OND had earlier approved. Although some have suggested legislation to compel FDA to reorganize the agency, others suggest organizational solutions that FDA already has the authority to implement. They have also recommended another way to increase ODS power relative OND, more staff, for example. While this certainly would be an organizational change, proponents point out that ODS also requires a bigger budget. We therefore discuss that option in the section titled FDA Budget. 35 (...continued) Directories, at [http://www.fda.gov/cder/cderorg.htm], visited Jan. 10, 2005. Inc., of Vioxx, FDA Statement, Nov. 18, 2004, at [http://www.fda.gov/bbs/topics/news/2004/ NEW01138.html]. The current acting CDER director stated, however, “Both the Office of New Drugs and the Office of Drug Safety report directly to me as the Director of the Center” (Statement by Dr. Steven Galson, Acting Director, Center for Drug Evaluation and Research (CDER), Regarding November 18, 2004, Committee on Finance of the U.S. Senate Hearing on Drug Safety and the Worldwide Withdrawal by Merck & Co. (Hereafter cited as Graham, Nov. 18, 2004.) 36 Graham, Nov. 18, 2004. 37 Marc Kaufman, “Many FDA Scientists Had Drug Concerns, 2002 Survey Shows,” Washington Post, Dec. 16, 2004, p. A1. HHS had not released those survey findings; they were obtained from FOIA material that public interest groups requested. 38 Richard Horton, “Vioxx, the Implosion of Merck, and Aftershocks at the FDA,” The Lancet, vol. 364, no. 9450 (Dec. 4-10, 2004), p. 1995. CRS-14 FDA Options. Put the Office of Drug Safety and the Office of New Drugs under different supervisors. Both now report to the Director of CDER. Some believe that FDA should maintain that structure because a drug’s risks cannot be assessed independently from its benefits. Others maintain that having the offices together may create pressure to keep CDER-approved drugs on the market. In a November 5, 2004 statement, FDA announced that it is asking the Institute of Medicine (IOM) of the National Academies to examine its post-approval safety program.39 Reports say that IOM will also examine whether a separate entity is needed to oversee drug postmarketing safety issues.40 Institute scientific dispute-resolution mechanisms. Right now, when a scientist at FDA disagrees with the decisions of his supervisor, there is no mechanism for resolving that disagreement except by discussion between the two of them. This may silence reviewers who want to raise drug safety concerns. In November 2004, FDA announced a one-year pilot program for “Documenting Differing Professional Opinions and Dispute Resolution.”41 This internal disputeresolution process, under consideration during the last year, will use ad hoc panels outside the direct supervisory chain to adjudicate cases involving scientific disagreement among agency reviewers. According to the acting director of the drug center, the intent is to formalize standard agency practices for resolving scientific disagreements.42 Critics, though, argue that keeping a dispute within FDA, no matter how the resolution is structured, makes scientific objectivity impossible. For example, after someone requests a review through the CDER ombudsman, the decision to proceed still involves the CDER director. Congressional Options. Move safety oversight to another federal agency. Supporters of this option compare such a move to the National Transportation Safety Board’s placement outside of the Department of Transportation, which separates it from the Federal Aviation Administration. Harvard Medical School professor Dr. Jerry Avorn suggests that assigning drug safety tasks to Centers for Disease Control and Prevention, the Agency for Healthcare Research and Quality, the National Institutes 39 Food and Drug Administration, “FDA Acts to Strengthen the Safety Program for Marketed Drugs,” FDA Statement, Nov. 5, 2004, at [http://www.fda.gov/bbs/topics/ news/2004/NEW01131.html]. 40 “FDA Drug Safety Review Will Weigh Need for a Separate Safety Agency,” The Green Sheet, Nov. 15, 2004, p. 1. 41 FDA, “Documenting Differing Professional Opinions and Dispute Resolution — Pilot Program,” Office of the Center Director, CDER, Manual of Policies and Procedures, MAPP 4151.2, Nov. 4, 2004. 42 “CDER Dispute Resolution Policy Will Test ‘Ad Hoc’ Arbitration,” The Pink Sheet, Nov. 15, 2004, p. 10. CRS-15 of Health, or a new unit in HHS could give safety reviewers the independence that he believes they need.43 Provide whistleblower protection. Dr. Graham’s testimony has drawn attention to the fact that the protection given corporate whistleblowers does not extend to those in government. Congress may consider doing that in order to give scientists recourse when they feel improper pressure to disregard safety concerns. FDA Budget Two aspects of FDA’s budget for post-approval activities attract criticism. One is the overall program level, the amount that FDA can spend on safety issues after drugs are on the market. The other is the presence of industry user fees, which can be perceived — by both FDA reviewers and industry — as an influence on safety judgments and FDA action.44 Total user fee contributions to FDA spending have increased at a quicker rate than the contributions from congressional appropriations, provoking further concern among those critics worried about undue industry influence.45 Congressional Options. Those who see budgetary solutions to postmarketing problems have offered solutions that are primarily legislative. Revise (or repeal) PDUFA. Some critics maintain that FDA could keep the current structure intact, but, by reducing the industry contribution proportion, proportionally decrease industry influence. Others recommend using more of the user fees to support post-marketing safety activities. Still others, such as Angell, believe that no amount of industry support is acceptable and that the public would be best served only when reviewers’ independence is rigorously maintained. They propose that Congress repeal PDUFA and increase FDA appropriations to cover (or exceed) current user fee levels. Increase FDA appropriations. Independent of any action regarding PDUFA, some analysts urge increases in congressional budget authority to FDA in general and the Office of Drug Safety in particular. Develop alternative funding. Avorn points out that there actually are a wide variety of ways to conduct postmarket reviews other than government. Some 43 Jerry Avorn, Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs (New York: Alfred A. Knopf, 2004), p. 213. (Hereafter cited as Avorn, 2004.) 44 A similar consideration occurred around Medicare inspection funding. Proposals to require Medicare and Medicaid nursing homes to pay user fees for the inspections that would determine their compliance with law and regulations have never been enacted, in part, because of concern that inspectors might become too influenced by nursing home owners. 