Registration in the Name of Patient Safety:

The Food and Drug Administration and the Past, Present, and

Future of Clinical Trials Registration

[redacted version]

David Sclar
Harvard Law School, Class of 2007

Submission in Satisfaction of both the Written Work Requirement

and the Food and Drug Law, Winter 2006, Course Requirement

Advisor: Professor Peter Barton Hutt

May 14, 2007

 ABSTRACT

Registration of clinical trials is an increasingly significant topic for the

pharmaceutical industry, in the United States and internationally. Since the Food and

Drug Administration Modernization Act (FDAMA) of 1997, registration of most clinical

trials at ClinicalTrials.gov has been mandatory, but this law has not been actively

enforced. Due to noncompliance and a plethora of competing private sector registries,

the status quo of clinical trials registration is a “black box” for many observers. This

paper clarifies that status quo and contextualizes efforts to expand clinical trials

registration in the history of Food and Drug Administration (FDA) regulation. In

particular, this paper explains the tendency for FDA regulatory authority to expand in

response threats to public safety. After examining the public safety rationales for clinical

trials registration, this paper demonstrates that the focus of clinical trials registration has

shifted from patient access to patient safety and argues that additional regulation is likely

forthcoming as a result. The paper concludes by considering proposals for expanding

clinical trials registration, along with the barriers to expansion, and asserts that future

regulation will likely focus on: enforcement of registration and centralization or

coordination of registration data. Finally, the paper highlights the ongoing tension

between patient advocacy and preserving productivity and innovation in the scientific

establishment.

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Depending solely on the accessible published medical literature for assessing a

treatment’s efficacy is akin to using only information from [Cal] Ripken’s home games to

calculate his batting average. - Kay Dickersin and Drummond Rennie, “Registering

Clinical Trials.”1

INTRODUCTION

Today, clinical trials are required to be registered in a central registry. This is

news to many Americans, even those working in the health care industry. Unfortunately

for nearly everyone concerned, the registration of clinical trials is a black box. There is,

however, a groundswell of change taking place. New forms of enforcement and

increased registration requirements may soon be forthcoming.

While parties may have opposing perspectives on these developments, there exists

a universal need for a clearer picture of the elusive status quo of clinical trials

registration. Actors in the health care system want to use this information to understand,

anticipate, and/or influence the registration requirements associated with clinical trials.

This paper aims to go some length towards meeting that demand.

This paper is comprised of six sections. Part I examines the history of food and

drug regulation leading up to the regulation of clinical trials. It highlights the story of

HIV/AIDS and the Health Omnibus Programs Extension (HOPE) Act of 1988 which

created a data bank for registering HIV/AIDS clinical trials. AIDS patients achieved a

good deal of success, although their movement also highlighted some of the nuances of

balancing the scientific mission and patient demands for influencing clinical trials.
1 Kay Dickersin and Drummond Rennie, “Registering Clinical Trials,” JAMA, 290;4 (2003) at 517.

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 Part II of this paper will examine how patient access was the primary driver

behind the creation of Section 113 of the Food and Drug Agency Modernization Act

(FDAMA) of 1997, which finally created a data bank for clinical trials registration.

Part III will examine the threats to patient safety from nondisclosure of clinical

trials data that were largely absent from Congress’ considerations of the FDAMA and are

now driving demand for new regulation supplementing the FDAMA. These drivers

focusing on patient safety include: academic arguments about a general harm to the

public from lack of access to complete drug information, ethical arguments about the

public’s right to clinical information, and recent deaths attributed to a widely publicized

case of misrepresentation and withholding of data on the efficacy and safety of

antidepressants for children and adolescents.

Part IV attempts to portray a single, unified picture of the status quo for clinical

trials registration. Since 1997 clinical trials are required to be registered in the United

States, but registration is not currently enforced. The absence of enforcement has created

widespread noncompliance by a pharmaceutical industry that prefers self-regulation and

has begun creating its own company-specific registries. At present, hundreds of registries

exist and efforts at developing a single comprehensive registry have yet to achieve their

goal. Thus, the status quo consists mainly of an amalgam of disparate public and private

sector clinical trial registries.

Part V examines the barriers to increasing clinical trials registration as well as

proposals for expanding registration, simplifying its status quo, and tightening

compliance requirements.

Part VI then draws conclusions about future of clinical trials registration. In

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particular, the paper concludes that as the focus of clinical trials registration has now

centered on patient safety, the history of FDA regulation suggests that new forms of

regulations are likely – particularly in the form of enforcement of compliance with

registration requirements and developing centralization or coordination of registration

data. In addition, this paper concludes by reconsidering the tension between patient

advocacy and the scientific mission in the current context of clinical trials registration.

PART I: A History of Clinical Trials Regulation and Lessons from the

Development of HIV/AIDS Clinical Trials Registration

The present and future regulation of clinical trials can only be understood in the

historical context of food and drug regulation. The history of clinical trials reveals that

safety concerns have driven the expansion of Food and Drug Administration (FDA)

regulatory authority. Safety concerns originally drove Congress and the FDA to regulate

the drug approval process, leaving the research process to the private sector. But with

time, FDA regulation of food and drugs has come to include clinical trials as well.

Regulation to Protect Patients: FDA Authority Expands to Protect Public Safety

The history of the FDA is a story of an agency with slowly yet steadily increasing

regulatory authority in response to a series of novel threats to public safety. Food

adulteration, a ubiquitous problem in the late nineteenth century, first caught the attention

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of the FDA’s predecessor, the Chemical Division of the U.S. Department of Agriculture.2

The FDA only began regulating prescription drugs in the early twentieth century when

the Bureau of Chemistry (a successor of the Chemical Division and another predecessor

of the modern FDA) began regulating adulterated medicines that represented an

additional threat to public health. The 1906 Pure Food and Drug Act finally criminalized

the sale of mislabeled or adulterated drugs in interstate commerce.3 Judge Judith Rogers

summarizes in a recent opinion by the United States District Court for the District of

Columbia:

Regulation of access to new drugs has a history in this country that is of recent
origin. Prior to 1906, there was essentially no drug regulation in the United
States…For over half of our Nation’s history, then, until the enactment of the
1906 Act, a person could obtain access to any new drug without any government
interference whatsoever.”4

A public health danger – in the form of the supposed elixir Sulfanilamide, which

was marketed as an antibiotic and implicated in the death of over 100 children – was once

again largely responsible for the next statutory expansion of the FDA’s authority in the

1938 Food, Drug, and Cosmetic Act (FDCA).5 After the tragic Sulfanilamide outcome,

the FDCA required that the FDA begin reviewing drug safety before allowing for

marketing and distribution.6

Even after the passage of the FDCA in 1938, the FDA still did not regulate drugs

for their efficacy. The FDA’s well-known role in regulating clinical trials and approving

prescription drugs for the marketplace was only fully established in the 1962 Kefauver-

2 Food and Drug Administration, “A Guide to Resources on the History of the Food and Drug
Administration: 2002.” Available at <http://www.fda.gov/oc/history/resourceguide/background.html>
3 Id.
4 Abigail Alliance v. Eschenbach, 370 U.S. App. D.C. 391, 481.
5 Food and Drug Administration, “A Guide to Resources on the History of the Food and Drug
Administration: 2002.”
6 Id. The FDCA “mandated that all new drugs be proved safe before marketing.”

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Harris Amendments which “required pharmaceutical companies to show the [FDA] that

their drugs were effective and gave the agency greater control over clinical trials.”7

Again, the expansion of FDA regulatory authority evolved in response to a public health

scare from Thalidomide, which was sold and prescribed in the late 1950s and early 1960s

as a sleeping pill to help treat pregnant women for morning sickness.8

Moreover, when implementing the Kefauver-Harris Amendments, the FDA paid

close attention to human subjects protection, again in response to publicized patient

injuries. A now famous 1966 article in the New England Journal of Medicine by Henry

Beecher lambasted unethical and risky clinical trials.9 Beecher’s article catalogued

examples of “unethical research” – including investigators risking patients’ health and

withholding drugs such as penicillin to test alternative therapies.10 Congressional

hearings in 1973 on the U.S. Public Health Service’s Tuskegee syphilis study – a 40 year

study in which African-American research subjects were denied existing treatment for

syphilis in order to study the “natural history” of the disease11 – made critiques of

inadequacies in clinical trials even more poignant. As a result, in 1974, Congress created

the National Commission for the Protection of Human Subjects, and the Commission

7 Jerome Groopman, “The Right to a Trial: Should Dying Patients Have Access to Experimental Drugs?”
The New Yorker, November 18, 2006. Once more, Groopman summarizes, “During the first four decades
of the twentieth century, drug companies often tested experimental medications by sending them to doctors
to give to their patients. The [FDA] required little information from drug-makers about side effects and
had no standard criteria for determining safety or efficacy.”
8 Food and Drug Administration, “Thalidomide: Important Patient Information,” Available at:
<http://www.fda.gov/cder/news/thalidomide.htm>
9 Henry K. Beecher, “Ethics and Clinical Research,” NEJM, 1966, 274: 1354-1360.
10 Jon Harkness, Susan E. Lederer, and Daniel Wikler, “Laying Ethical Foundations for Clinical
Research,” Bull World Health Organ vol.79 no.4 Genebra 2001. See also, Steven Epstein, Impure
Science: AIDS, Activism, and the Politics of Knowledge (1996). Beecher published his article despite harsh
criticism from physicians colleagues who resisted his challenges to their professionalism. He also
published a front-page Boston Globe article entitled, “Are Humans Used as Guinea Pigs Not Told?” and a
1967 book, Human Guinea Pigs.
11 “U.S. Public Health Service Syphilis Study at Tuskegee: The Tuskegee Timeline,” Center for Disease
Control and Prevention, available at: <http://www.cdc.gov/nchstp/od/tuskegee/time.htm>.

7
issued guidelines on research.12 Once again, the FDA’s authority was expanded

somewhat reluctantly in the name of public safety – upon a medical and pharmaceutical

industry that did not always welcome its regulations.

To summarize, the history of the expansion of FDA regulatory authority consists

of a series of protective responses to safety threats rather than entrepreneurial attempts to

accomplish novel public benefits. The regulation of clinical trials, in particular, is a

modern phenomenon that only emerged once the FDA became concerned over the safety

of drugs and drug testing.

Access to AIDS Clinical Trials Represents a New Kind of Regulation

Despite the expansion of FDA regulation, the pharmaceutical industry conducts

clinical trials with a large measure of independence. As a result, clinical trials have

largely lacked transparency: their very existence frequently goes unpublicized, their

protocol is known only to the corporation funding the trial and the scientists involved,

and their results only made public at the discretion of the sponsoring company if/when it

decides to publish them in scientific publications or if receives FDA approval for its drug.

The Health Omnibus Programs Extension (HOPE) Act of 1988 represents a new

form of regulation, as it was the first federal legislation to create a clinical trials database

for industry-run trials. The story behind and the contents of the HOPE Act is instructive

since recent clinical trials legislation (the FDAMA of 1997) is modeled upon the HOPE

Act and aspects of current debates echo the debates of the 1980s. Moreover, the

12 Epstein at 189. At the same time, the NIH began requiring that institutions establish an institutional
review board (IRB) to evaluate the safety of proposed research using federal funding. Epstein at 190.

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FDAMA, like the HOPE Act is modest in scope and implementation. The lesson of the

HOPE Act is that it was focused on access rather than safety, and therefore the

implementation of its clinical trials registry has been limited in scope and only

moderately effective.

HIV/AIDS Patients’ Demands for Access to Clinical Trials Lead to the HOPE Act

In the 1980s, AIDS activists desperate for treatments for a deadly disease became

frustrated with the dearth of effective drugs available. They successfully organized to

lobby not only for greater access to clinical trials for new AIDS drugs, but also for

layman influence over the direction of pharmaceutical research. A social movement took

hold in which a new class of “lay experts” sought influence over clinical trials and

control over “the very contents of science and the process by which it is produced.”13

AIDS activist-experts succeeded in integrating their voice into the scientific community

through a number of mechanisms, including winning a seat at the table of the AIDS

Clinical Trials Group (ACTG). 14

This was a dramatic “turning point” in the history of clinical trials because it

provided patients with new access to information and a new voice to influence the

direction of clinical research.15 Steven Epstein captures this turning point in a long but

illustrative description of the significance of AIDS trials in his book, Impure Science:

AIDS, Activism and the Politics of Knowledge:

13 Id. at 17 and 13.

14 Id. at 246-7
15 Id. at 34. While the AIDS activists’ agenda is of primary relevance here, their methods were also
radical and included the development of a national organization called ACT UP (the AIDS Coalition to
Unleash Power) which demonstrated at the FDA, NIH, and Harvard Medical School, staged die-ins, and
negotiated with the FDA and NIH. Epstein at 1 and 284-7.

