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[DOHRMAN] FINAL 5/11/2006 1:10:21 PM Rethinking and Restructuring the FDA Drug Approval Process in Light of the Vioxx Recall Amanda J. Dohrman * I. INTRODUCTION ........................................................................................................ 204 II. BACKGROUND: THE DRAMA OF MERCK, VIOXX, AND THE FDA ............................. 204 A. The Drama of the Vioxx Recall........................................................................... 204 B. Merck’s Involvement in the Matter..................................................................... 205 C. The FDA’s (Not So Innocent) Role..................................................................... 207 D. An Overview of the Drug Approval Process ...................................................... 210 1. Functions and Foundations of the FDA......................................................... 210 2. Clinical Drug Trials ...................................................................................... 211 III. ANALYSIS: CRITICAL PROBLEMS WITH THE FDA DRUG APPROVAL PROCESS ......... 212 A. Disagreements About the Drug Approval Process Between the FDA and Drug Manufacturers ....................................................................................... 212 B. Specific Inconsistencies that Fracture the FDA ................................................. 213 1. The Prescription Drug User Fee Act: The Drug Industry’s Powerful Influence on the FDA Approval Process .................................................... 213 2. The FDA Modernization Act of 1997: The FDA Failing to Enforce Its Congressionally Granted Powers............................................................... 215 C. The Imperative Need to Restructure the FDA .................................................... 217 IV. RECOMMENDATIONS: STEPS TO SAVE THE FDA DRUG APPROVAL PROCESS .......... 217 A. The FDA Needs to Establish an Independent Review Board to Oversee the FDA Approval Process ................................................................................... 217 B. The FDA Needs to Enforce the Clinical Trial Registry Provision of the FDAMA ........................................................................................................... 220 1. An Independent Review Board Needs to Embrace and Manage the Clinical Trial Registry................................................................................ 220 a. Establish a Comprehensive Clinical Trial Registry in the FDA Protocol ................................................................................................. 220 b. Clinical Trial Registry Must Comply with FDAMA and Include Registry Oversight ................................................................................. 221 2. Clinical Trial Registry Could be Funded by the Prescription Drug User Fee Act ....................................................................................................... 221 V. CONCLUSION ........................................................................................................... 223 * J.D. Candidate, The University of Iowa College of Law, 2006; B.S., University of Northern Iowa, 2002. I thank the writers and editors of the Journal of Corporation Law for their abundant help. Most importantly, I thank my family for their unfailing and unconditional love and support. [DOHRMAN] FINAL 204 5/11/2006 1:10:21 PM The Journal of Corporation Law [Fall I. INTRODUCTION On September 30, 2004, Merck & Co. (Merck) announced that it would immediately withdraw its second most profitable drug, Vioxx, from worldwide markets. 1 The company’s announcement ignited serious concerns about the Food and Drug Administration’s (FDA) pre-market approval procedures for prescription drugs. Although Merck voluntarily chose to withdraw its widely popular and profitable drug without FDA mandate, critics contend that the FDA cannot rely on private drug manufacturers to selfregulate their products. Merck’s decision is a mere indicator of the substantial problems that cripple the effectiveness of FDA pharmaceutical regulatory approvals, particularly in regard to the management and use of clinical trials in the research and approval process. 2 In light of the Vioxx recall, the FDA must develop a new protocol for approving commercial drugs that properly balances timely prescription drug commercialization with mindful, effective, and commercially reasonable safety standards. The FDA must do so as a collaborative effort with private drug manufacturers so that it can hold them responsible if they fail to disclose vital information to consumers or impede the FDA’s drug approval review. This Note reviews the events that caused Merck to recall Vioxx and uses Vioxx as an example to critically analyze the policies and politics of the FDA drug approval process. After outlining the basic drug approval process, this Note analyzes two significant problems that cripple the FDA drug review system. First, drug manufacturers have too much financial influence on the drug review process and pressure the FDA to approve drugs too quickly. Second, current FDA review practices are inadequate because the FDA has failed to implement a national clinical drug trial registry that would inspire transparent drug development and peer review by the scientific community. To minimize these harms, the FDA ought to establish a national clinical trial registry that could be partially funded by fees paid by drug manufacturers. Lastly, this Note recommends that the FDA establish an independent review board funded by the Prescription Drug User Fee Act to regulate the clinical trial registry. This board will ensure that both the FDA and drug manufacturers comply with their responsibilities to disclose all pertinent drug information to consumers, which will make the drug approval process more translucent and effective. II. BACKGROUND: THE DRAMA OF MERCK, VIOXX, AND THE FDA A. The Drama of the Vioxx Recall Merck’s decision to withdraw Vioxx (generically named rofecoxib) from worldwide markets in the fall of 2004 was based on clinical trial data indicating that chronic use (18 months) of Vioxx resulted in an increased risk of cardiovascular events such as heart 1. See Press Release, Merck & Co., Merck Announces Voluntary Worldwide Withdrawal of VIOXX (Sept. 30, 2004) [hereinafter Press Release], available at http://www.vioxx.com/vioxx/documents/english/direct_purchasers.pdf. 2. See FDA Failed Public on Vioxx, Scientist Says, Nov. 19, 2004, http://www.msnbc.msn.com/id/6520630/ (stating that the FDA may be incapable of ensuring the safety of pharmaceuticals with such strong financial connections to the drug industry). [DOHRMAN] FINAL 2005] 5/11/2006 1:10:21 PM Restructuring the FDA Drug Approval Process in Light of Vioxx 205 attacks and strokes. 3 The recall was the largest and most expensive drug withdrawal in recent history; nearly 20 million Americans used Vioxx for arthritis and similar pain relief and were affected by Merck’s decision. 4 The withdrawal was significant because Merck had promoted Vioxx as its powerhouse prescription by investing more than $500 million in consumer and professional advertising, including a widely recognizable television ad featuring champion skater Dorothy Hammel effortlessly skating without arthritis pain by using Vioxx. 5 Specifically, Vioxx is a nonsteroidal anti-inflammatory drug (NSAID) similar to aspirin and ibuprofen. It is popularly used to treat arthritis because, like all NSAIDs, Vioxx has anti-inflammatory and analgesic properties. 6 Vioxx is distinct from other NSAIDs, however, because it mechanistically works as a COX-2 inhibitor. A COX-2 inhibitor specifically blocks the cyclooxygenase-2 (COX-2) enzyme that is known to cause severe gastrointestinal (GI) bleeding, but does not block the cyclooxygenase-1 (COX-1) version of the enzyme that produces desirable anti-inflammatory and analgesic effects. 7 Patients who take traditional NSAIDs suffer severe GI side effects, such as GI bleeding and ulcers, because those NSAIDs operate by inhibiting both COX-1 and COX2. As a COX-2 inhibitor alone, Vioxx significantly helped reduce GI complications associated with traditional NSAIDs, and seemed to live up to its expectation as a champion arthritis drug that could drastically prevent GI bleeding and polyps. 8 Despite Vioxx’s seemingly great success, the wonder drug eventually plummeted from its reign when Merck recalled the drug in late September 2004. The recall was based on a study that Merck initiated in 2000 called Adenomatous Polyp Prevention of Vioxx (APPROVe). APPROVe was designed to study the protective effects of Vioxx in preventing colon polyps, but the study unexpectedly indicated that patients had an increased chance of developing heart attacks or strokes after taking Vioxx for more than 18 months. 9 Merck insists it pulled Vioxx immediately after learning of these adverse results. 