This paper by Aceme Nyika provides a comprehensive review of the ethical issues in research using indigenous medicines, focusing in particular on the use of traditional medicine to treat HIV/AIDS in Africa. The author suggests that the superstition attached to African traditional medicine, together with a laxity in the regulations governing its practice, means that ethical issues have not been adequately addressed.

Nyika argues that it is especially important to demystify diagnosis and therapy if African traditional medicine is to meet minimum ethical and regulatory standards. This can only be done through research on traditional medicine, following the same stages — from animal model to human trials — as conventional medicine. There is also a need for ethical approval, first person informed consent, monitoring for adverse reactions and dissemination of findings. In this paper, Nyika discusses why these have proved difficult to implement and suggests some of the ways in which they could be put into practice.

In this article Costello and Zumla suggest that much foreign-led research in developing countries remains semi-colonial in nature and may have negative effects on the countries in which it is conducted. In light of these concerns they ask what principles should lie behind investment in research in developing countries.

To enable research to be translated into practice, the authors suggest that national academic leaders and institutions need to be involved. As a result, academic infrastructure in developing countries needs to be developed through research partnerships. Research led by expatriates should be phased out and replaced by a partnership model in which nationals lead research projects, receiving only external technical support

In this thoughtful article, Emanuel and Miller outline the stances taken by those on both sides of the debate about using placebos in research. The first is that placebos should be used as a control unless this would increase the risk of death or irreversible morbidity as a result. The other view is that if an effective therapy exists then the use of a placebo group should be prohibited (the stance taken in the Declaration of Helsinki).

The authors conclude that both positions are indefensible and that a middle ground on the use of placebo-controlled trials is needed. They argue that placebo-controlled trials are permissible when proven therapies exist, but only if certain ethical and methodological criteria are met.

In this editorial Huston and Peterson suggest that the concern about withholding treatment in research has been inappropriately focused on placebos. They note the difference between the Declaration of Helinksi’s criterion of ‘no proven treatment’ and the regulatory criterion of ‘no irreversible harm’ as standards for the appropriate use of placebo groups in clinical trials, and the debates that have arisen as a result.

The authors propose that instead a broader understanding of the ethics of withholding treatment is required. They question whether concerns about withholding treatment can be addressed solely by identifying an acceptable level of risk and providing careful monitoring of participants. Examples are given of instances in which placebo groups receive adjunctive treatment as part of research, and where placebo groups have outperformed patients who decline to participate in the research and received standard care. They conclude that to protect the best interest of research participants the ethics of withholding treatment needs to be considered in the broader context of clinical trials.

In this article Fitzgerald and M-T Behets outline four incidents that arose while conducting HIV clinical research with women in African and Caribbean countries to illustrate the "massive ethical challenges for researchers in HIV prevention trials". The cases include an HIV-positive husband refusing to use condoms with his HIV-negative spouse, cervical cancer being identified within a country which did not have the facilities to treat it, and the fatal consequences of one participant seeking an illegal abortion and another delaying surgical removal of a dead foetus on the advice of a traditional attendant and a lack of funds for treatment.

The authors note that much HIV research will involve women of reproductive age, particularly that focussed on preventing mother-to-child transmission of HIV. The four cases discussed outline the issues that can arise when research is being conducted among vulnerable women without access to basic medical services, where physical and sexual violence against women is relatively common and social injustice is widespread. In such circumstances the authors ask what responsibilities researchers have to participants who have built up a trusting relationship with them over time. They conclude that meaningful discussion between researchers and relevant communities is required, leading to a participatory research model in which potential participants and community members are involved in study design and implementation.


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Roy Widdus discusses reasons for inadequate access to treatment for infectious diseases in developing countries, and reviews methods to address these. Noting that drugs and vaccines may not be available for a number of reasons — including the lack of incentives for their development or inadequate infrastructure for their delivery — the role of public-private partnerships in addressing these issues is outlined. The author suggests that if appropriately motivated, pharmaceutical companies can contribute expertise in product development, manufacturing, marketing and distribution which are lacking in the public sector. A number of recommendations for action are made to the public sector, private sector and public-private partnerships, including:

• establishing public health priorities for drugs, vaccines, diagnostics and other health products;
• increasing the use of devices such as licensing, tiered royalties, market segmentation, and tiered pricing to make products more accessible to all in need;
• estimating the need, demand and uptake for existing and new products in developing countries collaboratively, since the public sector has the data and the private sector has the expertise.

This collection of short papers from the 'health and human rights' section of The Lancet focuses on the provision of long-term care for participants who become infected with HIV-1 during HIV-1 vaccine trials in resource-poor countries.