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 AIDS trials are distinctive not only because of the militancy of many of the
patients, but because their representatives have mobilized to develop effective
social movement organizations that evaluate knowledge claims, disseminate
information, and insert laypeople into the process of knowledge construction.
The activist representatives not only facilitate the flow of information to and
among them, but also press demands about what should be studied in the first
place and how the research protocols should be worded. Highly technical details
such as entry requirements for trials, the types of controls employed, and the
endpoints to be used in studies have all been the subject of vociferous debates.
Such developments pose substantial complications for the “politics of therapeutic
evaluation.”16

On the other hand, after they developed a coherent voice, AIDS activists were

also divided by a backlash against their attempts to influence clinical trial protocols and

the speed of FDA approvals. The HIV/AIDS community was divided by a debate over

whether the use of surrogate markers in clinical trials led to unreliable results and hasty

drug approvals. After AIDS activists had pushed for access to AZT, negative results

from a European trial resulted in a divide between advocates for access to faster drugs

approvals and those who felt that excessive advocacy for access was getting in the way of

16 Id. At 34 citing Evelleen Richards, The Politics of Therapeutic Evaluation: The Vitamin C and Cancer
Controversy, New York, St. Martin’s, 1991. AIDS patients were not alone. Cancer patients had sought
access to unapproved drugs in the 1970s when they made their case for Laetrile, a drug compound
chemically similar to amygdalin which is found in apricot pits. Despite a lack of scientific evidence on
Laetile’s efficacy, advocates’ demands were strong enough to bring about two studies by the National
Cancer Institute, as well as Congressional hearings and even a legal challenge in which the U.S. Supreme
Court rejected a constitutional right to use unapproved drugs. Benjamin Wilson, “Laetrile: The Making of a
Myth,” FDA Consumer, December 1976/January 1977; U.S v. Rutherford., 99 S. Ct. 2470, 442 U.S. 544
(1979)
Although the Laetrile story reflects on the excesses of advocates of unorthodox cancer treatments,
there are many more moderate examples of patient enthusiasm for access to new therapies. For instance,
the New York Times reported in 1986 that 74,000 cancer patients were enrolled as subjects in studies of
experimental treatments. Yet, even more cancer patients wanting access to clinical trials are denied that
access:
[T]he rapid advance of medical science is producing a cruel paradox in the United States. Every
time scientists report the slightest hint of an advance in devising experimental therapies against an
intractable killer like cancer, they are inundated with more requests than they can handle from
desperate patients who want immediate access to that particular treatment, which is often in short
supply. The experience leaves many patients with a frustrating sense that life-saving therapies are
being unjustifiably denied them, and that other people with more money or power are gaining
access to the coveted treatment.
Philip M. Boffey, “Thousands in US Receive Treatment in Experiments” The New York Times, January 7,
1986.

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good science and patient safety.17 “AZT dissidents” subsequently challenged AIDS

organizations for misleading them and pressuring them to take AZT – even calling

accusing advocates of “murder.”18 As Epstein summarizes:

Some reacted defensively to such charges, while others were despondent. Yet all
the responses seemed to reflect the same underlying disquiet. It wasn't just the
study; it was the whole state of the science, and Concorde was merely the last
straw.19

Despite these divisions within the patient and research communities, most voices

united behind establishing a clinical trials registry for HIV/AIDS trials. Indeed, a

combination of the efforts of HIV/AIDS patient activists seeking access to trials and the

need to better understand the efficacy of treatments such as AZT led to passage of the

Health Omnibus Extension Act (HOPE) Act of 1988.20

17 In the wake of U.S. studies seemingly demonstrating the effectiveness of azidothymidine (AZT), a
European study known as the Concorde study, questioned not only the efficacy of AZT, but also the U.S.
approach to clinical trials. Whereas the U.S. studies were shorter in duration and had only measured AZT’s
impact on CD-4 counts as a surrogate market for patients’ condition, the Concorde study was a longer
study and found that AZT failed to extend either survival or disease-free state. Epstein at 300-301.
The U.S. had previously approved two AIDS drugs, DDI and DDC, based clinical trials using CD-
4 counts as an endpoint; whereas, the British government had refused to approve DDI. The British Medical
Research Council (MRC), which cosponsored the Concorde study along with French health officials,
concluded, that the Concorde study “casts serious doubts on the value of using changes in CD-4 count as a
predictive measure for the effects of antiviral therapy on disease progression and survival.” Lawrence K.
Altman, “AIDS Study Casts Doubt on Value of Hastened Drug Approval in U.S.” The New York Times,
April 6, 1993.
New York Times columnist, Lawrence K. Altman, voiced a popular opinion when he praised the
Concorde study researchers for their cautious approach to research:
Many researchers and advocates for AIDS patients pressured the Concorde organizers to halt their
trial in its early stages after a federally financed study in the United States was stopped ahead of
schedule in 1989... With AZT's benefit "proved," many asserted, the continuation of the European
trial would be unethical because half the participants would be denied the benefits of the drug.
But the Concorde team persisted. Its leaders said they did not believe the American study had
continued long enough to resolve the issue of whether AZT might give short-term benefits but fail
in the longer run.
Altman, “AIDS Study Casts Doubt on Value of Hastened Drug Approval in U.S.”
18 Epstein at 302. Project AIDS, International argued to AZT “victims,” “’You need to know your rights.
Ask yourself the following questions: Were you misled by the U.S. studies or information that was given
you through the FDA or CDC? Were you pressured into taking AZT … by your doctors or an AIDS
organization? … If you have answered yes …, you have a right to compensation…” Epstein describes how
“a London group calling itself Gays Against Genocide picketed an AIDS organization and a hospital where
a clinical trial of AZT in children was in progress, accusing their targets of ‘murder.’”
19 Epstein at 302.
20 Health Omnibus Programs Extension of 1988. 100 P.L. 607. See also FDA Notice, “Health Omnibus
Extension Act; Establishment of Clinical Trial Data Bank,” July 21, 1989.

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 The HOPE Act created a clinical trials register specifically for HIV/AIDS

therapies in development, imposed mandatory trial listing upon manufacturers, and

provided access to the database to the general public. The Act was enacted on November

4, 1988 and added section 2317 to the Public Health Service Act. That section tasked the

Secretary of Health and Human Services (HHS) to establish a Data Bank of information

on clinical trials for HIV treatments.21 That Data Bank was originally created in 1989 as

the AIDS Clinical Trial Information Service (ACTIS) and has since merged with a

similar service to form AIDSInfo.22 While debates continued of the state of AIDS

treatments and the future of AIDS research, patient advocates, researchers, and Congress

coalesced around an AIDS clinical trials registry.

The Modest Scope and Limited Implementation of the HOPE Act and its Implications

for the FDAMA

The HOPE Act was modest in its scope and limited in its implementation; as

such, the HOPE Act provides multiple salient lessons for analyzing the FDAMA and

recent debates about establishing a clinical trials registry. First, the clear goal of the Data

Bank was limited to enhancing the public’s access to HIV/AIDS clinical trials – rather

than promoting patient safety. Second, the HOPE Act was modest in its scope, and for

each trial, the Data Base contained simply: “the name of the drug; the name and address
21 42 U.S.C. 300cc-17(d). An FDA Notice from July 21, 1989 announced the establishment of the Data
Bank and its accessibility as of July 17, 1989. FDA Notice, “Health Omnibus Extension Act;
Establishment of Clinical Trial Data Bank.”
22 AIDSInfo is available at http://www.aidsinfo.nih.gov/.

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of the sponsor; a contact person and telephone number; the protocol title; the purpose of

the protocol; the eligibility criteria; the trial sites; and whether the trial is currently

enrolling patients.”23 Additional information could be accommodated but was not

required.24

Third, the HOPE Act included no enforcement mechanism for ensuring that trial

sponsors register their trials. While the Act mandates that sponsors submit information to

the Data Bank “within 21 days after the start of a trial to test efficacy,” and the FDA

Notice provides guidance for determining whether trials are “efficacy trials” under the

HOPE Act, the Act failed to provide the FDA with authority to punish a sponsor for

failing to list its trials.25

Fourth, while the HOPE Act attempted to make information readily available to

the public, the Internet was not yet available, and the ACTIS database was initially a

telephone service. Members of the public had to call a toll-free number to learn free

information about particular trials, or they could subscribe to the NLM computer system

and then use the system to access the system for a fee of $17-25 per hour.26 In 1996, the

database went online, and whereas ACTIS received 23,786 phone calls in 1995, by 1999

it received 284,305 website hits.27

Fifth, patient demand was a powerful driver behind changes in the clinical trials

process. Collectively, patients combated a “medical elitism” perceived cynically as “the

pursuit of elegant science leading to the destruction of [their] community.”28 Sixth,

23 FDA Notice, “Health Omnibus Extension Act; Establishment of Clinical Trial Data Bank.”
24 Id.
25 FDA Notice, “Health Omnibus Extension Act; Establishment of Clinical Trial Data Bank.”; Health
Omnibus Programs Extension of 1988. 100 P.L. 607.
26 FDA Notice, “Health Omnibus Extension Act; Establishment of Clinical Trial Data Bank.”
27 Deborah G. Katz et al., “The AIDS Clinical Trials Information Service (ACTIS): A Decade of Providing
Clinical Trials Information.” Public Health Rep. 2002 Mar–Apr; 117(2): 123–130 at 125.
28 Epstein at 1.

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patient demands shouldn’t go so far as to undermine good science in the name of access.

Advocates will deservedly meet with resistance if their advocacy appears to ultimately

threaten patient safety. These considerations about the power dynamic between patients

and the scientific establishment will return in contemporary debates over clinical trials

registration.

PART II: Access as the Primary Driver of the Creation of a Clinical

Trials Registry in the FDAMA of 1997

Historical Lack of Reporting of Clinical Trials

For over 30 years, academics have advocated for the establishment of clinical

trials registries, but apart from the creation of registers specifically for HIV/AIDS and a

few other specific diseases, they have met with little success until the late 1990s.29

According to Professors Kay Dickersin and Drummond Rennie,

It has been known since the seminal work of Simes in 1986 that basing reviews
on the results of trials registered in advance is likely to produce an estimate of
effect free of publication bias. The idea is that even if a trial were never reported,
one would be able to examine a trials register and observe that the trial had taken
place; this in turn could lead to finding out more about the trial's design and
outcome.30

Despite the potential for a clinical trials registry to address the many concerns cited

29 Dickersin and Rennie tell the story of how in 1974, Mary Lasker began advocating for the National
Cancer Institute to follow President Nixon’s pronouncement of a “War Against Cancer” by publishing a
book, to be updated every six months, that would increase participation in clinical trials by listing all
ongoing cancer trails in the United States. A few years later, Tom Chalmers, former director of the National
Institutes of Health (NIH) Clinical Center, “extended this concept to include registers of clinical trials in all
areas” for the purpose of reducing bias in trial reporting. Dickersin and Rennie at 516.
30 Dickersin and Rennie, “Registering Clinical Trials” at 518 citing Simes, “The Case for an International
Registry of Clinical Trials,” J. Clin Oncol. 1986;4: 1529-1541.

14
above, Dickersin and Rennie estimate that of a total of approximately 1 million clinical

trials ever carried out, only about half have been reported.31 In addition, many trials that

are terminated early go unpublished as well.32 Even the NIH didn’t register its clinical

trials before 1975 or from 1979 until 1997.33 In the first decade of the twenty-first

century academics continue to lament that, “no comprehensive system for tracking,

organizing, and disseminating information about ongoing clinical trials currently

exists.”34

Continued Growth in Demand for Access to Clinical Trials

Nevertheless, the perceived need for a central registry to connect patients with

trials has continued to develop over time. Two larger trends have spurred continued

growth in demands for access to clinical trials. First, a primary driver is the growing

reach and significance of clinical trials.35 As the importance of clinical trials has

expanded, patients’ recognition of the potential benefit from drugs in clinical trials has

begun to reach into new circles.

31 Id. at 516. “At the very least,” Dickersin and Rennie explain, an initiative by the Cochrane Central
Register of Controlled Trials coordinated by the Cochrane Center demonstrated that, “one third of RCTs
since 1966 have not been indexed on MEDLINE, and thus are effectively lost to the majority of searchers
who limit their searching in this way.” Dickersin and Rennie, “Registering Clinical Trials” at 517.
32 Id. at 517 citing Pich J et al., “Role of a Research Ethics Committee in Follow-up and Publication of
Results,” Lancet, 361:1015-1016 (2003).
33 Dickersin and Rennie, “Registering Clinical Trials” at 518.
34 Manheimer E and Anderson D, “Survey of Public Information About Ongoing Clinical Trials Funded
by Industry: Evaluation of Completeness and Accessibility,” BMJ cited in Dickersin and Rennie,
“Registering Clinical Trials” at 516.
35 Both the body of research and the amount of money at stake in clinical trials have increased
dramatically: industry spent $3.2 billion for investigator grants and $1.6 billion for the services of contract
research organizations (CROs) in 1994, and a decade later these totals reached $10 billion and $ 7.6 billion
respectively. Robert Steinbrook, “Gag Clauses in Clinical-Trial Agreements,” NEJM, Vol. 352: 2160-2162.
Lengthening FDA review times have also come under scrutiny – both for delayed timing and too hasty
approvals – and patients have increasingly sought earlier access to medicines still in trials but with the
promise of efficacy.

15
 Second, the development of the Internet has been at least an equally influential

driver of patient demand for access to trials in general and trial registration in particular.