10 B. Merck’s Involvement in the Matter Initially, commentators praised Merck for its responsible decision to withdraw Vioxx, but others accused Merck of unreasonably delaying the recall and even concealing its knowledge about the cardiovascular effects of Vioxx long before the APPROVe study. After the recall, cardiovascular and pharmaceutical researchers contended that based on other studies and research Merck ought to have known about the cardiovascular effects 3. See Press Release, supra note 1. 4. See 60 Minutes: Prescription for Trouble (CBS television broadcast Nov. 14, 2004) (transcript on file with author) [hereinafter 60 Minutes]. 5. Id. 6. See Peter Juni et al., Risk of Cardiovascular Events and Rofecoxib: Cumulative Meta-analysis, 364 LANCET 2021, 2021 (2004). 7. Id. (illustrating the mechanism of cyclooxygenase inhibitors). 8. See Press Release, supra note 1. 9. Id. 10. See Kim Norris, CEO: Pulling Vioxx Was Duty, DETROIT FREE PRESS, Nov. 11, 2004, at 1F (reporting that Merck CEO Raymond Gilmartin believed Merck acted appropriately in the Vioxx recall by waiting until fall 2004 to pull the drug). [DOHRMAN] FINAL 206 5/11/2006 1:10:21 PM The Journal of Corporation Law [Fall long before their recall. 11 Merck repeatedly denied knowledge of such side effects, but further evidence continues to indicate that Merck may have known about these side effects much earlier than admitted. In August 2001, Dr. Eric Topol, the top cardiologist at the nationally respected Cleveland Clinic, and his colleagues published a paper in the Journal of the American Medical Association entitled “Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors.” 12 The paper described the results of a meta-analysis based on research available at that time regarding the incidence of cardiovascular events associated with COX-2 inhibitors. It focused on the two most prominent studies available: Vioxx Gastrointestinal Outcomes Research (VIGOR), sponsored by Merck, and Celecoxib Long-term Arthritis Safety Study (CLASS), sponsored by Pfizer. The paper also analyzed two smaller studies, including Study 090, which Merck sponsored but never published. Although the VIGOR study was designed to measure the GI toxicity of Vioxx for patients with rheumatoid arthritis, it actually demonstrated that patients taking Vioxx suffered over twice as many cardiovascular events than the naproxen control group. 13 Study 090 produced similar results. 14 Based on these studies and the meta-analysis as a whole, in 2001 Topol strongly urged researchers to conduct a specific investigation regarding the cardiovascular effects of COX-2 inhibitors and warned physicians to be cautious in prescribing them. 15 Despite such a clear warning, Merck ignored Topol’s recommendation and did not even acknowledge the cardiovascular risks of Vioxx until 2004, three years later. Although Merck claims to have just recently learned of the Vioxx complications, internal documents indicate that Merck knew about the cardiovascular risks of Vioxx as early as 2000, 16 but intentionally chose to ignore Topol’s and others’ warnings. An internal Merck memo dated February 1997 suggested Vioxx use was related to more blood clots than comparable drugs and urged colleagues to “kill [the] drug.” 17 More substantially, on March 9, 2000, Merck’s senior research chief, Edward Scolnick, e-mailed Merck colleagues saying that cardiovascular problems in the VIGOR trial “are clearly there” and that he believed the problems were “mechanism based,” meaning that they could have 11. See Barry Meier, Earlier Merck Study Indicated Risks of Vioxx, N.Y. TIMES, Nov. 18, 2004, at C1 (reporting that in 2000 Merck considered conducting a large-scale study on the cardiovascular effects of Vioxx but decided not to pursue the clinical trial, which implicates its knowledge). 12. Eric Topol et al., Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors, 286 J. AM. MED. ASS’N 954, 954 (2001). 13. Id. at 955. 14. See id. at 956 (concluding that patients taking Vioxx in Study 090 were 2.2% more likely to develop cardiovascular complications). In Study 090, 1.5% of patients taking Vioxx reported serious cardiovascular events compared to only 0.05% in the nabumetone and placebo groups. Merck contests that this study based on 978 patients was too small to be seriously significant. Id. Merck also argues that the VIGOR study was too small to be significant because it was based on only 8076 patients. See 60 Minutes, supra note 4. 15. See Topol, supra note 12, at 958. “Given the remarkable exposure and popularity of this new class of medications, we believe that it is mandatory to conduct a trial specifically assessing cardiovascular risk and benefit of these agents. Until then, we urge caution in prescribing these agents to patients at risk for cardiovascular morbidity.” Id. 16. Meier, supra note 11, at C1 (reporting that “in 2000 Merck researchers debated the possibility of starting a large-scale study to determine specifically the cardiovascular risks of Vioxx[] but company documents indicated that Merck . . . decided not to conduct that study”). 17. Ron Winslow, Researcher Raises Flag on Painkiller, WALL ST. J., Nov. 11, 2004, at D6. [DOHRMAN] FINAL 2005] 5/11/2006 1:10:21 PM Restructuring the FDA Drug Approval Process in Light of Vioxx 207 been linked to COX-2 inhibition. 18 Despite such troubling data, Merck did not disclose these concerns to the public. By 2001, the FDA became concerned about Vioxx and wrote Merck, “accusing it of misleading the public about Vioxx’s cardiovascular safety.” 19 The FDA urged Merck to add a disclaimer about these risks, but Merck refused, contending that the FDA incorrectly interpreted the available clinical data and only focused on the negative effects of Vioxx. 20 In a compromise to appease the FDA, Merck added warnings about the cardiovascular effects of Vioxx, but merely listed them in the precautions section that followed claims touting the GI protective effects of Vioxx. 21 Throughout these challenges, Merck publicly insisted that the cardiovascular concerns of Vioxx were misguided because the research studies compared Vioxx to naproxen, “a wonder drug” that seemed to reduce the risk of heart complications. 22 Privately, however, Merck was training its sales representatives to dodge questions about potential cardiovascular risks and to advertise Vioxx as a safe drug to physicians. In a company training document entitled “Dodge Ball Vioxx,” Merck taught its sales representatives how to respond to physicians’ specific concerns about the potential cardiovascular side effects of Vioxx. 23 Representatives were trained to assure physicians that naproxen had aspirin-like characteristics that gave it heart protecting effects, rather than admitting that Vioxx could be linked to cardiovascular incidents. 24 Merck insists that it trained its representatives to be honest and straightforward, and found the term “dodge” “unfortunate.” 25 These reports frame Merck as a dubious drug company that may have willfully denied potential deadly side effects of its drug just to maintain profits or to avoid taking responsibility for its actions. C. The FDA’s (Not So Innocent) Role While Merck ruthlessly supported Vioxx, some commentators claim that the FDA stood idly by or even suppressed vital information about health concerns related to Vioxx. The FDA contends that it acted appropriately in reviewing Vioxx based on the available evidence. Sandra Kweder, acting director of the FDA’s Office of New Drugs, reinforced that “this is a very difficult scientific issue. We really left no stone unturned to get the answers.” 26 However, internal FDA documents and e-mails suggest that FDA examiners questioned the cardiovascular safety of Vioxx before Merck’s recall. The FDA’s Dr. Villalba told the [Senate Finance] committee it was “not very 18. Id. 19. Id. 20. Id. 21. See Anna Wilde Matthews, Did FDA Staff Minimize Vioxx’s Red Flags?, WALL ST. J., Nov. 10, 2004, at B1. 22. See 60 Minutes, supra note 4 (noting that Merck believed that naproxen reduced cardiovascular complications, rather than believing that Vioxx caused them). 23. Id. 24. Id. 25. See id. 26. Withdrawal from the Market of Vioxx Arthritis Pain Medication: Hearing Before the S. Fin. Comm., 108th Cong. 2 (2004) [hereinafter S. Fin. Comm. Hearing] (statement of Dr. Sandra Kweder, Deputy Director of New Drugs at the Center for Drug Evaluation and Research). [DOHRMAN] FINAL 208 5/11/2006 1:10:21 PM The Journal of Corporation Law [Fall convincing to us that” good effects from naproxen were the whole explanation, according to a transcript. A different FDA doctor wrote that “it would be difficult to imagine” including the Vigor [sic] results on the Vioxx label without flagging the cardiovascular issues in the warnings sections. 27 David Graham, a 20-year veteran of the FDA, is now known as the agency whistleblower. He argued that current oversight of the FDA is “a profound regulatory failure.” 