Ethics of experimental research is now a main concern of civil society because biotechnology is perceived by the lay people as a possible personal menace. This is why many international organisations, like OMS, CIOMS and others are devoting time and resources, to discuss the scientific and ethical aspects of the experimental research on animals and humans, including embryos and foetus.
In my presentation I will refer only to research in adult humans and in the field of healthcare. The case for animals and plants, as subjects of research, being clearly important for humans and deserving attention in the future is not in the scope of the present communication.
There are different kinds of research related to healthcare. According to a recent publication of the Nuffield Council on Bioethics (1) the more important are:
social and behavioural research
intervention studies, including clinical trials and community-based trials
health services and operational research
Basic research is usually laboratory-based and includes studies at the cellular level, and of immunity and pathogenesis. Such research is often dependent on the use of samples from patients.
Clinical research is often conducted with patients in a medical setting, such as a hospital, and is designed to obtain better information on the natural history or pathogenesis of a condition that may lead to improved strategies for diagnosis, treatment or prevention of a disease.
Epidemiological research usually involves population-based investigations, which may be cross-sectional surveys of selected populations (case-control studies) or all members of a community, or may involve longitudinal study of a population over time (cohort studies). Such research is conducted to obtain an improved understanding of the natural history of a disease or to identify factors that increase or decrease the risk of a disease in individuals. Often such investigations involve the study of large populations and they may be observational or interventional in nature. The aim is to identify strategies for the better prevention or treatment of disease, through an improved understanding of risk factors for disease or for progression of disease.
Social and behavioural research is often a component of epidemiological research and focuses on the study of behavioural and social factors that may modify risk of disease in individuals or in populations. Such research may involve the collection of sensitive information about a person and their lifestyle (e.g. sexual behaviour). While some forms of research may only involve observation others may involve studying or testing ways of changing behaviour or social circumstances.
Intervention studies are conducted to evaluate the impact of specific interventions on the prevention of disease, often in the context of community-based intervention trials, or in modifying the clinical course of disease, often in the context of clinical trials. Such research may provide the basis for policy decisions and priority setting. Intervention studies usually involve the comparison of different treatment or prevention strategies in which the current intervention method is compared with another method, often new, that may be more efficacious than the existing intervention. If there is no existing effective intervention, a placebo or “no intervention” may be used as the comparison against which to assess the impact of the new intervention. Ideally, individuals are randomly allocated to receive the different interventions being compared in the trial.
Health services and operational research are concerned with the study of methods of delivery of healthcare, access to treatment and quality of care, with the aim of finding improved methods that lead to better care. Such studies often include an evaluation of the cost of providing the intervention and the benefit it provides.
In the field of research on adults, human and women, a lot of problems deserve attention to the catholic opinion.
There are many international documents and guidelines after de Code of Nuremberg but I will present here the Protocol on Biomedical Research, prepared by the Steering Committee on Bioethics (CDBI) and open to public discussion which final version will be approved in 2002 and proposed to the signature of member-states in 2003.The Protocol covers the full range of biomedical research activities involving any kind of intervention on human beings, but does not apply to research on embryos in vitro; it does apply to research on foetus and embryos in vivo as well as pregnant women.
The catholic opinion is not against the research on humans providing that the human dignity and human rights are fully respected.
In this sense the Protocols state, like the Convention, that the interests and the welfare of the human being participating in research shall prevail over the sole interest of society and science.
To protect the human dignity and human rights the Protocol states that any research project must be approved by a competent authority after independent examination of it’s scientific merit, including assessment of the importance of the aim of research and multidisciplinary review of its ethical acceptability.
The ethical revision by a independent and multidisciplinary committee is the key point for the protection of human dignity and human rights. This point is also stressed by the Helsinki Declaration (Edinburgh, 2000) which states “the committee must be independent of the investigator, the sponsor or any other kind of undue influence”: The Protocol states that the members of the ethics committee shall declare all circumstances that might lead to a conflict of interest. Should such conflicts arise, those involved shall not participate in that review.
