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Medical News & Perspectives
December 20, 2000

Helsinki Discord? A Controversial Declaration

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JAMA. 2000;284(23):2983-2985. doi:10.1001/jama.284.23.2983

Washington—A long-awaited fifth revision of the Declaration of Helsinki, widely acknowledged as the foundation of medical research ethics, is receiving mixed reactions for discouraging placebos in clinical trials and mandating researchers to provide "best proven" therapy to participants after a trial.

Patient protection advocates, who lobbied hard for the new language, hail the revision as a major step toward abolishing what they see as unethical research, especially in developing nations. Delon Human, MD, secretary general of the World Medical Association (WMA), which put forth the declaration, is equally enthusiastic. He says the revision is an ideal—not a "manual of protocols and procedures"—but that it sets an ethical standard "which I don't think can be set high enough."

Or can it be? Some researchers and bioethicists are calling the recommendations on placebo use unwarranted and unnecessary, a possible bane to future research. And the US agencies responsible for protecting patients in medical studies, namely the Food and Drug Administration (FDA) and the Department of Health and Human Services (DHHS), are noncommittal about whether they will subscribe to the revision, which provides no means of enforcement.

"I think it's scientifically and ethically incorrect," said Robert Temple, MD, director of the FDA's Office of Drug Evaluation. "We'll have to see if the Declaration of Helsinki remains the ethical standard for the world." Temple cautioned that he was speaking only for himself, not for the FDA, but he later added that he would try to persuade others in the agency to his point of view.

Greg Koski, MD, PhD, director of the DHHS's Office for Human Research Protections, simply said, "This is an area of active discussion in the department. There will be more information forthcoming as we try to offer some guidance to researchers."

Both the DHHS and FDA are reviewing the new declaration with one eye on their own policies and another on parallel ethics statements being prepared by the National Bioethics Advisory Commission and the Commission for International Organizations of Medical Sciences, part of the World Health Organization. If these groups issue statements straying from Helsinki's policy—a very real possibility, according to several sources—researchers will have to play "pick the doctrine" when planning new studies.

Placebo, anyone?

Helsinki's paragraph 29 is clear: new treatments should be tested against the "best current" treatment, not a placebo, unless no proven treatment exists. But the interpretation and practical implications of such a sweeping statement are murky. "This will be where we have our biggest debate in the years to come," said Human.

Nancy Dickey, MD, former president of the American Medical Association and chair of the WMA work group that hammered out the revision, takes a pragmatic stance. "We are asking scientists to give a lot more consideration to when they use placebos and why they're using placebos," she said. "I think the declaration makes it very clear that it is not acceptable to take a new treatment and test it only against placebo. An adequate research protocol will test proposed new treatments against the best proven treatment."

But Dickey, who is now interim dean of the College of Medicine at Texas A & M University, said it may be justified, in cases where currently commonly used treatments have not been proven or have been proven in substantially different populations than the study group, to test a new treatment against both a placebo and the best current treatment. Such three-armed studies—while prohibited by a strict interpretation of the revised declaration—are quite useful, according to study design experts. "They're an excellent design," said Temple, who has recently published on this topic (Ann Intern Med. 2000;133:455-463). They provide the maximum amount of information about the existing drug and the one being tested, something Temple and Dickey agree on.

In contrast, comparing a new treatment with only the established treatment, the study design mandated by a literal interpretation of Helsinki , is less optimal, according to Temple. If no difference in effect emerges between the standard drug and the new one, "you don't know if either of them worked."

Conditions for which there are no proven treatments are clearly excepted from the placebo restriction. Studies of nondebilitating, short-term illnesses like headaches and colds also should not be subject to the requirement, said Peter Lurie, MD, MPH, who pushed hard for the antiplacebo language as deputy director of Public Citizen, a consumer rights group in Washington, DC.

But this gray area has led to confusion. "I wish they would have clarified their intent," said Temple. He interprets Helsinki literally, and believes the framers meant the placebo restriction to apply to all clinical trials, no matter how trifling or transient the condition under study. He was surprised to learn that Dickey supports three-armed studies.

As an alternative model, Temple points to the standards of the International Conference on Harmonisation (ICH), an international consortium of drug regulatory agencies. The ICH posits that "whether or not it's OK to use a placebo depends on what happens to the person who isn't getting the usual treatment," said Temple. In other words, if no harm comes to the patient, a placebo is allowable.

Whose standard of care?

The placebo debate aside, the term "best current" swings open another wide door of interpretation, especially when considering trials in developing nations. For researchers conducting trials outside the United States, does it mean the best care available in the United States, or the best available locally?

Human acknowledged that it is "extremely difficult" to define the term but that, in most cases, it means the standard of care in the developed world. "The intent was to give the patient access to the best potential or possible or current treatment of the day." That interpretation has the drug industry and some academic researchers on edge.