28 Graham strongly criticized the FDA shortly after Vioxx was recalled and testified at the Senate Finance Committee congressional hearings in November 2004. At the congressional hearings, Graham repeatedly insisted that the Vioxx incident “could have, should have been largely or completely avoided . . . . In my opinion, the FDA has let the American people down, and sadly, betrayed a public trust.” 29 Graham became concerned about the cardiovascular safety of Vioxx shortly after Merck published the VIGOR study in 2000. He designed his own epidemiological study to measure the incidence of cardiovascular effects related to Vioxx, which “was carefully done and took nearly [three] years to complete.” 30 Graham planned to present his findings as a poster presentation in August 2004. However, when his FDA supervisors learned that his study “concluded that high-dose Vioxx significantly increased the risk of heart attacks and sudden death and that the high doses of the drug should not be prescribed or used by patients,” FDA supervisors prohibited Graham from presenting the findings. 31 Essentially the FDA insisted that “since the FDA was ‘not contemplating’ a warning against the use of high-dose Vioxx, [Graham’s] conclusions should be changed.” 32 Now, as the agency’s most prominent whistleblower, and in light of the FDA suppressing nearly three years of data regarding Vioxx safety, Graham insists “that the FDA, as currently configured, is incapable of protecting America against another Vioxx.” 33 Graham’s testimony and the conflicting reports from FDA’s Dr. Kweder and Dr. Villalba indicate that the FDA is “virtually defenseless.” 34 As supported by Graham, “it is important that this [Senate Finance] Committee and the American people understand that what has happened with Vioxx is really a symptom of something far more dangerous to the safety of the American people. Simply put, FDA and its Center for Drug Evaluation and Research are broken.” 35 In addition to internal FDA documents, public research investigators also insinuated that the FDA should have questioned the cardiovascular safety of Vioxx much sooner. Dr. Eric Topol, the Cleveland Clinic cardiologist, argues in another report that the FDA 27. Matthews, supra note 21, at B1. 28. See FDA Failed Public on Vioxx, Scientist Says, supra note 2. 29. S. Fin. Comm. Hearing, supra note 26, at 2 (statement of Dr. David J. Graham, Associate Director Science, Office of Drug Safety, Center for Drug Evaluation and Research). 30. Id. 31. Id. 32. Id. 33. Id. 34. S. Fin. Comm. Hearing, supra note 26, at 2 (statement of Dr. David J. Graham, Associate Director of Science, Office of Drug Safety, Center for Drug Evaluation and Research). 35. Id. [DOHRMAN] FINAL 2005] 5/11/2006 1:10:21 PM Restructuring the FDA Drug Approval Process in Light of Vioxx 209 made its first mistake in Vioxx oversight when the drug was initially approved. 36 In 1999, the FDA approved Vioxx based on data only submitted to the FDA. That data was not published or made available for peer review until Merck published the data of its VIGOR trial in November 2000. 37 Peer review is essential to the drug approval process. It facilitates an open evaluation and discussion of a proposed drug by experts in the research field to comprehensively determine if a drug is truly safe. 38 Currently, the best method for distributing that information is by publishing the data in a respectable journal, but many commentators suggest that the data should also be consolidated into a centralized and national clinical trial registry. 39 Topol also argues that the FDA waited too long to conduct a clinical meeting regarding the potential cardiovascular effects of Vioxx and other COX-2 inhibiting drugs. The FDA coordinated an Arthritis Advisory Committee meeting in 2001 to evaluate these issues, but it was instituted a full two years after Vioxx was approved for commercial use. 40 Topol and his colleagues used information from this committee to conduct their 2001 study, which specifically called for greater attention to the cardiovascular effects of Vioxx, 41 but neither the FDA nor Merck acknowledged this warning. Moreover, numerous government regulatory bodies question whether the FDA adequately fulfilled its duty to ensure that approved drugs were safe and appropriate for consumer use. These inconsistencies motivated the federal government to actively investigate the FDA’s role in the Vioxx matter. Currently, the U.S. Justice Department is conducting a general investigation on the matter, the Securities and Exchange Commission is investigating Merck’s specific contributions to the Vioxx incident, and the Senate Finance Committee, spearheaded by Senator Chuck Grassley (Republican-Iowa), is conducting a thorough inquiry into the FDA and Merck. The Finance Committee investigation includes the striking testimony of Dr. Graham, the unsettling testimony of Dr. Kweder, and testimony by Merck’s president and CEO, Raymond Gilmartin. 42 Additionally, the House Committee on Government Reform and the Senate Committee on Health, Education, Labor, and Pensions are conducting independent investigations. 43 Furthermore, Merck is also facing an onslaught of private legal actions from Vioxx users who claim death or injury from taking the medication. On August 19, 2005, in the nation’s first Vioxx trial, a Texas jury held Merck liable for causing the death of Robert 36. See Eric Topol, Failing the Public Health–Rofecoxib, Merck, and the FDA, 351 NEW ENG. J. MED. 1707, 1707 (2004) (describing the FDA’s approval process for Vioxx). 37. See id. at 1707. 38. See John D. Graham, Administrator, Office of Information and Regulatory Affairs, Address at the National Academy of Sciences Workshop: Office of Management and Budget Proposed Bulletin on Peer Review and Information Quality (Nov. 18, 2003), available at http://www.whitehouse.gov/ omb/inforeg/speeches/031118_graham_slides.pdf (remarking that “peer review improves the technical quality of information products . . . and enhances the credibility of governmental information”). 39. See infra Parts III and IV for further examination of this issue. This Note ultimately suggests that a national clinical data registry be established to disseminate all trial results and to ensure that all research developments are freely accessible and available. See infra Part IV. 40. See Topol, supra note 36, at 1707. 41. Id. “It remains unclear why the FDA waited two years after its review and approval of rofecoxib to conduct this meeting. My colleagues and I reviewed the data from the meeting . . . and published an analysis of all the available data on rofecoxib and celecoxib on August 22, 2001.” Id. 42. See 60 Minutes, supra note 4. 43. Id. [DOHRMAN] FINAL 210 5/11/2006 1:10:21 PM The Journal of Corporation Law [Fall Ernst, a 59-year-old man who ran marathons and taught aerobics classes. 44 Ernst’s widow alleged that Merck caused her husband’s death after he took Vioxx for over eight months and developed an arrhythmia, an irregular heartbeat, which was caused by a Vioxx-induced blood clot or heart attack. 45 The Texas jury found Merck liable for causing Robert Ernst’s death and awarded $253.4 million in damages to his widow. In addition to many state court cases currently pending like Ernst’s, the first federal Vioxx case against Merck is scheduled for November 2005. 46 Overall, these federal investigations and private legal actions expect to shed considerable light onto the Vioxx recall, and ought to motivate the FDA to critically analyze current pharmaceutical regulatory procedures. D. An Overview of the Drug Approval Process These federal investigations suggest that the FDA was not an innocent actor in the Vioxx debacle and may have directly enabled Merck to continue to market and sell Vioxx despite compelling evidence against the drug’s safety. For this reason, the process and procedures of the FDA in approving prescription drugs must be seriously evaluated and perhaps redesigned. Although Merck is undoubtedly responsible for the Vioxx problem, it is even more disconcerting that the FDA, the government institution designed to specifically prevent such issues, may have willfully allowed this to happen or at least enabled Merck to set its own standard of care in this matter. The following Part will describe the relevant powers, acts, and responsibilities regarding the FDA’s role in the drug approval process and will examine the two most prominent faults of the FDA regulatory commission: the drug industry’s powerful hold over the feeble FDA, and the FDA’s failure to enforce important congressionally granted powers. 1. Functions and Foundations of the FDA Congress established the modern FDA through a progression of statutes that granted the federal government the regulatory power to monitor food and drugs. In 1906, President Theodore Roosevelt passed the original Food and Drugs Act 47 to “prohibit interstate commerce in misbranded and adulterated foods, drinks, and drugs.” 