The Internet makes a central registry feasible by providing a novel ability to list trials

without space limitations and to make listings available to the entire U.S. and even the

world. The Internet also allows for electronic publishing – bringing clinical results to

patients’ desktops. Finally, new online patient communities and support groups have

flourished on the Internet, and they have shared news of clinical trials and generated new

demands for access.36

The FDAMA Attempts to Expand Patient Access to Clinical Trials

Twenty years after AIDS activists began pressing for access to clinical trials,

Congress finally addressed patients’ demand for access to all clinical trials, not just trials

for specific diseases. Section 113 of the Food and Drug Agency Modernization Act

(FDAMA) was modeled on the HOPE ACT for HIV/AIDS37 and amended section 402 of

the Public Health Service Act (42 U.S.C. 282) to direct the Secretary of Health and

Human Services to “establish, maintain, and operate a data bank of information on

36 One well-known example is the online community among patients with Chronic Mylogenous Leukemia
(CML). In the late 1990s, CML patients learned of the remarkable success of a novel, molecularly targeted
cancer drug called Gleevec (then known as STI571) produced by Novartis. News of Gleevec’s phase I
success in treating this form of cancer spread through an Internet CML support group and led patients to
clamor for an expanded Phase II trial: “In October of 1999, [patients] sent Novartis a 3,030-signature
petition and deluged the company with letters, e-mail and calls – pressuring the manufacturer to scale up
production of STI571,” and Novartis subsequently developed an expanded access program which provided
Gleevec to 7,000 additional patients prior to FDA approval. Valerie Fleishman and Robert Sayoc Nocon,
“Targeting Cancer: Innovation in the Treatment of Chronic Myelogenous Leukemia,” New England
Healthcare Institute, March 2004 at 17.
37 Dickersin and Rennie, “Registering Clinical Trials” at 519. An FDA report on the FDAMA entitled,
“Food and Drug Modernization Act (FDAMA) Section 113: Status Report on Implementation” groups the
FDAMA and HOPE Act together with the summary, “Congress has demonstrated a longstanding interest in
improving public access to information about opportunities to participate in clinical trials of promising new
treatments.” Theresa Toigo, “Food and Drug Modernization Act (FDAMA) Section 113: Status Report on
Implementation,” J. Biolaw & Bus., Vol. 7 No. 2, 2004.

16
clinical trials for drugs to treat serious or life-threatening disease and conditions.”38 HHS

created a single clinical trials registry at ClinicalTrials.gov, and existing disease-specific

databases such as ACTIS and Physician’s Data Query (PDQ) (NCI’s cancer trials

database) were integrated into ClinicalTrials.gov.39 Like the HOPE Act, the FDAMA

mandates that sponsors submit the required information to the data bank within 21 days

after approval of the trial protocol – for all Phase II, III, and IV trials to test efficacy.40

Also like the HOPE Act, the FDAMA provided no enforcement mechanism for ensuring

compliance with these requirements, as Part IV of this paper will further discuss.

The FDAMA responded to growing demand from cancer patients much like

AIDS patients before them41 by expanding patient access to all clinical trials.42 As noted,

the Internet was an unmistakable driver for a comprehensive new clinical trials database.

Whereas the implementation of the HOPE Act initially required toll-free phone calls and

a subscription-based computer system, the Internet made clinical trials registries far more

feasible and valuable for the public.

Legislative history of the FDAMA reveals that, in fact, there was relatively little

debate around the issue. Congress simply found an easy opportunity to assist patients

seeking access to new clinical trials and to provide trials with willing enrollees. Section
38 Food and Drug Administration Modernization Act of 1997, P. L. 105-115; “Guidance for Industry:
Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions; Draft
Guidance January 2004.” FDA Center for Biologics Evaluation and Research (CBER).
39 www.ClinicalTrials.gov; Toigo, “Food and Drug Modernization Act (FDAMA) Section 113: Status
Report on Implementation.”
40 FDAMA Section 113 – CITE ; Toigo, “Food and Drug Modernization Act (FDAMA) Section 113:
Status Report on Implementation.” The FDA has interpreted this requirement to mean 21 days after the
trials is open for enrollment because the FDA doesn’t approve trial protocols. “Guidance for Industry:
Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions; Draft
Guidance.”
41 Dickersin and Rennie, “Registering Clinical Trials” at 519. See DeMarinis AD, “Current
Considerations: Regulatory: Clinical Trials Databank.” Res. Practitioner 2002:3: 105-106.
42 Abbey S. Meyers, president of the National Organization for Rare Disorders, and Paul Kim, a former
staff member for Senator Edward M. Kennedy, told The Washington Post that, “the original purpose of the
registry was to link patients who wanted to join clinical trials with the researchers.” Shankar Vedantam,
“Drug Makers Prefer Silence on Test Data,” The Washington Post, July 6, 2004, front page.

17
113, the section that establishes a data bank in the form of a clinical registry, was added

as an amendment offered to a late iteration of a much larger reform bill – it appears

almost as an afterthought. The provision itself was brief and the information it required

was limited to provisions that would help patients to access clinical trials:

Information provided shall consist of eligibility criteria for participation in the

clinical trials, a description of the location of trial sites, and a point of contact for
those wanting to enroll in the trial, and shall be in a form that can be readily
understood by members of the public.43

(See Appendix for the full language of Section 113 of the FDAMA.) The only

commentary recorded in transcripts from Congress is a glowing endorsement of the

concept of facilitating access to clinical trials to for patients with “serious or life

threatening diseases and conditions”44 Senator Jim Jeffords articulated:

It is critical that those people who are suffering from the diseases of this nature be
able to find out how they can get involved and be able to take part in a program
which is designed to bring them back to health.45

In transcripts of the Congressional record, Senators Jeffords and Mosley Braun reiterated

the emphasis on access in the bill:

I would like to comment on the involvement of patient and consumer groups…

The bill reflects changes to address their concerns patients will have access to a
registry of clinical trials information; and additional safeguards were built into the
provision allowing expanded access to products under clinical investigation.46

Along the same lines, the bill also establishes a national registry of clinical trials.
The primary impediment to patients’ access to potentially lifesaving treatment is
not the FDA but actually a lack of knowledge about ongoing research. A national
database, which patients can access, will greatly assist people across the Nation
who are searching for hope for their illnesses. This important reform is long
overdue and absolutely necessary to continue providing Americans the best in
medical treatment and technology.47

43 Food and Drug Administration Modernization Act of 1997, P. L. 105-115.

44 Id.
45 Senator Jim Jeffords, 143 Cong Rec S 9133, S9153.
46 Id.
47 Senator Carol Moseley Braun, 143 Cong Rec S 9811

18
In February 2004, Mark McClellan, who was Commissioner of the FDA at the time,

shared his focus on expanding patient access as he guided the FDA in implementing the

FDAMA:

More than ever before, there are studies being conducted in patient populations
that historically have not had as much evidence as we'd like, such as minority
populations, populations of seniors, and women. The only way that we can find
out if treatments really work is if we get the participation of the public and this is
our tool to try to let the public know about the opportunities out there.48

In light of the FDA’s historical focus on safety, the fact that patient access rather

than safety was front of mind when Congress created the FDAMA helps explain why the

implementation of the FDAMA has been constrained in practice. As Part IV of this paper

will demonstrate, the FDAMA’s implementation has been inhibited and by many

measures made unsuccessful because the FDAMA provided neither mechanisms for

enforcement, authority for the FDA to regulate clinical trial registries, nor funding for

such initiatives.

PART III: Safety As the Primary Driver Behind New Legislation

Considering Expanding Clinical Trials Registries

Of course, Congress’ establishing a clinical trials registry has implications for

patient safety that go well beyond patients’ access to trials. It also offers potential for

promoting public safety by increasing the transparency of clinical trials, expanding the

pool of knowledge available to future patients and researchers, and enhancing the

accuracy of their published data by avoiding investigators’ and sponsors’ biases in favor

48 Mark McClellan cited in “Host Marie Osbourne’s Interview with Dr. Mark McClellan,” Health Mind &
Body Radio Program, February 25, 2004.

19
of selectively publishing only positive results.

None of these powerful rationales were primary drivers behind the passage of the

FDAMA, with its focus on patient access. However, Part III of this paper examines how

all of these patient-safety driven rationales are at the heart of current debates over

expanding the scope of clinical trials registration.

Academic Research on the Harms of Publication Bias and Selective Publication

Of course, there are ample patient safety issues surrounding clinical trials – issues

that clinical trial registration might be expected to address. The general public suffers

when patients and physicians lack accurate or thorough scientific information in deciding

about treatment decisions.49 Academics have lamented the serious problems such as

49 As Drummond Rennie succinctly remarks in JAMA, “No clinician can possibly practice evidence-based
medicine if prevented from seeing the evidence.” Drummond Rennie, “Trial Registration: A Great Idea
Switches From Ignored to Irresistible,” JAMA, 2004; 292: 1359-1362. Barry Perlman, president of the
New York State Psychiatric Association, echoes this concern about the cost of incomplete disclosure of
negative trial results: “Whenever we don’t have the complete picture,” he explains, “ we can’t prescribe
ethically and appropriately, and that’s an enormous obstacle to good care.” Barry Perlman cited in Gardner
Harris, “Spitzer Sues a Drug Maker, Saying it Hid Negative Data,” The New York Times, June 3, 2004.

20
publication bias50, undisclosed results51, duplicate publication52, and selective

publication53 for decades.54 (See Appendix for “Examples of Major Discrepancies

Between Trial Protocols and Published Articles in the Specification of Primary

Outcomes.”55) The damage that results from these practices is that relevant scientific

findings go unpublished and receive less attention. Negative results that might challenge

50 Drummond Rennie, “Fair Conduct and Fair Reporting of Clinical Trials,” JAMA November 10, 1999,
Vol. 282, No. 18; Easterbrook P.J. and Berlin J.A. “Publication Bias in Clinical Research,” Lancet April
13, 1991, Vol. 337, Issue 8746. Publication bias refers to scientists’ tendency to submit and publish results
more frequently than they publish negative findings. A 1991 study in Lancet by Easterbrook and Berlin
“confirmed the presence of systematic selection bias in the publication process according to study results.”
The study found an adjusted odds ratio of publication of 2.32 in favor of studies with statistically
significant results over studies with null results. A similar study found an odds ratio of 2.7. Dickersin K,
Meinert C. “Risk Factors for Publication Bias: Results of a Followup Study,” Controlled Clin Trials 11;
255 (1990) (abstr.).
51 “Kamran Abbasi, “Compulsory Registration of Clinical Trials,” BMJ, 2004; 329: 637-638. Scientists
underreport their findings from their research and thereby deny the public access to their results. Iain
Chalmers writes that this underreporting is “scientific misconduct.” Ian Chalmers, “Underreporting
Research is Scientific Misconduct,” JAMA 1990; 263: 1405-1408. For example, one review of 37 trials of
nonsteroidal anti-inflammatory drugs reported in FDA reviews found that only 1 study had been published.
MacClean CH, Morton SC, Olfman JJ, et al. for the Southern California Evidence-Based Practice Center,
“How Useful Are Unpublished Data from the Food and Drug Administration in Meta-Analysis?” J Clin
Epidemiol, 2003; 56: 44-51 cited in Dickersin and Rennie, “Registering Clinical Trials” at 519.
Moreover, according to Drummond Rennie, “Heatherington et al. have shown that retrospective
attempts to obtain data about unpublished trials are usually unsuccessful.” Rennie adds, “Prospective
registration overcomes this problem, will help avoid confusion as to whether different authors are
describing the same trial, and will prevent double-counting of data and patients.” Rennie, “Fair Conduct
and Fair Reporting of Clinical Trials citing Heatherington J. et al. “Retrospective and Prospective
Identification of Unpublished Clinical Trials: Lessons from a Survey of Obstetricians and Pediatricians.”
Pediatrics, 1989; 84: 374-380.
52 Jerome Kassirer and Marcia Angell, “Redundant Publication: A Reminder” NEJM August 17, 1995,
Vol. 333; 449-450. Duplicate or redundant publication results when scientists publish results from the
same study in two or many more journals. The harmful result is that “multiple reports of the same
observations can overemphasize the importance of findings, overburden busy reviewers, fill the medical
literature with inconsequential material, and distort the academic rewards system.” As a result, journals
such as the New England Journal of Medicine have discouraged duplicate publication for years.
53 In another form of publication bias, a 2004 study from JAMA provides direct evidence that “the
reporting of trial outcomes is not only frequently incomplete but also biased and inconsistent with
protocols.” An-Wen Chan et al., “Empirical Evidence for Selective Reporting of Outcomes in Randomized
Trials: Comparison of Protocols to Published Articles.” JAMA, May 26, 2004; 291: 2457-2465. The study
compared published articles with protocols and found that 51 of the 82 trials studied (62%) had “major
discrepancies” between the primary outcomes defined in the published articles and those originally
identified in the protocols. Wen Chan et al. at 2461. The study also noted incomplete reporting of efficacy
and harm outcomes, including primary outcomes, as well as denial by researchers since “eighty-six percent
of survey-responders denied the existence of unreported outcomes despite clear evidence to the contrary.”
54 In an overview of the clinical trials landscape, Kay Dickersin and Drummond Rennie write, “For
decades scientists have complained about the over-reporting of ‘positive’ results (results that favor the new
therapy).” Dickersin and Rennie, “Registering Clinical Trials” at 517.
55 Chan et al. “Empirical Evidence for Selective Reporting of Outcomes in Randomized Trials:

21
the efficacy or safety of prescription drugs are effectively swept under the rug.56

Spurious results are highlighted, ineffective or even injurious drugs are promoted, and

patients tend to have an unduly optimistic view of trials and may therefore enroll in trials

to their detriment.57 In addition, the cost-effectiveness of more expensive therapies may

be over-estimated.58 Arthur Levin, Executive Director of the Center for Medical

Consumers summarizes:

The fact is that published drug studies are hugely biased toward good news – the
drug works and is safe – and that studies reaching the opposite conclusion never
see the light of day. The ability of drug companies to pick and choose the
research they provide doctors in support of their product is an outrageous conflict
of interest and puts us all in harm’s way.59

Finally, investigators and the FDA are largely unable to overcome these

shortcomings or to provide wider information to the public. Mandatory gag clauses in

research contracts have long precluded researchers in clinical trials from disclosing

negative outcomes without the permission of the sponsoring manufacturer.60 For

instance, in trials of antidepressants in children (discussed below), industry sponsors

denied access to unpublished data about the risk of suicide associated with the drugs to

Comparison of Protocols to Published Articles” at 2462.

