E-drug: FDA pursues exceptionalism on Declaration of Helsinki
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Greetings.
We are writing to ask that you write to the FDA to express your concerns
about the agency's proposal to strike reference to the Declaration of
Helsinki, the touchstone for international research ethics, from FDA
drug regulations. The agency proposes instead to rely on its Good
Clinical Practice guidelines, which are not principally concerned with
ethics, for certain studies that are conducted outside the United States
but are later submitted to the FDA for approval. In a letter to the FDA
(attached, pasted into the email below, and at this URL:
http://www.citizen.org/publications/release.cfm?ID=7330 ), we described
the proposal as "exceptionalism" and motivated by the FDA's historical
hostility toward the Declaration, particularly 1. its restrictions on
the use of placebos and 2. the requirement that study participants
received medications proved effective during the trial once the study is
over.
The FDA is accepting comments on the proposal through September 8. The
proposal is available at
http://a257.g.akamaitech.net/7/257/2422/06jun20041800/edocket.access.gpo
.gov/2004/04-13063.htm.
The easiest way to submit would be through email to
fdadockets@oc.fda.gov. Include the docket number (2004-N-0018) in the
subject line. Please cc me on any comments you submit and feel free to
share this email with any others you think might be interested,
including relevant listserves.
Thanks in advance
Peter
September 1, 2004
David A. LepayOffice for Science and Health CoordinationGood Clinical
Practice Programs (HF-34)Food and Drug Administration5600 Fishers
LaneRockville, MD 20857 Re: Docket No. 2004N-0018: Human Subject
Protection; Foreign Clinical Studies not Conducted Under an
Investigational New Drug Application Dear Dr. Lepay: Beneath the
seemingly innocuous veneer of this proposal to require foreign clinical
studies conducted without a U.S. Investigational New Drug application
(IND) to comply only with Good Clinical Practice (GCP) guidelines is
FDA's ongoing pursuit of a long-held goal: the undermining of the
Declaration of Helsinki (DOH) as the international touchstone for the
ethical conduct of clinical studies. This agenda began with a series of
articles by Food and Drug Administration (FDA) employees that raised
questions about certain DOH principles.[1],[2],[3],[4],[5],[6] It
continued with FDA efforts to weaken both the DOH and the Council for
International Organizations of Medical Sciences (CIOMS) International
Ethical Guidelines for Biomedical Research Involving Human Subjects, and
has now reached its apotheosis in this proposal that would literally
purge any reference to the DOH from FDA drug regulations. The last
decade has seen an exponential growth in the number of foreign clinical
trials, including those conducted in developing countries. The number
of new foreign investigators in the FDA=s database grew from 988 in the
1990-1992 period to 5,380 in the 1996-1998 period.[7] Some of these
studies were preceded by INDs, which allow a company to administer a
drug under investigation to humans, while others were not. For example,
a Swedish drug manufacturer might decide to conduct a study of a new
drug in Sweden and/or other non-U.S. countries and the study may never
come to the attention of the FDA until the company seeks approval in the
United States. In that case, current FDA regulations require the
studies submitted to have been conducted in a manner consistent either
with the DOH or any local laws, whichever is more protective for
patients.[8] The FDA's current proposal would remove this requirement
and require instead that the submitted studies only be consistent with
the GCP guidelines of the International Conference on Harmonisation
(ICH). The DOH is not a perfect document. But at least it has the
virtue of being the product of a quasi-democratic process. The DOH is
produced by the World Medical Association, which in turn is comprised of
82 national medical associations such as the American Medical
Association. The DOH can only be amended with a formal vote before the
full World Medical Assembly, which meets annually. By contrast, the ICH
guidelines, of which the GCP[9] is but one, are the product of
negotiations by just six parties: the regulatory authorities and
pharmaceutical industries of the U.S., the European Union and Japan.
Consumer and developing country input into the development of the ICH
guidelines asymptotically approaches zero. (The GCP guideline has been
formally adopted as a Guidance by the FDA and parts of it have been
incorporated into FDA regulations.[10]) The FDA offers three reasons for
revising its regulations on foreign non-IND research: 1. International
ethical standards have been updated recently. This is certainly true,
but what is left unsaid is that the FDA has objected to many of the
substantive changes in the updates, particularly the DOH. These are the
true source of the FDA hostility toward the DOH. (We shall not reargue
the merits of these particular changes, as our positions have been
repeatedly made clear and are available in numerous publications on our
website.[11]) In particular, the FDA has been a leading force in
attempts to undermine restrictions on placebo use in clinical trials,
both domestically and abroad (DOH, Paragraph 29). For example, in a
forthcoming book chapter, an FDA employee will defend the use of
placebos in developing countries even when the condition under study is
life-threatening and the country has approved effective drugs for the
condition. Ironically, Paragraph 29 has already been weakened due, in
significant part, to FDA objections (as a result, a confusing
"clarification" was added to the DOH), but the agency is apparently not
yet satisfied. The Department of Health and Human Services (which
includes the FDA) has also objected to the extremely reasonable DOH
requirement that effective medications be provided to all study
participants at the conclusion of the research (Paragraph 30).[12]
FDA's efforts to undermine this Paragraph may also yield fruit, as the
WMA Council has adopted yet another "clarification" that seeks to weaken
the stronger language in the actual body of the DOH. Although the FDA
may not be on record with respect to Paragraph 19, which requires that
the local community benefit from the research, this may be an additional
source of FDA discontent. 2. "Ensuring quality of data."