48 Later the government required that drugs be both safe and effective by enacting the Federal Food, Drug, and Cosmetic Act 49 in 1938 and the Kefauver-Harris Drug Amendments in 1962. 50 Armed with nearly a century of statutory history, Congress officially established 44. See Widow Awarded $253 Million, HERALD-LEADER (Lexington, Ky.), Aug. 20, 2005, at A1 (reporting on the first personal injury verdict against Merck). 45. Id. 46. See Alex Berenson, Jury Calls Merck Liable in Death of Man on Vioxx, N.Y. TIMES, Aug. 20, 2005, at A1 (reporting that 4000 Vioxx-related court cases are currently filed against Merck, and between 20,000 and 100,000 may eventually be filed). 47. See Federal Food and Drugs Act of 1906, 21 U.S.C. §§ 1-15. 48. Milestones in U.S. Food and Drug Law History, FDA BACKGROUNDER, May 3, 1999, available at http://vm.cfsan.fda.gov/mileston.html [hereinafter Milestones of the FDA]. 49. Federal Food, Drug and Cosmetic Act, 21 U.S.C. §§ 301-97 (1938) (requiring “new drugs to be shown safe before marketing”); Milestones of the FDA, supra note 48. 50. Kefauver-Harris Drug Amendments, Pub. L. No. 87-781, 76 Stat. 780 (1962) (requiring that drugs be effective before being marketed to consumers). [DOHRMAN] FINAL 2005] 5/11/2006 1:10:21 PM Restructuring the FDA Drug Approval Process in Light of Vioxx 211 the FDA as an agency of the Department of Health and Human Services in 1988 with the adoption of the Food and Drug Administration Act. 51 This Act made the FDA “an agency of the Department of Health and Human Services . . . and broadly spells out the responsibilities of [the FDA] for research, enforcement, education, and information regarding the regulation of food, drugs and devices.” 52 Based on such a long regulatory history devoted to protecting the safety and efficacy of drugs, the FDA has a duty to ensure that only drugs that are truly safe and effective will be approved and marketed to the American people. 2. Clinical Drug Trials Clinical trials are the most essential tool used by the FDA in considering whether to approve a drug as safe and effective for use. The trials are important because they provide tangible data about the safety and efficacy of a drug in patients and indicate potential problems or side effects associated with a drug in diverse populations. The trials are divided into four stages that provide progressively more information about a drug’s safety and efficacy. 53 Phase I trials provide preliminary information about drug doses and metabolism characteristics based on very small patient populations ranging from 20 to 80 patients. 54 Phase II trials, which are based on slightly larger populations of 100 to 300 patients, provide more specific information about patients’ reactions to the drug by testing the drug in populations that have the “relevant disease or medical condition” that the drug intends to treat. 55 These trials help to clearly define appropriate dosages and realistic side effects of the drug. Phase III trials are traditionally the final stage of a clinical investigation because they test a very large population of 1000 to 3000 patients, 56 or even 10,000 patients in some studies. 57 By testing such large populations, these studies “nearly always involve a comparison group of patients” to appreciate the drug’s safety in the general population and to allow investigators to engage in risk-benefit analyses to determine for which populations the drug is suitable and safe. 58 Despite such a regimented system, “not all drugs go through all phases. Sometimes the process is greatly truncated to one or two trials. If the trials are successful, FDA approval follows.” 59 After FDA approval, some manufacturers engage in post-marketing trials to either further evaluate the drug’s safety as required by the FDA, or most commonly, to discover new uses for the drug. These trials are termed Phase IV trials. The FDA may request that a manufacturer conduct Phase IV trials to provide more specific information about the drug, but the FDA only mandates such trials in two limited situations: “fast-track 51. See Food and Drug Administration Act, 21 U.S.C. § 393 (1988). 52. Milestones of the FDA, supra note 48. 53. See W. Christopher Matton & F. Scott Thomas, The Continuing Balance: Federal Regulation of Biotechnology, 44 JURIMETRICS J. 283, 297 (2004) (describing the importance and structure of clinical trials). 54. Id. 55. MARCIA ANGELL, THE TRUTH ABOUT DRUG COMPANIES 906 (2004) (describing the clinical trial process). 56. Matton & Thomas, supra note 53, at 298. 57. See ANGELL, supra note 55, at 907. 58. Id. (describing how clinical trials are tailored to specific population groups). 59. Id. at 908. [DOHRMAN] FINAL 212 5/11/2006 1:10:21 PM The Journal of Corporation Law [Fall products approved on an accelerated basis, and products for which deferred pediatric studies are needed to establish safe use in children.” 60 III. ANALYSIS: CRITICAL PROBLEMS WITH THE FDA DRUG APPROVAL PROCESS A. Disagreements About the Drug Approval Process Between the FDA and Drug Manufacturers The FDA has the tools and congressionally granted authority to regulate the general safety and efficacy of drugs. Yet, like any large government body, the FDA can be a cumbersome beast. The complexities of reconstructing the FDA drug approval process are highlighted by disagreements between the FDA and private drug manufacturers about the purposes and interests that should prevail in administering the review process. Specifically, the FDA and drug manufacturers view the approval process structure very differently. Drug manufacturers argue that the approval process is too lengthy and timeconsuming for them to make a profit proportionate to the many years and financial resources invested to develop a drug. The FDA conversely asserts that it must uphold its primary function of ensuring that drugs marketed to consumers are both safe and effective, and this process inherently takes some time for review. Drug manufacturers primarily assert that they are interested in bringing their products to the public as soon as possible because they want to reap the reward of their investigational research dollars used to develop new drugs. The manufacturers claim that in 2000 they spent nearly “$802 million for each new drug they [brought] to market,” 61 which was mostly dedicated to research and development costs. Some critics argue that these numbers are deceptive because the research processes are too opaque to truly discern how drug manufacturers distribute such expenses. They remind analysts that manufacturers probably spend more money on excessive advertisement and promotion during the lifetime of the drug, compared to initial research and development costs. 62 Drug manufacturers also argue that they need to bring truly innovative and progressive drugs to market faster for those patients that suffer from chronic and fatal diseases, like AIDS and cancer. By bringing innovative drugs to the market, patients will benefit more by using them even though the drugs may not be entirely safe. In this respect, the benefits of bringing a drug to market faster outweigh risks that the drug may not be completely safe. These interests tend to accelerate the approval process. The FDA respects the drug manufacturers’ interests because its primary purpose is to deliver safe and effective drugs to those in serious need of medications. However, the FDA must balance this interest with its constant duty to ensure the safety and efficacy of every new drug. No drug is ever safe, but a truly unsafe drug should not be allowed into the market, where it could potentially do more harm than good. Therefore, the FDA argues that fast track commercialization of drugs is inappropriate. The process fails to 60. Phil B. Fontanarosa et al., Postmarketing Surveillance—Lack of Vigilance, Lack of Trust, 292 J. AM. MED. ASS’N 2647, 2650 (2004). 61. ANGELL, supra note 55, at 87. 62. See id. at 40 (arguing that drug manufacturers inflate the real cost of research and development in order to explain away the high cost of drugs, when in fact research and development does not account for the majority of drug development expenses). [DOHRMAN] FINAL 2005] 5/11/2006 1:10:21 PM Restructuring the FDA Drug Approval Process in Light of Vioxx 213 establish a comprehensive understanding of the side effects and physiological impact of drugs without appropriate time to thoroughly evaluate the drug in different populations or to recognize side effects from chronic use. 63 B. Specific Inconsistencies that Fracture the FDA Differences regarding the procedural interests in the FDA approval process illustrate just one polarized problem of the FDA approval process. In fact, the FDA suffers from a number of internal problems that impede the agency from adequately fulfilling its duties. Two important problems specifically relate to the drug approval process and help to further explain how issues like the Vioxx recall breed on the fragmented FDA regulatory process. These issues are rooted in the Prescription Drug User Fee Act (PDUFA) and the Food and Drug Administration Modernization Act of 1997 (FDAMA). 