56 Gary Smith, a professor of pharmaceutical science at the University of Maryland comments,
“Suppression of studies has always been a problem. In research as in clinical practice, the things that don’t
work are just as important as what does work.” Gary Smith cited in Fred Gebhart, “Calls Mounting for
Drug Research Transparency,” Drug Topics, September 13, 2004.
57 “Drug Company Experts Advised Staff to Withhold Data About SSRI Use in Children,” CMAJ, Mar. 2,
2004; 170(5).
58 Chan et al. “Empirical Evidence for Selective Reporting of Outcomes in Randomized Trials:
Comparison of Protocols to Published Articles.” Dickersin and Rennie draw a clever analogy to baseball
statistics when they write:
In baseball, it is easy to find out just how well Cal Ripken has hit against various pitchers in the
past, at home or away games, in recent weeks or during his career…Depending solely on the
accessible published medical literature for assessing a treatment’s efficacy is akin to using only
information from Ripken’s home games to calculate his batting average.
Dickersin and Rennie, “Registering Clinical Trials” at 517.
59 Arthur Levin cited in “Major Pharmaceutical Firm Concealed Drug Information: GlaxoSmithKline
Misled Doctors About the Safety of Drug Used to Treat Depression in Children.” Press Release, Office of
the New York Attorney General, June 2, 2004.
60 Rennie, “Trial Registration: A Great Idea Switches From Ignored to Irresistible”; Robert Steinbrook,
“Gag Clauses in Clinical-Trial Agreements.”

22
the researchers who had conducted the studies.61 Academic investigators have had

difficulty overcoming gag clauses on their own,62 so in 2005 Congress attempted to

address the issue of gag clauses in the Fair Access to Clinical Trials (FACT) Act. The

Senate version of the bill was sponsored by Christopher Dodd and seven cosponsors,

while the House version was sponsored by Henry Waxman and 42 cosponsors.63 Despite

support from the American Medical Association (AMA) House of Delegates and the

Association of American Medical Colleges (AAMC) the parallel versions of the FACT

Act failed to move beyond referral to the Senate Health, Education, Labor, and Pensions

Committee and the House Subcommittee on Health respectively. In addition, while the

FDA receives substantial information from manufacturers seeking approval for their

drugs, the agency may not lawfully disclose trials data on drugs that are not ultimately

approved.64

The Ethical Case in Favor of Disclosure

61 Barry Meier, “Contracts Keep Drug Research Out of Reach,” The New York Times, November 29, 2004,
available at: <http://www.nytimes.com/2004/11/29/business/29research.html?
ei=5090&en=1e7bc27ab44a181a&ex=1259384400&pagewanted=print&position=>. One investigator of
paroxetine (Paxil), E. Jane Garland, explains. “Those researchers, including myself, who did see the results
of negative paroxetine industry studies were prohibited by nondisclosure contracts from discussing them.”
Garland EJ, “Facing the Evidence: Antidepressant Treatment in Children and Adolescents,” CMAJ, 2004;
170; 489-491, available at: <http://www.cmaj.ca/cgi/content/full/170/4/489>. In a similar case, Merck
essentially hid data by failing to inform authors about safety data from the Advantage study of rofecoxib
for the treatment of osteoarthritis. Alex Berenenson, “Evidence in Vioxx Suits Shows Intervention by
Merck Officials,” New York Times, April 24, 2005, available at:
<http://www.nytimes.com/2005/04/24/business/24drug.html?
ex=1271995200&en=e0f84f2e5e0931c7&ei=5088&partner=rssnyt&emc=rss>.
62 In the 1990s, Dr. Nancy Oliveri, a hematologist in Toronto, signed a confidentiality agreement before
entering a research contract with a pharmaceutical company, Apotex, the sponsor of the trial. When she
tried to publish data about the lack of safety for the medication (an orally active iron chelator) studied in the
trial Apotex brought two law suits totaling $20 million against her. David G. Nathan and David J.
Weatherall, “Academic Freedom in Clinical Research,” NEJM, 347:1368-1371 (2002).
63 S.5470, THOMAS available at: <http://thomas.loc.gov/cgi-bin/bdquery/z?d109:s.00470:>; H.R.3196,
THOMAS, available at: <http://thomas.loc.gov/cgi-bin/bdquery/z?d109:h.r.03196:>.
64 Rennie, “Trial Registration: A Great Idea Switches From Ignored to Irresistible.”

23
 There is also an ethical argument that inadequate transparency about clinical trials

cheats the public out of data to which it is entitled. Dickersin argues that there is an

ethical imperative to provide the general public with full information about clinical trials,

including their protocol and results, in exchange for the public’s willingness to

voluntarily accept exposure to risks without any certainty of benefit when it enrolls in

such trials.65 She writes that the “covenant” between researchers and patients, is broken

when sponsors fail to disclose trial results.66 Dickersin rejects excuses for not submitting

a paper for publication, including “lack of time, uninteresting results, and beliefs that the

submission would be rejected by journals.”67 She explains:

Some investigators report that ‘publication wasn’t an aim for our study…That
raises ethical issues: You can’t do research and say publication is only an option.
The research is as good as not done if you don’t get the results out there.”68

Others make an additional argument that the pharmaceutical industry has a particular

obligation and owes the general public in return for the tax benefits, patent protection,

and other regulatory support that it receives.69

A Meta Analysis of Antiarrhythmic Drug Studies Reveals the Harm of Publication

Bias

To take one specific example of harms to patients that are both evident and

65 Id.
66 Drummond and Rennie at 517.
67 Chan et al. reported similar excuses for not reporting both efficacy and harm outcomes – namely lack of
statistical significance, journal space restrictions, and lack of clinical importance. Chan et al., “Empirical
Evidence for Selective Reporting of Outcomes in Randomized Trials: Comparison of Protocols to
Published Articles.”
68 Kay Dickersin quoted in Tom Reynolds, “Researchers Push for Publication, Registration of All Clinical
Trials,” Journal of the National Cancer Institute, 2003; 95(11):772-774.
69 Shankar Vedantam, “Drug Makers Prefer Silence on Test Data.”

24
ethically troubling, a meta analysis of studies of antiarrhythmic drugs demonstrates the

significant risks that the public accepts to its safety due to the current limitations of

clinical trials’ transparency. Dickersin notes that the clear weight of the evidence from

over 50 trials of antiarrhythmic drugs reveals no clear benefit to outcomes but suggests an

increase in sudden death for patients with ventricular arrhythmias.70 Nevertheless,

sponsors have not always published data from these studies – or done so in a timely

manner – and physicians continue to prescribe the drugs. As a result, each year as many

as 20,000 to 75,000 patient deaths result from antiarrhythmic drugs prescribed for

preventing myocardial infarction.71

Litigation over Withholding of Antidepressant Data in Adolescents and Children

Brings Home the Risk to Public Safety from Misrepresented or Withheld Trial Results

While these concerns about harms to patients are very real to academics, a recent

lawsuit accusing pharmaceutical company, GlaxoSmithKline (GSK), of withholding

negative data on antidepressants brought home to the general public the inadequate level

of transparency in clinical trials. In June 2004, New York Attorney General, Eliot

Spitzer brought a widely publicized case with significant implications72 against GSK for

consumer fraud.73 Spitzer argued that GSK concealed and misrepresented data, including

70 Drummond and Rennie at 517.

71 Moore T, Deadly Medicine: Why Tens of Thousands of Heart Disease Patients Died in America’s Worst
Drug Disaster, New York (1995) cited in Drummond and Rennie at 517. As Dickersin and Rennie
summarize, “A crucial question is whether the distortion of available evidence, aside from being unethical,
actually harms patients. There is evidence that it does.”
72 Attorney General Spitzer sought disgorgement of profits that GSK obtained by its misrepresentations –
profits that could be substantial since Paxil sales reached $553 in the first quarter of 2004 alone. Rennie,
“Trial Registration: A Great Idea Switches From Ignored to Irresistible.” Moreover, Spitzer’s suit could be
the first in a new line of high stakes lawsuits against pharmaceutical companies that misrepresent or
conceal their clinical trials results. Attorney General Spitzer notes, “This is an area that we’re interested in,
and I think there are other cases out there that are analogous.” Eliot Spitzer cited in Harris, “Spitzer Sues a
Drug Maker, Saying it Hid Negative Data.”
73 Spitzer’s lawsuit was joined by parallel initiatives against GSK, including an investigation by the

25
safety risks and mixed efficacy results among children and adolescents, from its clinical

trials for paroxetine (Paxil in the U.S. and Seroxat in Canada), a selective serotonin

reuptake inhibitor (SSRI) used to treat depression.74

The lawsuit highlights the disjoint between GSK’s marketing statements and its

clinical trials results and alleges that GSK “engaged in a concerted effort to withhold

negative information concerning Paxil.”75 This accusation acquired new salience when

the public gained access to an GSK internal document entitled “Seroxat/Paxil Adolescent

Depression: Position Piece On the Phase III Clinical Studies.”76 Despite acknowledging

that results trials of children and adolescents were “insufficiently robust” to support

changing Paxil’s label to indicate treatment of pediatric depression, the document

emphasized that, “Positive data from Study 329 will be published” and “It would be

commercially unacceptable to include a statement that efficacy had not been

demonstrated, as this would undermine the profile of paroxetine.”77 Indeed, the company

practices followed the document’s strategy: GSK failed to disclose its negative results in

Medicines and Healthcare products Regulatory Authority (MHRA) in Britain. In June 2003, the MHRA
advised doctors that paroxetine “should not be prescribed to patients under the age of 18 because evidence
from various clinical trials showed that episodes of suicidal behaviour were between 1.5 and 3.2 times
higher in children taking the drug that in those taking the placebo.” The U.S., France, and Ireland have also
limited Paxil’s indications for patients under 18 years of age. “Drug Company Experts Advised Staff to
Withhold Data About SSRI Use in Children,”
74 The lawsuit notes that the company undertook at least five trials of Paxil on adolescents and children in
an attempt to obtain a six-month extension of the drug’s patent – but only published one of the trials, Study
329 which found Paxil to be no more effective than placebo. The lawsuit alleges that the other trials
suggest that Paxil is ineffective in treating depression (or in the case of Trial 377 less effective than
placebo) and may even increase the risk of suicide in children. “Major Pharmaceutical Firm Concealed
Drug Information: GlaxoSmithKline Misled Doctors About the Safety of Drug Used to Treat Depression in
Children”; “Drug Company Experts Advised Staff to Withhold Data About SSRI Use in Children,”
75 “Major Pharmaceutical Firm Concealed Drug Information: GlaxoSmithKline Misled Doctors About the
Safety of Drug Used to Treat Depression in Children.”
76 “Drug Company Experts Advised Staff to Withhold Data About SSRI Use in Children.”
77 “Seroxat/Paxil Adolescent Depression: Position piece on the phase III clinical studies.” cited in AA3
The internal document goes on to add that GSK’s explicit strategy is to “manage the dissemination of data
in order to minimize any potential negative commercial impact.” cited in “Major Pharmaceutical Firm
Concealed Drug Information: GlaxoSmithKline Misled Doctors About the Safety of Drug Used to Treat
Depression in Children.”

26
the “Medical Information Letters”78 and allegedly told its sales representatives (who can

be expected to pass this information on to doctors) that, “Paxil demonstrates remarkable

efficacy and safety in the treatment of adolescent depression.”79 GSK settled the cased in

August 2004 for $2.5 million and agreed to establish an online, publicly available registry

for all of its clinical trials.80

The investigation of GSK and the revelations from the GSK’s internal document

vividly demonstrate companies’ capacity to hide clinical data and misrepresent results to

the public. The repercussions of practices such as those alleged by GSK represent

undisclosed risks to a substantial number of patients. In 2002 alone, physicians wrote

over 2 million Paxil prescriptions for children and adolescents.81

Congress Considers Responding to Safety Concerns with the proposed Fair Access to

Clinical Trials Act (FACT)

The House version of the FACT Act mandated that sponsors report a summary of

clinical trials’ results to ClinicalTrials.gov, including primary and secondary outcomes,

subject drop outs, and significant adverse events – within 12 months of the last data

collection.82 The FACT Act included an enforcement mechanism for non-compliance by

allowing the government to impose civil penalties of up to $15,000 per day, by denying

eligibility for government funding, denying future investigational new drug (IND)

78 “Major Pharmaceutical Firm Concealed Drug Information: GlaxoSmithKline Misled Doctors About the
Safety of Drug Used to Treat Depression in Children.”
79 Harris, “Spitzer Sues a Drug Maker, Saying it Hid Negative Data.”
80 Kate Fodor, “Trials of the Pharmaceutical Industry,” The Scientist, 2004; 18(22): 40.
81 “Major Pharmaceutical Firm Concealed Drug Information: GlaxoSmithKline Misled Doctors About the
Safety of Drug Used to Treat Depression in Children.”
82 H.R.3196, “The Fair Access to Clinical Trials Act: Bill Summary,” Representative Henry Waxman,
available at: <http://www.henrywaxman.house.gov/pdfs/summary_fact_act_7.1.05.pdf>.