"The worry in anything like this declaration are the exceptions where we have a standard of care in the United States and you're doing an overseas study and that standard of care is not available. What do you do then?" asked Gillian Woollett, PhD, senior vice president of the Pharmaceutical Research and Manufacturers of America (PhRMA), a Washington, DC, lobbying group.

For patients' rights activists like Lurie, the answer is clear: "The most simple reading is that you must provide the best proven universal therapy. It's a scientific standard, not an economic one."

But economics certainly factor into the equation. The most contentious debate—and, according to many, the very reason Helsinki was revisited—involves HIV/AIDS studies in Africa. Human says that triple-drug therapy is the standard of care and that anyone who wants to do an HIV/AIDS study in Africa or anywhere else should provide such treatment to everyone in the study. But researchers who have spent time in the field say this is not only expensive but practically impossible.

Thomas Quinn, MD, a Johns Hopkins and National Institute of Allergy and Infectious Diseases researcher whose studies in Thailand and Uganda have been attacked as unethical—despite approval by multiple institutional review boards, including those in the study countries—said many places lack the resources to provide basic needs, let alone the close medical supervision HIV/AIDS therapy requires. "They don't have running water and they don't have watches, they use the sun to tell time," said Quinn, referring to the strict schedule called for by the complex drug regimens. In addition, physicians and clinics may not be available to deal with severe adverse effects if they occur. "It's an infrastructure problem," Quinn said, a very distressing situation, but one too large for medical researchers alone to solve.

Public Citizen's Lurie dismisses these considerations as "ethical relativism," saying, "We object to studies that would be unethical in rich countries, but are deemed OK in the developing world because they have no medical care." Quinn and others warn that this stance could slow the pace of research.

Inclusiveness an issue

First adopted in 1964 and revised four times previously, the latest revision of Helsinki was unanimously ratified by the WMA's General Assembly in October. But it took 3 years of wrangling about language and semantics, a divisive first draft that many said weakened the statement, and constant prodding by Lurie and others to reach the accord.

Despite all this, several researchers charged the WMA with not being open enough during the process. Dickey and Human countered that the WMA canvassed a wide range of viewpoints during the ordeal. Dickey said the group "took pains to make the process inclusive" by soliciting comments via the Internet and presenting drafts at international meetings. Human said he "aggressively" consulted with other ethics groups, including the National Bioethics Advisory Commission and the Commission for International Organizations of Medical Sciences.

These efforts apparently did not reach the drug industry. Woollett said she was not aware of any efforts by the WMA to contact drug companies: "After all, it's much easier to recommend that somebody else volunteer something."

The "something" she referred to—namely, supplies of drug provided to study participants after a trial—could be expensive for drug makers. Paragraph 30 of the revision addresses this issue for the first time, stating that all participants in a clinical trial should have access to the best therapy after the study. Making drug companies bear this burden could slow new trials, argues Woollett. Asking the governments of developing nations to pay for the treatments is another option, but developing nations generally spend woefully few dollars on health care as it is.

Research participants always subject themselves to risks, asserted Dickey, "So what's the benefit? If the benefit is that we've now proven it for the sake of the rich Americans . . . and we're not going to give it to you, that's a problem." She added that the details of who pays for what should be negotiated before the study begins.

Quinn points to his Ugandan study of sexually transmitted diseases (STDs) as an example of effective posttrial treatment (Lancet.1999;353:525-535). While the study did not support its main hypothesis—that treating STDs would reduce the rate of HIV transmission—all participants eventually received antibiotic therapy, significantly reducing the prevalence among them of syphilis and other diseases.

While answers to the "who should pay" question remain unclear, it is clear that with the weight of a revised Declaration of Helsinki behind them, developing nations now have the leverage to demand more consideration from medical researchers.

Whether or not they actually get it, despite the Declaration of Helsinki's good intentions, remains to be seen.

Other helsinki highlights

The revised declaration makes several other recommendations that affect publication of research. These points include the following:

  • Researchers should disclose all relevant financial interests to ethical review boards, to potential study participants, and in published articles.

  • Research should be carried out only if the potential benefits of a study outweigh any potential harms.

  • The well-being of study participants takes precedence over the interests of "science and society."

  • Negative studies—those that do not support a treatment's effectiveness—also should be published. "Science unpublished is in effect science that was never done," says Lurie.

  • Journals should reject reports of studies that do not adhere to the principles of the declaration.

Although the recommendation regarding the publication of research articles that do not follow the declaration's principles is not new, journal editors might have problems with it because of the placebo policy. According to Catherine DeAngelis, MD, editor of JAMA, "In some cases good science dictates studies with placebo arms. These might include new studies of populations different from those previously studied, including differences in age group (children vs adults), sex, or racial/ethnic origin."

The full text of the Declaration of Helsinki is available online at http://www.wma.net/e/policy/17-c_e.html.

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