Ethics For Biomedical Research Involving Humans Research Paper

At the close of World War II, in Nuremberg, Germany, certain leaders of the Nazi regime were put on trial for having committed ‘crimes against humanity.’ During the course of one of these trials, the so-called doctors’ trial, the first international code of research ethics, the Nuremberg Code, was written. Subsequent international codes were designed to improve on or to interpret the efforts of their predecessors. WMA began its project in 1953 because it recognized ‘… a need for professional guidelines designed by physicians for physicians (as opposed to the Nuremberg Code, which was formed by jurists for use in a legal trial).’ The result of this project was its code of research ethics which was adopted at the World Medical Assembly in Helsinki, Finland in 1964. CIOMS introduced its Guidelines in 1982 by stating that they were designed to provide guidance for the correct application of the principles of Helsinki, particularly when the research is initiated by researchers and sponsors in technologically developed countries and carried out in developing countries. However, in the revised Guidelines, published in 1993, there are several substantial departures from Helsinki’s requirements. At the time of this writing, CIOMS Guidelines are once again being revised. (For further discussion of the subject matter of this paragraph, see Levine 1996.)

1. Ethical Universalism Or Pluralism?

Discussions of international codes of ethics generally reflect a tension between ethical universalism and cultural pluralism. Universalists hold that ethical principles are identical in all human societies and in all historical periods. It is as if ethical principles exist in nature and are waiting to be discovered. The reason that they appear to change from time to time is that our ability to discern and understand them changes (one hopes for the better). The pluralistic position, by contrast, is that ethics are invented (not discovered) in the course of conversations conducted within particular societies; the results will necessarily reflect the histories and traditions of the cultures in which the conversations are conducted (Levine 1996).

The writers of Nuremberg and Helsinki each attempted to create universal documents. By contrast, the CIOMS Guidelines, which although they recognize some ethical principles as ‘transcendent,’ also acknowledge the validity of some degree of cultural pluralism. The writers of the CIOMS Guidelines aspire to ‘global applicability,’ a document that provides adequate ethical guidance for all known contemporary societies with the understanding that revisions will be required from time to time as ethics change in response to changing circumstances and understandings (Levine 1996).

International codes of research ethics have no legal authority except to the extent that parts or all of them are incorporated in the laws of nations or other political entities having the authority to enact and enforce laws. This point notwithstanding, these documents have important moral status in that those who wish to criticize the ethics of various research activities generally rely on one or more of these documents to ground their judgments.

2. The Content Of The Ethical Codes

Three ethical principles generally are recognized as ‘basic’ or ‘fundamental’ in the ethics of biomedical research and practice. These principles, which were first articulated in their most widely used form by the US National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission), are ‘respect for persons,’ ‘beneficence,’ and ‘justice.’ The first—and to this date, only—explicit reference to these principles in the international codes is in the 1993 revision of the CIOMS Guidelines. However, the National Commission found in Nuremberg and Helsinki implicit statements of respect for persons and beneficence (National Commission 1978, Levine 1988); concern for justice is also implied in the introduction to Nuremberg. Whether or not these principles are universally valid is the topic of a controversy beyond the scope of this research paper (Levine 1996, Macklin 1992).

The purpose of the ethical codes is to provide guidance on how research involving human subjects should be carried out so that it is responsive to the requirements of the basic ethical principles. Because they are considered relevant to virtually all fields of human behavior, the principles themselves are stated at such a level of abstraction that they do not provide clear direction on what behaviors are required or forbidden. Ethical norms (or rules) are incorporated in ethical codes to clarify what behaviors are prescribed or proscribed by the document. Ethical norms are either substantive or procedural. A substantive norm specifies behaviors that are required (or forbidden) because they are morally right (or wrong). Some procedural norms specify procedures that should be performed to determine the most appropriate behavior when the behavior has not been specified by a substantive norm. Other procedural norms are designed to provide documentary evidence that re- search has been conducted in accord with the relevant substantive norms (Levine 1988).

