Order Code RS21944
Updated February 14, 2005
CRS Report for Congress
Received through the CRS Web
Clinical Trials Reporting and Publication
Erin Williams and Susan Thaul
Specialists in Social Legislation
Domestic Social Policy Division
In 2004, concerns arose that certain antidepressants, other medicines (e.g., Vioxx),
and medical devices (e.g., coronary stents), had been marketed to consumers despite
unresolved safety issues. Data from clinical trials conducted both before and after a
product goes to market are central to assessing its safety and effectiveness, but there is
currently no centralized system for reporting results. Due to medical journal practices
and drug sponsor and researcher incentives to publicize positive results, many trials with
inconclusive or negative results are not publically reported. Although Food and Drug
Administration (FDA) regulations require sponsors of trials that test the effectiveness
of new drugs for serious or life-threatening conditions to register with the Department
of Health and Human Services (HHS) at clinicaltrials.gov, not all such trials are listed
there. A voluntary registry of recent controlled trials results was created in October
2004 by the Pharmaceutical Research and Manufacturers of America (PhRMA).
Several groups have called for public access to standardized clinical trials data,
including notice of trial launch and research results through a centralized system such
as a registry. Proposals for registries for these purposes raise issues regarding the goals
of public access, the appropriateness and presentation of information, the timing of a
trial’s inclusion, whether they will compromise intellectual property rights, whether
reporting should be mandatory, potential conflicts of interest, and whether medical
device trials should be included.
In October 2004, Representative Edward Markey and Senator Christopher Dodd
introduced companion bills H.R. 5252 and S. 2933, the Fair Access to Clinical Trials
Act, which would have required registration of clinical trials before the enrollment of
human subjects, and the subsequent posting of results, at clinicaltrials.gov or a similar
forum. Similar legislation is likely to be introduced in the 109th Congress. This report
will be updated on a regular basis.
In 2004, Congress and others raised questions about the safety and effectiveness of
several FDA-approved biomedical products on the market. These included certain
antidepressants, Merck’s pain relief drug, Vioxx, Boston Scientific’s cardiac stents, and
other drugs and medical devices. Discussion about ways to help ensure safety and
Congressional Research Service ˜ The Library of Congress
effectiveness of biomedical products focused primarily on two questions: whether data
from all clinical trials should be made publically available, and whether FDA’s processes
for product approval and post-market surveillance and study are adequate. This report
focuses on the first of these questions.
Clinical trials, which are the gold standard for assessing drug and device safety and
effectiveness both before and after they are marketed in the United States, are scientific
studies that systematically test interventions on human beings. They may include
behavioral studies or other biomedical investigations, such as those that test drugs and
medical devices. As described by FDA, clinical trials are generally conducted in four
phases following successful animal testing.1 Phase I trials study a new drug or device in
a small group of people (20-80) to evaluate its safety, determine a dosage range for drugs,
and identify gross side effects. Phase II trials study the product in a larger group of people
(100-300) to see if it is effective for a specific purpose and to further evaluate its safety.
Phase III trials investigate the product in a large group of people (1,000-3,000), to confirm
the product’s effectiveness, monitor side effects, and collect information that will allow
the drug, treatment or device to be used safely. Phase IV trials are usually large-scale
studies, conducted after the FDA approves a product for marketing in order to
demonstrate effectiveness in a broader clinical context and to watch for rare side effects
that may not be identified until a significant number of people have used the product.
The federal government has historically regulated certain aspects of some clinical
trials by attaching conditions to those conducted with federal research funds, and/or by
creating requirements that must be met before a drug or device can be marketed in the
United States. Most federal funding occurs through HHS’ National Institutes of Health.
Both pre-market approval and post-market monitoring of medical drugs and devices
marketed in the US are the responsibility of HHS’ FDA. Each FDA center that reviews
and approves biomedical products for human use — the Center for Drug Evaluation and
Research, the Center for Devices and Radiological Health, and the Center for Biologics
Evaluation and Research — posts summaries of safety and effectiveness data from
clinical trials that support approved applications for new products, or new uses of
approved products; FDA does not otherwise post clinical trials data.