• S Berkley argues for provision of antiretroviral treatment to entire communities rather than to individual trial participants.
• D Fitzgerald and colleagues discuss how the HIV Vaccine Trials Network plans to fund treatment at its trial sites.
• J Mukherjee describes how the first step to providing HIV-1 treatment in Haiti was to revitalise the public-health infrastructure.
• T Tucker and C Slack outline plans for a public-private partnership to care for infected trial volunteers in South Africa.

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One frequently-raised issue relating to standards of care in research is the responsibilities researchers have if they identify medical conditions unrelated to the study during the course of research in developing countries. In this article, Leah Belsky and Henry Richardson propose an ethical framework to assist in determining research responsibilities in such circumstances.

The article begins by considering the two extremes of view, the first is that researchers must provide care for unrelated conditions, because they have a duty to help those in need, particularly when they can do so at minimal cost to themselves. The opposing view is that researchers owe nothing to research participants beyond what’s needed to complete the study safely and successfully.

The authors show more sympathy for the first of these two views and propose a model for research-participant relationship that lies between the extremes, but can leave researchers with some responsibility to care for conditions unrelated to the study. A case study of providing HIV treatment in a tuberculosis treatment trial is discussed. 

The authors conclude that attempts should be made by scientists and research ethics committees to anticipate researchers’ responsibilities for conditions unrelated to the study in advance and appropriate funding included in research budgets.

In this review article, Zulfiqar Bhutta focuses on recent developments in informed consent and highlights issues relevant to developing countries. This paper provides a very brief history of consent to medical research, before summarising the provisions on consent provisions in recent reports and guidance. Current areas of concern are identified and briefly discussed, including: procedures for obtaining and documenting consent; community versus individual consent; consent on complex issues; ethical review and feedback, consent from vulnerable populations and the lack of research on consent processes in developing countries. The review concludes by making a number of recommendations for improving consent processes. These involve focusing on improving participant understanding, using innovative materials and processes to explain research, finding alternative and more user-friendly means of documenting consent and involving senior staff and communication experts in the consent process.

This editorial is one of three articles that started the current debate about appropriate standards of care in clinical trials (the other two were an article by Peter Lurie and Sydney Wolfe in the same edition of the New England Journal of Medicine (see below), and an editorial in The Lancet). Marcia Angell criticises the placebo-controlled trials that were conducted to test an intervention to reduce mother-to-child transmission of HIV.

The article refers to the importance of researchers being in equipoise (i.e. not knowingly giving some groups of participants inferior treatment) and of not subsuming the interests of individual participants for the greater good. The author lists justifications that were given by research sponsors for this work: that participants were not being denied treatment that they would otherwise receive and that a placebo-controlled trial was the fastest and most efficient way to obtain information of relevance to the areas where the research was being conducted.

Angell concludes that these justifications were reminiscent of those of the infamous Tuskegee study where participants in the United States were not informed that they were enrolled in research, and were denied effective treatment for syphilis when this became available. Concern is expressed that the HIV study appears to mark a retreat from ethical principles about research conducted in developing countries as set out in international guidance - for example, participants received a local standard of care rather than the ‘best’ current treatment as required in the Declaration of Helsinki - and the reasons for this are critically examined.

This "education and debate section" focuses on the 2000 revision of the Declaration of Helsinki, and comprises four articles commissioned from researchers working in the developing world, the developed world, the pharmaceutical industry, and a patient representative.

South African researcher Stephen Tollman argues that "despite the increasingly inclusive aspirations of the revised declaration, some of the absolute and exclusionary language could unintentionally endanger research in developing countries". Consumer advocate Hilda Bastian lists nine gains for consumer rights arising from the revision, but goes on to discuss a number of perceived problems in more detail. UK researcher Richard Doll distinguishes five different types of medical research and claims that "strict application of the declaration’s principles would make a wide range of clinical, biological and epidemiological research impracticable or invalid".

To some extent this conclusion is mirrored in the article from two members of the pharmaceutical industry. Laurence Hirsch and Harry Guess of Merck Laboratories say that several provisions in the revision do not provide better protection of research participants in clinical trials, and inadvertently hamper the development of safe and effective vaccines and drugs.

Evelyne Shuster opens this article with the Nuremberg Code - the precursor to the Declaration of Helsinki and other international and national guidance on the ethics of medical research. 

Shuster discusses the role of physicians in the formulation of the Code during the famous Nuremberg trials of Nazi physicians. The lawyers' arguments about unethical research conducted in Germany, France, the Netherlands, Britain and the United States demonstrate how views about what constitutes acceptable and unacceptable research have changed over the last century. 