An illustration. The principle of respect for persons requires that human persons must never be treated only as means to the ends of others. The substantive norm that requires informed consent is a specification of one way in which this principle is to be made operational in the conduct of research involving human subjects. The procedural norm that requires review and approval by an institutional review board affords a method for determining what specific bits of information must be divulged to prospective subjects in a particular research protocol. Another procedural norm that requires the signing of a consent form provides documentary evidence that the behavior required by the substantive norm has been accomplished.

Ethical codes written by ethical universalists tend to have a high proportion of substantive norms. Those that espouse cultural pluralism tend to have a larger proportion of procedural norms. Substantive norms predominate in Nuremberg and Helsinki while the CIOMS Guidelines contain a relatively large number of procedural norms along with abundant commentary on how the norms should be interpreted in various specific circumstances.

All of the substantive norms articulated in the leading international codes of ethics are variations on and elaborations of seven general normative statements (Levine 1988). The first three of these are most closely related to the principle of beneficence which requires that those who perform research should maximize possible benefits and minimize possible harms and, further, that they should not deliberately injure any human being.

(a) There should be good research design. This norm is linked inextricably to the purpose of doing research—to contribute to the development of generalizeable new knowledge. If the research is not designed adequately, there is little or no chance that it will make the desired contribution to the development of knowledge. As stated in the CIOMS Guidelines (1993, p. 38), ‘… scientifically unsound research is ipso facto unethical in that it may expose subjects to risk or inconvenience to no purpose.’

(b) There should be competent investigators. One purpose of this norm is identical to that of the first; competent investigators are much more likely than incompetents to succeed in producing beneficial new knowledge. In addition, there must be at least one member of the team of researchers who has the clinical competence to monitor the health of the subjects with a view toward prompt intervention as indicated to preserve the health of the subject by (e.g.) ending the individual’s participation in the research or by administration of an antidote to some toxic substance. As stated in Helsinki (Article 15): ‘Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person …’

(c) There should be a favorable (or reasonable) balance of risks and benefits. This is a judgment that must be made by the investigator and affirmed by the research ethics committee before the prospective subject is presented with an invitation to participate. The risks of interventions and procedures that hold out the prospect of direct benefit to the subject are justified much the same as they are in the conduct of medical practice—in terms of the anticipated benefit to the subject. The risks and benefits of interventions and procedures that do not hold out the prospect of direct benefit for the individual subject (nonbeneficial procedures) must be justified in terms of the anticipated benefit to society. Nuremberg (Principle 6) requires that: ‘The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved.’ Plans to employ nonbeneficial procedures that present more than minimal risk in vulnerable populations require special justification. If in the course of conducting the research, the balance of risks and benefits ceases to be favorable, the investigator is required to intervene appropriately. Nuremberg requires: ‘During the course of the experiment the scientist … must be prepared to terminate the experiment … if he has probable cause to believe … that a continuation … is likely to result in injury, disability or death … . (Principle 10) Helsinki does not call for separate analysis of the risks and benefits of individual components of research as described above. Rather, it calls for the evaluation of entire research protocol as either beneficial or nonbeneficial. ‘The physician may combine medical research with medical care, only to the extent that the research is justified by its potential prophylactic, diagnostic or therapeutic value.’ (Article 28) This is a remnant of Helsinki’s historical distinction between therapeutic and nontherapeutic research; reliance on that distinction undermines the validity of the entire document (for further discussion of the problems created by this illogical distinction, see Levine 1999).

The next two of the general substantive norms are most related to the principle of respect for persons:

(d) There should be informed consent. The first principle of Nuremberg set forth the definition of informed consent that, with minor variations, has been incorporated in all subsequent codes and regulations.

The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment.

 (Principle 1) In this way, the prospective subject is invited to accept the researcher’s goals as if they were his or her own at least for the duration of his or her participation. The result is that the subject is not treated as merely a means to the researcher’s goals.

(e) There should be respect for privacy and maintenance of confidentiality. ‘Privacy’ and ‘confidentiality’ are often incorrectly used as synonyms. ‘Privacy’ refers to the ‘freedom of the individual to pick and choose for himself the time and circumstances under which, and most importantly, the extent to which his attitudes, beliefs, behavior and opinions are to be shared with or withheld from others’ (Kelman 1977). ‘Confidentiality’ refers to a mode of management of private information; if a subject shares private information with (confides in) an investigator, the investigator is expected to refrain from sharing this information with others without the subject’s authorization or some other justification. CIOMS Guidelines require:

‘The investigator must establish secure safeguards of the confidentiality of research data. Subjects should be told of the limits to the investigators’ ability to safeguard confidentiality and of the anticipated consequences of breaches of confidentiality’ (Guideline #12).

