Declaration of Baltimore

Guideline 10: Equitable distribution of burdens and benefits (p. 29)

"... Special justification is required for inviting vulnerable individuals and, if they are selected, the means of protecting their rights and welfare must be particularly strictly applied." (p. 29) [A, B] [DD, EE, II, LL]

COMMENTARY:

"General considerations. ...Equitable distribution of the burdens and benefits of research participation is generally more difficult when the intended subjects include vulnerable individuals or groups. Classes of individuals traditionally considered vulnerable are those with limited capacity or freedom to consent. They are the subject of specific guidelines in this document and include children, persons who because of mental or behavioral disorders are incapable of giving informed consent, and prisoners. Ethical justification of their involvement usually requires that investigators satisfy ethical review committees that: [A, B[ [DD, EE]

- the risks attached to research that is not intended to benefit individual subjects will be minimal, unless an ethical review committee authorizes a slight increase above minimal risk; (p. 30) (emphasis ours) (other points noted) [E, G] [GG, II, MM]

"Other vulnerable social groups. ... Other groups or classes may also be considered vulnerable. They include residents of nursing homes, people receiving welfare benefits or social assistance and other poor people and the unemployed, patients in emergency rooms, some ethnic and racial minority groups, homeless persons, nomads, refugees, and patients with incurable disease. To the extent that these and other classes of people have attributes resembling those of classes identified as vulnerable, the need for special protection of their rights and welfare should be considered." (p. 31) [A] [EE]

Guideline 12: Safeguarding confidentiality (p. 35)

COMMENTARY:

"General considerations: The Declaration of Helsinki, Article I.6, states: "the right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject." (p. 35) (emphasis ours) [A, J] [GG]

Guideline 13: Right of subjects to compensation (p. 36)

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. In the case of death, their dependents are entitled to material compensation. The right to compensation may not be waived. [J, K, L, M] [NN]

COMMENTARY:

"Equitable compensation. Compensation is owed to subjects who sustain significant physical injury from procedures performed solely to accomplish the purposes of research. Justice requires that every subject of biomedical research be automatically entitled to fair compensation for any such injury. Compensation is generally not owed to research subjects who suffer expected or foreseen adverse reactions from investigational therapies or other procedures performed to diagnose or prevent disease. Such reactions are not different in kind from those that occur in medical practice. (p. 36-37) [J, K, L, M] [NN]

"Subjects should not be required to waive their rights to compensation or to show negligence or lack of a reasonable degree of skill on the part of the investigator in order to claim compensation. The informed consent process or form should contain no words that would absolve an investigator from responsibility in the case of accidental injury, or that would imply that subjects would waive their legal rights, including the right to seek compensation for injury." (p. 37) [I, J, K, L, M] [KK, NN]

Guideline 14: Constitution and responsibilities of ethical review committees (p. 37)

COMMENTARY:

"Scientific review. The Declaration of Helsinki, Article I.1, states that "biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature." [FF]

"Committees competent to review and approve scientific aspects of clinical trials must be multi-disciplinary ... (p. 38)

"Risks and benefits. The Declaration of Helsinki forbids the imposition of unwarranted risks on human research subjects. Article I.4 requires that "the importance of the objective is in proportion to the inherent risk to the subject..." (p. 39) (emphasis ours) [E, G, J] [GG, II, MM]

"In Phases II and III of drug testing ..., when benefits are intended for the subjects and they are reasonably likely to be realized, it is permissible to involve members of vulnerable groups and persons with limited capacity to consent. However, as required by the Declaration of Helsinki, Article II.3, "every patient - including those of a control group, if any - should be assured of the best proven diagnostic and therapeutic method." Therefore, if there is already an approved and accepted drug for the condition that a candidate drug is designed to treat, placebo for controls usually cannot be justified. (p. 39) (emphasis ours) [F, G, J] [DD, EE]

"Ethical justification to begin a randomized clinical trial also meets the requirement of Article II.3. The therapies ... to be compared must be regarded as equally advantageous to the prospective subjects: there should be no scientific evidence to establish the superiority of one over another. Moreover, no other intervention must be known to be superior to those being compared in the clinical trial, unless eligibility to participate is limited to persons who have been unsuccessfully treated with the other superior intervention or to persons who are aware of the other intervention and its superiority and have chosen not to accept it. (p. 39-40) (emphasis ours) [E, G, J] [DD]

