NEWS

Declaration of Helsinki Revised

Tom Reynolds

After years of controversy over proposed changes, the World Medical Association last month adopted a revised version of the Declaration of Helsinki, a landmark international agreement on ethical principles guiding medical research.

First published in 1964, the statement was intended to repudiate the Nazi atrocities committed in the name of research during World War II and to codify ethical conduct for physicians who use their patients in research.

The latest round of changes, the fifth in the document’s history, was approved by the WMA general assembly at its October meeting in Edinburgh, Scotland. The revisions address issues raised by the rapid expansion of biomedical research in recent years, including its international scope—developments unforeseen by the declaration’s original framers. But perhaps the biggest news is what did not change.

A major bone of contention was how to address the use of placebo controls in clinical trials carried out in the developing world. The flash point in this debate was a U.S.-run trial of the antiviral drug AZT to prevent perinatal transmission of HIV. Infected African and Thai women and their infants were given either a short course of the drug or a placebo.

Critics blasted the trial as unethical, arguing that the control group should instead have received a longer and far more costly course of AZT, the standard in developed countries. They pointed to a Declaration of Helsinki clause stating that "In any medical study, every patient—including those of a control group, if any—should be assured of the best proven diagnostic and therapeutic method."

The trial’s defenders argued that since none of the women would have received any treatment outside the trial—the AZT regimen being unaffordable in poor countries—no harm was done and some benefit was possible.

This brouhaha spurred WMA to reconsider the Declaration of Helsinki, and in 1998 the association chose Robert Levine, M.D., a professor of medicine at Yale School of Medicine, New Haven, Conn., to head a study group charged with drafting a revision. Levine, a bioethics specialist who chairs Yale’s Human Investigations Committee, has frequently criticized the declaration’s wording as out of step with current research methodology. He has pointed out, for example, that a strict reading would prohibit placebo controls even in trials of analgesics, antihypertensive drugs, and other situations where they are widely regarded as acceptable and even necessary.

In a March 1999 draft, Levine’s committee amended the declaration to read that every patient-subject should get "the best proven diagnostic, prophylactic, or therapeutic method that would otherwise be available to him or her." Such a change would have offered researchers an ethical loophole, permitting placebo controls in poor countries under circumstances where they would be impermissible in the affluent sponsoring country.

This proposal sparked outrage among critics who maintained it legitimized a two-tier standard of care and the exploitation of poor societies by and for the benefit of wealthy ones. The controversy led to Levine’s ouster from the revision process, and Levine said WMA subsequently "decided to take the project on revisions ‘in-house.’ "

As Peter Lurie, M.D., of Public Citizen’s Health Research Group in Washington, D.C., sums up the events, "There was an attempt to water down the declaration to introduce economic relativism, and it was rejected." Lurie and colleagues at the advocacy organization were among those who strenuously protested the changes drafted by Levine.



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Dr. Peter Lurie

 
However, Robert Eiss of the Fogarty International Center, who participated in a 1999 meeting where the Levine revisions were discussed, said he felt afterward that the highly politicized issue of the AZT trials had the unfortunate effect of diverting the potential for a more constructive and careful discussion on the use of placebos.

Re-closing the proposed international loophole, the new declaration returns to familiar language on placebo controls, adding the stipulation that "At the conclusion of the study, every patient entered into the study should be assured of access to the best proven . . . methods identified by the study."

Bette Crigger, Ph.D., a medical ethicist at The Hastings Center, Garrison, N.Y., said that while this new proviso is "still open to wiggle room" in interpretation, "it seems to toe something of a middle path between two polarized positions: that the best proven care should be provided for all participants during the trial—essentially arguing for an active control—versus the position that placebos should be allowed, and the ‘best available therapy’ should be interpreted to mean the standard of care at the host site, however poor that may be."



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Dr. Bette Crigger

 
Reflecting raised sensitivities about potential exploitation of the developing world, it also states for the first time that "Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research."

The ambiguous phrase "reasonable likelihood" ensures heated debate over its interpretation, Crigger added, but at least "it puts that question explicitly on the table."

In the declaration as a whole, Crigger sees an enhanced emphasis on the primacy of individual research subjects’ protection, reflected in the move to a more prominent position of the statement that "considerations related to the well-being of the human subject should take precedence over the interests of science and society"— another change that in part reflects the legacy of the AZT trial furor.

The revised declaration remains silent on the question of placebo ethics in another setting—trials for treatments of less serious conditions, where placebo controls are routinely used and generally accepted. In making no exception for them, the declaration apparently views such trials no differently than trials for cancer, AIDS, or other life-threatening conditions.

Levine and other critics have seen this as a serious flaw that compromises the document by taking, at least tacitly, an extreme position that would prohibit nearly all placebo-controlled trials and cripple the development of new therapies. Levine’s committee attempted to address this issue by endorsing placebo controls unless withholding treatment could result in death or disability.

Lurie counters that Levine’s argument "may have some theoretical merit but it has zero merit on the ground. . . . Obviously, new therapies have been introduced at a substantial rate for decades," as investigators and review boards use discretion in interpreting the declaration. Lurie rejects the "death or disability" clause—as did the WMA—as leaving open too broad a middle ground between these dire outcomes and the mild, transient levels of placebo-induced harm that most investigators (and through informed consent, research subjects) are willing to accept as a necessary evil.

One aspect of Levine’s critique that was accepted by WMA is reflected in the new document’s dropping of the distinction between "therapeutic" and "non-therapeutic" research. As Crigger pointed out, nearly all clinical research has components of each, making it fruitless to assign a given study to one or the other category.

Another major addition to the declaration is the explicit acknowledgment that "Medical research involving human subjects includes research on identifiable human material or identifiable data." Crigger said this statement could apply to tissue specimens, DNA samples, computerized genetic information, and even medical records, and implies that the use of any of these kinds of material or data in research carries an obligation to consider the best interests of the people who provided them. It also raises questions about the scope of a subject’s informed consent given at the time the tissue or information is first gathered.

Another new section addresses issues of increasing concern surrounding the integrity of published research results: "Negative as well as positive results should be published or otherwise publicly available," the new declaration states. "Sources of funding, institutional affiliations and any possible conflicts of interest should be declared in the publication."

The revised Declaration of Helsinki can be found on the WMA Web site, http://www.wma.net.



             
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