[as published in Adil E. Shamoo, Proceedings of the First Baltimore Conference on Ethics - Ethics in Neurobiological Research With Human Subjects (New York: Gordon and Breach Science Publishers, 1996]
1. To reaffirm the internationally accepted principles and guidelines of ethical research using human subjects, as stated in the International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS, 1993)2 and the Declaration of Helsinki (1989)3, particularly with respect to the mentally ill as a vulnerable group4 when used as human subjects in neurobiological research.
2. To specifically indicate, where appropriate, the need to refine or to further address in practice some of these principles.
For the purposes of this Declaration, "persons with neurobiological disorders" (NBD) includes those who participate in neurobiological research through hospitals, clinics, nursing homes, emergency facilities, private physicians' offices, "half-way homes", "group homes", private research investigators or institutional research centers. It also includes those who are homeless, or who have no known next-of-kin.
Certain types of medical research on human beings, when kept within reasonably well-defined bounds, and which conform to the ethical principles and guidelines as stated in the Declaration of Helsinki (1989) and the International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS 1993), are important and vital acts for ensuring the progress of diagnosis and treatment of the mentally ill.
As clearly stated in the CIOMS 1993 Guidelines, however, the mentally ill, because of their often weakened, dependent, and incompetent conditions, are considered a "vulnerable group" when used in any clinical research. These guidelines therefore further require that certain restrictions and precautions are specified and put into practice when persons with mental illness are to participate in clinical research, in order to protect their rights and welfare as human subjects.
Although clear in principle, there is concern that some of these guidelines are not being translated into practice, or that some refinements may be in order. Thus, given the status of persons with NBD as a vulnerable group, and to ensure the protection of their rights and welfare as human subjects, the following basic principles and guidelines of the CIOMS document relevant to competent and incompetent persons with mental illness are here reaffirmed in Section I. Section II contains a list of issues which have been identified as in need of further discussion, clarification and attention. Those issues which are of concern to many involved in the ethics of research using persons with mental illness in neurobiological research, many of which were included in the first draft of the Declaration of Baltimore, are listed by single letters. Those issues which were of concern to others, as graciously expressed in their comments on the first draft of the Declaration of Baltimore, are listed by double letters. Where appropriate, these letters are inserted, in bold, within the context of the relevant principles and guidelines of the CIOMS 1993 text (below).
"Advances in biomedical science and technology, and their application in the practice of medicine, are provoking some anxiety among the public and confronting society with new ethical problems. Society is expressing concern about what it fears would be abuses in scientific investigation and biomedical technology. This is understandable in view of the methodology of biomedical experimental research [because when applied to human subjects, certain risks are involved] ... This risk is justified, not by any personal benefit to the researcher or the research institution, but rather by its benefit to the human subjects involved and its potential contribution to human knowledge, to the relief of suffering or to the prolongation of life (p. 5) (emphasis ours). [A, B, E, G] [GG, LL, MM]
"Society devises measures to protect against possible abuses ... In 1966 the United Nations General Assembly adopted the International Covenant on Civil and Political Rights, which entered into force in 1976, and which states (Article 7): "No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment. In particular, no one shall be subjected without his free consent to medical or scientific experimentation" (p. 5) (emphasis theirs). It is through this statement that society expresses the fundamental human value that is held to govern all research involving human subjects - the protection of the rights and welfare of all human subjects of scientific experimentation ... (p. 5). [A] [GG]
"The guidelines [CIOMS 1993] reflect the paramount ethical concern for vigilance in protecting the rights and welfare of research subjects and of vulnerable individuals or groups being considered as prospective subjects (p. 7) (emphasis ours). [A, B, E, G] [DD, EE, GG, MM, LL]
"In all these circumstances it appeared timely to revise the [Proposed International Guidelines for Biomedical Research Involving Human Subjects, CIOMS 1982] Guidelines, with a view to reaffirming in today's conditions their original purpose - the protection of the rights and welfare of human subjects of biomedical research ...(p. 9). [A, B] [GG]
"Respect for persons incorporates at least two fundamental ethical considerations, namely:
a) respect for autonomy, which requires that those who are capable of deliberation about their personal choices should be treated with respect for their capacity for self-determination; and
b) protection of persons with impaired or diminished autonomy, which requires that those who are dependent or vulnerable be afforded security against harm or abuse (p. 10) (emphasis ours) ... [A, B] [DD, EE, GG]
"... Beneficence further proscribes the deliberate infliction of harm on persons; this aspect of beneficence is sometimes expressed as a separate principle, non-maleficence (do no harm) (p. 10). [E, G, J] [GG, II, MM]