The FDA Modernization Act of 1997 (FDAMA, P.L. 105-115, Section 113) required
the Secretary of HHS to establish a clinical trials registry, intending the availability of
information to increase the access of individuals to cutting-edge medical care available
only through research protocols. Sponsors of trials testing the effectiveness of
life-threatening disease or condition treatments (drug and biological products, but not
devices) that are either not yet on the market, or are new uses of treatments on the market,
are required to register. In response to FDAMA, the National Library of Medicine (NLM)
established a clinical trials registry and made it available to the public in 2000
[http://www.clinicaltrials.gov]. It was later reported that an FDA analysis found that in
2002 only 48% of trials of cancer drugs had been registered, and a preliminary review
now indicates the listing rate for drugs for some other serious diseases is in the single
digits. Some companies have listed no studies; some trials are listed without identifying
For further information on the role of federal agencies in evaluating biomedical products, see
CRS Report RS21962, From Bench to Bedside, by Michele Schoonmaker.
the sponsoring company or the drug being tested.2 In March 2002, FDA issued a guidance
document, instructing industry how and when to participate in the registry
Despite the centrality of clinical trials in assessing biomedical products’ safety,
particularly phase III and IV studies, a presentation of all results related to a product can
be difficult to find. Researchers have traditionally reported pre- and post- market trial
results in peer-reviewed medical journals, which have historically tended to favor
publication of clinical trials demonstrating successful intervention; the results of negative
or inconclusive trials often go unpublished.3 Other venues for the dissemination of
research results are industry, government, or university press releases and presentations
at medical conferences. Researchers — who may be affiliated with a product’s
manufacturer, a university, the government, or an association established to find better
treatments for a particular disease — may have various motives for publishing or not
publishing results. Some observers have expressed concern that the concealment of
negative data could adversely affect medical decision-making.4
Clinical trials reporting can mean public access to results after a trial’s conclusion,
to a proposed plan before a trial is begun, or both. There is no centralized system for
either type of reporting, so different trials may have the same title, one trial may be
reported in several places under different titles, and many trials are never reported.
Discussions of clinical trials reporting have largely focused on post-market trials
concerning drugs’ and devices’ long term effects, and their safety and effectiveness in
specific sub-populations such as children or persons with heart conditions.
In 2004, a number of national and international groups recommended that clinical
trial reporting be centralized, standardized, and/or include both positive and negative
results. In April 2004, the World Health Organization (WHO), which supports and funds
much of the international research on marginalized populations, announced a system
designed to facilitate the sharing of research. The system will assign standardized
numbers to each randomized controlled trial the WHO ethics review board approves. A
London-based company will maintain a no-charge, online register of these numbered trials
at [http://www.controlled-trials.com] to identify and track them throughout their life
cycle. The system is designed to avoid the problem of publication bias by posting
information on trial starts and their results.
In June 2004, the American Medical Association (AMA) recommended that HHS
create a comprehensive, centralized clinical trials registry. The AMA further called on
all institutional review boards to make registration in this database a condition of their
Sharon Vedantam, “Drugmakers Prefer Silence on Test Data,” Washington Post, July 6, 2004, p. A1.
“Pressure Mounts for Clinical Trial Registry,” Medicine & Health, June 21, 2004.