"For each randomized clinical trial there should be a data and safety monitoring committee, responsible for monitoring the data obtained in the course of a study and for making recommendations to the sponsors and investigators about modifying or terminating the study, or about amending the informed-consent process or form. Such recommendations are made in response to the committee's detection of adverse events of which the nature, frequency or magnitude had not been anticipated by the investigators or sponsors as they planned the study, or of evidence that one of the therapies or preventive measures being tested in the clinical trial is superior to another. During the planning stage of a clinical trial, stopping-rules should be established to guide the data and safety monitoring committee in determining when it should recommend termination of the study. (p. 40) (emphasis ours) [I,L] [MM]

"National or local review. Review committees may be created under the aegis of national or local health administration, national medical research councils or other nationally-representative bodies. In a highly centralized administration, a national review committee may be constituted for both the scientific and the ethical review of research protocols ..." [H, O] [QQ]

"Committee membership. Local review committees should be so composed as to be able to provide complete and adequate review of the research activities referred to them. They should include physicians, scientists and other professionals, such as nurses, lawyers, ethicists and clergy, as well as lay persons qualified to represent the cultural and moral values of the community. The membership should include both men and women. Committees that often review research directed at specific diseases or impairments ... should consider the advantages of including as members or consultants patients with such diseases or impairments. Similarly, committees that review research involving such vulnerable groups as children, students, aged persons or employees should consider the advantages of including representatives of, or advocates for, such groups. (p. 40-41) [H] [OO, PP]

"Need for particularly stringent review requirements. The requirements of review committees should be particularly stringent in the case of proposed research involving ... persons with mental or behavioral disorders, ... and other vulnerable social groups, and in the case of invasive non-clinical research... (p. 41) [A, B] [DD, EE, GG, PP]

"Sanctions. Should sanctions become necessary, they should be directed at the non-compliant investigators or sponsors. They may include fines or suspension of eligibility to receive research funding, to use investigational therapies, or to practice medicine. Refusal to publish the results of research conducted unethically, as prescribed in the Declaration of Helsinki, Article I.8, may be considered, as may refusal to accept unethically obtained data submitted in support of an application for drug registration ... (p. 42) (emphasis ours) [C, I, K, N] [KK, NN]

"Publications of reports of the results of research involving human subjects should include, when appropriate, a statement that the research was conducted in accordance with these guidelines. Departures, if any, from these guidelines should be explained and justified in the report submitted for publication. (p. 42) (emphasis ours) [C, I, K, N]

"Information to be provided by investigators. Whatever the procedure adopted for ethical review, such review should be based on a detailed protocol comprising: (all emphases ours) (not all points included) [KK]

a clear statement of the research objectives, having regard to the present state of knowledge, and a justification for undertaking the investigation in human subjects; [J]
a precise description of all proposed interventions, including intended dosages of drugs and planned duration of treatment; [J] [NN]
a description of plans to withdraw or withhold standard therapies in the course of the research; [L] [GG]
the criteria determining admission and withdrawal of individual subjects, including full details of the procedure for seeking and obtaining informed consent; [B] [JJ, KK]
an account of any economic or other inducements to participate, such as offers of cash payments, gifts, or free services or facilities, and of any financial obligations assumed by the subjects, such as payment for medical services; [B] [NN] and,
for research carrying more than minimal risk of physical injury, an account of plans, if any, to provide medical therapy for such injury and to provide compensation for research-related disability or death. (p. 42) [E, G, K, L, M] [NN, MM]