45 From FY1997 to proposed FY2005, FDA’s congressional appropriation just about doubled. During the same period, PDUFA fees — FDA’s other source of income — almost quadrupled. The change from FY2004 to FY2005 is especially dramatic: a 0.02% decrease in congressional dollars, but a 12.5% increase in user fees (FDA, Justification of Estimates for Appropriations Committees, Fiscal Years 1998-2005). CRS-16 alternatives, all of which would require legislation to implement, include: research by organizations such as HMOs, universities, or insurers. He suggests as possible ways to fund such reviews: a 10-cent fee per filled prescription; a user fee by payers on a per person-covered basis; or fees paid by manufacturers — although those studies would need to be managed independently. Industry Role In some ways, criticism of the pharmaceutical industry is the most complicated issue in this list. While it has drawn sharp criticism, and while the pharmaceutical industry is at once immensely profitable and widely resented, making it an attractive target, many of the specific criticisms of its role are passionately rebutted, not just by industry spokespeople but by academics, and with substantive arguments. Many observers believe that FDA’s dependency on industry user fees has gradually worn away at the agency’s willingness to confront drug makers. More than a funding issue, they say, the problems represent a cultural issue: FDA does not exercise its tremendous moral authority and extraordinary public relations power to combat corporations interested only in the bottom line, instead seeing its role as pleasing industry. Again, Dr. Graham’s testimony46 articulated this point, and, because he argues from within FDA, his remarks attracted wide attention. The corporate culture within CDER is also a barrier to effectively protecting the American people. The culture is dominated by a world-view that believes only randomized clinical trials provide useful and actionable information and that postmarketing safety is an afterthought. This culture also views the pharmaceutical industry it is supposed to regulate as its client, over-values the benefits of the drugs it approves and seriously under-values, disregards and disrespects drug safety. The criticism of industry traditionally coalesces around one argument: that in its zeal to market drugs, companies will overlook dangers evident to unbiased researchers. Thus, Hilts writes that in the case of thalidomide, the “marketing department, not the medical department, ran the ‘trial.’”47 Accounts of the Vioxx controversy, four decades later, indicate that Merck scientists did argue for further study of the drug but were met with objections from marketing divisions.48 46 Graham, Nov. 18, 2004. 47 Hilts, 2003, p. 151. 48 Anna Wilde Mathews and Barbara Martinez, “Warning Signs: E-Mails Suggest Merck Knew Vioxx’s Dangers at Early Stage,” Wall Street Journal, Nov. 1, 2004, p. A1. (Hereafter cited as Mathews and Martinez, Nov. 1, 2004.) CRS-17 Certainly, industry makes its influence felt in many ways. For example: Data. Information on which FDA approval is based comes from studies funded by the manufacturer. While industry argues that its sense of social responsibility and concerns about litigation keeps reporting honest, critics have found that difficult to square with the events in cases like Vioxx for which data about increased risk were available to the manufacturer four or five years before it withdrew the drug. Funding. User fees have been mentioned elsewhere in this report because they influence issues such as FDA organization and, of course, budget. But there are those who are primarily interested in it as an example of inappropriate industry role. User fees support new drug reviews. In 2005, industry paid FDA $200 million, almost all of it directed to new drug reviews by law. This influx of money also allows FDA to pay for staff conferences, travel, and training — but is limited primarily, some say, to new-drug reviewers. Independent research. Although this is changing, journals, conferences, and researchers themselves do not always clearly identify their funding sources. Researchers presumed to be independent often receive grants, vacations, status, patients, or fees from industry that give the appearance of compromising objectivity. At universities, traditionally perceived to be the bastion of unbiased research, industry funding has become so pervasive that former Harvard University president Derek Bok, pointing to research showing clinical trials supported by industry are “more ... favorable to sponsors” than independent research, has warned, “the dependence on corporate support has reached such a point that it will be difficult for medical schools to free themselves of industry influence.”49 Whether researchers are influenced by industry funding consciously, unconsciously, or not at all, the perception of influence on both pre-market and post-approval research contributes to some people’s lack of trust in findings. Direct-to-consumer (DTC) advertising. The United States is one of only two countries in the world that allow pharmaceutical companies to advertise directly to consumers — the other is New Zealand.50 Industry argues this is a powerful tool for informing consumers about diseases and the treatments available for them. Industry critics agree that it is powerful tool — for misinforming consumers about the same issues. These concerns regarding industry influence are listed elsewhere in this paper. The reason is that not everyone sees these problems in the same way. For example, is it the fault of industry for supporting a solution, such as user fees, that could compromise objectivity? Or does the fault lie with Congress because it has not appropriated enough money for safety — forcing, as one writer put it, “a marriage 49 50 Avorn, 2004, p. 213. Presentation by Dean G. Smith, Lynne Eagle, Kerry Chamberlain, and Lawrence C. Rose, “The Views of Healthcare Professionals and Consumers on Direct-to-Consumer Promotion of Prescription Drugs in New Zealand,” FDA Public Meeting, Washington, D.C., Sept. 23, 2003, at [http://www.fda.gov/cder/ddmac/p6smith/tsld001.htm]. See also CRS Report RL31603, Direct-to-Consumer Advertising of Prescription Drugs, by Donna U. Vogt. CRS-18 between the agency and industry years ago for the rich dowry that industry offered?”51 Despite debate over detail, there seems to be widespread consensus that FDA needs to be objective about the industry it regulates. Suggestions for revamping the industry role to reduce postmarketing problems lie almost entirely within the legislative arena. FDA and Administration Options. Fill