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More Information on Ethics and Clinical Trials

Letter Opposing Proposed Changes to Declaration of Helsinki

August 28, 2003

Dr. Delon Human
World Medical Association
28 Avenue des Alpes
01212 Ferney-Voltaire Cedex
France

Dear Dr. Human:

In October 2000, the long, contentious path that led from the debate over the placebo-controlled perinatal HIV prevention trials in Africa and Thailand to a revised Declaration of Helsinki appeared to reach its end in Edinburgh. Hundreds of researchers and community members from around the world had inundated the World Medical Association (WMA) with their ideas on three successive drafts of the Declaration. Ultimately, a revised Declaration passed the WMA’s ethics committee, its Council and then the full WMA Assembly at the annual meeting in Edinburgh.  Whatever the document’s defects, and there were several, it at least had the virtue of being the product of a more-or-less open process in which all the relevant issues were aired.  Not everyone may have been satisfied with the resulting document, but it had the air of finality.

But it was not to be. No sooner had the ink on the new Declaration dried than the WMA came under pressure from the pharmaceutical industry, the U.S. Food and Drug Administration and the U.S. National Institutes of Health to revise the controversial Paragraph 29, which addressed what treatments had to be provided to participants in the control arms of clinical trials. This pressure resulted in a meeting in Johannesburg, South Africa, then a note of “clarification” to the Declaration (which most observers agree clarified little and muddied much) and finally, in 2002, to the incorporation of the “clarification” into the full Declaration as a footnote. The net effect of this undemocratic process and the footnote has been to create uncertainty with respect to Paragraph 29, an uncertainty that is likely to lead to the provision of placebos and less-than-optimal treatments to residents of developing countries who are in the control arms of clinical trials.

Having had such “success” with Paragraph 29, the U.S. government and the pharmaceutical industry have now trained their sights on Paragraph 30. If this assault leads to a change in the Declaration at the WMA Assembly in, ironically, Helsinki on September 10-14, 2003, it will be the third change in four years to a document that was altered only five times between 1964 and 1999, and then only in minor ways. The “clarification” of Paragraph 29 appears to have set in motion a process whereby the U.S. government and the pharmaceutical industry can use their muscle to run roughshod over international agreements, one paragraph at a time. Three out of four people who have so far testified before the WMA are from the U.S and only one of the five members of the Workgroup charged with revising Paragraph 30 is from a developing country, South Africa. (The other Workgroup members are from the U.S., Canada, Germany and France.)  We suspect that it will be quite some time before developing countries or patient groups have the same success in having their concerns addressed.

Historically, one of the attributes of the Declaration has been its brevity. As a necessary consequence, each issue in the Declaration has been addressed relatively succinctly.  Until the Paragraph 29 footnote, the explication of the more complex sections of the Declaration was consigned to the Council for International Organizations of Medical Sciences (CIOMS) in its International Ethical Guidelines for Biomedical Research Involving Human Subjects. Now, in defiance of the Declaration’s traditions, we are beginning to see the sudden proliferation of footnotes and “clarifications.” These share two asymmetrical characteristics: 1. they seek to water down relatively strong language in the body of the Declaration, never to strengthening that language; and 2. they are instigated by the U.S. and the pharmaceutical industry, never by developing countries or patient groups. Where, for example, is the footnote explaining in greater deal how informed consent should be obtained? Or how ethics committees should be constituted? Or how conflict or interest should be reduced or eliminated? Such footnotes are unlikely to ever see the light of day because those with sway over the WMA would be opposed. This is a sad shadow over a document with universalist pretensions.

Because the “Proposed Note of Clarification on Paragraph 30” is more detailed than the “Proposed Amended Version of Paragraph 30,” in this letter we will discuss the Note rather than the new language itself. The Note recognizes at least four conditions that must be fulfilled before patients can receive therapy at trial conclusion. Two of these, Conditions (ii) and (iv) are relatively clear-cut and need not even be mentioned in the document, particularly one as brief as the Declaration. 