Robert Steinbrook, “Public Registration of Clinical Trials,” JAMA, vol. 351, no. 4, July 22,
2004, p. 315.
approval of the bioethical aspects of clinical trials.5 Noting the AMA’s position, Senators
Tim Johnson and Christopher Dodd called for a national clinical drug trial registry in a
July 8, 2004, letter to the heads of NIH and FDA6
In July 2004, the FDA announced that clinical trial sponsors could use a standard
format, the Study Data Tabulation Model (SDTM) developed by the nonprofit
organization, Clinical Data Interchange Standards Consortium (CDISC), to submit data
to the agency [http://www.cdisc.org/index.html]. According to the FDA, providing a
consistent framework and format for clinical trial information is expected to enhance data
integration opportunities and thereby reduce data management barriers for sharing the
latest clinical trial data.7
In September 2004, the International Committee of Medical Journal Editors
(ICMJE), which comprises the editors of 12 major journals including the New England
Journal of Medicine, The Lancet, and the Journal of the American Medical Association,
announced a new clinical trials publication policy. The policy requires, for publication
of clinical trial results, that a sponsor have posted its trial in a public registry before
enrolling patients.8 The policy is expected to go into effect on July 1, 2005. The ICMJE
said it did not advocate any particular registry, but cited clinicaltrials.gov as the only
database currently meeting its requirements.”
In an effort that dovetails with the ICMJE policy, NIH announced that as of May 2,
2005, it would request that investigators with manuscripts that are accepted for
publication, and that are the result of research supported in whole or in part with direct
costs from NIH, submit them voluntarily to NLM’s PubMed Central.9 This effort would
only enable free access to results published elsewhere and would not facilitate access to
previously undisclosed results. The NIH announcement was preceded by a July 2004
House Committee recommendation that NIH provide free public access to the complete
text of articles and supplemental materials generated by NIH-funded research.10
Joseph M. Heyman, “AMA Encouraged by Early Signs of Industry Support for National
Clinical Trials Registry,” American Medical Association, press release, June 18, 2004, at
“Senators Call for National Registry of Clinical Drug Trials,” Senator Tim Johnson, press
release, July 8, 2004, at [http://johnson.senate.gov/~johnson/releases/200407/2004708B20.html].
“FDA Announces Standard Format That Drug Sponsors Can Use to Submit Human Drug
Clinical Trial Data,” FDA News, July 21, 2004, at [http://www.fda.gov/bbs/topics/news/2004/
Catherine De Angelis, et al., “Clinical Trial Registration: A Statement from the International
Committee of Medical Journal Editors,” New England Journal of Medicine, vol. 351, no. 12 Sept.
16, 2004, p. 1250, at [http://content.nejm.org/cgi/content/full/351/12/1250].
Policy on Enhancing Public Access to Archived Publications Resulting from NIH-Funded
Research,” National Institutes of Health, NOT-OD-05-022, Feb. 2, 2005, at [http://grants2.nih.gov/
Report of the House Committee on Appropriations, H.Rept. 108-636, Departments of Labor,
Health and Human Services, and Education and Related Agencies Appropriations Bill, 2005,
Sept. 7, 2004.
The pharmaceutical industry’s reaction to clinical trials reporting has been mixed,
although as litigation and FDA and congressional interest have increased, some individual
manufacturers and groups have volunteered to make some of their clinical trials data
public. How the industry defines the types of trials to include (e.g., hypothesis-testing or
late-phase only) could affect a registry’s utility. Initially skeptical, PhRMA introduced
its own clinical trials database in October 2004 at [http://www.clinicalstudyresults.org].
Companies that market drugs in the United States can voluntarily post the positive and
negative results of controlled trials (mainly Phase III and IV studies) completed after
October 2002 on the PhRMA database. As of January 10, 2005, 13 companies had posted
results for 27 drugs. According to FDA, more than 10,000 drugs are approved for
marketing in the United States. In January 2005, PhRMA additionally called for its
members to voluntarily post all hypothesis-testing clinical trials on the NLM site.
Legislation Introduced in the 108th Congress
In October 2004, Representative Edward Markey and Senator Christopher Dodd
introduced companion bills H.R. 5252 and S. 2933, the Fair Access to Clinical Trials Act
(FACT). The FACT bills would have required the registration of clinical trials in a
publically accessible HHS database prior to their enrollment of human subjects, with
results to be added within a year of a trial’s conclusion. They would have applied to all
clinical trials conducted in the United States, as well as to foreign trials used in requesting
FDA approvals. They would have also established enforcement mechanisms with
monetary penalties for clinical trial sponsors who did not comply. Similar legislation is
likely to be introduced in the 109th Congress.