vacant positions in FDA. Right now, FDA has acting directors of the Center for Drug Development and Evaluation and its Office of Drug Safety. Acting officials throughout government tend to act with caution, in part because they are not perceived (even by themselves) as having the political backing to stand up to industry, researcher, and consumer pressure.52 Many observers have urged the President to move quickly to appoint a commissioner so that the agency could act to fill its vacant science management slots.53 On February 15, 2005, the President nominated Acting Commissioner Lester Crawford to be Commissioner of Food and Drugs, three days after Michael Leavitt was sworn in as HHS Secretary.54 Congressional Options. Reassign conduct of pre-market studies away from manufacturer to government. Angell believes that marketing considerations unduly influence even pre-market studies. She argues that government — whether FDA or NIH — should control the clinical trials designed to test safety and effectiveness. One drawback: right now, according to PhRMA, its member companies spent over $33 billion dollars in 2003 “on research to develop new treatments for diseases,55 an expense Congress might find difficult to fund. Some observers have proposed assessing industry for those costs but legislating ways to eliminate industry influence in how the funds are spent. Diminish marketing role in study design. As the Vioxx story makes clear, marketing is where pharmaceutical employees have the sharpest conflict of 51 Harris, Dec. 6, 2004. 52 Marc Kaufman, “FDA’s Reliance on Unconfirmed Chiefs Is Faulted,” Washington Post, Dec. 19, 2004, p. A1. 53 For example, see the letter, dated Feb. 1, 2005, from Senators Enzi, Kennedy, and 15 other members of the Senate Committee on Health, Education, Labor and Pensions to the Hon. George W. Bush. 54 The White House, Personnel Announcement, Office of the Press Secretary, Feb. 14, 2005, at [http://www.whitehouse.gov/news/releases/2005/02/20050214-3.html]; and The White House, President Thanks HHS Secretary Leavitt at Swearing-In Ceremony, Office of the Press Secretary, Feb. 11, 2005, at [http://www.whitehouse.gov/news/releases/ 2005/02/20050211-3.html]. 55 PhRMA, Research & Development: Overview, at [http://www.phrma.org/issues/ researchdev/], visited Jan. 7, 2005. CRS-19 interest when it comes to scientific decisions.56 With 93 million Vioxx prescriptions having been written since its approval in 1999, with worldwide sales in 2003 of about $2.5 billion, it is not surprising that, in the gray area where research is not crystalclear, marketers will clamor for more proof of safety or effectiveness concerns. Greater available funding for independent research would mitigate the pressure that marketing considerations place on research decisions. Create transparency in funding of academic research. Congress could mandate full and open disclosure of industry contributions to pre-market and postapproval research in the same way it has mandated the disclosure of campaign contributions. Reduce conflicts of interest in consumer and physician education. An essential ingredient in industry marketing efforts is its use of sales representatives, conferences, and direct advertising. Pharmaceutical companies argue that such efforts play a constructive role in educating consumers and doctors. Suggestions for limiting direct-to-consumer advertising range from the minor to outright banning it. Industry promotion to physicians, too, spurs a range of suggestions. Some, such as Angell, say that these provide little health benefit and those could be accomplished in other ways. She argues that the majority of Phase IV clinical trials are marketing opportunities to introduce their products to clinicians and the public. Some have proposed banning or limiting such practices as industry sponsoring of conferences, gifts, and other practices compromising objectivity; alternatively, sponsors could announce their support publicly and physicians could declare receipt of the benefit. In particular, some recommend that members of the advisory committees that review data and make recommendations to FDA should not receive financial or other benefit from pharmaceutical companies. The members of the FDA advisory committees that met in February 2005 regarding Vioxx, Celebrex, and Bextra addressed consumer and physician advertising. They discussed a range of approaches, including a complete ban on direct-to-consumer advertising, something FDA officials said was beyond their authority. The committees also suggested various ways to restrict DTC ads, some of them severely. One, for example, would require government-produced alternative ads focused on a drug’s risks.57 Maintain tort claim option. Former Secretary of Labor Reich readily acknowledges that both regulation and torts “can function far better than they do now.” However, he went on to point out that when FDA is weak, “the tort liability system is our only real defense against corporate negligence.”58 At a time when Congress is exploring tort reform, it may consider what such action could do to influence industry behavior when it comes to keeping drugs safe and effective. 56 Mathews and Martinez, Nov. 1. 2004. 57 Gardiner Harris, “FDA Is Advised to Let Pain Pills Stay on Market,” New York Times, Feb. 19, 2005. 58 Reich, Jan. 9, 2005. CRS-20 Opportunities to Use the Drug Approval Process to Enhance Postmarket Activities Aside from whether FDA is wholly independent, there is broad agreement among those who have looked closely at FDA’s process for drug approval that a number of specific changes in the evaluation process could make FDA more likely to anticipate, identify, and handle problems in the safety and effectiveness of drugs. FDA has the power now to implement these changes. Congress may choose to act, however, if it appears that FDA is declining to act. Is it possible to identify more problems during Phase III trials before a drug goes to market? Not without slowing the process down. Pre-market trials assess the safety and effectiveness of a drug when it is used for a specific purpose in a specifically defined group of people. But some problems may occur in one user out of a hundred thousand. Only when millions of people are using that drug can such an effect become apparent. But that is not to say there can be no changes in process for approving new drugs. Some problems, pointed to by a wide range of critics, include the following: Inability to attach strings to new drug approval. Some critics think that FDA assesses safety disproportionately at the approval stage by providing close to a onetime, all-or-nothing, approval. This severely restricts FDA’s ability to act once a drug is on the market. Companies are under no obligation to continue research for safety