27
applications, and requiring studies to be registered with ClinicalTrials.gov in order to

receive IRB approval.83 (See Appendix for a table of the “Proposed Information in the

Clinical Trials Data Bank Under the Fair Access to Clinical Trials Act.”84)

While the FACT Act has failed to move beyond Senate and House Committees,

Congress and the public have become aware of the safety imperative, raised by the

antidepressant tragedies, for greater transparency and accountability in clinical trials.85

The AMA and AAMC Demand Full Registration of Clinical Trials

In light of concerns over publication bias and its associated safety concerns, the

AMA openly endorsed a comprehensive U.S. clinical trials register in June 2004.86 The

AMA also proposed that IRBs mandate that trials be registered in order to receive IRB

approval. In January 2006, the AAMC followed suit and endorsed clinical trial

registration within 21 days of enrolling participants and registration of results for public

83 Id.
84 Robert Steinbrook, “Registration of Clinical Trials – Voluntary or Mandatory?” NEJM, 351; 18: 1820-
1822 (2004).
85 The FACT Act is hardly the only patient-focused legislation regarding clinical trials. Although not
within the scope of this paper, Senator Sam Brownback made headlines in November 2005 for introducing
the ACCESS (Access, Compassion, Care and Ethics for Seriously-Ill Patients) Act, S.1956 (also known as
“Kianna’s Law”) which proposed to allow the FDA to approve drug companies for marketing drugs on the
basis of Phase I testing and preclinical evidence to “seriously ill patients who had exhausted other treatment
options, if they waived the right to sue the manufacturer and permitted collection of their clinical data.”
Susan Okie, “Access before Approval – A Right to Take Experimental Drugs?” NEJM, Vol. 355;5:437-440
(2006).
In May 2006, in the case of Abigail Alliance v. Eschenbach, a three-judge panel of the U.S. Court
of Appeals for the D.C. Circuit ruled 2-1 that:
[P]atients with life-threatening and otherwise untreatable diseases have a constitutional right to
seek experimental treatments for which efficacy is not yet established and that the government
cannot interfere unless it proves it has a “compelling interest.”
Susan Okie, “Access before Approval – A Right to Take Experimental Drugs?”
The debates that underlie this legislation and legal challenge weigh desperate patients’ need for access to
drugs against concerns over fraud and difficulty getting data on safety and efficacy.
86 Barry Meier, “A.M.A. Adds Its Voice to Call For Disclosure On Drug Trials,” The New York Times,
June 16, 2004, available at: <http://query.nytimes.com/gst/fullpage.html?
sec=technology&res=9A02E3D81E30F935A25755C0A9629C8B63&n=Top%2fReference%2fTimes
%20Topics%2fOrganizations%2fF%2fFood%20And%20Drug%20Administration%20>.

28
availability within 18 months of a their submission for publication.87 The AAMC’s

endorsement of clinical trial registration was also driven by a concern for patient safety

and the parallel goals of “assur[ing] integrity and credibility in the conduct and reporting

of clinical trials.”88

PART IV: The Status Quo of Clinical Trials Registration

The status quo of clinical trials registration is complicated and difficult to

ascertain. The existence of a plethora of private registries, international variation, and

noncompliance with the FDAMA create unpredictability for patients, manufacturers, and

researchers alike.

This section of the paper outlines that status quo as follows: A large and growing

number of private registries are being promoted by industry and non-governmental

organizations, but these registries are of limited value because they are not centralized or

coordinated, and they do not make registration mandatory. While Congress made clinical

trials registration mandatory in the FDAMA, this initiative has been greatly limited by its

modest informational demands, lack of enforcement, and lack of compliance. The

International Committee of Medical Journal Editors (ICMJE), a group of leading medical

journals, is adding new requirements for clinical trial registration as a condition of

publication in its member journals, but these requirements are not a solution on their own.

The result is that despite increasing demands for a single, comprehensive,

87 Susan Ehringhaus and David Korn, “Principles for Protecting Integrity In the Conduct and Reporting
Of Clinical Trials,” Association of American Medical Colleges, January 6, 2006 at 3-4, available at:
<http://www.aamc.org/research/clinicaltrialsreporting/clinicaltrialsreporting.pdf>.
88 Id. at 2.

29
mandatory clinical trials database, manufacturers can frequently avoid registration

requirements and patients must navigate a disorganized maze of trials data. In this

compromise, access to trials is increased, but the public has not realized the wider

potential benefits for patient safety.

A Multitude of U.S. Private Registries

One factor that makes the status quo so confusing is the multitude of private

clinical trials registries, each with its own requirements and standards. There are

currently at least 200 registries based in the United States alone.89 A number of drivers –

ranging from the influence of opinion leaders, expert panels, journals, and government

actors – have led to the establishment of private registries and broader clinical trials

registration. (See Appendix for “Selected Events Supporting and Leading to Trial

Registration.”90) Many companies began their own registries in recent years after

Attorney General Spitzer’s lawsuit against GSK and the passage of the FDAMA. Today,

many of the top 10 largest pharmaceutical companies in the world run their own clinical

trial registers. A private online registry called CenterWatch attempts to provide a central

listing of clinical trials and claims to have over 41,000 trials listed.91 However, Dickersin

and Rennie argue that CenterWatch is flawed because users cannot directly access much

of the information about trials (funding sources are not publicly accessible, and the

registry lacks a unique identifier for each trial that would facilitate searching).92
89 Drummond and Rennie, “Registering Clinical Trials” at 519.
90 Dickersin and Rennie, “Registering Clinical Trials” at 518.
91 CenterWatch (Accessed May 12, 2007 at www.centerwatch.com).
92 Drummond and Rennie, “Registering Clinical Trials” at 519.

30
 These private registers suffer from limitations in that they are not uniform across

companies and may include different information, trials at different stages, and different

timing for making disclosures.93 Moreover, they frequently only go back a few years, and

they often have exceptions for delaying or not including results from ongoing trials.94

Researchers or patients attempting to collect information about all clinical trials for a

class of drug in which multiple companies are developing products would have difficulty

gathering complete information across individual company registers. To illustrate the

challenge of searching existing private registries, Kay Dickersin and Diana Anderson

have created and maintain an online “registry of registries” called TrialsCentral.95 This

central listing does not allow users to search all registries in a single search; instead, users

must search each registry individually. As a result, Dickersin cynically describes the

website’s primary function as “a demonstration project to show how sad and ridiculous

this situation is, rather than being of great use to patients.”96

Registration Requirements under the FDAMA

The FDAMA creates a central registry that could greatly simplify this situation.

Therefore, it is important to examine the specific requirements under Section 113 of the

FDAMA and consider whether industry is complying with those requirements in practice.

The FDAMA was enacted on November 21, 1997. On February 29, 2000, the

93 Rennie, “Trial Registration: A Great Idea Switches From Ignored to Irresistible.” For instance,
Drummond Rennie, criticizes GSK’s clinical trials registry that it announced in June 2004 for not
committing to disclose trial information at the start of trials.
94 See e.g. the policies for clinical trial registers from GSK and Bristol-Myers Squibb, available at:
<http://ctr.gsk.co.uk/welcome.asp> and < http://ctr.bms.com/ctd/policy.do>.
95 www.TrialsCentral.org
96 Dickersin cited in Reynolds, “Researchers Push for Publication, Registration of All Clinical Trials.”

31
National Library of Medicine made the registry at ClinicalTrials.gov available to the

public for the first time.97 The FDA subsequently issued formal draft guidance in

multiple iterations with its most recent revised version from January 200498 following

Congress’ passage of the Best Pharmaceuticals for Children Act (BPCA).99

As outlined at a general level in Part II, the FDAMA required that industry

sponsors of clinical trials register all Phase II, III, and IV trials to test efficacy at

ClinicalTrials.gov and provide the required information within 21 days after the trial first

opened enrollment. More specific required listings include the condition being studied,

the intervention, eligibility criteria (including gender and age), the location of the trial,

contact information, the unique protocol ID number, and the study sponsor name.100 (See

Appendix for a full list of registration requirements at ClinicalTrials.gov.101)

Shortcomings Inherent in the FDAMA – Lack of Awareness and Lack of an

Enforcement Mechanism

To implement Section 113 of the FDAMA, the FDA made significant outreach

attempts to both manufacturers and patients. In 2002, the FDA established a program to

reach out to pharmaceutical companies and other IND sponsors. The FDA sent letters to

97 “Guidance for Industry: Information Program on Clinical Trials for Serious or Life-Threatening
Diseases and Conditions; Draft Guidance January 2004.”
98 Id.
99 The BPCA is relevant because it amended Section 113 of the FDAMA to require that sponsors
additionally submit whether and through what procedures they will allow protocol exceptions for individual
patients of expanded access use of the investigational drug, particularly for children. “Guidance for
Industry: Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions;
Draft Guidance January 2004.”
100 “Guidance for Industry: Information Program on Clinical Trials for Serious or Life-Threatening
Diseases and Conditions; Draft Guidance January 2004.”
101 “ClinicalTrials.gov Registration Requirements,” available at: <http://prsinfo.clinicaltrials.gov/trial-reg-
requirements.html>.

32
industry sponsors reminding them that they are required to list studies in

ClinicalTrials.gov, describing how to list data online, and bringing their attention to the

draft Guidance for Industry.102 To raise patient awareness, the FDA broadcast one-

minute health features (and an interview with Commissioner Mark McClellan) 762 times

on over 399 radio stations and reaching approximately 2,291,095 Americans.103 (See

Appendix for examples of FDA outreach materials for patients104 and researchers.105)

Nevertheless, despite the FDA’s outreach attempts, the fact that Section 113 of

the FDAMA requires sponsors to register their clinical trials is not well known. This

provision of the FDAMA was news to Catherine De Angelis, Editor-in-Chief of JAMA,

who told The Washington Post in July 2004, “That’s a surprise to me. Tell me why it’s

not enforced.”106 Rich Koenig, a spokesman for GSK, explains that while his company

was aware of the FDAMA, they were unaware of its requirements. Explaining why the

GSK failed to list trials under the company’s name (even though that is explicitly

mandated by the law): he told The Washington Post, “We didn’t understand that to be a

requirement or the sort of information that is of use to a patient looking into where that

patient might enroll in a trial.”107

Indeed, both the FDAMA’s lack of an enforcement mechanism and its lack of

funding to ensure compliance significantly limit the law’s influence of industry behavior.

As The Washington Post reported in 2004, “The FDA acknowledges it has not enforced
102 Theresa Toigo, “Food and Drug Modernization Act (FDAMA) Section 113: Status Report on
Implementation.”
103 “Food and Drug Modernization Act (FDAMA) Section 113 and ClinicalTrials.gov,” Food and Drug
Administration.
104 “Behind Every New Medicine are the Volunteers. who Take Part in Clinical Research Studies,”
Available at: < http://www.fda.gov/oashi/clinicaltrials/psa2005/lowres.pdf>.
105 “Registering Clinical Trials With ClinicalTrials.gov,” available at:
<http://prsinfo.clinicaltrials.gov/registering.pdf>.
106 Catherine De Angelis cited in Shankar Vedantam, “Drug Makers Prefer Silence on Test Data.”
107 Shankar Vedantam, “Drug Makers Prefer Silence on Test Data.” It is noteworthy that Koenig’s
explanation alludes to the FDAMA’s primary focus on patient access, as discussed in Part II of this paper.

33
the law – officials said the statute did not spell out penalties or explicitly give the agency

the authority to crack down on violators.”108 Finally, the FDAMA is also limited to trials

for “serious conditions,” leaving a hole in the registry since a number of other trials are

unaffected by the law’s registration requirements.109 As a result of these shortcomings, in

an interview for this paper with Professor Kay Dickersin, she described the FDAMA as a

“flawed law.”110

Noncompliance with the FDAMA

Whether because of ignorance or willful disregard, the pharmaceutical industry

has had widespread noncompliance with the registration requirements of the FDAMA.

Dr. Jeffrey Drazen, editor of the New England Journal of Medicine, has accused

pharmaceutical companies of “making a mockery” of the government database at

ClinicalTrials.gov.111 The desired transparency at the website is lacking because

companies are either failing to list their trials, providing insufficient information, or

providing misleading information apparently intended to hide the reality of their trials.

Many clinical trials are still not registered at ClinicalTrials.gov despite the

FDAMA’s explicit requirements. In 2003, the FDA’s Office of Special Health Issues

analyzed the 366 commercial cancer protocols that the FDA received between January 1,

2002 and September 30, 2002 and determined that 187 of these would be required to be

108 Id.
109 Manheimer S. and Anderson E. “Survey of Public Information About Ongoing Clinical Trials Funded
by Industry: Evaluation of Completeness and Accessibility,” BMJ, 2002; 325; 528-31.
110 Interview with Kay Dickersin, August 31, 2006.
111 Rachel Zimmerman and Robert Tomsho, “Medical Editor Turns Activist On Drug Trials,” Wall Street
Journal, May 26, 2005, B.1.

