FDA abandons Declaration of Helsinki for international clinical trials

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At the end of April the US Food and Drug Administration (FDA) published a regulatory change ending the need for clinical trials conducted outside of the US to comply with the Declaration of Helsinki. The FDA’s decision had been in the making for several years and is a major victory of corporate interests which have sought to loosen the ethical standards for international clinical trials. Integrity in Science has written a critique of this decision in which Peter Lurie of Public Citizen’s Health Research Group is quoted as saying that it is “in line with other U.S. efforts to flout international mores.” [Lurie had made a detailed critique of the proposal in the Lancet in 2005.]

In effect the FDA will now allow the pharmaceutical industry to run international clinical trials in which patients in the control group (i.e. those who are not getting the experimental drug) can be treated with placebos instead of the best standard medical care. The change will have important practical implications as more and more medical research is being done overseas by for-profit Clinical Research Organizations (CRO’s). Doing research in poorer countries offers several benefits for CRO’s including lower costs and – now- the possibility to use placebos in control groups.

What is the Declaration of Helsinki?

The Declaration of Helsinki was adopted by the World Medical Association in 1964 as “as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects.” It has been amended five times, the most recent version being in 2000. [Oddly, enough FDA regulators, noblesse oblige, prefer to use the 1989 version rather than the current 2000 version.]

In general the Declaration takes the position that “extreme care must be taken in making use of a placebo-controlled trial” when there is an existing proven therapy. In other words new treatments should be tested against old treatments instead of placebos. This assures that participants in a clinical trial are not denied the benefits of proven treatments. The Declaration does, however, allows for the use of placebos in certain circumstances.

Why is there concern over the use of placebos in international trials?

In 1997 Peter Lurie and Sidney Wolfe published an article in the New England Journal of Medicine criticizing trials of maternal to child HIV transmission prevention in several countries around the world. In these trials some pregnant women were given placebo treatment at a time when the benefits of AZT for preventing maternal to child transmission had been demonstrated. This meant that some women gave birth to children with HIV infection whose disease might have been prevented by the investigators. Many people found this troubling. And it is not an anomaly. Public Citizen has also criticized a Latin American trial of surfactant in preterm babies with respiratory distress syndrome which included a placebo arm.

There are generally two advantages for the pharmaceutical company for doing a trial in which their drug is compared to placebo and not to existing effective drugs. It is easier to show that a drug is better than placebo than existing therapies. Equivalence studies (which compare old and new drugs) require more patients and consequently more time and money. Secondly, if the new drug doesn’t do as well as the old drug, then doctors will prefer to prescribe the old drug.

The use of placebo groups overseas is justified by arguing that patients in poorer countries would not have access to existing standard treatments outside of the trial. The trial simply compares a new treatment against the existing “standard of care” in the country where the trial is conducted. In defense of the African HIV trials an NIH official remarked: “”Studies are designed with the people of the country and take into account the standard of care. They’re really looking at regimens which would work in that country.” (see BMJ 1997;315:763-766)

This is a very difficult argument to accept and let us speak clearly about what it means: If a study is unethical in the US, why should US researchers be allowed to do it in another country? Why should they be allowed to let children die or become infected with HIV in a clinical trial they finance and run? Let us remember that participants in a trial are providing a valuable service to the investigators. This has always implied a special requirement that the investigator protect the interests of the subjects.

What is the FDA proposing instead of the Declaration?

Replacing the Declaration will be Good Clinical Practice (GCP) a system for clinical trials that was developed by International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

Who exactly makes up the International Conference on Harmonization, the new arbiters of research ethics? Well, it’s the drug regulators from the US, EU and Japan as well as representatives of the pharmaceutical industry in the US, Europe and Japan. There are also three observers (the WHO, the European Free Trade Association and Health Canada) as well as the International Federation of Pharmaceutical Manufacturers & Associations. This is obviously a group of the governmental agencies and industry groups of the world’s wealthiest countries.

One wonders just whose interests the International Conference represents: the countries funding the research or the countries where the research will be done. Under what right did these bodies abrogate the authority to set international ethical standards for research? It is within this context that the abandonment of the Declaration assumes its significance.

Can’t countries set their own standards?