and effectiveness — even though some kinds of dangers take years to spot. Inability to enforce postmarket research deadlines. Critics note that manufacturers do not always complete the postmarket studies the law requires in certain approval categories or that were otherwise agreed-to by the manufacturer. FDA reports industry-committed study status annually in the Federal Register,59 but many feel that not only does FDA not have adequate authority to compel compliance, it does not sufficiently follow through with the tools it does have to enforce those commitments. Inability to stimulate comparative effectiveness analysis. Right now, premarket approval requires evidence of effectiveness and safety only in comparison to a placebo treatment. Because most new drugs offer incremental changes to older products, a comparison to placebo is not particularly relevant. Observers argue that consumers and physicians need to know — from unbiased sources — whether it is better than others on the market. The Vioxx controversy brought into sharp relief the potential value of comparing one drug against other drugs used to treat the same illness. Even if Vioxx had proven perfectly safe, consumers and physicians would have wanted to know whether it was safer or more effective than ibuprofen. And was 59 See, for example, FDA, Federal Register Report and FDA website on Postmarketing Studies, FDA Talk Paper, May 22, 2003, at [http://www.fda.gov/bbs/ topics/answers/2003/ans01223.html]; and HHS, FDA, Report on the Performance of Drug and Biologics Firms in Conducting Postmarketing Commitment Studies; Availability; 69 Federal Register 12162, Mar. 15, 2004, at [http://www.fda.gov/cber/pstmrkt/ pstmrkperf0304.pdf]. CRS-21 it safer for everyone or just the tiny number of people for whom NSAIDs produce gastric distress? Inability to approximate anticipated circumstances of use. FDA accepts as evidence of safety and effectiveness data from trials that do not include what some critics see as a reasonable range of patient, disease, and care characteristics. That is, clinical trials often limit study to people without problems other than the one being studied. The initial trials of COX-2 inhibitors, such as Vioxx, therefore, excluded patients likely to have heart attacks or strokes. Yet, once the drugs went on the market, such patients became COX-2 users — as one might expect of a drug prescribed for arthritis because both arthritis and increased cardiovascular risk are associated with getting older. Excluding groups from clinical trials is a wellestablished approach to drug research. If it is reasonable to expect that those groups not represented in the trials will buy the drug, it is argued that there must be alternative ways to make sure the drug is safe for them. Reluctance to set limits on the use of approved drugs. Right now, physicians can use any approved drug for any illness they deem appropriate. Such off-label use has been particularly controversial recently in the issue of antidepressants and children. An FDA Task Force noted that “[o]nce medical products are on the market, however, ensuring safety is principally the responsibility of healthcare providers and patients, who make risk decisions on an individual, rather than a population, basis.”60 No one recommends banning off-label use because it can offer relief not otherwise available. Some urge that mechanisms be set up to monitor it. Congressional Options. Drug approval requirements are set in law. So most options to change the process would require legislation. Institute two-phase approval process that includes mandatory reevaluation. Abandoning the all-or-nothing approach means that FDA could reevaluate safety using postmarket data concerning prescribing patterns, use patterns, adverse events, and effectiveness, for example. One approach could be to routinely set license-renewal dates. FDA’s broader mission, supported by the FFDCA and related regulations, is to protect the public from unsafe and ineffective drugs. Require specific postmarket surveillance and study commitments for initial approval. FDA has the authority now. With increased resources, FDA could increase these requests, set due dates, and strengthen their enforcement. Congress could also give FDA the authority to assess and enforce penalties for noncompliance. As a condition of approval, FDA could require the postmarket continuation of pre-approval clinical trials to assess, for example, the ramifications of long-term use or latent safety risks that may become evident years after use. FDA could require rigorous postmarket trials of samples of whatever off-label uses become evident. 60 FDA, Managing the Risks From Medical Product Use: Creating a Risk Management Framework, Executive Summary of the Report to the FDA Commissioner from the Task Force on Risk Management, May 1999, at [http://www.fda.gov/oc/tfrm/1999report.html]. CRS-22 Require comparative effectiveness trial commitments for initial approval. These trials would assess the comparative safety and effectiveness of a new drug relative to other available drugs and treatments for the condition. Require commitment to study likely users not considered in preapproval trials. FDA approval could require future studies that would be designed to test safety and effectiveness across the range of people to whom and conditions for which physicians will prescribe the drug. Restrict use of newly approved drugs when first on the market. There are a few critics who argue for banning all off-label prescribing. More common are those who recommend limiting it and rigorously monitoring it. So far, we have looked at problems that become apparent in the postmarket period that may have been avoided by actions in the pre-approval process. But whatever the limitations of the pre-market review and approval procedure, it produces useful and peer-scrutinized data and analysis. The focus of postmarket data collection and analysis dramatically shifts, with changed incentives and statutory and regulatory requirements for both the manufacturer and the FDA. Critics and even some supporters of the system find that postmarket information on safety and effectiveness of FDA-approved drugs is insufficient to support the kinds of decisions clinicians and patients need to make. We divide these problems into two groups: ! ! insufficient postmarket information, and lack of access to existing information. Insufficient Postmarket Information Analysts of the current FDA system point out that it is one of passive surveillance. Rather than reaching out to identify problems, FDA waits for consumers and physicians to voluntarily report concerns with drugs; manufacturers are required to pass on to FDA the reports they receive. Such reports are valuable aids to researchers looking for potential risks. In its FY2003 Annual Report, the ODS notes it received 369,839 reports that year.61 A 2000 study by the General Accounting Office (GAO, renamed the Government Accountability Office in 2004) estimated that FDA receives reports on no more than 10% of all adverse drug events. The picture painted by the data, therefore, is “fragmentary and inconsistent.”62 What are the limitations of a passive approach? First, in relying on anecdotal evidence, it provides an incomplete and distorted picture of actual problems. Second, the system relies on a physician or consumer making the connection between an adverse event with a drug. Physicians are much more likely to report rare conditions 61 FDA, Office of Drug Safety Annual Report FY 2003, created Dec. 28, 2004, at [http://www.fda.gov/cder/Offices/ODS/AnnRep2003/default.htm#Adverse]. 