34
listed in ClinicalTrials.gov.112 The FDA determined that of these 187 protocols that

should have been registered, only 48% of the pharmaceutical industry protocols were

registered. In contrast, 91% of NIH trials were submitted to ClinicalTrials.gov.113 In

2002, only 17 of 32 ongoing industry-funded prostate and colon cancer trials were

registered at ClinicalTrials.gov.114 This noncompliance is also evidenced by the fact that

companies continue to highlight pipelines of ongoing studies in their reports to

shareholders while not having listed any trials in the ClinicalTrials.gov registry.115

An additional issue is the problem of incomplete registrations where a sponsor

lists a trial but provides deficient information about the trial.116 In December 2005, Zarin

et al. found that companies were providing meaningless entries in the Intervention Name

field in the vast majority of registrations. While Merck improved its record over a period

of months during the study, GSK and Pfizer provided meaningless entries in this field

21% and 11% of the time, respectively.117 In a second measure studied, Zarin et al. found

that 24% of records left the Primary Outcome (results) field blank, and Novartis and

Merck completed this field only 3% and 20% of the time, respectively.118 In March 2006,

Zarin noted that since her report, industry had substantially improved its completion of

the Intervention Name field, but the companies had rarely improved their completion of

112 Derbis et al. “FDAMA Section 113: Information Program on Clinical Trials for Serious or Life
Threatening Diseases: Update on Implementation,” Poster presented at: 9th Annual FDA Science Forum;
April 24, 2003; Washington, DC cited in Dickersin and Rennie, “Registering Clinical Trials.”
113 Id.
114 Manheimer E and Anderson D, “Survey of Public Information About Ongoing Clinical Trials Funded
by Industry: Evaluation of Completeness and Accessibility.”
115 Shankar Vedantam, “Drug Makers Prefer Silence on Test Data.” While there are surely many
examples one could cite, to take one example reported in The Washington Post, Forest Laboratories
published a study showing positive results for its antidepressant drug, Celexa, at a time when it had no
trials registered with ClinicalTrials.gov.
116 Zarin et al., “Trial Registration at ClinicalTrials.gov between May and October 2005.” NEJM,
December 29, 2005, Vol. 353; 26: 2779-2787.
117 Id.
118 Id.

35
the Primary Outcome field.119 A representative for Pfizer argues in response that the “in

rare cases” it delays disclosure until proprietary issues are resolved - and that regulatory

agencies, IRBs, investigators, and enrolled patients all receive complete information.120

On the other hand, Dr. Drazen notes that Pfizer was responsible for a disproportionate

share of nonspecific entries in the Intervention Name field.121 In all cases, the fact that

most other companies were in full compliance weakens the possible argument that

commercial demands preclude full compliance.

The Success of the International Committee of Medical Journal Editors and its

Limitations

While the FDAMA has had rather mixed results in generating clinical trials

registration, an initiative by the International Committee of Medical Journal Editors has

had far more success. The ICMJE is a group of elite medical journals in which sponsors

and researchers would desire to publish their most significant research. In September

2004, the ICMJE issued a statement simultaneously in all of its member journals, that

each would require as a condition of consideration for publication that all trials be

registered in a registry meeting the ICMJE’s minimum registration requirements.122 The

ICMJE’s statement echoes the above descriptions of an ethical and practical duty to make

119 Zarin et al., Letter to the Editor, NEJM, Volume 354:1426-1429, March 30, 2006.
120 Joseph Feczko, Letter to the Editor, NEJM, Volume 354:1426-1429, March 30, 2006.
121 Jeffrey Drazen, Letter to the Editor, NEJM, Volume 354:1426-1429, March 30, 2006.
122 Catherine De Angelis et al., “Clinical Trial Registration: A Statement From the International
Committee of Medical Journal Editors,” JAMA, September 15, 2004, Vol. 292, No. 11. ICMJE’s
membership currently includes 12 leading general medical journals from around the world including:
Annals of Internal Medicine, Canadian Medical Association Journal, Croatian Medical Journal, JAMA,
Nederlands Tijdschrift voor Geneeskunde, New England Journal of Medicine, New Zealand Medical
Journal, The Lancet, The Medical Journal of Australia,Tidsskrift for Den Norske Llegeforening, and
Ugeskrift for Laeger. ICJME, “Frequently Asked Questions,” available at: <http://www.icmje.org/faq.pdf>.

36
all trials results public and the currently limited realization of this ideal.123

The ICMJE noted that at that time of its first statement, ClinicalTrials.gov was the

only registry to meet its requirements.124 At an April 2005 meeting, the World Health

Organization’s (WHO) registration advisory group created a 20-item data set of minimal

registration requirements. In June 2005, the ICMJE noted that these 20 items “address

every key item that we established in our September 2004 editorial” and announced that

it would formally adopt the WHO’s minimal data set as its requirement.125 In the wake of

the study by Zarin et al., the ICMJE made clear that acceptable completion of data fields

with meaningful information is a priority.126 Among the ICMJE requirements for trials

registries, its members emphasize:

The registry must be electronically searchable and accessible to the public at no

charge. It must be open to all registrants and not for profit. It must have a
mechanism to ensure the validity of the registration data.127

(See Appendix for a listing of the WHO/ICMJE minimal registration data set128 and a

comparison of WHO/ICMJE requirements with those required by ClinicalTrials.gov.129)

The ICMJE has achieved notable success in compelling companies to register

their clinical trials. In their study of registrations with ClinicalTrials.gov, Zarin et al.

attributed the 73% increase in trial registrations during their study to both industry and
123 The ICMJE’s statement cited ideals of “altruism and trust” in the research enterprise and the research
enterprise’s “obligation to conduct research ethically and report it honestly.” “Honest reporting,” it
continued, “begins with revealing the existence of all clinical studies, even those that reflect unfavorably on
a research sponsor’s product.” As for the status quo in September 2004, the ICJME commented, “We are
far from this ideal at present, since trial registration is largely voluntary, registry data sets and public access
to them varies, and registries contain only a small proportion of trials.” De Angelis et al., “Clinical Trial
Registration: A Statement From the International Committee of Medical Journal Editors.”
124 De Angelis et al., “Clinical Trial Registration: A Statement From the International Committee of
Medical Journal Editors.”
125 De Angelis, “Is This Clinical Trial Fully Registered?: A Statement from the International Committee
of Medical Journal Editors,” JAMA, June 15, 2005, Vol. 293, No. 23 at 2928.
126 Id. at 2928.
127 Id.
128 Id. at 2929.
129 “ClinicalTrials.gov Registration Requirements,” available at: <http://prsinfo.clinicaltrials.gov/trial-reg-
requirements.html>.

37
nonindustry data providers changing their behavior around the time of the ICMJE

deadline. Zarin et al. concluded, “Our findings support the conclusion that ICMJE policy

has had an effect on trial-registration practice…these new providers seem to have

registered in order to comply with ICMJE policy.”130

Despite the success of the ICMJE in instigating more frequent and accurate trial

registration, the ICMJE’s influence may not be a sufficient solution on its own. To begin

with, compliance with the ICMJE is not mandatory for all trials – only for those trials that

sponsors anticipate publishing. In addition, the ICMJE stops short of requiring that

companies post results when trials are completed – as the FACT Act would have

required.131 Moreover, some would criticize the fact that the ICMJE only requires listing

trials in Phase II and above.132

The case of ICMJE requirements regarding gag clauses is also instructive, as

ICMJE requirements have had only limited influence on industry behavior. In 2001, the

ICMJE revised its "Uniform Requirements for Manuscripts Submitted to Biomedical

Journals: Writing and Editing for Biomedical Publication" to require study authors to

disclose their role in studies. Subsequently, the editors from the ICMJE member journals

believed that “[m]any of us will ask the responsible author to sign a statement indicating

that he or she accepts full responsibility for the conduct of the trial, had access to the

data, and controlled the decision to publish.”133 Nevertheless, Duke University

130 Zarin et al., “Trial Registration at ClinicalTrials.gov between May and October 2005.” An editorial by
Jeffrey Drazen and Alastair Wood reflecting on the Zarin et al. study concurs that, “the ICJME requirement
that clinical trials be registered if they are to be considered for publication has been a resounding success.”
Jeffrey M. Drazen and Alastair J.J. Wood, “Trial Registration Report Card,” NEJM, December 29, 3005,
353;26.
131 Kate Fodor, “Trials of the Pharmaceutical Industry.”
132 See e.g. Rennie, ““Trial Registration: A Great Idea Switches From Ignored to Irresistible” (“[S]ince
there is a tendency for even phase 1 trials to be used for gathering data not only on safety but on efficacy as
well, trials at all phases should be registered”).
133 Davidoff F. et al., “Sponsorship, Authorship, and Accountability,” NEJM, 2001; 345; 825-827.

38
researchers in a 2002 survey of clinical trial agreements between medical schools and

industry sponsors found that, “[a]cademic institutions routinely engage in industry-

sponsored research that fails to adhere to ICMJE guidelines, regarding trial design, access

to data, and publication rights.134 Moreover, the NEJM reported that adherence to ICMJE

guidelines hardly improved as of 2005.135

Since the ICMJE guidelines had limited success in influencing gag clauses in

clinical trials agreements, ICMJE requirements for clinical trials registration may have

similar limitations. On the other hand, the ICMJE member journals may be more willing

to enforce its guidelines for clinical trials registration than those regarding gag clauses –

since these guidelines would primarily punish industry sponsors rather than academic

researchers. Moreover, compliance with the ICMJE checklist may be easier to monitor

without the hurdle of gaining access to academic institutions’ clinical trials agreements

with industry sponsors.

Thus, while the ICMJE policy has impacted trial registration, it has limitations

and may be only an incomplete solution to the issue of clinical trials registration.

Legislation, like the proposed FACT Act that provides an enforcement mechanism and

funding to ensure listing of trials with ClinicalTrials.gov, may still be necessary to

supplement the ICMJE guidelines.

134 Schulman KA et al., “A National Survey of Provisions in Clinical-Trial Agreements Between Medical
Schools and Industry Sponsors”, NEJM 2002; 347: 1335-1341.
135 For instance, despite the Duke Clinical Research Institute’s creation of model contract language for
clinical trial agreements, standardized agreements have yet to be adopted by most medical schools and
academic medical centers (AMCs). The NEJM reports:
In 2005, has anything changed? The short answer is no. Dr. Robert M. Califf, the director of the
Duke Clinical Research Institute, noted recently, "I do not see any evidence that the average
contract of a site participating in a multicenter study is any better now than when we wrote the
article." According to Dr. Steven E. Nissen, the director of the Cleveland Clinic Cardiovascular
Coordinating Center, "There has been little progress. The main reason is that commercial sponsors
still exclusively control the database for most clinical trials.”
Robert Steinbrook, “Gag Clauses in Clinical-Trial Agreements.”

39
The European Experience

While the focus of this paper is on clinical trials registration in the U.S., it is

helpful to examine Europe’s experience with clinical trials registries and the lessons for

the U.S. Like the multitude of private registries in the United States, Europe has

witnessed the proliferation of disparate registries with varying characteristics and limited

access.136 Europe has also had problems with compliance that parallel the U.S.

experience.137 A 2002 editorial in the British Medical Journal, entitled “A Clinical Trials

Register for Europe: Stop Talking and Start Making it Happen” lamented:

[T]he European effort adds up to little more than a proliferation of national

registers, many of which are confined to trials of new drugs and closed to
everyone but the national regulatory body for medicines. Information about
ongoing clinical trials remains inaccessible to the people who need it most.138

136 As Charlotte Haug Peter C. Gøtzsche, and Torben V. Schroeder summarized in December 2005:
[P]ublicly accessible national registries of clinical trials have been established in several European
countries, Japan, and Australia. There has also been a proliferation of registries based on trials
involving specific diseases. In addition to public registration, the confidential registration of most
clinical trials already exists in France, Italy, Spain, and the Netherlands.
Haug C., Gotzshe P., and Schroeder T., “Registries and Registration of Clinical Trials,” NEJM, December
29, 2005, 353; 26. Spain, for instance, has created a database of clinical trials since the 1980s by
leveraging data from a 1982 Ministerial Order required that all protocols involving INDs be approved
before implementation. However, Spain’s registry is not publicly accessible and is only available to an
ethics committee. Kay Dickersin and Fernando Garcia-Lopez, “Regulatory Process Effects Clinical Trial
Registration in Spain,” Controlled Clinical Trials 13:507-512 (1992); Reynolds, “Researchers Push for
Publication, Registration of All Clinical Trials,” The United Kingdom, the Netherlands, and Germany have
all endeavored to establish clinical trials registries. In the United Kingdom, all National Health Service
(NHS) trials must be registered publicly in order to receive Medical Research Council funding. Tom
Reynolds, “Researchers Push for Publication, Registration of All Clinical Trials”; “A Clinical Trials
Register for Europe: Stop Talking and Start Making It Happen,” Editorial, BMJ, Vol. 325, December 7,
2002.
137 In May 2003, the Association of the British Pharmaceutical Industry (ABPI) established a voluntary
register of phase III and phase IV clinical trials in the U.K. However, the first fifteen months of experience
with this voluntary registry yielded listings from just six out of the 40 pharmaceutical companies expected
to participate, and very few trials or drugs were listed. The information provided in the early experience
with the APBI falls well short of what the ABPI press release initially promised. Rennie, “Trial
Registration: A Great Idea Switches From Ignored to Irresistible.”
138 ‘A Clinical Trials Register for Europe: Stop Talking and Start Making It Happen,” Editorial, BMJ, Vol.
325, December 7, 2002.

40
 With mixed success, Europe is attempting to address the challenge of creating

pan-European clinical trial registration. Following over a decade of European meetings

to discuss trial registration,139 the European Union passed legislation requiring that:

Since May 2004, all clinical trials conducted in member states of the European
Union had to be registered in the EudraCT database, supervised by the European
Medicines Agency.140

However, the EudraCT registry is not publicly accessible, as it is only available to

regulatory bodies and research funding organizations. In December 2005, a group of

European authors concluded, “Unfortunately, no pan-European agreement has been

struck with regard to how to move forward with public registration of clinical trials.”141

However, since 1998, a private company Current Controlled Trials (CCT) has

been providing a freely searchable database of clinical trial known as the metaRegister of

Controlled Trials (mRCT) using a unique identifier scheme known as the International

Standard Randomized Controlled Trial Number (ISRCTN).142 Current Controlled Trials

has received support from the European Science Foundation (ESF),143 and it is a broad

composite of at least 26 registers from 4 continents (as of June 26, 2003), including

ClinicalTrials.gov.144 Current Controlled Trials and ClinicalTrials.gov request similar

information, although ClinicalTrials.gov requests certain information that may more

easily facilitate patient enrollment. (See Appendix for a comparison of “Trial Details

Requested by Current Controlled Trials and ClinicalTrials.gov.”145) Since being

139 The first European meetings to discuss trial registration were held in 1991, and in 2001 and 2002 the
European Science Foundation provided broad support for requiring trial registration as a condition of
public funding, as well as contributing to an international meta-register of controlled trials, and using
unique trial identification numbers. Dickersin and Rennie, “Registering Clinical Trials” at 519.
140 Haug C., Gotzshe P., and Schroeder T., “Registries and Registration of Clinical Trials.”
141 Id.
142 Current Controlled Trials, available at: <http://www.controlled-trials.com/>.
143 “A Clinical Trials Register for Europe: Stop Talking and Start Making It Happen.” Editorial, BMJ,
Vol. 325, December 7, 2002.
144 Dickersin and Rennie, “Registering Clinical Trials” at 519.
145 Id. at 520.