In order to promote a good and sound opinion of the ethics committee the Protocol detail, in successive Articles, the informations the researchers and promote are obliged to present, the demonstration that no undue influence, including financial gain, is exerted on persons to participate in research, with particular attention to dependent and vulnerable persons. Also important is the information to be presented to research participants which needs to be complete and comprehensible. This information is a sine qua non condition to obtain the consent of the proposed research participant. The main topics of information are: the nature, extent and duration of the procedures involved, in particular, details of any burden imposed; the risks involved; the rights and safeguards prescribed by law for their protection; their right to refuse consent or to withdraw consent at any time, without prejudice to their right to appropriate and timely medical care, and without suffering any other detriment; the arrangements for responding to adverse events or the concern of participants; arrangements to ensure respect for private life and ensure the confidentiality of personal data; arrangements for access to information relevant to the participant arising from the research and to it overall results; the arrangements for appropriate compensation in the case of damage; any foreseen potential further uses, including commercial uses, of the research results, data or biological materials.
The more difficult point is the protection of persons not able to consent to research. If the research have the potential to produce real and direct benefit to his or her health and with safeguards prescribed by law these researches can be acceptable. Without such benefits the acceptability is problematic and open to discussion. Even with minimal risk and minimal burden the research in subjects not able to consent, including minors, with a consent by representation, and with any potential to produce results of direct benefit to the health of the person concerned appears to me as manipulation not in accordance with the emphatic sentence that the welfare of human beings participating in research shall prevail over the sole interest of society or science. In general the catholic opinion is not in favour of this kind of research.
The clinical trials promoted by the Pharmaceutical Industry are another point to be considered. There are four separate phases of such trials:
Phase I trials
Phase I studies will be the first time human subjects are exposed to the potential novel medicine. The objectives behind the study will be to investigate pharmacodynamics, dose-response. and in the case of vaccines, immune response, and to determine the maximum dose that can be tolerated by participants.
In the case of most new medicines these studies will be undertaken in a small number of healthy volunteers. It is not expected that evidence of efficacy of the medicine will be provided by Phase I studies.
Phase II trials
Using the information regarding the safe dosage range obtained from the Phase I studies, the compound will be administered to patients suffering from the target disease and now significant numbers of individuals will be recruited into the trial. Almost always these trials will be conducted in a number of clinical centres. The objective of the Phase II studies will be to seek evidence of the efficacy of the medicine against the specific disease. More information about the safety of the medication will emerge from these studies as larger numbers of individuals are exposed to it. In Phase II trials the patient will often be randomly assigned to the novel treatment group or to a group receiving a placebo (a compound possessing no therapeutic effect) or, more usually, a conventional and established treatment.
Phase III trials
Where a compound has shown evidence of efficacy without significant side effects it will enter Phase III trials in which many hundreds, or sometimes a few thousand patients will be enrolled. These trials will generally seek not only to confirm the clinical efficacy of the novel compound, but also to establish its efficacy in comparison with existing treatments. These studies will often be multicentre and sometimes undertaken on an international basis. Again. careful attention is paid to possible side effects as larger numbers of patients are exposed to the intervention. The end-points for Phase III studies include the demonstration of a statistically significant improvement in the efficacy of the novel medicine over the established therapies. if any such exist.
Phase IV trials
Once a new medicine reaches the market it will be subjected to post-marketing surveillance in order to identify side-effects and other adverse effects which would only become evident as much larger numbers of individuals are treated with. In addition. formal clinical trials continue in order to develop a greater understanding of the compound and its effects in a wider clinical environment, but also to extend its use for other indications or for different patient groups, such as children or the elderly. Special study designs may be used according to the objectives of the study to evaluate safety or efficacy. These may include study of temporal trends. case-control studies, or the phased introduction of an intervention in different areas. Phase IV studies may also be designed to measure the impact of the intervention on the epidemiological pattern or transmission of an infectious disease.