62 GAO, Adverse Drug Events: The Magnitude of Health Risk Is Uncertain Because of Limited Incidence Data, GAO/HEHS-00-21, Jan. 18, 2000. CRS-23 that follow drug use than more common conditions that could be expected in an older user even without the drug. So, liver failure and anaphylactic shock get reported, but fatigue and heart attacks do not. There are other reasons that reports do not present a balanced picture. A 63year-old, weekend tennis player taking a COX-2 inhibitor for knee pain may not even consider reporting a heart attack as a drug reaction. Meanwhile, consumers and physicians report many events that occur immediately after a drug’s use that may have nothing to do with that drug. Furthermore, the system relies on physicians or consumers actually following through and reporting their concerns that adverse events are related to the drug. Finally, data from surveillance reports do not include sufficient information about the medical, behavioral, and sociodemographic characteristics of the patient. Scientists analyzing the data need that information to clarify what appear to be associations between drugs and events. MedWatch provides a count of events but does not provide the total number of people taking the drug. MedWatch may get 100 reports of adverse events. But, are 1000 people taking the drug or a million? Without the denominator, a cluster of events reported to a system such as MedWatch serves only as a red flag to prompt further investigation. There is a second, more aggressive way to find postmarket drug effects. Researchers can design studies to address the suspected association of the drug and the adverse event by trying to hold constant other characteristics of the illness and the patient. Researchers also can design studies to test hypotheses suggested by a drug’s mechanism of action, or based on findings concerning other drugs in its class. They may also measure a drug’s safety and effectiveness for known off-label uses; and to comply with commitments made as part of the drug approval process. Postmarket effort to identify safety and effectiveness problems requires a twopronged approach: first, an accurate assessment of what is happening to patients — the warning signs that something may be wrong; and, second, carefully designed, rigorously impartial research to see what is wrong. FDA Options. Reassess criteria qualifying as a “signal”. Whatever the surveillance mechanism, FDA could reassess the criteria it uses to decide that there may be a problem — called a signal — in surveillance data and clarify what steps it could then take. The next two postmarket activities also appear among pre-approval options. There, the issue is commitment to do the studies. Here, in the postmarket options section, the issue is actually doing them. Periodically assess the range of off-label use. FDA could actively collect prescribing or pharmacy data, by characteristics of patient and medical reason for prescribing. CRS-24 Design and conduct rigorous studies, including clinical trials, to test the safety and effectiveness of drugs used off-label. FDA and the manufacturer could design studies based on anticipation of likely off-label use and postmarket data on off-label use. Use administrative, financial, and clinical databases. FDA could develop data collection and analysis procedures that validly capture necessary information. In doing so, FDA would need to establish privacy and confidentiality mechanisms that allow patient-level linkages among diagnostic, sociodemographic, treatment, coverage, and outcome data. Other approaches might include the use of automated databases and targeted medical record reviews or patient interviews when necessary. The President’s budget submission for FY2006 refers to increases in these kinds of activities. Congressional Options. Mandate more activist surveillance. Some critics urge a drug surveillance system similar to FoodNet, which aggressively seeks food poisoning reports from doctors and laboratories in nine states across the country. Others urge what GAO calls a “proactive examination of a random sample of patient records.” The Institute of Medicine urges a Center for Patient Safety to collect adverse drug event data. Who would fund this system, and how? It is a question that applies to many of the solutions presented in this paper. There are not an infinite series of choices: increased federal appropriations, industry generated funds — with restrictions on industry influence — are those mentioned most often by public health analysts. Authorize FDA to require postmarket studies of situations that had not been anticipated at the time of approval. Right now, FDA can only request studies, using an implied or stated threat of action to withdraw a drug from the market. Congress could authorize FDA to require them, avoiding the current gamesmanship and asserting FDA’s role. There is another approach: Congress could give FDA authority to take specific enforcement steps other than the current all-ornothing threat of revoking approval and, therefore, licensure. Require comparative effectiveness studies. The clinical trials that manufacturers field to support applications to FDA usually compare outcomes in two groups: people with the disease who are given the new drug and people with the disease who are given a placebo. What this approach does not provide, though, is any comparison of the new drug with other available treatments. A clinician who is deciding whether to prescribe drug A wants to know more than whether drug A is better than nothing; the clinician also wants to know whether drug A is better — more effective or safer — than drug B. In part because FDA does not require comparative effectiveness studies, manufacturers rarely mount them. And, in part, because comparative effectiveness studies are expensive, neither do other researchers. In the 108th Congress, bills were CRS-25 introduced bills to require — and fund — comparative effectiveness