41
transferred to non-profit ownership, Current Controlled Trials meets all the ICMJE

requirements. However, sponsors must voluntarily register with Current Controlled

Trials for their trials to be listed, and the registry charges a fee for registration.146 These

current limitations of Current Controlled Trials may likely mean that many in Europe

will continue to call for a mandatory, publicly accessible, pan-European register.

PART V: Barriers and Proposals

Given that the status quo has resulted in mixed success in promoting clinical trials

registration, debates continue about whether to expand the scope of clinical trials

registries and how best to do so. Before considering these proposals, it is helpful to

consider the barriers that stand in the way of initiatives to increase registration.

The primary barriers to expanding clinical trials registration are industry

resistance and lack of enforcement. This section will explore these barriers in depth.

Before doing so, it is worth noting three additional barriers up front. First, there are

practical difficulties in establishing an effective registry that is comprehensive and

accessible and easy to navigate.147 A second barrier is lack of funding for the costs of

developing registries, enforcing compliance, and covering the costs of registration.

Though not insignificant, neither of these barriers should be insurmountable. Registries

are already handling the practical challenges of implementation, and the costs of

registration are relatively minor in comparison to the pharmaceutical industry’s overall

146 Haug et al., “Registries and Registration of Clinical Trials.”

147 Dickersin cited in Reynolds, “Researchers Push for Publication, Registration of All Clinical Trials.”
For a discussion of the design and development challenges faced by its creators, see Alexa T. McCray and
Nicholas C. Ide, “Design and Implementation of a National Clinical Trials Registry,” Journal of the
American Medical Informatics Association 7:313-323 (2000).

42
budget.148 Moreover, as Dickersin and Rennie note, “the savings to society effected by a

comprehensive register would exceed many-fold the money that is at present wasted on

inaccessible and unnecessarily duplicative knowledge.”149 Finally, a third barrier is a

general lack of awareness about the existence of clinical trial registries.150 As clinical

ClinicalTrials.gov expands its scope and trials registration becomes more widespread,

awareness may increase. Ironically, if clinical trials registration becomes more

contentious, greater coverage in medical journals and the lay press may also generate

increased awareness.

Industry Resistance and Noncompliance

There is reason to believe that industry benefits from registering clinical trials.

Registering trials online facilitates patient enrollment. It also can help avoid public

relations difficulties. One study of a pharmaceutical company’s experience with a

clinical trials register encourages pharmaceutical companies to develop trial registers in

anticipation of enjoying net benefits from establishing those registers.151

Nevertheless, as the initial experience of FDAMA demonstrates, industry does not

readily comply with registration that is voluntary or lacking an enforcement mechanism.

148 Current Controlled Trials estimated that its expenses totaled approximately $830,000 between 1998
and July 2003 in comparison with, for instance, pharmaceutical spending on research and development that
totaled $30.3 billion in 2001. Dickersin and Rennie, “Registering Clinical Trials” at 520 citing Iain
Chalmers written communication, May 27, 2002.
149 Dickersin and Rennie, “Registering Clinical Trials” at 520. Drummond Rennie adds, “The financial
cost of an effective, independent, and transparent clinical trial register would amount to a tiny fraction of
the costs of the trials themselves, or the costs of not knowing their results, while the personal costs of
allowing the present chaotic system to continue are incalculable.” Rennie, “Trial Registration: A Great Idea
Switches From Ignored to Irresistible.”
150 Dickersin and Rennie, “Registering Clinical Trials” at 521.
151 Gibbs T.G. and Wagner E., “Realities of Trial Registration: The Glaxo Wellcome Experience,”
International Journal of Pharmaceutical Medicine, 14(4): 203-205, 2000. The Glaxo Wellcome registry
studied was established in 1999 and may have been abandoned following the company’s merger.

43
Pharmaceutical companies may wish to avoid the hassle of registering trials152 or they

may wish to avoid disclosing the focus of their research or their research methods to

competitors. This concern is especially poignant with regard to calls for requiring

registration of protocols (as required by the FACT Act).153 Companies may worry about

losing trade secrets or competitors encroaching on their patient networks.154 More

cynically, they may wish to avoid receiving additional patient petitions for medicines on

“compassionate grounds.”155 In a competitive industry, companies will resist any threat

to their competitive edge.156

If it is going to register clinical trials, industry prefers that this initiative be

voluntary. Therefore, industry claims to support voluntary registration of clinical trials.157

However, the ICMJE has concluded that, “Volunteer doesn’t work”158 Drummond

Rennie echoes this assessment in condemning the possibility of an enduring status quo of
152 Alison Tonks, an associate editor at the British Medical Journal, writes, “In an ideal world people
would declare their trials for the greater good, to help with recruitment, and to make their work more
visible. In reality, a few extra forms on top of the mountain of paper work already generated by a trial are
often too much.” “A Clinical Trials Register for Europe: Stop Talking and Start Making It Happen,”
Editorial, BMJ, Vol. 325, December 7, 2002.
153 Alan Goldhammer, associate vice president for regulatory affairs for PhRMA, explains, “Companies
are not going to want to disclose a protocol in a public venue so that competitors will have a good
understanding of their drug-development program.” Alan Goldhammer cited in Kate Fodor, “Trials of the
Pharmaceutical Industry.”
154 Kay Dickersin cited in Shankar Vedantam, “Drug Makers Prefer Silence on Test Data.”
155 Kay Dickersin cited in Shankar Vedantam, “Drug Makers Prefer Silence on Test Data.”
156 Again, the experience of gag clauses is instructive. The reluctance of academic medical centers to
fully comply with ICMJE guidelines regarding gag clauses and clinical trials registration is understandable
since institutions compete for industry’s clinical trials contracts. Dr. Robert Steinbrook reports in the
NEJM:
An academic institution whose standards for access to data and publication rights are stricter than
those of its competitors may lose trials -- unless it has access to unique groups of patients or its
researchers have some unique expertise.
Dr. C. David Naylor, dean of the University of Toronto Faculty of Medicine agrees with this assessment
and asserts that the University of Toronto has lost clinical trials contracts because its standards for those
contracts prevent sponsors from suppressing results and retain researchers’ rights to disclose safety issues
discovered during a study. Robert Steinbrook, “Gag Clauses in Clinical-Trial Agreements,”
157 PhRMA claims it “strongly supported establishing [ClinicalTrials.gov] and has actively encouraged
[its] member companies to participate.” ClinicalStudyResults.org, “Differences Between the Clinical Study
Results Database and a Clinical Trials Registry,” Available at
<http://www.clinicalstudyresults.org/primers/registry_differences.php>.
158 De Angelis et al., “Clinical Trial Registration: A Statement From the International Committee of
Medical Journal Editors.”

44
myriad private registries without new legislation creating an enforcement mechanism.

The worst outcome would be for some companies to forestall legislation by

announcing individual registers that are obscure, hard to access, idiosyncratic in
the sorts of data they post, contain only what marketing departments allow them
to contain, and are temporary and dependent on the company’s institutional
memory and will.159

He continues:

Widespread flouting of the law of 1997 showed that a central register cannot work
unless it…is made mandatory…and unless all aspects of the enterprise are taken
out of the hands of the pharmaceutical industry.160

Even though industry generally complies with the FDA, it can be expected to

resist any threats to its self-regulation – sometimes through subtle means. For example,

when PhRMA launched a database of results from Phase III and IV trials at

ClinicalStudyResults.org, some viewed this initiative as a half-hearted “apparent effort to

forestall legislation of the FACT Act”161 Other forms of industry resistance may be more

direct. Abbey S. Meyers, president of the National Organization for Rare Disorders,

notes the significant barrier that industry will place in the way of implementing an

enforcement mechanism for clinical trials registration:

Obviously [the FDAMA] needs an enforcement mechanism attached to it…I can

guarantee you, however, that the full force of the drug industry will stop it. They
don’t want you to know about clinical trials that fail. They are afraid what it will
do to their stock price. A lot of trials are for drugs already on the market, and it
would ruin their sales if the news got out.162

Proposals for Expanding Clinical Trials Registries and the Push for a Worldwide

Standard or International Clinical Trials Registry

159 Rennie, “Trial Registration: A Great Idea Switches From Ignored to Irresistible.”
160 Id.
161 www.ClinicalStudyResults.org; Kate Fodor, “Trials of the Pharmaceutical Industry.” This assessment
gained credibility when the site contained very few studies for a number of months, although PhRMA
claimed that companies had committed to participate and that the database would grow with time.
162 Abbey S. Meyers cited in Shankar Vedantam, “Drug Makers Prefer Silence on Test Data.”

45
 Despite barriers such as industry resistance, advocates for expanding the scope

and impact of clinical registration recommend a number of proposals.

Expanding Enforcement

The first such proposal is to add an enforcement mechanism to the requirements

of the FDAMA. As noted earlier, the FDAMA failed to provide the FDA with the power

to punish companies for failing to register their trials or register them with complete,

accurate information. Nor did the FDAMA provide funding for the FDA to monitor and

enforce compliance. As a result, while industry may register an increasing percentage of

its trials, “industry also knows that any adverse consequences of failure to comply fully

with the mandate are unlikely.”163

Proponents of expanding enforcement have suggested a variety of proposals. As

the FACT Act would have established, Congress could impose civil penalties for failure

to register. Journals beyond the ICMJE could require that trials are registered with

ClinicalTrials.gov as a condition of accepting studies for publication. 164 IRBs could

require registration with an approved database as a condition of approving trials.165

Private market solutions may also evolve; companies such as the MedicoLegal

Investigations in the U.K. are beginning to provide governments with solutions for

investigating underreporting.166

163 Dickersin and Rennie, “Registering Clinical Trials” at 520.

164 Id.
165 Id.
166 Peter Jay, “Compulsory Registration of Clinical Trials Under-Reporting is Not an Option,” BMJ,
329:1044 (2004). Jay writes, “To date, MedicoLegal Investigations has not been called on to investigate
biased under-reporting of research, but we believe it is just a matter of time.”

46
 Expanding enforcement appears to be a reasonable proposal since Congress has

produced the strange situation of a law without an enforcement mechanism. If Congress

is serious about requiring trial registration, then it will provide enforcement authority and

funding to ensure registration in practice. One important challenge would be to ensure

that enforcement measures do not prevent effective drugs from reaching patients.

Therefore, Congress would do best to impose mainly financial penalties that do not

prevent companies from receiving approval for effective drugs. On the other hand, the

AMA argues that even financial penalties would be unnecessary if Congress tied IRB

approval to whether studies are registered.167 As Dickersin and Rennie conclude:

Legislation mandating funding, and enforcing registration of all clinical trials

initiated in the United States is needed immediately. The mandate must carry
with it sufficient funding for start-up and continuation, as well as assignment of
the authority to monitor the process and to take action against those not
complying with the law.168

Requiring the Registration of Results and Protocols

Secondly, governments and medical journals could require that companies

register the results of their trials.

The ICMJE does not currently require trial sponsors to publish their results. The

FACT Act, however, would have required their listing. However, the value of requiring

the listing of results is debatable. There are questions about how extensive the published

results should be – Should they include only primary endpoints? Should they include

secondary endpoints or beyond? There is also cause for concern about whether patients

167 Kate Fodor, “Trials of the Pharmaceutical Industry.”

168 Dickersin and Rennie, “Registering Clinical Trials” at 522.

47
are capable of benefiting from published results – or may even be harmed by them.

Patients may misinterpret results and modify their drug regimen in an inappropriate

manner. Moreover, given the influential nature of results, there are particular concerns

about their reliability. According to Gregory Curfman, executive editor of NEJM, the

ICMJE declined to require that sponsors publish trial results since posted results would

not be subject to peer review:

There was concern that the results might not have undergone an unbiased peer
review and would just be any old results that a drug company wanted to put up…
It’s our experience that you can’t really trust those kinds of results, to be perfectly
frank.”169

However, ICMJE editors felt that the requirement that registered trials have unique

identification numbers “would go a long way to prevent results from being buried

later.”170

A similar solution would be to require that companies publish their trial protocols.

Registration of protocols also would have been required by the FACT Act. Marissa

Lassere and Kent Johnson have argued that registration of clinical trials is insufficient

without the additional listing of trial protocols. Protocols, they argue are necessary to

prevent manipulation of results and analysis of those results. In 2002, Lassere and

Johnson published a commentary in Lancet arguing for a clever plan in which a third

party would sequester trial results while the trial is still ongoing, results would be made

available only to reviewers when a sponsor submits results for publication, and results

would only be made available to the general public thereafter.171 While this plan would

help protect proprietary information during drug development, the pharmaceutical

169 Gregory Curfman cited in Kate Fodor, “Trials of the Pharmaceutical Industry.”
170 Id.
171 Marissa Lassere and Kent Johnson, “The Power of Protocol,” Lancet, 360; 9346; 1620-1622
(November 2002).

