September 1, 2004

David A. Lepay

Office for Science and Health Coordination

Good Clinical Practice Programs (HF-34)

Food and Drug Administration

5600 Fishers Lane

Rockville, 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

Director

Public 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;](http://content.nejm.org/cgi/content/short/345/2/136)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.