Time for universal rules for a fair trial

August 31, 2001

We are near consensus on ethics for medical research worldwide, says Jimmy Whitworth.

Nowhere is the need for health research more pressing than in developing countries, which suffer 90 per cent of the burden of illness yet enjoy only 10 per cent of health expenditure. But medical researchers face a dilemma. Although there are many urgent health problems in developing countries, it has become increasingly difficult in the third world to conduct research that everybody regards as ethically sound.

There are several problems. Developing world populations are generally poorer, less powerful and more vulnerable than those in developed countries. They are sometimes exploited for studies just because they are more convenient, less troublesome or simply cheaper.

There are many examples. A trial was recently planned in Latin America to test a drug to prevent death by respiratory failure in prematurely born infants. If found to be effective, the drug would have been primarily for use in developed countries and not by the likes of those on whom the treatment was tested. Several years ago in Uganda, a trial was done to determine the best dose regimen for antifungal drugs for Aids patients. Today that drug is still unaffordable to those who took part in the testing.

There are also serious concerns about gaining fully informed consent from those agreeing to take part in a trial. These revolve around low literacy levels, cultural attitudes to individual autonomy and difficulties in conveying to participants what is actually meant by "research", "trials" and the use of placebo treatment.

Finally, there is the dilemma of deciding what therapy the control group should use so that a meaningful comparison can be made with the new drug or intervention. The ethical guidelines in the Helsinki Declaration state that "the best available treatment" should be used for the control group, but what does that entail? One famously controversial trial compared drug treatment to prevent mother-to-child transmission of HIV in Africa with placebo. The rationale was that this was the local standard - mothers received nothing because they could not afford the drug treatments that had been shown to be effective in the United States and Europe.

We are now groping towards a consensus on reasonable research ethics guidelines. First, it has to be recognised that although there should be one set of ethical standards worldwide, regional interpretations and procedures may differ. This was highlighted by a set of workshops on HIV vaccine trials organised around the world by UNAids. These meetings agreed on the broad principle of informed consent but they reached different conclusions about the inclusion of pregnant women in such studies and the level of access to treatment if patients became infected with the virus.

To avoid exploitation, trials should focus on issues relevant in the host country. The treatment should be likely to be affordable and available after the trial, and the local health system should be able to distribute and use it. Informed consent should always be obtained from the individual enrolling in the study, although in some cultures participants may have to seek permission from local leaders or husbands. Such cultural attitudes should be respected.

A signature on a piece of paper is easily verifiable, but it is no guarantee of informed consent. Properly witnessed verbal consent can be much more valid. In some cases, it may be necessary to provide education in simple language about the trial, and then to test potential participants' understanding of the trial before enrolling them.

It is possible to explain research concepts even to villagers who still believe in the omnipotence of the medical profession. For example, the idea of testing different treatments can be understood in rural communities by comparing a trial with farmers testing different seed varieties; randomisation can be explained with reference to the lottery; and the concept of placebo can be likened to blank ammunition.

The toughest question is what treatment to provide for control groups. Requiring researchers to provide the best therapy available in the world could prevent some ethical and necessary research from being conducted. The alternative is to provide what is attainable in the host country or locality. In some circumstances, however, that could be seen as exploiting the study population.

One solution would be to insist on the best treatment available anywhere unless the only useful study design is to compare the intervention with what is available locally. For example, a trial of a cheap oral treatment to prevent mother-to-child transmission of HIV conducted in Tanzania by French researchers might compare the oral treatment with an expensive but proven treatment involving hospital admission and intravenous infusions. But the results of the trial would be more relevant to France than Tanzania, and that would be unethical exploitation.

Alternatively, the treatment could be compared with nothing, which would be the "treatment" that most Tanzanian women were actually receiving. The results of the trial would be relevant to Tanzania, but the trial would not be using the best treatment attainable and so could also be seen as unethical. A reasonable compromise might be to compare the new treatment with a more expensive oral treatment, which might not be the best and still not affordable or available in Tanzania. But it might be the best attainable in the circumstances.

The central problem is that of trying to be as fair as possible in what is an unfair and unequal world. The medical problems of the developing world are immense and urgent. We cannot wait for politicians to create global equity.

Jimmy Whitworth is head of the Medical Research Council programme on Aids in Uganda. He will speak in the "Society's contribution to medical research" session on Tuesday, September 4, at the BA Festival of Science in Glasgow.

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