48
industry could still be expected to strongly oppose any requirement that they publicize

their trial protocols for their competitors to view, even after a trial’s completion. In

addition, there are similar questions about whether the general public would

misunderstand trial protocols. Finally, although a somewhat tangential concern for

academics but certainly not for drug companies, full transparency about trial protocols

and results may demonstrate ambiguity in scientific research and undermine the public’s

confidence in the pharmaceutical industry as a whole.

A Worldwide Standard or International Clinical Trials Registry

Finally, advocates have proposed creating a comprehensive worldwide clinical

trials database using internationally recognized standards for registration. The Ottawa

Group – a group of “investigators, consumers, journal editors, policymakers, and industry

representatives” – met in Ottawa, Canada on October 4, 2004 and subsequently drafted

the Ottawa Statement calling for an international clinical trials registry.172 Parts 1 and 2

of the statement have been completed and define both the rationale and the proposed

contents of the proposed clinical trials registry, and Part 3 is in development.

For proponents of a single comprehensive registry for U.S. clinical trials, creating

an international clinical trials database or at least a single worldwide standard for national

registries is an obvious next step. It would avoid repeating the problems associated with

multiple clinical trials registries on an international scale. In 2005, the ICMJE endorsed

the concept of facilitating collaboration across international trial registries; its member

journal editors concluded, “[A] worldwide uniform standard for a minimal database is

172 “Ottawa Statement on Clinical Trial Registration,” available at:

<http://ottawagroup.ohri.ca/background.html>.

49
necessary.”173

PART VI: The Future of Clinical Trials Registration

Enforcement of Registration and Centralization or Coordination of Registration Data

While this paper provides a clearer picture of the status quo for clinical trial

registration, the historical perspective in the early sections of this paper is especially

helpful for understanding that status quo. The landscape for clinical trials registries has

changed dramatically since 1997 when the FDAMA was passed – and even more

dramatically since the decades before the FDAMA. In 1997, access to clinical trials was

the primary concern of lawmakers. Today, patient safety – via greater trial transparency

and data availability, along with reduced publication bias, undisclosed results, duplicate

publication, and selective publication – has become the primary concern. The mounting

stories of hidden data, noncompliance, and patient injuries or deaths also parallel the

kinds of threats to patient safety that have historically prefaced and helped produce prior

regulatory expansions. Since patient safety has historically been the primary driver of

increased FDA regulation, this current focus on patient safety is likely to instigate

expanded requirements for registering clinical trials and for the contents of registration.

While there are a number of competing proposals and significant barriers to

overcome, the most likely forms of regulation to follow in the near future will focus on:

1) Enforcement of registration and 2) Centralization or coordination of registration data.

173 De Angelis, “Is This Clinical Trial Fully Registered?: A Statement from the International Committee
of Medical Journal Editors.”

50
 Enforcement is a critical missing link from the FDAMA. Future regulation is

likely to focus on ensuring that sponsors register their trials and provide accurate

representations of information from those trials. The most likely enforcement mechanism

appears to be civil fraud penalties for omissions or misrepresentations since financial

penalties would be minimally disruptive to patients’ access to drugs.

Centralization or coordination of registration data will also be high on the

regulatory agenda. These solutions will respond to the difficulties associated with the

multitude of disparate clinical trials registries that currently exists. Centralization and

coordination represent distinct alternatives on an ideological spectrum. Pharmaceutical

companies will likely advocate very strongly for maintaining private registries and for

coordination of those registries’ data rather than centralization in single data bank.

Centralization, however, might occur if the need appears especially strong, and it would

not be unprecedented. The NIH currently maintains the GenBank database which serves

as a repository for over 100,000 different organisms’ genetic sequences.174 If it serves the

public interest to coordinate all clinical trials registration data in a single repository, it is

possible that ClinicalTrials.gov might be expanded to include all registration data in a

database that parallels GenBank.

The Importance of Patient Advocacy – and its Challenges

The role of patient advocacy, which was so critical in the case of HIV/AIDS

during the 1980s, is equally decisive in contemporary debates over clinical trials

registration. While patient demand for access to trials is already high, patients are only

174 Dickersin and Rennie, “Registering Clinical Trials” at 521.

51
beginning to develop a unified voice in favor of trial registration in the name of safety.

The recent Paxil litigation along with the increasing salience of years of academic

research on the dangers of undisclosed trials and biased or selective publication are

generating increased interest in clinical trials and skepticism of the pharmaceutical

industry, as evidenced by numerous headlines in the mainstream press. Moreover,

patients have experience challenging the pharmaceutical industry in recent years over

topics such as drug reimportation and patents in developing nations. Advocates of

clinical trials registries recognize that patients are not merely interested in clinical trials

on a macro level – they are also essential participants in each individual clinical trial.

Thus, some have argued that patients can have their greatest influence by not agreeing to

enroll in a trial unless it is registered.175

The power dynamic between patients and the scientific establishment, so critical

in the context of HIV/AIDS, is once again a fundamental issue in the context of clinical

trials registration. The experience of HIV/AIDS was that activism helped advance

science but also bumped up against limits when it began to threaten the quality of

scientific research.

Patients will again seek to find a balance between challenging the scientific

establishment by creating transparency and accountability and protecting innovation and

competition in the pharmaceutical industry. To achieve the ideals of clinical trials

registration, patients must seek to advance a more transparent, trusted, and responsive

form of science, while protecting drugs companies’ incentives and even unique

175 Kay Dickersin encourages patients to wield the power of nonparticipation in trials in order to influence
companies’ registration behavior: “One way to increase registration, said Dickersin, is for patients to insist
trials be registered before participating.” Shankar Vedantam, “Drug Makers Prefer Silence on Test Data”;
See also Drazen and Wood, “Trial Registration Report Card,” (“If a company continues to register trials
using meaningless data, with no respect for the registration process and the patients who participate in those
trials, investigators and patients should refuse to participate.”)

52
characteristics in producing the most advanced and cutting edge pharmaceutical products.

53
 APPENDIX

Note: The contents of this appendix are materials drawn from other sources.
They are included for reference purposes only. They are not presented as my own work.

Section 113 of the Food and Drug Administration Modernization Act of 1997176

Sec. 113. INFORMATION PROGRAM ON CLINICAL TRIALS FOR SERIOUS OR

LIFE-THREATENING DISEASES.

(a) In General.--Section 402 of the Public Health Service Act (42 U.S.C. 282) is
amended--

(1) by redesignating subsections (j) and (k) as subsections (k) and (l), respectively; and

(2) by inserting after subsection (i) the following:

"(j)(1)(A) The Secretary, acting through the Director of NIH, shall establish, maintain,
and operate a data bank of information on clinical trials for drugs for serious or life-
threatening diseases and conditions (in this subsection referred to as the 'data bank'). The
activities of the data bank shall be integrated and coordinated with related activities of
other agencies of the Department of Health and Human Services, and to the extent
practicable, coordinated with other data banks containing similar information.

"(B) The Secretary shall establish the data bank after consultation with the
Commissioner of Food and Drugs, the directors of the appropriate agencies of the
National Institutes of Health (including the National Library of Medicine), and the
Director of the Centers for Disease Control and Prevention.

"(2) In carrying out paragraph (1), the Secretary shall collect, catalog, store, and
disseminate the information described in such paragraph. The Secretary shall disseminate
such information through information systems, which shall include toll-free telephone
communications, available to individuals with serious or life-threatening diseases and
conditions, to other members of the public, to health care providers, and to researchers.

"(3) The data bank shall include the following:

"(A) A registry of clinical trials (whether federally or privately funded) of

experimental treatments for serious or life-threatening diseases and conditions under
regulations promulgated pursuant to section 505(i) of the Federal Food, Drug, and
Cosmetic Act, which provides a description of the purpose of each experimental drug,
176 Food and Drug Administration Modernization Act of 1997, P. L. 105-115.

54
either with the consent of the protocol sponsor, or when a trial to test effectiveness
begins. Information provided shall consist of eligibility criteria for participation in the
clinical trials, a description of the location of trial sites, and a point of contact for those
wanting to enroll in the trial, and shall be in a form that can be readily understood by
members of the public. Such information shall be forwarded to the data bank by the
sponsor of the trial not later than 21 days after the approval of the protocol.

"(B) Information pertaining to experimental treatments for serious or life-threatening

diseases and conditions that may be available--

"(i) under a treatment investigational new drug application that has been submitted to
the Secretary under section 561(c) of the Federal Food, Drug, and Cosmetic Act; or

"(ii) as a Group C cancer drug (as defined by the National Cancer Institute).

The data bank may also include information pertaining to the results of clinical trials of
such treatments, with the consent of the sponsor, including information concerning
potential toxicities or adverse effects associated with the use or administration of such
experimental treatments.

"(4) The data bank shall not include information relating to an investigation if the
sponsor has provided a detailed certification to the Secretary that disclosure of such
information would substantially interfere with the timely enrollment of subjects in the
investigation, unless the Secretary, after the receipt of the certification, provides the
sponsor with a detailed written determination that such disclosure would not substantially
interfere with such enrollment.

"(5) For the purpose of carrying out this subsection, there are authorized to be
appropriated such sums as may be necessary. Fees collected under section 736 of the
Federal Food, Drug, and Cosmetic Act shall not be used in carrying out this subsection.".

(b) Collaboration and Report.--

(1) In general.-- The Secretary of Health and Human Services, the Director of the
National Institutes of Health, and the Commissioner of Food and Drugs shall collaborate
to determine the feasibility of including device investigations within the scope of the data
bank under section 402(j) of the Public Health Service Act.

(2) Report.-- Not later than two years after the date of enactment of this section, the
Secretary of Health and Human Services shall prepare and submit to the Committee on
Labor and Human Resources of the Senate and the Committee on Commerce of the
House of Representatives a report--

(A) of the public health need, if any, for inclusion of device investigations within the
scope of the data bank under section 402(j) of the Public Health Service Act;

55
 (B) on the adverse impact, if any, on device innovation and research in the United
States if information relating to such device investigations is required to be publicly
disclosed; and

(C) on such other issues relating to such section 402(j) as the Secretary determines to
be appropriate.

Examples of Selective and Inadequate Outcome Reporting in Randomized Trials177

[redacted]

Proposed Information to be Included in the Clinical Trials Data Bank

Under the Fair Access to Clinical Trials (FACT) Act178

[redacted]

“Selected Events Supporting and Leading to Trial Registration”179

[redacted]

177 Chan et al. “Empirical Evidence for Selective Reporting of Outcomes in Randomized Trials:
Comparison of Protocols to Published Articles” at 2462.
178 Robert Steinbrook, “Registration of Clinical Trials – Voluntary or Mandatory?” NEJM, 351; 18: 1820-
1822 (2004).
179 Dickersin and Rennie, “Registering Clinical Trials” at 518.

56
 Registration Requirements at ClinicalTrials.gov –
As Compared with Additional WHO/ICMJE Requirements (July 2005)180

* Required by ClinicalTrials.gov.
WHO Additionally required by WHO/ICMJE. For more information see
WHO Minimal Data Set.

Required by Data Element Comments

Descriptive Information
* Brief Title (lay language)
WHO Official Title
* Brief Summary (lay language)
Detailed Description
* Study Phase
* Study Type (Interventional/Observational)
* Study Design
WHO Primary Outcome Measure(s)
WHO Secondary Outcome Measure(s)
* Condition(s)
* Intervention: Type/Name
MEDLINE PMID: Citation/Results Reference
Link: URL/Description
Recruitment Information
* Overall Recruitment Status
WHO Start Date
Completion Date
Other Dates
* Eligibility Criteria
* Gender
* Age: Minimum/Maximum
Accepts Healthy Volunteers?
WHO Target Number of Subjects

180 “ClinicalTrials.gov Registration Requirements,” available at: <http://prsinfo.clinicaltrials.gov/trial-reg-

requirements.html>.

57
Location and Contact Information
* Facility Location
* Facility Recruitment Status
* Contact Information (Central or per Facility)
Facility Investigators
* Overall Study Official(s) Not required for FDA
IND/IDE trials.
Administrative Data
* Unique Protocol ID Assigned by sponsor.
WHO Secondary ID(s) May be none.
* FDA IND/IDE Protocol? (yes/no) Not made public.
Additional information
required for IND/IDE
trials.
* Human Subjects Review/Oversight Not made public. Not
required for IND/IDE
trials.
* Study Sponsor
WHO Collaborators
* Record Verification Date
* First Received Date Assigned by system.

58
 FDA Outreach Materials for Patients181 and Researchers182

[redacted]

WHO/ICMJE Minimal Registration Data Set183

[redacted]

“Trial Details Requested by Current Controlled Trials and ClinicalTrials.gov”184

[redacted]

181 “Behind Every New Medicine are the Volunteers. who Take Part in Clinical Research Studies,”
Available at: < http://www.fda.gov/oashi/clinicaltrials/psa2005/lowres.pdf>.
182 “Registering Clinical Trials With ClinicalTrials.gov,” available at:
<http://prsinfo.clinicaltrials.gov/registering.pdf>.
183 De Angelis, “Is This Clinical Trial Fully Registered?: A Statement from the International Committee
of Medical Journal Editors,” JAMA, June 15, 2005, Vol. 293, No. 23 at 2929.
184 Dickersin and Rennie, “Registering Clinical Trials” at 520.

59