"... [Justice] Differences in distribution of burdens and benefits are justifiable only if they are based on morally relevant distinctions between persons; one such distinction is vulnerability. "Vulnerability" refers to a substantial incapacity to protect one's own interests owing to such impediments as lack of capability to give informed consent, lack of alternative means of obtaining medical care or other expensive necessities, or being a junior or subordinate member of a hierarchical group. Accordingly, special provisions must be made for the protection of the rights and welfare of vulnerable persons (p. 11) (emphasis ours). [A] [DD, GG, II, JJ, LL]
"... Research is defined as "clinical" if one or more of its components is designed to be diagnostic, prophylactic or therapeutic for the individual subject of the research. Invariably, in clinical research, there are also components designed not to be diagnostic, prophylactic or therapeutic for the subject; examples include the administration of placebos and the performance of laboratory tests in addition to those required to serve the purposes of medical care...(P. 11) (emphasis ours)... [E, G, J] [GG, II, MM]
"... Research involving human subjects is to be distinguished from the practice of medicine, public health and other forms of health care (p. 12) ... [A, B] [KK, NN]
"... Research involving human subjects should be carried out only by, or strictly supervised by, suitably qualified and experienced investigators and in accordance with a protocol that clearly states: the aim of the research; the reasons for proposing that it involve human subjects; the nature and degree of any known risks to the subjects; the sources from which it is proposed to recruit subjects; and the means proposed for ensuring the subjects' consent will be adequately informed and voluntary. The protocol should be scientifically and ethically appraised by one or more suitably constituted review bodies, independent of the investigators." (p. 12) [B, C, D, E, F, G, I, J] [GG, II, KK, LL, NN, MM]
For all biomedical research involving human subjects, the investigator must obtain the informed consent of the prospective subject or, in the case of an individual who is not capable of giving informed consent, the proxy consent of a properly authorized representative. (p. 13)
"Informed consent is consent given by a competent individual who has received the necessary information; who has adequately understood the information; and who, after considering the information, has arrived at a decision without having been subjected to coercion, undue influence or inducement, or intimidation. (p. 13) (emphasis ours) [B, J] [DD, EE, II, JJ, LL]
"Informed consent is based on the principle that competent individuals are entitled to choose freely whether to participate in research. Informed consent protects the individual's freedom of choice and respects the individual's autonomy.
"In itself, informed consent is an imperfect safeguard for the individual, and it must always be complemented by independent ethical review of research proposals. Moreover, many individuals, including young children, many adults with severe mental or behavioral disorders, and many persons who are totally unfamiliar with modern medical concepts, are limited in their capacity to give adequate informed consent. Because their consent could imply passive and uncomprehending participation, investigators must on no account presume that consent given by such vulnerable individuals is valid, without the prior approval of an independent ethical-review body. When an individual is incapable of making an informed decision whether to participate in research, the investigator must obtain the proxy consent of the individual's legal guardian or other duly authorized representative. (p. 13) (emphasis ours) [A, B, C, F] [DD, EE, II, JJ, LL]
"Before requesting an individual's consent to participate in research, the investigator must provide the individual with the following information, in language that he or she is capable of understanding:
"Process. Obtaining informed consent is a process that is begun when initial contact is made with a prospective subject and continues throughout the course of the study ..." (p. 14) [I] [EE, II, JJ, KK, LL, MM]
"Language. ... (T)he investigator must convey the information in words that suit the individual's level of understanding. The investigator must bear in mind that ability to understand the information necessary to give informed consent depends on the individual's maturity, intelligence, education and rationality." (p. 14-15) [A, I, J] [DD, EE]
"Comprehension. The investigator must then ensure that the prospective subject has adequately understood the information. This obligation is the more serious as risk to the subject increases. In some instances the investigator might administer an oral or a written test to check whether the information has been adequately understood ..." (p. 15) [I] [EE, II, MM]
"Risks. ...[Prospective subjects] must be informed of all risks that a reasonable person would consider material to making a decision about whether to participate. An investigator's judgment about what risks are to be considered material should be reviewed and approved by the ethical review committee ..." (p. 15) [E, G] [II, KK, MM, NN]
"The investigator's responsibility for medical care. If the investigator is a physician, the subject must be told clearly whether the investigator will act only as an investigator or as both an investigator and a physician to the subject. However, an investigator who agrees to act as physician-investigator undertakes all of the legal and ethical responsibilities of the subject's primary-care physician. In such a case, if the subject withdraws from the research owing to complications related to the research or in the exercise of the right to withdraw without loss of benefit, the physician has an obligation to continue to provide medical care to the subject, or to see that the subject receives the necessary care in the community or district health-care system, or to offer assistance in finding another physician. [B] [KK, NN]
If the investigator is to act only as an investigator, the subject must be advised to seek any necessary medical care, outside the context of the research." (p. 15) [B] [KK, NN]