studies63 and in its Medicare legislation, the 108th Congress directed the HHS Agency for Healthcare Research and Quality (AHRQ) to “conduct and support research” dealing with “the outcomes, comparative clinical effectiveness, and appropriateness of health care items and services (including prescription drugs)....”64 Increase funds to FDA. A larger budget would enable intramural scientists to analyze data and design and carry out follow-up studies based on data-suggested hypotheses. Alternatively, or in addition, Congress could increase funds that FDA can provide to extramural researchers for this work, as well as supporting training programs. Explore alternative systems. Congress may choose to examine some of the systems adopted in other countries — the “pharmaco-vigilance centers” used by doctors in France, or Great Britain’s “green card” requests that researchers send to doctors asking for more information when they spot a possible problem.65 Existing Information Unavailable to All Groups Lack of research into the kinds of safety and effectiveness questions that clinicians and patients could use in treatment decisions is one problem. But there is also significant research that exists — but is not available. The reasons are more complicated than what some critics assert: that drug companies keep unfavorable results secret. Among other reasons: Publication bias. Medical journal editors have traditionally paid more attention to positive findings — that a treatment works — than to reports of no differences or statistically insignificant differences between new treatments and old or no treatments. As a result, many researchers, whether industry-affiliated or not, often decide not to submit negative studies for publication. Insufficient FDA resources. We have already described FDA’s system for collecting possible adverse drug event information. Whether because of budget constraints or the unlikely prospect of identifying valid associations within haphazardly collected and incomplete reports, FDA leaves much of these surveillance data unanalyzed. In addition, the agency lacks enough trained pharmacologists, epidemiologists, pharmacoeconomists and other researchers with the specialized skills necessary for analysis. FDA’s budget justification of the FY2006 request appears to recognize this by referring to “the wealth of data in its Adverse Event 63 For example, H.R. 2356, introduced by Rep. Allen on June 5, 2003, and S.Amdt. 1000 to S. 1, introduced by Sen. Clinton on June 23, 2003. 64 65 Section 1013, P.L. 108-173. Anna Wilde Mathews, “As Drug-Safety Worries Grow, Looking Overseas for Solutions,” Wall Street Journal, Dec. 31, 2004, p. A1. CRS-26 Reporting System (AERS) to assist medical officers involved in the review process by providing a data mining tool to identify trends in adverse event data.”66 Industry use of information as marketing. Drug manufacturers do not release all their findings to the public.67 Critics note that when manufacturers do publicize their findings, in direct-to-consumer advertisements68 and marketing materials aimed at physicians, they may provide an incomplete and distorted view of a drug’s indications, safety, and effectiveness. Physicians — relying on information packaged by the manufacturer or provided by its detailers — therefore may not have full safety and effectiveness information. Industry suppression of bad news. Researchers report that the companies sometimes move to suppress the publication or presentation of findings when they could harm a product’s sales. This raises complicated matters of policy and scientific procedure. What should FDA do when researchers uncover a risk? What is FDA’s duty to disclose industry data? Incorrect decisions can result from action taken too quickly or action delayed from an excess of caution. The problem is that in scientific research, chance, poor study design or analysis, or an unrelated event can imply that a drug is risky when it is safe. Limiting or withdrawing a drug, in that case (based on erroneous conclusions), protects no one — and hurts those who would have been helped by it. Labeling requirements. Labeling does not refer to the little sticker on a vial of prescription drugs. It is the more detailed insert that comes with medicines to drugstores. The law requires that pharmacists include them for patients, but that does not always occur. We have mentioned that once FDA approves a drug and the manufacturer puts it on the market, physicians are mostly free to prescribe it as they wish. A doctor may prescribe a drug approved for adults to a child; prescribe a lipid-lowering or anti-inflammatory drug as a possible preventive measure against dementia; or prescribe a drug that the manufacturer tested for six-week use at one dose to someone at a higher or lower dose or for months, years, or a lifetime.69 Neither the clinician nor the patient — nor FDA — can look up possible side effects of off-label use, either because these uses have not been tested or results not been revealed. 66 FDA, Human Drugs, CDER, budget documents, at [http://www.fda.gov/oc/oms/ofm/ budget/2006/PDFs/Summary/Pages156thru193.pdf], visited Feb. 10, 2005. 67 Manufacturers must report all studies to FDA. 68 For a discussion of issues involved in the DTC advertising of prescription drugs, see CRS Report RL31603, Direct-to-Consumer Advertising of Prescription Drugs, by Donna U. Vogt. 69 For examples, see Shankar Vedantam, “FDA Links Antidepressants, Youth Suicide Risk,” Washington Post, Feb. 3, 2004, p. A1; David Tuller, “Seeking A Fuller Picture Of Statins,” New York Times, July 20, 2004, p. F5; or consider use of medication for chronic conditions, such as diabetes or hypertension. CRS-27 Why? The FDA’s passive system for picking up such problems certainly limits it usefulness. In addition, industry is not likely to ask questions that might hurt the drug’s financial prospects. The result: even when off-label uses are widely known and suspected of being unsafe or ineffective, the labeling does not change. FDA Options. Enhance drug-information dissemination options. Especially with use of the Internet, opportunities exist beyond traditional peer-reviewed professional journals, while maintaining standards of scientific quality. For example, the not-forprofit Public Library of Science (PLoS) established a Web-based public forum for published research results.70 The National Library of Medicine announced that, beginning in May 2005, NIH-funded researchers can voluntarily submit their reports (after peer review and acceptance by a research journal) to its PubMed Central database, which will be publicly accessible.71 Many applaud these types of actions. Others worry that, while these two activities involve only published material, other websites posting unpublished