Condition (ii) requires that the particular study in which the patient was enrolled be placed in the context of other similar trials; thus if one trial of a drug is positive but several others are negative, the drug may reasonably be considered ineffective and the drug can be withheld from the control group in the positive trial. If this language must remain in the document, however, we assume that it will be applied in symmetrical fashion: if a participant is enrolled in the control arm of a negative trial and the preponderance of evidence from other trials suggests that the drug is effective, that participant, as well as all those in the control arm of the positive trials, should receive the drug. As currently written, the condition allows the downgrading of the rights of those in positive trials, but not upgrading for those in negative trials. Somehow, we are not surprised. 

Condition (iv) is even more redundant: obviously, no one is suggesting that patients receive medications that are inappropriate for them just because they happen to have been in a clinical trial.

While Conditions (ii) and (iv) may not be necessary, Conditions (i) and (iii) are imminent threats to the rights of study participants, and their health. Condition (i) stipulates that only methods that are “superior” to other methods must be provided. Thus, sponsors need not provide methods that are simply as good as other methods. In many cases, of course, it will be unclear if the method is superior, as the pharmaceutical industry is loath to design head-to-head studies that might demonstrate a product to be inferior (hence the need for the previous attack on Paragraph 29), and the sponsor will then be off the hook. 

Condition (iii) adds a wholly new dimension: “appropriate authorities” must have approved the method under study before the researcher is obligated to provide it to those in study control arms. This condition threatens to entirely nullify Paragraph 30. Assuming that the trial is intended to be part of an application to a regulatory authority for approval, the drug will almost never have been approved at trial completion, so researchers will be exempt from Paragraph 30. For developed countries with national health insurance systems, Paragraph 30 is, in effect, no more than a “compassionate use” provision, which would bridge the gap from trial completion until the drug is approved. In such countries, therefore, the proposed amendment is thus a retreat from what are now widely accepted programs.  In developing countries or others without national health insurance, the proposed amendment will produce scenarios inimical to patient health: patients who have been stabilized on anti-hypertensives or oral hypoglycemics will have their drugs withdrawn summarily because the short follow-up period necessary for a company to demonstrate efficacy on some surrogate marker will have been completed. Of course, patients in placebo arms will not even have had the transient benefits of such treatments.

Finally, there is what might be called Condition X: the Note states that these four are merely examples of conditions that need to be fulfilled in order for the researcher to be obligated to ensure post-trial access to study participants.  Researchers are thus left to their own devices to conjure up still more excuses to evade their ethical responsibilities.

Inevitably, there will be a roar from multi-billion dollar pharmaceutical companies that actual enforcement of Paragraph 30 (as opposed to the planned symbolic, yet gutless, retention of the paragraph now being proposed) will be enormously costly and that pharmaceutical research will come to a grinding halt. In fact, Paragraph 30 could apply to a minority of studies. In some cases, such as the perinatal HIV transmission studies, the patients’ fates will already have been sealed (they will either have been perinatally infected or not) by the time of study completion and they would thus not be eligible for any drug. In others, the treatments may be for symptomatic relief or for self-limited conditions. Such patients would also not have to receive medication at trial completion. The real concern, therefore, is for trials of drugs for the treatment of chronic conditions. However, as mentioned above, in most developed countries the provision would simply act as a short-term holdover under drug approval and health insurance kick in. Pharmaceutical companies now frequently provide this, at times for free, and sometimes do so for far more patients than enroll in clinical trials.

Under pressure from the U.S. government and the pharmaceutical industry, the WMA has now opened the door to the paragraph-by-paragraph undermining of those aspects of the Declaration objected to by researchers and large corporations. The Workgroup notes that “there was concern that the proposed amendment might weaken the intent and provisions of paragraph 19,” the paragraph that requires researchers to seek to ensure that effective therapies are available to the general community after the trial. If the proposed changes to Paragraph 30 carry the day, Paragraph 19 may be the next in the firing line, even if the WMA has decided, for now, to leave Paragraph 19 untouched. For if researchers can, with limited effort, escape the requirement to provide drugs to their own participants/patients at the conclusion of a trial, how can they be required to provide medications to those who have never been under their care?

Yours sincerely,

Peter Lurie, M.D., M.P.H.
Deputy Director

Sidney M. Wolfe, M.D.
Director
Public Citizen’s Health Research Group

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