SciDev.Net

Summary

The need for case-by-case review of proposed medical research has been on the international agenda for several decades. But the main operational mechanism used to ensure that clinical research conforms to ethical standards, and that participants in such research are protected – in the form of ethical review committees (ERCs) – is still inadequate in the developing world. Zulfiqar A. Bhutta sets out the constraints faced by members of ERCs in developing countries, and offers suggestions of what could be done to improve the situation.

Introduction: the need for ethical review

While examples of unethical research had been debated prior to the 1930s, it was the large-scale and systematic atrocities committed in the name of medical research during the Second World War that prompted the first international guidance on research ethics in 1964, the Declaration of Helsinki. A mechanism for the case-by-case review of proposed research is first mentioned in the initial revision of the Declaration, published in 1975: “The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted to a specially appointed independent committee for consideration, comment and guidance”.

The proposed process for ethical review was intended to be the way in which the general principles of research ethics could be translated into actual protection for research participants. Since 1975, provisions about the composition and role of committees reviewing research have become increasingly detailed in international guidance. As well as being addressed in the most recent revisions of the Declaration of Helsinki [1] and Council for International Organisations of Medical Sciences (CIOMS) guidance (which sets out how Helsinki should be applied in developing countries) [2], many examples of national guidance now set out specific critieria for the ethical review of research, and the World Health Organisation (WHO) has also published detailed guidance for such review [3].

Today, the main operational mechanism used to ensure that clinical research projects conform to ethical standards and that participants are protected is through an ethics review committee (ERC). The role of ERCs is to independently assess the ethical acceptability of research to the participant populations. For example, the guidelines published by WHO state: “ERCs are responsible for acting in the full interest of potential research participants and concerned communities, taking into account the interest and needs of the researchers, and having due regard for the requirements of relevant regulatory agencies and applicable laws”.

The WHO and CIOMS guidelines provide useful direction on the routine tasks to be undertaken by ERCs. However, the international and national guidance is not consistent as to the composition and optimal number of members of an ERC. And although guidelines recommend that ERCs must have administrative and financial support, it is presently unclear as to how this might be optimally achieved.

ERCs in developing countries

While the tradition of ethical review committees is well established in developed countries, and the selection and training of members is relatively well organised, this is not the case in developing countries. Indeed, until recently, the concept of local ethics committees – especially established ‘standing’ committees – was unfamiliar.

Given the paucity of indigenous and locally sponsored research in developing countries, the principal ethical review process for internationally sponsored research took place in the developed-country institution or organisation. Local ethical review, when undertaken, was frequently though an ad hoc committee or group with scant training or exposure to the ethical review processes, and fulfilling a largely procedural requirement. Furthermore, the difference between an ethical and scientific review process was not always readily apparent, as review committees were mainly composed of researchers or scientists.

This situation has improved considerably in recent years with the development of national guidelines for the ethical conduct of research, training of staff and trainers in bioethics, and a global recognition of the need to invest in developing local capacity. This has resulted in the establishment of national or ‘representative’ ERCs in many countries. Additionally, several institutions are now developing training programmes in this area, and gradually achieving international recognition. In some instances this has also led to the development of regional associations of ethics committees such as the Forum for Ethical Review Committees in Asia and the Western Pacific (FERCAP) the Latin American Forum of Ethics Committees in Health Research (FLACIES), and the Pan-African Bioethics Initiative (PABIN).  

It is encouraging to see such advances in equipping developing countries to conduct ethical review of clinical trials. Nevertheless, there clearly remain a number of constraints and problems that affect the way ethical review and oversight of research is undertaken. Although not exhaustive, the following represent some of the issues that concern the effective ethical review and functioning of ERCs in developing countries.

Constraint (1): lack of training in medical ethics

One of the key difficulties faced by ERCs is the limited number of people trained in medical ethics – or even exposed to the principles of ethical review – particularly given that sponsoring organisations are placing increasingly stringent requirements on local or national ERCs.

A recent review of 47 leading health science institutions in Pakistan, for example, revealed that only 25 per cent had established full-time ERCs and that there was no national ethics review body [4]. Similarly, a review of the status of health ethics among several countries in South East Asia indicated that although a central mechanism for ethical review existed in many countries, it did not translate into adequate capacity at an institutional level [5].