64 First, funds generated through PDUFA are inappropriately used to quickly shuffle drugs through the approval process without adequate consideration, which leads to more drug recalls. Second, the drug approval process is failing because the FDA has not enforced a provision in FDAMA to establish a national clinical trial registry that would streamline and disseminate information about clinical drug trials to researchers and the public. 1. The Prescription Drug User Fee Act: The Drug Industry’s Powerful Influence on the FDA Approval Process The Prescription Drug User Fee Act underscores one of the most pressing concerns about the structure of the FDA drug review process. In 1992, the FDA gave way to the pressures of drug manufacturers when it adopted PDUFA. 65 The Act “requires drug and biologics manufacturers to pay fees for product applications and supplements, and other services” provided by the FDA. 66 The FDA in turn is required “to use these funds to hire more reviewers to assess applications,” which expedites the drug approval process. 67 Dr. Phil Fontanarosa and his colleagues recently noted that “the FDA has received approximately $825 million in fees from drug and biologic manufacturers from fiscal years 1993 through 2001. During that time, median approval times for standard (i.e., ‘nonpriority’) drugs decreased from 27 months in 1993 to 14 months in 2001.” 68 Essentially, these funds “put the FDA on the pharmaceutical industry’s payroll” 69 which critics call a blow to the FDA. The Act must be renewed every five years and “the 2002 version, which was tacked on to a bioterrorism bill that swept though Congress without a murmur . . . increased [fees] to about $576,000 per new drug application. User fees now 63. Fontanarosa et al., supra note 60, at 2649 (noting that manufacturers ought to test their drugs in various populations, such as the elderly, children, and women that may react to drugs differently than the traditional control groups, and ought to conduct long-term chronic use studies). 64. See generally infra Parts III.B.1 & III.B.2 (analyzing PDUFA, which authorized fees paid by those applying for drug approval to be used to expedite FDA drug review, and FDAMA, which reinstated PDUFA provisions in 1997 and instituted further measures to accelerate the review and approval of drugs). 65. See Prescription Drug User Fee Act of 1992, Pub. L. No. 102-571, 106 Stat. 4491. 66. Milestones of the FDA, supra note 48. 67. Id. 68. Fontanarosa et al., supra note 60, at 2647. 69. ANGELL, supra note 55, at 208. [DOHRMAN] FINAL 214 5/11/2006 1:10:21 PM The Journal of Corporation Law [Fall account for about $260 million a year.” 70 The fees are strictly reserved for the drug approval process, and cannot be used for any other segment of the FDA. According to Marcia Angell: Although a small fraction of [PDUFA fees] can be used for some limited safety monitoring, the lion’s share is still earmarked to speed drug approvals. Since the act was passed, about a thousand new FDA employees have been added to handle new drug applications, and another five hundred are called for in the 2002 renewal. Altogether, these industry-paid employees constitute more than half of the FDA staff involved in approving drugs. 71 These figures demonstrate that the prescription drug industry has an immense hold over the FDA through its financial influence on the drug approval process. Even though drugs are being approved faster, PDUFA has not improved the quality of drug review or approval. In fact, “as drugs enter the market faster, it becomes increasingly difficult for the FDA to perform its other functions—including monitoring drug safety, ensuring manufacturing standards, and regulating marketing.” 72 According to Fontanarosa and his colleagues, drug recalls are “an inevitable consequence of faster approvals.” 73 Fontanarosa attributes the increase in recalls to the faster drug approval process. He comments: The drug review process has been described as structurally similar to many decisions made by other regulatory industries, such that it is characterized by high uncertainty, avoidance of observable error, and low [reputational] reversibility, with drug recalls harming the reputation of the FDA for a faulty approval decision, and often severely affecting the manufacturer. 74 Angell also remarked that “over the decade since [PDUFA] was enacted, a record thirteen prescription drugs have had to be withdrawn from the market after they caused hundreds of deaths.” 75 In light of the Vioxx controversy, it is even more important to reexamine the FDA drug approval process to ensure that its system is both effective and efficient as a more accelerated process. Yet, at this point, one may question if the drug approval process is even minimally meeting its goals of approving safe drugs under such a hastened system. Finally, the decline in drug approval quality is also attributed to the strong industry power that tethers the financial livelihood of the FDA examiners to drug manufacturers through basic industry lobbying 76 and under PDUFA. If PDUFA were repealed, thousands of FDA government employees would lose their jobs and congressional representatives would face heavy pressure from drug manufacturers to find an alternative mechanism to expedite the approval process. “When added to the business-friendly 70. Id. 71. Id. at 208-09 (reporting that “drug recalls following approval increased from 1.56% for 1993-1996 to 5.53% for 1997-2001”). 72. Id. at 209. 73. Fontanarosa et al., supra note 60, at 2647. 74. Id. 75. ANGELL, supra note 55, at 209 (discussing drug manufacturers’ political influence over the FDA). 76. See Fontanarosa et al., supra note 60, at 1247 (“[I]n 2003, the pharmaceutical industry earmarked $4.9 million to lobby the FDA.”). [DOHRMAN] FINAL 2005] 5/11/2006 1:10:21 PM Restructuring the FDA Drug Approval Process in Light of Vioxx 215 pressure from its politically appointed leadership, PDUFA has undoubtedly constrained the FDA’s independence and influenced its decisions.” 77 Therefore, the FDA is in constant flux between the prescription drug industry’s financial interests and the government’s suppressed safety interests. In such an imbalanced and unstable system, it is no surprise that as drugs are approved more quickly, more unsafe drugs, like Vioxx, will be on the market and available to consumers. 2. The FDA Modernization Act of 1997: The FDA Failing to Enforce Its Congressionally Granted Powers In addition to being sloppy with an accelerated drug approval process, the FDA is also lazy. Since enactment of the Food and Drug Administration Modernization Act of 1997, the FDA has yet to enforce a valuable provision that was intended to enhance the agency’s regulatory authority. The FDA’s lax enforcement of this provision is a prime example of the regulatory body electing to enforce some important powers, but failing to enforce other equally important ones. In 1997, Congress enacted the Food and Drug Administration Modernization Act, 78 which established “the most wide-ranging reforms in agency practices since 1938.” 79 FDAMA streamlined FDA regulatory procedures by including provisions “to accelerate the review of devices, regulate advertising of unapproved uses of approved drugs and devices, and regulate health claims for foods.” 80 FDAMA also required the FDA to establish a database of clinical drug trial information so that patients with life-threatening diseases could have access to experimental clinical trial experiments, and to circulate clinical trial data more freely. 81 The commissioner of the FDA had the responsibility to “collect, catalog, store, and disseminate the [clinical trial] information.” 82 The information about each clinical trial needed to include “a description of the purpose of each experimental drug, . . . eligibility criteria for participation, . . . location of trial sites, . . . and a point of contact for those wanting to enroll in the trial.” 83 By establishing this database, the bipartisan FDAMA legislation was “principally designed to ensure the timely availability of safe and effective drugs, biologics, and medical devices by expediting the premarket review process for new products, while maintaining the FDA’s ‘gold standard’ for product approval.” 84 In 2000, the FDA established a national clinical trial registry to enable drug manufacturers to disclose clinical trial data about life-threatening diseases and pharmaceuticals for children. The registry was posted at www.clinicaltrials.gov through the National Library of Medicine. 85 The database complied with most substantial 77. ANGELL, supra note 55, at 210. 78. 42 U.S.C. § 282. 79. Milestones of the FDA, supra note 48. 80. Id. 81. See 42 U.S.C. § 282. 