reports, thereby circumventing the current system of anonymous peer review and editorial oversight, would weaken the protection and integrity the traditional system of research publication provides. Transfer current information to prescribers. FDA might explore developing an education outreach program to physicians. Such a system might use computer software; round-the-clock opportunities for telephone and e-mail consultations; and visits to physician offices, a practice called “academic detailing” in reference to the promotional visits, called “detailing,” of drug company representatives. Extend collaborative data collection and analysis activities. Comparative effectiveness studies and safety monitoring need not await government’s taking them on. Diverse groups have begun sharing data and results and making them available to others. Examples of such work are the Cochrane Collaboration,72 the British Medical Journal’s Clinical Evidence website,73 the 70 According to its website, the Public Library of Science is a “nonprofit organization of scientists and physicians committed to making the world’s scientific and medical literature a public resource” ([http://www.plos.org/about/index.html], visited Feb. 4, 2005). 71 National Institutes of Health, NIH Calls on Scientists to Speed Public Release of Research Publications: Online Archive Will Make Articles Accessible to the Public, NIH News, Feb. 3, 2005, at [http://www.nih.gov/news/pr/feb2005/od-03.htm]. 72 The Cochrane Collaboration, “an international non-profit and independent organisation, dedicated to making up-to-date, accurate information about the effects of healthcare readily available worldwide,” produces the Cochrane Database of Systematic Reviews; see website at [http://www.cochrane.org/docs/descrip.htm], visited Feb. 11, 2005. 73 Clinical Evidence is a website owned by BMJ Publishing Group Limited, at [http://www.clinicalevidence.com/ceweb/about/index.jsp], visited Jan. 10, 2005. CRS-28 Oregon Drug Effectiveness Review Project,74 and the Centers for Education and Research on Therapeutics (CERTs) program funded by the Agency for Healthcare Research and Quality.75 Many urge that, with funding contributed by government, as well as by foundations, healthcare payers, and industry, the information could — and should — be made public and free. Congressional Options. Require that labeling address off-label uses. Right now, labeling addresses the indications for which the manufacturer requested approval. When it is apparent that clinicians are prescribing a drug for other purposes or to populations other than those included in the approval application and supporting safety and effectiveness data, FDA could require that the label include known information and an assessment of hypothesized safety and likely effectiveness in the off-label use. A less ambitious approach would be to require that the label clearly acknowledge that the safety and effectiveness of the common off-label uses have not been studied with the rigor (or at all) required by FDA for new drug approval. This information could be updated regularly. After a drug has been used long enough or by enough people, FDA could require formal assessment (with controlled clinical trials and welldesigned observational studies) of safety and effectiveness for those off-label uses. Remove postmarket study responsibility from both manufacturers and FDA. Avorn suggests that HMOs, academics, insurers, contract research organizations, and other private groups should carry out postmarket studies under government or industry contracts. He gives as examples a 10-cent fee for every filled prescription, or user fees from payers on a per person-covered basis. If the funding came from a line-item in the federal budget or from industry contributions, a mechanism could be imposed to guarantee that the studies were managed independently, without input from the government or industry. That way, the data would not be owned by entities potentially reluctant to release them to the public. Require clinical trial registration. Congress acted in 1997 to require sponsors to publicly list any clinical trial at its outset to enable individuals to participate.76 This public notice had a collateral effect: the public could follow-up, years later, what the sponsor had found. Discussion in the 108th Congress focused on registration as a way to compel openness. Incentives suggested to increase 74 The Oregon Evidence-based Practice Center, Oregon Health and Science University, webpage describes the collaborative program, at [http://www.ohsu.edu/drugeffectiveness/ description/]. 75 76 The CERTs fact sheet, at [http://www.ahrq.gov/clinic/certsovr.pdf]. The Food and Drug Administration Modernization Act. For more information about clinical trial reporting, see CRS Report RS21944, Clinical Trials Reporting and Publication, by Erin Williams and Susan Thaul. CRS-29 compliance included linking registration either to permission to begin clinical studies in humans77 or to publication of studies’ results.78 Make data public. This would avoid the potentially dangerous withholding of data. It would present the opportunity to others to validate findings and conclusions or to analyze the data differently. Making data public could cause problems, too. If a proposed study might yield findings that would hurt a drug’s sales, the manufacturer might choose not to pursue the research. If data were widely disseminated before they were replicated, understood, or rejected, they could prematurely form the basis of ill-informed treatment decisions. The enormity of data collected would be unwieldy and difficult to analyze (or analyze within a useful timeframe) without sophisticated statistical knowledge and computer software. Give FDA enhanced authority to regulate DTC advertisements. Much of the information available to physicians and the public about drugs comes directly from the pharmaceutical industry. Although the law and regulations require that material include description of risks as well as benefits, the DTC advertisements are designed to sell the product, and some think that the balance of information is distorted in favor of the product. Currently FDA reviews a DTC advertisement if it becomes aware of a problem. Some would prefer a total ban on DTC advertising; others urge stronger controls. Examples include requiring that FDA review and approve advertising copy before it is published. This may require budget action; according to Angell, in 2001 FDA had 30 reviewers for 34,000 direct-to-consumer advertisements submitted.79 Give FDA ability to institute penalties for misleading ads. This may require coordination with Federal Trade Commission regulations. Conclusion No drug is completely safe. In fact, the Federal Food, Drug, and Cosmetic Act even defines a prescription drug as one with “toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such drug.”80 Physicians have a responsibility to weigh benefits against risks when prescribing drugs. To do so requires, in addition to their training and experience, available information. Many ethicists say that the public, too, must have enough information 77 For example, H.R. 5252, introduced by Reps. Markey and Waxman on Oct. 7, 2004. 