The final two general substantive norms are most closely related to the principle of justice which requires fairness in the distribution of both the burdens and benefits of research.

(f ) Selection of subjects should be equitable. From the 1940s through the mid-1980s, the prevailing attitude among commentators on and policy makers in the field of research ethics was that participation in research was dangerous to the subjects and that researchers were likely to exploit the socially and economically less powerful individuals who were most likely to serve as research subjects. For this reason, the ethical codes and regulations of that time focused on the protection of the prospective subject from bearing an unfair share of the burdens of research. The criterion for determining whether an individual (or a class of individuals) was in need of ‘special protections’ was ‘vulnerability.’ In the 1970s, vulnerability tended to be equated with ‘limited capacity to give informed consent’ and special procedural and substantive norms were developed to protect the rights and welfare of children, prisoners, the institutionalized mentally infirm, and fetuses (Levine 1998). The category ‘vulnerable’ has been expanded subsequently to include others including ‘subordinate members of hierarchical groups, persons with limited financial resources and persons living in developing countries or communities’ (CIOMS 1993, p. 30). Since the mid-1980s, research participation increasingly has been recognized as beneficial to both individuals and the class of persons they represented. This change began as a response to the AIDS activists who in 1986 pointed out that participation in a placebo-controlled clinical trial of AZT was not to be considered burdensome; it was, they argued, beneficial in that it was the only way people could have access to the only drug that anyone believed might be directed at the cause of their disease. Since then, ethical codes and regulations have begun to interpret the requirement for equitable selection of subjects as requiring also that vulnerable persons be assured of receiving a fair share of the benefits of participation in research.

(g) There should be compensation for researchinduced injury. CIOMS Guidelines require: ‘Research subjects who suffer physical injury as a result of their participation are entitled to such financial or other assistance as would compensate them equitably for any temporary or permanent impairment or disability.’ They note, however, that ‘In some societies the right to compensation is not acknowledged’ (CIOMS 1993, pp. 35–6). One such society is the United States.

3. Exploitation Of Subjects In Developing Countries

In the past, industrial sponsors and investigators from technologically developed countries occasionally conducted research designed to evaluate their therapeutic innovations in developing countries. This was done to lower the costs of the research and to take advantage of the less complex and sophisticated regulatory systems typical of developing countries. This was unfair in that these innovations, once proved safe and effective, were generally not available to the residents of developing countries owing to economic factors.

With the aim of preventing such exploitation CIOMS Guidelines require special justification for conducting research in developing countries (e.g., the research must be responsive to the health needs and priorities of the ‘host’ country) and special obligations for the sponsors (e.g., they must engage in capacitybuilding in the host country to enable it to conduct independent ethical and scientific review). The 1993 version of the CIOMS Guidelines requires that any product demonstrated safe and effective in such research should be made ‘reasonably available’ to the residents of the country at the conclusion of the research.

Helsinki requires that a new therapy it must be ‘… tested against those of the best current prophylactic, diagnostic, and therapeutic methods’ (Article 29). This standard, which is designed to prevent exploitation of all patients including those residing in developing countries, may also have the undesired effect of obstructing the development for use in developing countries inexpensive alternatives to expensive therapies employed in developed countries. The latter are generally the ‘best current … therapeutic methods.’ An alternative standard which would not have this disadvantage currently is being considered by CIOMS: ‘the highest attainable and sustainable’ standard (Levine 1999, 2000). ‘Highest attainable’ means that one should provide the best one can offer under the circumstances of the research rather than settle for the standard prevailing in the host country (often no therapy at all). The upper limit of what should be provided is defined by ‘sustainability.’ It would be unethical to develop a therapy that could not be made available to residents of the host country (sustained) after the research has been completed. Such research would not have been responsive to the health needs and priorities of the host country.

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