Although there are a few training programs in research ethics, these are still insufficient to meet the growing need for ethical review in developing countries. Furthermore, the field of ethics is continually evolving and research projects are increasingly sophisticated and complex. It is therefore crucial that ERC members have access to continuing education – as has been recognised by regional initiatives such as FERCAP and PABIN.

The guidelines for ERCs developed by the Tropical Diseases Special Programme of the WHO [3] are a good starting point, but have yet to be developed into comprehensive models for continuing education. The Internet also offers great potential for training ERC members. It is important to underscore, however, that many of the existing online programmes for continuing medical education are perfunctory and based on institutional and regulatory requirements for the rapid certification of investigators. 

Constraint (2): ethical versus scientific review

There is an important relationship between scientific and ethical review processes: clearly scientifically unsound research is by definition unethical to undertake, and it is not permissible to undertake unethical research for the purpose of yielding good scientific knowledge. It is therefore desirable that ERC members should be aware of the scientific design and merit of planned research.

However, there is a lack of consensus regarding the optimal level of scientific knowledge required of ERC members. Some guidelines indicate that the role of the ERC should extend to a full scientific review, or at least to ensuring that a scientific review has taken place [2,6]. Others say that ERCs should merely have access to research syntheses (i.e. meta-analyses of data from previous trials) and scientific reviews [7].

In theory, any ERC should include scientific members who are able to provide this input. But given the volume of research and its diversity, and the increasing sophistication of clinical trial protocols, most developing country ERCs are unlikely to fulfill this role. In reality, developing country ERCs range from the scientifically naïve to those that are so dominated by scientists that the nature of the review is more scientific than ethical. One possibility is for ERCs to co-opt additional members to advise on the scientific design of research and the possibility of alternative processes or designs.

Constraint (3): institutional and resource pressures

Many of the international agencies that fund clinical research – such as the WHO – do not provide for indirect costs incurred by institutions, which includes the operation of an ERC. The financial burden of such activities therefore tends to fall upon the institution itself; for many developing country institutions – especially public sector universities with limited budgets – these running costs can be considerable.

As a result, members of institutional ERCs are often expected to undertake ethical review activities in addition to their own duties, without compensation for time or effort. Not only does this create understandable backlogs in the processing of applications, but also reduces the number of people willing to devote their time and energy to this process. Persuading individuals from civil society, lawyers or journalists to participate in ERC work is not easy, especially on a purely voluntary basis.

With limited manpower, institutions in developing countries may have difficulty in appointing and maintaining ERCs. One consequence of this may be middle grade staff being required to review applications from colleagues in positions of relative seniority and authority. Even if these individuals are appointed, the lack of a culture of questioning and confronting authority, especially at different academic ranks, can pose problems. 

It should be noted that ERCs may also be subject to indirect institutional “pressure” to facilitate the acceptance of internationally sponsored research projects that bring with them substantial resources (in some cases, more than the entire annual budget of the institution). This risk may be particularly marked for ad-hoc ERCs largely set up for specific needs.

Constraint (4): lack of ERC guidelines

Even though guidelines exist on broad ethical principles, most ERC members in developing countries have little opportunity to be educated on how to resolve the application of such principles in specific cases, for example, those related to the standards of care to be provided during the trial (see Looking after participants in clinical trials). Although some national guidelines have assisted in providing advice in this area, ERC members are often left to resolve issues on the basis of personal knowledge or group consensus, or ignore them altogether. Given the increasingly varied and complex nature of research, there is also a need to develop guidelines for specific areas of research such as vaccine trials, reproductive health research and health systems research.

An additional emerging problem stems from the increasing number of multi-country research projects that involve several ERCs. Such scenarios increase the scope for disagreements and differences of opinion between committees. At present there are no formal mechanisms to resolve disputes between ERCs. Nor is there a system of ‘ombudsmen’ to consider petitions, either from the community being researched or from the researchers/sponsors. However, the use of communication technology, such as teleconferencing, may make it possible for ERCs located in different locations to work together more closely.

Constraint (5): community representation and participation

Most research ethics guidelines require that community representatives and members of civil society are included in ERCs. However, individuals usually chosen to represent civil society are typically journalists and social scientists who may be socially far removed from the actual research participants. Even the inclusion of local political leaders in the deliberations of ERCs does not necessarily guarantee that they truly represent the populations they are supposed serve.

These challenges reflect wider issues surrounding the general level of development and democratisation of developing-world societies, and cannot be addressed by regulatory processes alone. Indeed, there are calls by some groups to extend the role of ERCs to disseminating research results [8] and engaging the public in these issues [9].

