SUMMARY REPORT OF THE INTERNATIONAL SUMMIT CONFERENCE ON BIOETHICS TOWARDS AN INTERNATIONAL ETHIC FOR RESEARCH INVOLVING HUMAN SUBJECTS

1987

Twenty-six delegates, nominated by the heads of state of the Economic Summit nations, by the European Economic Community, and by the World Health Organization, met at the fourth Bioethics Summit Conference in Ottawa, Canada, on April 5–10, 1987. The Summary Report addresses the major areas discussed at the conference and presents both the background and the major recommendations of the delegates for improving the protection of research subjects throughout the world. The recommendations are shown in boldface within the text.

1. Introduction

Rapid progress in bioscience has created an urgent need for continuing development of national standards of ethics in research with human subjects. The growing interdependence of nations throughout the world has stimulated a need for internationally agreed upon standards and practices based on a careful continuing dialogue and reflection on values. The delegates at the fourth International Summit Conference on Bioethics worked towards these goals. They focused not only on the principles, but more specifically on the practice and procedures guaranteeing their implementation.

The fourth in a series of annual bioethics summit meetings initiated by Prime Minister Nakasone in 1984, this meeting reflected deeply on an area important to the entire practice of bioscience and medical research. It is hoped that the discussions and recommendations will benefit national practices, and contribute to improved international standards.

We, the delegates to this meeting, invite the Prime Minister of Canada, the Right Honourable Brian Mulroney, to present this report to the next Economic Summit Conference, to be held in Italy in June, 1987.

2. Underlying Principles and Practices: Development and Implementation of National Ethics Standards

The underlying principles for the ethics of research with human subjects are defined in national and international codes. These include respect for individuals, contribution to the well-being of peoples, and the equitable distribution of potential risks and benefits throughout society. Even though only very general international guidelines have been accepted, as yet, uniform practices are not widely accepted due to national and cultural differences.

Though need for societal review of research proposals is generally accepted, there are great differences in how countries and even institutions within some countries carry out this review. Only some of these variations can be ascribed to the cultural differences which are an essential background to societal standards.

As national standards are established, consideration must be given to evolving international guidelines for research involving human subjects. These will permit research jointly undertaken between nations and amongst groups of nations using common protocols, stimulate sharing of research results amongst nations and avoid unnecessary duplication and multiplication of research efforts.

The question of how common standards can best be developed and implemented considering the present diversity in practice and the complexity of the biomedical research enterprise occupied much of the discussion.

For that reason, the delegates recommend that, in order to safeguard the rights and well-being of patients and research subjects, research ethics committees should be established in all countries. All research projects involving human subjects must be submitted for approval to a research ethics committee.

It is further recommended that these committees should be comprised of medical experts, and of experts outside the medical profession (e.g. theologians, moral philosophers, lawyers and lay members who represent the general public). Lawyers acting professionally for an institution, and others having a financial interest or potentially conflicting interest in the institution or the research in question should not serve on the ethics committee adjudicating that research. Furthermore, the committees should be of a size which is sufficient to allow for the inclusion of the three groups (medical experts, outside experts and lay members) and small enough to make efficient work possible.

Delegates also considered the means of operation, freedoms and accountabilities of the research ethics committees. The decisions which they must take often reflect finetuning of competing values, and the scientific, technical or cultural environments within which they work may vary. Therefore, some differences of views between research ethics committees should be expected. Delegates were of the view that, while there may well be a need for nations to monitor the functioning of local research ethics committees, the highest standards can best be assured if they are given responsibility and authority for the review of research ethics in their institutions; as well, their effect will be enhanced if seen by researchers and society as working with the research process in a collegial sense rather than in an adversarial mode.

3. Sharing the Risks

Three groups in society can be identified as carrying risks and benefits. The researchers or clinicians who carry out the trials and other research carry the primary burdens of ethical responsibility for protection of the research subjects. In the context of drug testing, the risks and costs of developing a new drug or device remain with the manufacturer. Nevertheless, the human beings on whom the research is performed carry the most direct risks of research, but can gain the benefits of the higher standards. Society or mankind as a whole is the ultimate beneficiary from research towards improved health standards, and for that reason, the delegates recommend that human research subjects be fully informed concerning the availability or the lack of availability of mechanisms of care and compensation to subjects who are injured as a result of their participation in research. The delegates encourage member nations to establish and implement appropriate mechanisms for care and compensation in areas where they do not presently exist.

4. Public Participation

The delegates agreed that the imposition of societal standards on the sensitive areas raised by medical research demand the involvement of the general public. Public involvement is required not only in the development of consensus but also in consideration of individual research proposals to ensure full and open discussion which might otherwise be uncritical or too narrowly based. The multidisciplinary character of research ethics committees provides for both public accountability and credibility.