82. Id. 83. Id. 84. Hyman, Phelps & McNamara, P.C., Modernization Act of 1997, RISK REVIEW, (CNA Healthpro, Chicago, Ill.), Apr. 1998, http://www.cnahealthpro.com /amt/modact97.html. 85. Alexa T. McCray, Better Access to Information about Clinical Trials, 133 ANNALS INTERNAL MED. 609, 612 (2000). [DOHRMAN] FINAL 216 5/11/2006 1:10:21 PM The Journal of Corporation Law [Fall requirements of FDAMA because it required drug manufacturers to register all clinical trials with the database and to include an adequate description of the experiment and eligibility information for potential research subjects. 86 Yet, after implementing the database, the registry had no teeth. The FDA did not require compliance with the clinical trial registry and did not encourage greater use of it. 87 Without enforcement provisions in FDAMA, the FDA’s website, clincialtrials.gov, has failed to adequately educate the public, protect potential research subjects, streamline scientific research, or, above all, ensure the safety and efficacy of pharmaceutical drugs through clinical trial experimentation. It is important for the FDA to establish a standardized clinical trial registry to prevent drug manufacturers from manipulating the FDA approval process. Some manufacturers do not register their clinical trials, and others, like Merck for instance, only submit positive clinical data about their drugs or bias the public’s perception with misleading advertisements regarding the safety and effectiveness of their latest wonder drugs. Unfortunately, “suppressing unfavorable research results is fairly standard practice in the pharmaceutical industry.” 88 Under the current standards, drug companies are required to conduct clinical trials to ensure that the new drug is safe and effective, but they are not required to publish the results of these trials. Neither is the FDA. 89 Furthermore, the research from these trials that does get published is often biased and filtered to only disclose the positive results of the trials, a practice known as “data dredging.” 90 Mandatory participation in the clinical trial registry by drug developers would alleviate these problems, but most drug manufacturers do not comply with FDAMA laws. Although designed to improve the safety of pharmaceutical drug development and to empower individuals with clinical information about specific drugs, the federal clinicaltrials.gov database fails to meet these objectives. “Many pharmaceutical trials are not participating in clinicaltrials.gov or are not fully participating,” 91 and most drug manufacturers do not participate in the database because it complicates the marketing and promotion of their drugs. With such powerful financial influence on the FDA, Abbey S. Meyers, President of the National Organization for Rare Disorders, notes, “I can guarantee . . . that the full force of the drug industry will stop [Congress from attaching an enforcement mechanism to FDAMA]. They don’t want you to know about clinical trials that fail. They are afraid what it will do to their stock price.” 92 Therefore, without an enforcement section in FDAMA that requires the FDA to establish a comprehensive clinical data registry and mandates compliance from all manufacturers, the pharmaceutical industry will continue to ignore the law. 86. See id. 87. See Shankar Vedantam, Drugmakers Prefer Silence on Test Data, WASH. POST, July 6, 2004, at A1 (discussing the failures of the clinicaltrials.gov database). 88. Marcia Angell, Time for a Drug Test Registry, WASH. POST, Aug. 12, 2004, at A6. 89. See id. (commenting on the lack of enforcement for the national clinical trial database). 90. Id. 91. Vedantam, supra note 87, at A1. 92. Id. [DOHRMAN] FINAL 2005] 5/11/2006 1:10:21 PM Restructuring the FDA Drug Approval Process in Light of Vioxx 217 C. The Imperative Need to Restructure the FDA Clearly, PDUFA and FDAMA are two key FDA provisions that are embedded in the functions and purposes of the FDA to ensure that drugs are safe and effective overall. Unfortunately, these provisions are largely ignored. In light of the Vioxx controversy, drug safety concerns will only compound and continue to magnify the inconsistencies in the FDA drug approval process. Therefore, the structure and purposes of the FDA need to be seriously reconsidered and the administration needs to be restructured. By merely concentrating on PDUFA and FDAMA, Congress can make simple changes in the FDA structure that ought to have tremendous results on the entire regulatory approval process. IV. RECOMMENDATIONS: STEPS TO SAVE THE FDA DRUG APPROVAL PROCESS The previous analysis highlights the imperative need to reform the FDA drug approval process. The FDA has already undergone comprehensive investigations regarding its role in the Vioxx matter, and will likely be subjected to more, which should give Congress a better understanding of the overall problems and issues with the FDA. Until those issues are fully explored, however, the FDA should take two specific actions to start mending its fractured and fragmented drug approval system. First, the FDA needs to establish an independent review board to oversee the approval process. This board would impartially facilitate a consistent dialogue between different offices of the FDA and between the FDA and drug manufacturers. Second, Congress should amend the FDAMA to require the FDA to establish and maintain a qualified clinical trial registry. It should also grant the FDA power to mandate and enforce private drug manufacturers to participate in the registry. This recommendation is discussed in greater detail below. A. The FDA Needs to Establish an Independent Review Board to Oversee the FDA Approval Process The Vioxx controversy highlights one of the most pervasive problems with the FDA: the drug industry has too much influence on the FDA approval process, because it directly funds FDA examiners, and the industry pressures the FDA too much to approve drugs faster under PDUFA. The industry’s influence has proven to be costly, and at times deadly, when unsafe drugs are left for consumer use. Therefore, the FDA first needs to ensure that it adequately and completely reviews drugs by establishing an independent regulatory agency within the FDA to oversee the entire drug approval process. Specifically, the FDA should establish a new department to be responsible for reviewing clinical trial data submitted by drug manufacturers to support approval of their drugs. The board would review the data to confirm that the manufacturers’ clinical evidence actually supported their claims, and ensure that the clinical trials could be replicated or confirmed by an independent and nonbiased authority, if necessary. Additionally, the board would be responsible for ensuring that drug manufacturers comply with FDA requests for post-marketing approval studies. It is important that the board be independent from industry influence and other sectors of the FDA. It should act as the final and most comprehensive screening stage of FDA drug review and should be unbiased by outside or even internal FDA influence. In his recent article, Dr. Fontanarosa [DOHRMAN] FINAL 218 5/11/2006 1:10:21 PM The Journal of Corporation Law [Fall and his colleagues reiterate that “[a]bove all, the agency must be completely independent of influence from the pharmaceutical industry, biotechnology firms, and medical device manufacturers.” 93 The FDA also needs the independent review board to act as a mediator among FDA employees and between the FDA and drug manufacturers. The conflict between Dr. Graham and the other FDA employees regarding Vioxx clearly indicates that the FDA should implement an internal and nonbiased agency to appreciate all perspectives of FDA employees. If a similar board was in place in 2000, perhaps the Vioxx incident would not have occurred because the FDA could have taken a more unified and knowledgeable approach to evaluate Vioxx and to adequately consider potential risks of newly approved drugs. Although it may be difficult to truly have an independent board that operates within the FDA, this board will at least be equipped to seek out and resolve similar internal problems within the FDA rather than simply ignoring them. The board will also help facilitate more interaction between the FDA and drug manufacturers because it can create a more informed stage for addressing issues that arise during or after the approval of a drug. Rather than simply waiting for someone in the FDA to discover and address a potential problem with a drug, the board would act as the initial reviewer of the drug and could then use the information obtained in the review process to identify a narrower set of examiners that should more closely scrutinize the drug. Therefore, the board could help to bridge the gaps between both the drug manufacturers and the FDA, and the internal FDA examiners across department lines in the drug approval process. Motivated by the Vioxx recall, on February 15, 2005 the FDA created a new independent monitoring board called the Drug Safety Oversight Board (DSB). 