When these trials are proposed to run out in the developing countries there are a risk that no true independent and multidisciplinary ethics committees exist to do a ethical opinion after reviewing of the research projects.
After the notice of abuses in some countries, namely in Africa, the OMS as well as some international organizations like the World Medical Association, The Council for International Organizations of Medical Sciences, and others have prepared a document – Operational Guidelines for Ethics Committees that Review Biomedical Research – to support the improving of organization, quality and standards of ethical review around the world: I think that this document can be approved by our Academy and this approval communicated to the OMS.
The European Forum for Good Clinical Practice as well as the European Parliament and European Commission has prepared documents to harmonize the laws and administrative provisions regulating the clinical trials on Phase II and Phase III.
The Catholic opinion support the values promoted by these documents; and reinforce the disposition on the use of placebo of the Helsinki Declaration on the “extreme care which must be taken in making use of a placebo–controlled trial and that, in general, this methodology should only be used in the absence of existing proven therapy”. The use of placebo can open the door to abuse of the persons involved in a therapeutic trial which can’t be informed that they can be not taking the true medicine but a similar one with no therapeutic action. There are some informations that certain SIDA’S therapeutic researches running in Africa, has been doing with drugs against placebo, in pregnant women – clearly against the Helsinki Declaration.
From a Catholic point of view what is always necessary is a clear statement of the moral imperative of respect for human dignity. This calls upon us to recognize that each person should be treated primarily as a person or an end in him/or herself, not as an object or as a means to an end; it means respecting the right to make free and informed decisions respecting the exercise of individual consent. The researchers may recognize and validate the reality that free and informed consent is a matter of process, it is not simply a matter of getting a signature on a consent form. It begins at the initial contact with potential participants, it includes dialogue and information-sharing, and it continues all the way through the project.
The moral requirements for substantial understanding, for substantial absence of control by others, and for deliberate authorisation of a researcher to do something to the participant are not susceptible to formularised assessments by researchers or Ethics Committees like Research Ethics Boards. This is a very sensible point and catholic institutions as well as catholic participants in Research Ethics Boards should always scrutiny very carefully the process of information to and consent by the persons involved in a research program. Mainly in development countries where cultural, social and political handicaps are so troubling that the promoters inform not the persons to be involved in the trial but the authorities, and those authorities, not the persons, will consent or not. Unfortunately, in certain countries, money and corruption are the most effective means to obtain authorization for research in human subjects.
Researches conducted in developing countries, on Malaria and HIV-infection, are being criticised because they use no-treatment of HIV-infected patients as placebo group. A well-balanced discussion on ethical questions has been presented by V. Leontis (2). In the reference (1) a comprehensive and very complete discussion of the ethical questions related to the research in developing countries can be found. Catholic opinion can agree with the issues that this Nuffield Report propose; they shall be considered when reviewing research proposals in developing countries.
In summary the catholic opinion on the ethics of experimental research in humans can presented in tree points.
a) In any kind of research, the sanctity of human life as a God’s creation, and the dignity of human beings are the main values to be respected. The principles deduced from these values are, in healthcare research, the duty to alleviate suffering, the duty to show respect for persons, the duty not to exploit the vulnerable. These principles must be translated into practice and for this a proper procedure may exist.
b) The research ethics committees with a broad field of intervention are a very important and necessary part of a proper procedure for the control of the respect of principles. However the research ethics committees needs to be staffing with independent and competent members, and produce opinions clearly justified and open to democratic public accountability.
c) The human beings, can never be used, in experimental research, as means to a end, without respect for their life, dignity and welfare, even if the end is presented as beneficial for the society or the health of the humanity.
1-The ethics of research related to healthcare in developing countries. Nuffield Council on Bioethics publication. London, 2002.
2-VASSILI LEONTIS – Ethical challenges posed by trials of biomedical intervention on human subjects conducted in developing countries. Information paper presented at the European Conference of National Ethics Committee. Porto (Portugal) 1998. CDBI/INF (98)2.