We, of course, share this goal and there is no question that the GCP
Guidance goes some way to securing this end. But it is a document
designed to improve data quality and is not primarily concerned with
research ethics. Of course, some aspects of ethics do come up (e.g.,
ethics committees, informed consent), but on the whole the GCP Guidance
is concerned with procedural issues, not overarching ethical ones. The
Guidance does not, for example, address conflict of interest or the need
to publish results, topics included in the DOH. The Guidance and the
DOH are thus complementary documents and there is no reason that the
regulations could not require that the affected studies comply with
both. 3. The DOH could be modified "independent of FDA authority."
However, the agency does acknowledge that any revisions "could not
supersede U.S. laws and regulations." It is also true that the ICH
might modify the GCP guidelines, perhaps triggering a change in the FDA
regulations. The FDA has already demonstrated its ability to evade the
2000 improvements in the DOH by declaring in 2001 that the reference to
the DOH in FDA regulations was actually to the 1989 version.[13]
Exactly what, then, is the problem? We also note that the reference to
compliance with the laws of the host country has been removed from the
proposed regulation. While it is certainly not the FDA's job to police
other countries, the notion that the FDA could accept data collected in
violation of local host country laws does not send an appropriate
message to pharmaceutical companies who see the United States as their
main market and might be willing to breach the law in less-important
markets as part of an effort to secure FDA approval. In closing, the
effort to strike reference to the DOH is sadly reminiscent of unilateral
U.S. actions in other spheres. From the International Criminal Court to
the Kyoto Treaty, the Treaty on the Limitation of Anti-Ballistic Missile
Systems, the Biological Weapons Convention, the Comprehensive Test Ban
Treaty, and the (Land) Mine Ban Treaty, the United States has developed
a flair for exceptionalism to international standards. The DOH is the
standard-bearer for international research ethics and enjoys particular
respect in the developing world. It would be tragic if this assault on
the DOH fell in line with other U.S. efforts to flout international
mores.
Yours sincerely, Peter Lurie, MD, MPH
Deputy Director
Sidney M. Wolfe, MD
DirectorPublic Citizen's Health Research Group
[1] Temple RJ. Special study designs: early escape, enrichment, studies
in non-responders. Communications in Statistics 1994;23:499-531.
[2] Temple RJ. When are clinical trials of a given agent vs. placebo no
longer appropriate or feasible? Controlled Clinical Trials
1997;18:613-20.
[3] Temple RJ. Problems in interpreting active control equivalence
trials. Accountability in Research 1996;4:267-75.
[4] Temple R. Difficulties in evaluating positive control trials.
Proceedings of the American Statistical Association, Biopharmaceutical
Section. 1983:1-7.
[5] Temple R, Ellenberg SS. Placebo-controlled trials and active-control
trials in the evaluation of new treatments. Part 1: ethical and
scientific issues. Annals of Internal Medicine 2000;133:455-63.
[6] Ellenberg SS, Temple R. Placebo-controlled trials and active-control
trials in the evaluation of new treatments. Part 2: practical issues and
specific cases. Annals of Internal Medicine 2000;133:464-70.
[7]. Office of the Inspector General. Recruiting human subjects:
pressures in industry-sponsored clinical research. Department of Health
and Human Services, June 2000. [8] 21 CFR 312.120(c)(1)
[9] International Conference on Harmonsation. Guidance for Industry: E6
Good Clinical Practice: Consolidated Guidance. April 1996. Available at:
www.fda.gov/cder/guidance/959fnl.pdf.
[10] 62 Fed Reg 25692, May 9, 1997.
[11] http://www.citizen.org/hrg/
[12] Koski G, Nightingale SL. Research Involving Human Subjects in
Developing Countries. New England Journal of Medicine 2001;345:136-8.
[13] Food and Drug Administration. Guidance for Industry: Acceptance of
Foreign Clinical Studies. March 2001. Available at:
http://www.fda.gov/ohrms/dockets/98fr/010079g2.pdf.
Peter Lurie, MD, MPH Deputy Director Public Citizen's Health Research
Group 1600 20th Street, NW Washington, DC 20009
Phone: (202)588-7781
Fax: (202)588-7796
Email: plurie@citizen.org
Web address: http://www.citizen.org
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