94 The DSB is designed to “provide independent oversight and advice to the Center [of Drug Evaluation and Research] Director on the management of important drug safety issues and to manage the dissemination of certain safety information through FDA’s Web site [Drug Watch] to health care professionals and patients.” 95 About 15 members will comprise the board, including representatives from the National Institutes of Health, Department of Veterans Affairs, the FDA Office of New Drugs, and government medical experts. 96 While the board will oversee the FDA’s drug approval process, its “role will be advisory, and members will not have authority to remove a drug from the market or make changes to a drug’s sales practices.” 97 With the overall mission to monitor prescription drug safety, the Drug Safety Oversight Board has three main goals. First, the DSB will create and update a Drug 93. Fontanarosa et al., supra note 60, at 2649. 94. See The Henry J. Kaiser Family Foundation, Prescription Drugs: FDA to Create New Independent Oversight Board to Monitor Prescription Drug Safety, Feb. 16, 2005, http://www.kaiser network.org/daily_reports/rep_index.cfm?hint=3&DR_ID=28196 (summarizing the news articles that reported on the formation of this new board). 95. CTR. FOR DRUG EVALUATION & RESEARCH, MANUAL OF POLICIES AND PROCEDURES 1 (2005), available at http://www.fda.gov/cder/mapp/4151-3.pdf [hereinafter DRUG SAFETY OVERSIGHT BOARD]. Public summaries of the Drug Safety Oversight Board are available on the FDA website. See Drug Safety Oversight Board Meetings Public Summaries, U.S. Food and Drug Administration, June 23, 2005, http://www.fda.gov/cder/drug/DrugSafety/DSOBmeetings/default.htm. 96. See The Henry J. Kaiser Family Foundation, supra note 94 (discussing the composition of the board). 97. Id. [DOHRMAN] FINAL 2005] 5/11/2006 1:10:21 PM Restructuring the FDA Drug Approval Process in Light of Vioxx 219 Watch webpage with emerging safety issues. The board will issue updates on “both previously and newly approved drugs about possible serious side effects or other safety risks that have the potential to alter the benefit/risk analysis of a drug, affect patient selection or monitoring decisions, or that can be avoided through measures taken to prevent or mitigate harm.” 98 Second, the DSB will resolve disagreements “between organizations over approaches to drug safety.” 99 Third, the DSB will educate physicians and the public about safety developments for previously and newly approved drugs. To educate physicians, the DSB will develop and distribute one-page Healthcare Professional Information Sheets “for all drugs on FDA’s Drug Watch and all drugs with Medication Guides . . . containing the most important new information for safe and effective product use.” 100 Similarly, the DSB will distribute one-page Patient Information Sheets to patients. These sheets will “contain[] new safety information as well as basic information about how to use the drug in a consumer friendly format for all products on Drug Watch.” 101 Although recognized as a positive step toward proper drug evaluation, most critics speculate that the board will be largely ineffective in its current form. Many FDA critics say that the board will not be truly “aggressive [or] independent enough.” 102 For example, Dr. David Graham, the FDA whistleblower who openly criticized the FDA drug review process, doubts that the board will actually influence FDA drug review. “It’s an important admission at the highest levels that the FDA hasn’t handled drug safety . . . [but] [u]ntil drug safety becomes as important as approving drugs quickly, the fundamental problem will remain and unsafe drugs will continue to be approved and will stay on the market.” 103 While echoing Graham’s concerns, Senator Chuck Grassley, who chaired the Senate Finance Committee investigation of the Vioxx recall, says that he will draft legislation to “clearly establish [the board’s] independence and provide the office the authority needed to do its job.” 104 Therefore, although the FDA has taken initiative to establish the DSB, without further evidence that the board will be a truly independent entity this is just one step in a complex process toward guaranteeing effective drug safety monitoring. 98. Press Release, U.S. Dept. of Health & Human Servs., Reforms Will Improve Oversight and Openness at FDA (Feb. 15, 2005) (on file with author) [hereinafter DHHS Press Release]. 99. DRUG SAFETY OVERSIGHT BOARD, supra note 95. 100. DHHS Press Release, supra note 98. 101. Id. 102. See The Henry J. Kaiser Family Foundation, supra note 94 (reporting that many FDA critics call for a more independent and authoritative board than the current DSB). 103. Marc Kaufman, FDA Plans New Board to Monitor Drug Safety, WASH. POST, Feb. 16, 2005, at A1. 104. Gardiner Harris, F.D.A. to Create Advisory Panel To Warn Patients About Drugs, N.Y. TIMES, Feb. 16, 2005, at A1. [DOHRMAN] FINAL 220 5/11/2006 1:10:21 PM The Journal of Corporation Law [Fall B. The FDA Needs to Enforce the Clinical Trial Registry Provision of the FDAMA 1. An Independent Review Board Needs to Embrace and Manage the Clinical Trial Registry If, and when, the FDA establishes and implements this regulatory body, it must create a system for examining the validity and accuracy of clinical trial data submitted to support the approval of new drugs. As Senator Grassley notes, the new independent review board must be supplemented with additional focus on clinical drug trials. 105 “It remains necessary that Congress require a clinical-trials registry to bring more transparency to the studies used to determine the safety of prescription drugs.” 106 Likewise, Fontanarosa and his colleagues note, “[t]his agency should be given full authority to ensure compliance with regulations and sufficient funding to establish an effective national active surveillance system with a prospective, comprehensive, and systematic approach for monitoring, collecting, analyzing, and reporting data on adverse events.” 107 Like other commentators, Fontanarosa recommends that protocols for “postmarketing studies . . . be mandated at the time [the] new drug is launched and the studies . . . be completed at least within the first [two] years after the new drug or device is marketed, with additional studies conducted as deemed necessary by the independent drug agency.” 108 Essentially, the board should have the authority to require manufacturers to submit substantial clinical data that support their conclusions and it should have the ability to later demand more research from the manufacturers than what was required at the time of drug approval. Although these proposals enthusiastically support supplementing the independent drug agency with clinical trial monitoring, to date they fail to specify an exact proposal to ensure that drug manufacturers will comply with the board’s recommendations. They also fail to articulate the best means to make the FDA drug approval process more transparent because drug manufacturers only need to submit their clinical data to this agency and they are not required to feasibly share it with other colleagues. If the FDA demanded that clinical trial data submitted to the review board be readily accessible to interested drug researchers and investigators, then the board could drastically revitalize the inadequate FDA drug approval process. The board would improve the FDA’s reputation among American consumers by creating a transparent system that fosters debate and comprehensive review of the pertinent clinical trial data. Therefore, as the FDA continues to restructure the agency, it ought to create an open and accessible clinical trial data registry in addition to an independent regulatory board. a. Establish a Comprehensive Clinical Trial Registry in the FDA Protocol As noted earlier, the FDA has the authority to create a comprehensive clinical data registry as proscribed by FDAMA. However, the FDA ignores this authority and allows 105. 106. 107. 