Issues surrounding the possibility of clinical trials reporting and publication have
focused on a range of topics:
Goals. Proponents of public access to clinical trials data cite the need to provide
information to members of the general public, health care workers, and researchers, both
to help inform treatment decisions, and to help eliminate abuses. Industry advocates have
also cited the potential benefits of public awareness of the resources necessary to get a
drug approved, and the elimination of duplicated failed efforts. PhRMA cites making
clinical trial results for U.S.-marketed pharmaceuticals more transparent, and providing
information to practicing physicians and their patients.
Appropriateness/Presentation. Some have questioned whether clinical trials
publication is the best mechanism for ensuring patient safety, both because the language
may be too technical for lay audiences, and because numerous trials may need to be
viewed together in order to draw meaningful conclusions — an analysis that would be
difficult for many doctors as well. (A single clinical trial may generate thousands of
pages of documentation.) These questions have led some to focus on how information
might be presented in an audience-appropriate way. PhRMA’s registry contains a link to
drug labels, a bibliography, and a summary of results in a format developed by industry
consensus.11 The registry proposed in the FACT bills would have included among other
things, trial descriptions, result summaries, and FDA actions.
Timing. Some have argued that only clinical study results are important to judging
effectiveness, so publication of a trial’s inception is not necessary. Others have argued
that some registration at inception is necessary to avoid abuse, and is helpful for
connecting potential subjects with various trials. FDAMA requires that notice of a
qualifying trial be submitted to clinicaltrials.gov no later than 21 days after the trial is
open for enrollment. PhRMA’s database only accepts results from completed trials.
Those in the FACT bills would have required registration at a trail’s inception, before
human subjects testing could have begun.
Intellectual Property. Some have expressed concern that publication of
information about clinical trials will lead to problems protecting both trade secrets and
copyright. Others maintain that the information needed to protect public safety is not the
type protected by trade secret or copyright law. PhRMA’s registry is voluntary, giving
companies control over what information is released. Although the FACT bills would
have required reporting, they would have allowed manufacturers to strip their submissions
of trade secret information.
Voluntary or Mandatory/Penalties. Concerns about the potential regulatory
burden on smaller drug and device manufacturers, and about the potential for intellectual
property problems have led some to call for voluntary publication. The desire to protect
public safety and to reduce abuse have led others to back mandatory reporting. PhRMA’s
registry is voluntary. The ones that were proposed in FACT would have been mandatory
and would have carried penalties for noncompliance.
Conflicts of Interest. Some commentators have focused on the need for public
disclosure of financial and other arrangements between researchers and sponsors in order
to demonstrate potential conflicts of interest that may affect clinical trial design,
interpretation of data, and presentation of results. The PhRMA database does not include
information about funding relationships, though products there are identifiable by
company, which may also be the trial funding source. The FACT bills would have
required the disclosure of funding source(s), among other things.
Devices. Some have questioned whether information about clinical trials related
to medical devices should be included in the registry. The medical device advocacy
group, Avamed, points out that FDA regulation of devices is different from its regulation
of drugs. Devices are often approved based upon analytical comparisons to existing
products rather than the conduct of new clinical trials. Devices as compared to drugs also
tend to present a lower risk to patients, tend to be manufactured by smaller companies,
tend to have a short market life due to frequent, incremental refinements rather than major
breakthroughs, and tend to require more financial incentives to test. PhRMA’s database
only contains information related to drug trials. Those proposed in the FACT bills would
have included information about device trials.
Structure and Content of Clinical Study Reports; Guideline approved by the International
Conference on Harmonization; July 1996 at [http://www.fda.gov/cder/guidance/iche3.pdf].