5. Research with Those with Restricted Ability to Give Consent

The overriding purpose of ethics review is the protection of the research subjects. An essential component of this protection, enunciated in all international codes of ethics is that each research subject must consent freely, and with full information, to participate in the research. However, those who are legally incompetent cannot, by definition, give their consent. Delegates focused their discussion of this issue on research with children, while recognizing that similar concerns arise with adults who are mentally handicapped and with other vulnerable populations.

All delegates accepted the need for therapeutic research with children. Such research would be of potentially direct benefit to the well-being of the individual subjects.

Non-therapeutic research with children poses special problems. While such research is necessary if treatment of childhood diseases is to advance, there was agreement that such research could only be considered under the following conditions: the specific project must be approved by a research ethics committee all needed knowledge must have been obtained through research with adults or animals, there must be no valid alternative to the use of children in the research; a valid proxy consent (by family, guardians, ombudsman, those with power of attorney or others) must have been obtained for each research subject; and, to the extent possible, the child should have given assent. Thus, it was the view of most delegates that needed non-therapeutic research on children, if within the limitations just mentioned and if involving minimal or no risk to such children, should not be precluded.

6. Research with Embryos

The integrity and uniqueness of human life in its earliest embryonic stages of formation must be accorded great respect. Generally, current forms of control of research procedures and manipulation of human embryos are not legislative in nature. In fact, in the almost total absence of legislation, research on the embryo is presently, for the most part, governed by the self-regulatory efforts of scientific and professional bodies, the centres themselves, and the review by ethics committees, local and national. Voluntary licensing control exists, for example in England, but there was consensus on the need to regulate the current anarchic proliferation and operation of in vitro fertilization centres in some countries as an interim measure while acquiring the experience necessary for effective legislation. Thus the delegates recommended the need to keep in balance the professional liberty for clinical treatment and for scientific inquiry in the interest of progress in medical knowledge and skill while upholding regard for the human interest in the embryo. To this end, the delegates recommend the supervision and control of centres offering in vitro fertilization, of related treatments for infertility and of those conducting embryo research. Procedure should be regulated according to appropriate guidelines administered by a competent authority.

All delegates recognized the preciousness of the human embryo. Nevertheless, different positions were taken with respect to the possibility of permitting research on the human embryo.

Several questions were raised with respect to the applicability of legal concepts of "ownership" (more properly discussed in terms of legitimate interest in) and control of human embryos during storage or after the death of the donors. Questions were also raised concerning penal sanction as opposed to professional regulation.

Considering the experimental nature of in vitro fertilization, its low success rate and the unknown long term effect of these procedures, which though "therapeutic" in nature for the infertile have implications for the manipulation and control of human life, any work with embryos even as a treatment for infertility should be regarded as developmental procedures that are experimental in nature and therefore should be closely monitored.

7. Pilot Studies and the Introduction of Novel Therapies

Delegates debated the special problem of ethics review of pilot studies or preliminary studies of medical innovations. Such studies were viewed as a phase between the initial observations on one or a few patients and the start of a full fledged protocol-based program.

Delegates recognized that it is often not easy to be sure whether an intervention by a physician should be regarded as a treatment undertaken only in the patient's best interest, or whether it is guided also by an intent to gain scientific knowledge.

The decision on when a research intent is present in therapy is a determination to be made by the physician. It was the opinion of the delegates that, if the health professional has any doubt whether the intervention is in fact research, the issue would best be brought to the attention of the ethics committee.

In reviewing the novel therapy of research, delegates recommended that they should be subject to the same ethical judgements that apply to all research protocols. Special consideration should be given to limiting the number of subjects entered into pilot studies and to monitoring closely and frequently.

In ethics review of pilot studies as in that of other proposed research, the delegates agreed that provision should be made for a mechanism to re-examine a research project rejected by a research ethics committee if the investigator should request it. Such a mechanism should be of a sort which would not invite the overriding of local decisions by a higher or distant authority. It should maintain the collaborative nature of the relationship between the researcher and the ethics committee, rather than encourage an adversarial relationship. It was also agreed that there should be a greater exchange of information between research ethics committees.

8. Industrial Research

Industries are a major source of medical innovation. Also much of their research is mandated by national standards for licensing drugs or devices. This research involves both animals and human beings and is often carried out in a number of countries. For that reason, the interactions between industries, governments and sometimes universities are of great concern.

Differences in the way ethics standards are interpreted and implemented can have direct economic effects. Lack of consistency can adversely affect national and commercial interests as well as the safety of research subjects. Delegates recommended that, at the very least, a nation should not allow or support, in other countries, research which does not conform to ethics review standards at least equivalent to those in force within the nation. Nations and industries should develop international accords which strive for common attitudes and the exchangeability of standards and for mutual trust. Nations and industries should also identify emerging technologies to foster early discussion of the ethical concerns. Such interaction might help the equitable distribution of effort in research and development.