108. Kaufman, supra note 103. Id. Fontanarosa et al., supra note 60, at 2649. Id. at 2650. [DOHRMAN] FINAL 2005] 5/11/2006 1:10:21 PM Restructuring the FDA Drug Approval Process in Light of Vioxx 221 drug manufacturers to selectively submit clinical trial information to the FDA and other clinical trial registries. In light of the Vioxx controversy and the major criticism about the adequacy of the FDA approval process, it is imperative that the FDA establish and maintain an enforceable, comprehensive, centralized, and systematic clinical trial registry. Without such a registry, the newly created FDA board may decide to regulate the approval process and mandate compliance with post-approval surveillance requirements, but it would not actively contribute to the scientific community. Rather, a centralized clinical trial registry managed by the FDA would facilitate peer review, investigation, and recommendations from other investigators in the specific scientific field. Therefore, this Note recommends that the FDA first enforce FDAMA clinical trial provisions that it is currently ignoring. Second, this Note suggests that Congress include a specific provision in the Act to create an independent board, either the DSB or a separate entity, that requires the FDA to establish and maintain a national clinical trial registry and to mandate compliance with the registry by both the FDA and private drug manufacturers. b. Clinical Trial Registry Must Comply with FDAMA and Include Registry Oversight Theoretically, it would be easy for the FDA to establish a clinical trial data registry under FDAMA because the current clincialtrials.gov database, although severely inadequate, would provide a basic framework for constructing a comprehensive and reliable clinical registry. The difficult part in establishing such a comprehensive registry is merging the current 300-plus databases that are currently used into one efficient system. Notably, the FDA clinical trial registry does not (and should not) eliminate these other databases, but merely lumps them together as a nationally centralized system of all clinical trials and trial data. 109 But because most clinical trial registries are hard to use, not comprehensive, and difficult to understand, “[w]e think it would be much easier for researchers, physicians and the general public to access this information if there is a onestop shopping registry.” 110 Therefore, the FDA ought to work cooperatively with drug developers, physicians, and public interest advocacy groups to develop a clinical trial registry that is comprehensive and effective to educate professionals and the public about current and proposed clinical drug trials. 2. Clinical Trial Registry Could be Funded by the Prescription Drug User Fee Act Although most commentators would disagree with this recommendation, the FDA clinical trial registry could be partially funded by fees generated under PDUFA. If the FDA increased user fees under the Act to support the clinical trial registry, it would directly involve private drug manufacturers in the support and development of a more comprehensive and transparent FDA clinical trial registry. Ultimately, this would help 109. Let Sun Shine on Clinical Results, AMNEWS, July 26, 2004, available at www.amaassn.org/amednews/2004/07/026/edsa0726.htm (discussing the role of the clinical trial database as a national reservoir of data, but not as an exclusive registry). Theresa Toigo, director of the FDA’s Office of Special Health Issues, notes that “currently, there are about 350 registries and they vary substantially.” Id. 110. Fiona Jones, Show Us Your Data, HONEYCOMB CONNECT, Sept. 24, 2004, http://www.honeycombconnect.com/People_In_Life_Sciences_(P.I.L.S.)/document_3317.ashx?page=Complian ce_Column&datasource=197 (quoting Ronald M. Davis, M.D., an American Medical Association Trustee). [DOHRMAN] FINAL 222 5/11/2006 1:10:21 PM The Journal of Corporation Law [Fall form a more cohesive FDA regulatory system with adequate funding. The drug industry ought to shoulder this financial burden because it lobbied for faster drug approvals under PDUFA. The industry also influenced the approval of more unsafe drugs, more drug recalls, and created potentially serious harms for innocent consumers. Therefore, the fast track appeal of PDUFA needs to be directly complemented with a provision that specifically works to reduce the harms of the fast track process. The drug industry should bear this burden to create a more comprehensive review of new drugs. Specifically, PDUFA should be expanded to require additional fees from the drug manufacturers that would be pooled in a generic fund to implement and maintain the clinical data registry. Admittedly, some critics argue that the FDA should repeal PDUFA completely because it grants drug manufacturers too much control over the drug approval process. 111 [The Act] authorizes drug companies to pay “user fees” to the FDA for every drug reviewed . . . [and] this arrangement creates a powerful conflict of interest for the FDA. Moreover, the very notion that private companies “use” a public regulatory agency is wrong, since the FDA is there to serve the public, not drug companies. 112 Critics support this argument because it illustrates an inherent contradiction in a system that requires the FDA to be dependent for its financial livelihood upon the very industry it regulates. However, if the clinical trial registry is established according to FDAMA guidelines and is administered by the newly created independent FDA review board, then the registry can be constructed to avoid the industry’s influence on the control of the registry. First, fees raised through PDUFA would be pooled in a general fund that would help maintain and support a clinical trial registry with which drug manufacturers are mandated to comply. Second, the registry would be regulated by an independent FDA review board, which would be unbiased and autonomous from all other FDA departments, and would be completely detached from industry pressures. Obtaining user fee funds to finance the trial registry will not put the FDA on the industry payroll because the board would ensure that the clinical trial registry funds would be detached and wholly removed from the traditional regulatory actions of the FDA. Finally, the user fees send a constant reminder to drug manufacturers that they have a responsibility to disclose all relevant information about their products, regardless if the information is supportive or damaging to their drugs. This system requires the drug manufacturers to uphold their duties to offer comprehensive clinical trial information about the drug to the FDA. It would force drug manufacturers to acknowledge incriminating data if it arises, and would provide a more translucent forum to truly assess the safety and efficacy of new and previously approved drugs. 111. ANGELL, supra note 55, at 241-42 (recommending that PDUFA “should be repealed—or allowed to expire in 2007”). 112. Id. at 243. [DOHRMAN] FINAL 2005] 5/11/2006 1:10:21 PM Restructuring the FDA Drug Approval Process in Light of Vioxx 223 V. CONCLUSION This Note suggests that the FDA could easily improve its drug approval process by simply establishing an independent review board and by enforcing FDAMA provisions that have already been delegated to the agency. If the FDA institutes the clinical trial registry in conjunction with an independent review board, then it will have greater power to ensure that valuable clinical trial information (such as Dr. Eric Topol’s hauntingly important research about the cardiovascular problems potentially associated with COX-2 inhibitors) is properly submitted to the FDA. Such information ought to be available for review by the FDA and private investigators and circulated to all interested consumers. Although the FDA is fractured by a number of administrative and regulatory problems, these two recommendations would at least form a more solid and objective foundation for the FDA. The Vioxx scandal is only a mere indication of the greater problems that infect the FDA drug approval process and the drug manufacturing industry. As the matter is further explored, both Merck and the FDA will be held responsible for allowing millions of consumers to take the deadly Vioxx drug. If this independent board was in place before Merck developed Vioxx, then Merck would have been forced to disclose all of its findings and scientific suspicions about Vioxx to the mandated clinical trial registry. Then the FDA or other researchers may have discovered the deadly effects of Vioxx before it was even considered for consumer use. By disclosing such telling evidence, Merck would have had a public responsibility to either test Vioxx specifically for its cardiovascular problems or abandon the drug in light of such serious risks. Moreover, the FDA would have been required to specifically address Merck’s questionable evidence and could have commanded Merck to at least address and research the cardiovascular effects of Vioxx more completely. Ultimately, the millions of American consumers that are dependent upon prescription drugs just want to be assured that their drugs are safe. They hope that drug manufacturers only sell drugs that are truly safe and effective, and they want to be assured that the FDA sufficiently protects and guards them from potentially harmful and deadly drugs. Although restructuring the FDA is a lofty task and would involve the cooperation of many actors and groups, instituting these changes should only improve the FDA drug review process. Under the recommended scheme, both the FDA and drug manufacturers would be fully responsible for fulfilling their duties to consumers. Overall, the framework would return the FDA to its original foundations in approving pharmaceutical drugs that are rooted in competency, efficiency, and, above all, safety.