Download Rethinking and Restructuring the FDA Drug Approval Process in

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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.
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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).
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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).
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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.
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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).
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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.
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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.
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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).
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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.
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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).
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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.
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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.”).
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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).
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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.
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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
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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.
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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.
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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.
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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).
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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.