The gap between guidelines and ERC practice

Despite the available guidance, there is still disquiet surrounding the issue of ethical conduct of research. One of the reasons for the continued debate is that while guidelines do help in cases of externally funded research, developing countries struggle to apply the recommendations against a backdrop of inequity and distributive justice. It must also be remembered that a large proportion of health research is still conducted at the national level, by national researchers and ERCs working with meager resources and mostly without the requisite background in medical ethics.

The consequences of such limitations on the ethical review processes range from inordinate delays in processing proposals to inadequate and largely cosmetic ethical reviews. Another aspect that is encouraged by the guidelines – but rarely achieved – is ongoing review of research projects, while they are being carried out. Although desirable, this requires considerable manpower and additional resources. Instead, ERCs largely depend upon reports by researchers and a review of signed informed consent forms in drawing inferences about ongoing research.

The following represent just a few examples of practical initiatives that may help reduce the 'ethics gap' in the context of developing-country ERCs.

1. There is an urgent need to develop and facilitate innovative ways of offering training and education in research ethics. As well as supporting and enhancing current training programmes it will be essential to build up a cadre of trainers located in developing countries, as well as establishing a process of mentoring for local ethics committees. Improved access to information technology – particularly the Internet – opens up the potential for both formal distance education and continuing education models to be explored.

2. Effective ethical review and oversight of research requires appropriate financial support. Even though some agencies may not offer to support indirect costs for research, such resources could be built within projects. In order to avoid conflicts of interests, these funds could be made directly available to an institutional pool that is set aside for the appropriate resource allocation of core ERC costs.

3. Many research projects need to deal with more than one ERC. It is both conceivable and desirable that there should be some contact between such ERCs, while at the same time ensuring that local specificity and relevance is not sacrificed. Although a single common ERC representing all countries and stakeholders may be entirely affordable for large multicountry projects [10], an alternative system of a hybrid or joint ERC would promote better communication [11]. Depending on circumstances, this could be achieved through email, teleconferencing or other Internet-based communication.

4. Given the importance of community involvement in research projects at an early stage, due consideration should be given to involving these groups in the ethical review process. Developing mechanisms for the ERC to interact with appropriate community representatives may also lead to a better understanding of the ethical underpinnings of research.

It should be recognised that any of these approaches will require a concerted investment of time and effort by both research sponsors and host institutions, and will involve a process of evolution rather than revolution. Nevertheless, the challenge of enhancing and supporting ethical research in developing countries is both real and immediate. It also offers a unique opportunity to promote equity and collaboration in the world of science.

What can be done?

The following represent just a few examples of practical initiatives that may help reduce the 'ethics gap' in the context of developing-country ERCs.

1. There is an urgent need to develop and facilitate innovative ways of offering training and education in research ethics. As well as supporting and enhancing current training programmes it will be essential to build up a cadre of trainers located in developing countries, as well as establishing a process of mentoring for local ethics committees. Improved access to information technology – particularly the Internet – opens up the potential for both formal distance education and continuing education models to be explored.

2. Effective ethical review and oversight of research requires appropriate financial support. Even though some agencies may not offer to support indirect costs for research, such resources could be built within projects. In order to avoid conflicts of interests, these funds could be made directly available to an institutional pool that is set aside for the appropriate resource allocation of core ERC costs.

3. Many research projects need to deal with more than one ERC. It is both conceivable and desirable that there should be some contact between such ERCs, while at the same time ensuring that local specificity and relevance is not sacrificed. Although a single common ERC representing all countries and stakeholders may be entirely affordable for large multicountry projects [10], an alternative system of a hybrid or joint ERC would promote better communication [11]. Depending on circumstances, this could be achieved through email, teleconferencing or other Internet-based communication.

4. Given the importance of community involvement in research projects at an early stage, due consideration should be given to involving these groups in the ethical review process. Developing mechanisms for the ERC to interact with appropriate community representatives may also lead to a better understanding of the ethical underpinnings of research.

It should be recognised that any of these approaches will require a concerted investment of time and effort by both research sponsors and host institutions, and will involve a process of evolution rather than revolution. Nevertheless, the challenge of enhancing and supporting ethical research in developing countries is both real and immediate. It also offers a unique opportunity to promote equity and collaboration in the world of science.