78 Catherine De Angelis et al., “Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors,” New England Journal of Medicine, vol. 351, no. 12, Sept. 16, 2004, p. 1250, at [http://content.nejm.org/cgi/content/full/351/ 12/1250]. 79 Angell, 2004, p. 124. 80 FFDCA Section 503(b)(1). CRS-30 about risks to make up their own minds. However, in-depth analysis is often required to assess the drug’s full effects. Some question whether individuals or even their physicians can meaningfully interpret all relevant information. The FDA’s task involves providing that in-depth analysis as it weighs benefits against risks. For example, codeine provides pain relief but is addictive; Tamoxifen keeps breast cancer at bay for those who have had a single mastectomy, but can cause uterine cancer and blood clots; ibuprofen relieves inflammation but can cause gastrointestinal distress; and statins lower cholesterol but may weaken muscle fibers. Manufacturers and researchers should find new ways to diminish or mitigate risk. If a drug is not effective, there is no potential benefit to counterbalance even the smallest risk. FDA’s advisory committees routinely tackle these tasks.81 But February’s joint advisory committee meeting made clear how hard it is to assess the unique and intertwined qualities of safety, benefit, and risk. The committees heard patients testify that they would rather die than live without the COX-2 inhibitor that allows them to function. They heard highly trained researchers present analyses of a drug’s risk and come up with different conclusions. Finally, they sat for three days surrounded by conversation and press releases carrying often sharply divergent views from drug companies, consumers, academic researchers, the media, Members of Congress, and the FDA itself. While few question that FDA applies the necessary statutory, regulatory, and procedural requirements for pre-market approval, there is broad criticism of its postmarket enforcement activities. Many observers maintain that the law does not provide sufficiently strong authority for FDA to act. As we approach the FDA’s 100th year, Congress is clearly poised to examine whether FDA needs more legal authority to do its job. It could also examine how FDA can better use the legal — and moral — authority it already has to (1) encourage and participate in developing, gathering, analyzing, and disseminating information; (2) act on that information when necessary; and (3) by its powers to both offer incentives and enforce penalties — and by its own example — encourage industry cooperation. There is broad agreement about what problems hamper postmarket activity. This paper has summarized what observers point to as possible solutions. Congress now has a much tougher job — picking the approaches that work best. 81 FDA, Human Drug Advisory Committees, at [http://www.fda.gov/cder/audiences/acspage/ index.htm#Introduction], visited Feb. 23, 2005. CRS-31 Table 1. Concerns and Options Raised by Observers Concerns FDA organization — Political pressure — Bureaucratic reluctance to restrict an already approved drug FDA budget — Imbalance in funding Industry role — FDA dependency on industry — Cultural issue — Influence over data — Influence over funding — Influence over research — Direct-to-consumer advertising Opportunities to use the drug approval process to enhance postmarket activities — Inability to attach strings to new drug approval — Inability to enforce postmarket research deadlines — Inability to stimulate comparative effectiveness analysis — Inability to approximate anticipated circumstances of use — Reluctance to set limits on the use of approved drugs FDA options — Put Office of Drug Safety and Office of New Drugs under different supervisors — Institute scientific dispute resolution mechanisms Congressional options — Move task of overseeing safety to another federal agency — Provide whistleblower protection — Revise (or repeal) PDUFA — Increase FDA appropriations — Develop alternative funding — Fill vacant positions in FDA — Reassign pre-market study responsibility from manufacturer to government — Diminish marketing role in study design — Create transparency in the funding of academic research — Reduce conflicts of interest in consumer and physician education — Maintain tort claim option — Institute two-phase approval process that includes mandatory reevaluation — Require commitments to specific postmarket surveillance and studies for initial approval — Require commitments to comparative effectiveness trials for initial approval — Require commitments to study likely users not considered in pre-approval trials — Restrict use of newly approved drugs when first on the market CRS-32 Concerns FDA options Congressional options Insufficient postmarket information — Passive surveillance provides fragmentary and inconsistent picture — Relies on physician or consumer to make event — drug connection and then report it — Surveillance reports do not include sufficient information about medical, behavioral, and sociodemographic characteristics of the patient — Without denominators, reported clusters of events serve only as red flags — Researchers also can design studies to test hypotheses — Reassess criteria qualifying as a “signal” — Periodically assess the range of offlabel use — Design and conduct rigorous studies, including clinical trials, to test the safety and effectiveness of drugs used off-label — Use administrative, financial, and clinical databases — Mandate more activist surveillance — Authorize FDA to require postmarket studies of situations that had not been anticipated at the time of approval — Require comparative effectiveness studies — Increase funds to FDA — Explore alternative systems Existing information unavailable — Publication bias — Insufficient FDA resources — Industry use of information as marketing — Industry suppression of bad news — Labeling requirements — Enhance drug-information dissemination options — Transfer current information to the prescriber — Extend collaborative data collection and analysis activities — Require that labeling address off-label uses — Remove the responsibilities for postmarket studies from both the manufacturers and FDA — Require clinical trial registration — Make data public — Give FDA enhanced authority to regulate DTC advertising — Authorize FDA to institute penalties for misleading ads