The article goes on to summarise how medical researchers have used the Code, and its effect on guidance and regulation over the five decades following its publication. 

In this article Asad Jamil Raja discusses some of the revised provisions in the 2000 revision of the Declaration of Helsinki and considers their implications for developing countries. Two points singled out for particular consideration are paragraph 19 (which requires a "reasonable likelihood" that research populations will benefit from the results of research) and the controversial paragraph 30 (which concerns what should happen after research).

The article goes on to consider the role of the pharmaceutical industry in medical research and proposes three measures to improve the ethics of healthcare: an examination of the ethics of the pharmaceutical and biotechnology industry, for the World Health Organisation to play a more proactive role in resource allocation for global healthcare and health research, and measures to strengthen the capacity for ethical review in developing countries.

This article discusses the development of guidelines to ensure that researchers work in culturally appropriate and non-exploitative ways with indigenous Australian populations. Reflecting the concerns of some research populations in developing countries, the authors note that indigenous communties in north-east Victoria had had negative experiences with research projects because of the lack of community control, lack of local benefits, and interpretation of data in isolation from social context.

The resulting guidelines are based on the Australian National Health and Medical Research Council (NHMRC) Guidelines on Ethical Matters in Aboriginal and Torres Straight Islander Health Research and include input from researchers and community representatives.

Issues covered include appropriate consultation measures before research is done in populations that work and act collectively, topics that needed to be agreed between the community and researchers before the start of research, ongoing community involvement in the research and implementation of any outcomes, administration of local ethical review of research, supervision of inexperienced researchers, and data storage and retention.

US-based ethicist Christine Grady argues that clinical trials of vaccines, including against HIV, require special considerations when it comes to deciding upon an ethical framework. Most clinical trials, she says, are for therapeutic drugs, with narrowly focused outcomes aimed at benefiting the individual. Vaccine trials have broader goals, including that of benefiting the community at large, rather than simply the individual.

The commentary is clearly written and aimed at general readers with a basic understanding of the concept of vaccines, but not requiring a specialised knowledge of vaccines or immunology terms. It uses examples drawn from different types of vaccine research, including against malaria, rotavirus, and hepatitis virus infections. 

The article summarises specific issues involved in vaccine trials that are worth considering when deciding upon ethical guidelines, including the need to ensure that the design of a trial is appropriate not only for the scientific question being asked, but also for minimising risks and maximising benefits to the trial volunteers. These include the questions of whether or not a placebo arm should be included, and the nature of placebos, as well as the process of selection and randomisation of volunteers into different groups within the trial.

In this article, Solomon Benatar and Peter Singer suggest that too much reliance has been placed on the role of international guidelines in suggesting what is ethical, and note that such guidance always needs to be interpreted.

They argue that the term 'standard of care' has not been clearly defined, and that this has hindered international debate on this topic. Criticising the idea that the standard set by developed countries should be considered the norm, the authors propose a new conception of 'standard' of care that takes account of the social, economic and political context within which a clinical trial is conducted.

This article from the Gambia Government / Medical Research Council Joint Ethical Committee is an early response to the criticisms in the New England Journal of Medicine and The Lancet that placebo-controlled trials to prevent mother-to-child transmission of HIV were unethical.

The authors express concern that important research in developing countries would be threatened if research practice were changed in response to such criticisms. In particular, research that only compared new interventions with the best available therapy in developed countries would fail to provide information about interventions that are relevant and affordable for the local situation.

The authors note that there is sometimes a need to re-examine interventions that have proved effective in developed countries before it is possible to make an informed public health decision about introducing them in the developing world. They conclude that "stopping trials in Africa that are trying to help improve the health of poor people so that those in affluent countries can have peace of mind seems a tortured form of ethical logic".

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This 1997 editorial from The Lancet is one of three articles that kicked off the current debate about appropriate standards of care in clinical trials. Commenting on the other two articles (published the week before in the New England Journal of Medicine) it concludes that placebo-controlled trials of antiretroviral drugs used to prevent mother-to-child transmission of HIV violated a fundamental ethical principle of medical practice, namely that doctors should do no harm. The reason given is that women were harmed because they received no effective treatment to prevent transmission of HIV to their children.

The article dismisses the argument put forward by those justifying the trials: that if they had not been conducted none of the women would have received an effective treatment. Instead, it focuses on "the fact remains that some women were given a treatment that the physicians in charge knew was not the best possible intervention". The editorial goes on to explain the need for the ‘ethics industry’ that comments on such matters to be "rooted in clinical practice and not in armchair moral philosophy".

[This article is reproduced with permission from The Lancet.]