Delegates also discussed the ethical concerns raised by the growing pace of commercialization of biomedical products. The increasingly close links between university-based and industry-based research mean that academic physicians or institutions may have financial interests in the outcome of the research; any such potential conflicts of interest should be declared in the research ethics review process. Moreover, it was the opinion of some delegates that we should develop and implement values which integrate ethics and economic interests.

Delegates also discussed the effects of confidentiality, and of compensation of research subjects. The confidentiality of commercially sensitive material may not be consistent with the requirements for ethics review. In addition, payment can induce subjects, especially those of more limited means, to participate in research, and may lead to financial competition for research subjects. With respect to both industrial and other research, concern was expressed over whether patients will be compensated for adverse effects which may on rare occasions arise from research.

Much industrial research and other biomedical research depends on research with animals. Delegates recommended that in all research we must continue to insist that animal research precede research on humans, while recognizing the obligation to reduce the number of animals required to a minimum wherever possible and to encourage alternative methods for assessing safety and efficacy.

Much of the regulatory testing of new drugs still requires the use of animals. In this regard, delegates recommended that governmental agencies continuously modernize their own regulatory requirements to ensure that they do not demand test results of safety and toxicology which are no longer relevant or which can be replaced by satisfactory alternatives requiring fewer animals.

9. The Selection of Research Topics and Directed Research

Researchers consider many scientific, social and other factors when choosing research topics; choices are also made in the context of national policies and systems of support as well as national policies and practices in respect to ethics. In some instances, this results in an apparent imbalance between the research topics being chosen and major global needs for research in fields such as fertility regulation and tropical diseases.

International research programs can provide a successful mechanism to promote and carry out research in those areas which are neglected, sensitive and/or economically unattractive to national researchers. These programs can make extensive use of the international scientific community and can apply high standards of scientific and ethical review to carry out research in the areas of high global priority which are difficult to address on a national basis. Those nations with the means to support research have an obligation to devote some of those resources to the research needs of nations without such means.

The group recommended that research should focus upon the development of knowledge in broad fields of science with the aim of achieving a fundamental understanding of biological processes, even those which might not appear to have direct application over the short or longer term. It is seen as a scientific infrastructure of further advance. It was also recommended that the results of research should be applied as rapidly and as effectively as possible.

Large scale support for narrowly focussed research on specific diseases without the necessary foundation of scientific knowledge was seen as rarely, if ever, successful. Also the failure to implement the results of research for the benefit of mankind has, in itself, serious ethical implications.

10. Towards Improved Ethics Standards: Biomedical Research in an Interdependent World

The last decade has witnessed profound growth in improved communication and common endeavor among nations. As well, movement has begun towards international agreement on research with human subjects.

Delegates are certain that meaningful international agreement is not only possible but necessary, and urge the Heads of States to work toward ensuring that practice accords with principles in all aspects of research involving human subjects.

The delegates accept that society should make the human subject an active and educated participant in a process in which he or she contributes from a sense of basic human altruism and a desire to serve the common good, rather than as a "subject of research" as has sometimes been the case in the past.

The further refinement and expansion of national standards of research ethics with human subjects across political and cultural boundaries demand continuing investigation into the ethical problems of biomedical research. Furthermore while agreeing on the necessity for this ethical review process, the delegates recommended that these committees themselves, their operations and their functions be studied.

According to the delegates, research ethics should always be integrated into clinical decision making. The delegates recommended that education in medical ethics for physicians, investigators and medical students be intensified and that the media and public be informed.

Delegates also recommended that special attention be given to the ethical issues involved in epidemiological studies which can be as intrusive of human dignity and privacy as medical intervention. In particular, the regulation of confidentiality, which may both restrict the exchange and gathering of information and may at the same time fail adequately to protect the subject of such epidemiological studies, requires examination.

In regard to dissemination of principles, statements by way of declaration are laudable and necessary. However, if such statements are to have proper binding power, they must be known and an effort made to ensure compliance with them. To assist in this endeavor and in view of the importance of continuing dialogue, delegates recommended the establishment of appropriate fora devoted to the issues arising in research with human subjects.

Conclusions

This conference affirmed the growing importance of international agreement and cooperation on both the elaboration of principle and on the implementation of ethics review processes in medical research involving human subjects. To this end, the establishment of multi-disciplinary research ethics review bodies for the examination of research protocols was considered essential, as was further study and communication among nations.

Implementation of effective ethics review processes demands the enhanced education in medical ethics both of those involved in research and of the greater public.

The development of national and international standards for research with human subjects and their implementation must continue to aim at the protection of more vulnerable subjects.

The promulgation of ethics standards for research across nations and cultures should focus on areas of concern, as well as on international needs that are not being met.