Clearly countries around the world are free to set their own standards for research that might incorporate the Helsinki Declaration. But the reality is that poorer countries are under intense pressure to loosen ethical standards in order to facilitate the clinical research “industry”.

A flavor for this pressure is found in a 2004 Lancet Article by Dinesh Sharma entitled “India pressed to relax rules on clinical trials.” The article begins: “India’s pharmaceutical companies are pressuring the Indian government to relax regulations governing clinical trials. If these changes go through, Indian companies will be able to capture lucrative outsourcing contracts from European and North American companies, and boost India’s research and development capacity.” The go-go nature of this pressure is captured by a proposal by the Council of Indian Industry that trials be given automatic approval if they are not cleared by regulators within a stipulated time. It is, of course, proposals like this that belie the any faith that loosening the ethical rules will not harm patient safety.

How does the FDA defend their decision?

Readers interested in hearing the FDA’s rationale can consult the new regulation published in the Federal Register. It is, however, a wonderful example of talking past criticisms. In response to concerns about placebos, the FDA simply repeat the Good Clinical Practice will assure protection of subjects.

For more information

Howard Wolinksy’s article in EMBO Reports provides a detailed description of this change and the background to it.

Other websites that have commented on this decision include GoozNews and the Global Bioethics Blog.

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17 Responses to “FDA abandons Declaration of Helsinki for international clinical trials”


  1. 1Dr.Yashvant Khaire

    So what FDA is going to achieve with this.DoH was concise ICH GCP which was no diffferent from it.
    All this kind of rules should be revised not abandoned

  2. 2Saqib Altaf

    Declaration of Helsinki is a key document that will always ans should always remain part of any guideline, may it be ICH – GCP.
    DoH is a policy and the guidelines are always made to clarify those policies in an elaborate manner.
    US FDA should also keep it as a reference document instead of trashing it.

  3. 3filip

    FDA was always the benchmark for good clinical practice. Now, using the name of Science and the all mightly dollar, it is abandoning the declaration of Helsinki. It is like abandoning the universal declaration of Human rights altogether. The Helsinki declaration safeguards humans from turning into experimented creatures… I wonder, movies showing mutants are in one step becoming a reality if the research becomes unregulated and unethical. I also wonder if the head of the FDA would allow his/her kids, his/her wife/husband be given ineffective drugs for the sake of research. I wonder, are we about to go back to Auschwitz experiments conducted by nazi doctors to jews, the infirm, the lame, the vulnerable population? The best thing the FDA can do is not recognizing research being done in Countries that do not follow the Declaration.

  4. 4BZ

    Helsinki document refers to populations that are underrepresented in medical research and states that should be provided appropriate access to participation in research.
    limiting clinical trials in some countries just beacuse some people /some trials went beyond the limits is not fair for all the other people getting benefit of new treatments like antibiotics, cancer drugs….
    if you limit research in those countries we would have only pills for obesity, hair grow, etc….is that ethical for those countries? Are US guilty or the rest of the world for not promoting reaserch at all?

  5. 5Odessa-man

    Such trials are resricted all over the world so why do the US think they can do whatever they want. Their attitude towards other nations makes me sick.

  6. 6Art-Light

    The US has always treated other nations as slaves!
    This practice shoul be stopped, the US should pay the life-long insurance to those who has been injured while the experiment!

  7. 7SouthMedia

    Clinical tryals should not be made in any countries while it’s restricted by the Declaration of Helsinki.
    Poor counties should be protected by the powerful ones and the assosiations

  8. 8nathan mulure

    There should be no trials for poor countries and those for rich countries. All must be the same, same guidelines, same laws, same everything. Otherwise, there is no harmonisation!

    Nathan Mulure from Kenya

  9. 9Michael Smih

    So the Declaration of Helsinki restrikts using placebo for the people who are realli sick?

  10. 10franklin

    It is indeed depressing that the growth of clinical research which is supposed to be ethical is currently being ignored just for the success of clinical trials at the expense of human subjects. It is sad that the helsinki declaration which had set rules for so many years is being by newer consolidated rules…Truly sad FAD ..SAD

  11. 11Nelson Robson Mendes de Souza

    It is very sad see an agency that has done so much for the world forget that sciences was made to mankind and must be governed by ethics and morals principles.

    Menguele returns the condition of doctor.

    Nelson from Brazil

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