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.