"Other considerations. For further details of the obligation to provide economic compensation in the event of death or disability resulting from specified types of research-related injury, see Guideline 13 ..." (p. 15) [K, L, M] [KK, NN]
"The investigator has a duty to:
"Necessary information. ... Other types of information that should be conveyed include the reasons for selecting prospective subjects ... and certain features of the research design (for example, randomization, double-blind, case-control), stated in language that the subjects can understand ... In general the standard for communicating information is that any and all information that a reasonable person would consider material to reaching a decision about whether to consent should be communicated. Investigators and ethical review committees should determine together what should be communicated in connection with particular studies." (p. 16) [A, H, J] [DD, EE, OO]
"Opportunity to ask questions. The investigator must be prepared to answer all of the subject's questions relating to the proposed research. Any restriction of the subject's ability to ask questions and receive answers before or during the research undermines the validity of the informed consent." (p. 16) [I] [EE]
"Deception. ...Deception of the subject is not permissible in research projects that carry more than minimal risk of harm to the subject .... A subject who disapproves of having been deceived is ordinarily offered an opportunity to refuse to allow the investigator to use information obtained from studying the subject ...". (p. 17) [E, G] [GG, MM]
"Undue influence. The investigator should seek to exclude any undue influence on the subject ... The investigator should not give the prospective subject any unjustifiable assurances about the benefits, risks or inconveniences of the research. An example of undue influence would be to induce a close relative ... to influence a prospective subject's decision or to threaten to withhold health services ..." (p. 17) [B, F] [JJ, LL]
"Intimidation. Intimidation in any form invalidates informed consent. Prospective subjects who are patients often depend upon the investigator for medical care, and the investigator has a certain credibility in their eyes. If the research protocol has a therapeutic component, the investigator's influence over them may be considerable. They may fear, for example, that refusal to participate would damage their relationship with the investigator. The investigator must assure the prospective subjects that their decision on whether to participate will not affect the therapeutic relationship or any other benefits to which they are entitled." (p. 17-18) [B] [JJ, LL]
"Documentation of consent. ... As a general rule, the subject should sign a consent form, or, in the case of incompetence, a legal guardian or other duly authorized representative should do so. The ethical review committee may approve the waiving of the requirement of a signed consent form if the research carries no more than minimal risk and if the procedures to be used are only those for which signed consent forms are not customarily required outside the research context ..." (p. 18) (emphasis ours) [E, F, G] [DD, EE, LL, MM]
"...However, the payments should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in the research against their better judgment ("undue inducement") ...". (p. 18) [A, B, F]
"Unacceptable recompense. Payments in money or in kind to research subjects should not be so large as to persuade them to take undue risks or volunteer against their better judgment. Payments or rewards that undermine a person's capacity to exercise free choice invalidate consent ... An unemployed person or a student may view promised recompense differently from an employed person. Someone without access to medical care may be unduly influenced to participate in research simply to receive such care ..." (p. 19) [A, B, F]
"Incompetent persons. Incompetent persons may be vulnerable to exploitation for financial gain by guardians. A guardian asked to give proxy consent on behalf of an incompetent person should be offered no remuneration except a refund of out-of-pocket expenses." (p. 19) (emphasis ours) [B, F] [DD, EE, LL]
Before undertaking research involving individuals who by reason of mental or behavioral disorders are not capable of giving adequately informed consent, the investigator must ensure that:
"Consent of the individual. People with mental or behavioral disorders may not be capable of giving adequately informed consent. The willing cooperation of such prospective subjects should be sought to the extent that their mental state permits, and any objection on their part to taking part in any non-clinical research should always be respected. When an investigational intervention is intended to be of therapeutic benefit to a subject, the subject's objection should be respected unless there is no reasonable medical alternative and local law permits overriding the objection." (p. 23) [B, F] [DD, EE]
"Proxy consent of the guardian. The Declaration of Helsinki states "In case of legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain informed consent ... permission from the responsible relative replaces that of the subject in accordance with national legislation" (Article I.11) [B, F] [LL]
"The agreement of an immediate family member - whether spouse, parent, adult offspring or sibling - should be sought, but is sometimes of doubtful value, especially as families sometimes regard persons with mental or behavioral disorders as an unwelcome burden." (p. 23) (emphasis ours) [F] [LL]
"Serious illness in persons who are unable to give adequately informed consent because of mental or behavioral disorders. ... Persons who are unable to give adequately informed consent by reason of mental or behavioral disorders are, in general, not suitable subjects for formal clinical trials except those designed to be responsive to their particular health needs ..." (p. 23) (emphasis ours) [E, G] [GG, MM]
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