"Information should also be included to establish:

the anticipated benefits and the risks of participation; (p. 42) [J] [GG]
the means proposed to obtain individual informed consent or, when a prospective subject is not capable of informed consent, satisfactory assurance that proxy consent will be obtained from a duly authorized person and that the rights and welfare of each subject will be adequately protected; [A, B, F] [DD, EE, JJ, LL]
the identification of the organization that is sponsoring the research and a detailed account of the sponsor's financial commitments to the research institution, investigators, research subjects and, when appropriate, the community; [K, L, M]
plans to inform subjects about harms and benefits during the study, and of the results of the study at its conclusion; [J] [MM]
an explanation of who will be involved in the research, their age, sex and circumstances, and, if any classes are excluded, the justification for the exclusion; [GG]
justification for involving as research subjects persons with limited capacity to consent or members of vulnerable social groups; [A] [DD, EE, GG]
evidence that the investigator is qualified and experienced and is assured of adequate facilities for the safe and efficient conduct of the research; [B] [II, JJ, KK, NN]
provisions that will be made for protecting the confidentiality of data; and,
the nature of any other ethical considerations involved, together with an indication that the principles of the Declaration of Helsinki will be implemented. (p. 43) [C, I, K, N] [AA]

II. SPECIFIC ISSUES OF CONCERN WHICH NEED FURTHER DISCUSSION TO REAFFIRM AND/OR REFINE THE CIOMS 1993 (AND SIMILAR) RESEARCH GUIDELINES

Because persons with mental illness are vulnerable (whether competent or incompetent), and thus should be provided with special procedures and precautions when they are used in neurobiological research in order to protect their human rights and physical as well as psychological welfare, the following list of issues of concern are provided for further discussion, in order to facilitate the further refinement of the CIOMS (and similar) research guidelines:

(Issues included in the first draft of the Declaration of Baltimore:)

A. Persons with mental illness (whether competent or incompetent) are a vulnerable group because, e.g., of their institutionalization, disease, frequent inability to give adequate informed consent, dependent relationships with the physician/researcher, and sometimes their economic and social conditions. Therefore, when used as human subjects in neurobiological research, special procedures and precautions must be in place in order to assure the protection of their human rights and physical as well as psychological welfare.
B. Because they are vulnerable, the competency or incompetency of the patient to give informed consent must be professionally determined. The person determining the patient's competency must be professionally qualified to make such judgments. If there is any indication that there is intimidation, "undue inducements", an overly dependent relationship between the patient and his/her physician/researcher or scientist/researcher, or if there is present any conflict of interests with the physician/researcher or scientist/researcher, then the determination of competency or incompetency should be made by a professional who is independent of the patient, the physician/researcher, the scientific researcher, or any sponsors of the research.
C. The judgment of competency or incompetency, and the professional responsible for the determination, must be recorded in the protocol submitted by the investigator to the review committee, in the patient's medical records and documented in any paper submitted for publication.
D. If a patient is properly and professionally judged to be competent, then the patient is allowed to give informed consent to participate in the research, other scientific and ethical conditions having been met.
E. Because a patient with mental illness is still vulnerable, even though judged to be competent to give informed consent to participate in the research, the patient may not participate in any research that carries more than minimal risk.
F. If a patient is properly and professionally judged to be incompetent, then consent for the patient to participate in research must be obtained by proxy consent from the appropriate authority. Due consideration should be given that proxy consenters themselves are not intimidated, unduly influenced, or consenting for inappropriate reasons.
G. Because an incompetent patient with mental illness is especially vulnerable, he/she may not participate in any research that carries more than minimal risk.
H. Persons who have experience with and who are concerned with the welfare and best interests of the patients participating in research should be members of review committees who consider protocols in neurobiological research, e.g., members of the National Association of the Mentally Ill. Education of the IRB members and investigators engaged in research on persons with mental illness should be emphasized.
I. Procedures for obtaining informed and proxy consent need to be monitored and documented. Procedures for the continuous monitoring of the consent conditions need to put in place and documented. Documentation of monitoring of the consent conditions should be included in reports to the review committee, the patients' medical records, and in papers submitted for publication.
J. The content of the informed and proxy consent forms might not always have been clear and adequate - either for the review committee or for the patients or their surrogates. Of particular concern is:
(1) the lack of information concerning the degree of possibility of relapse, especially when (a) washouts, (b) "challenge" drugs, e.g., L-dopa and amphetamines, (c) placebos, or (d) double-blind protocols are part of the research; and,
(2) the lack of information concerning all of the purposes of the experiment, e.g., to study the process of relapse itself.
It is possible that patients or their surrogates have signed consent forms without clearly understanding either of these two conditions.
K. All occurrences of relapses, the conditions under which they occurred, the psychological and medical condition and treatment of the patients, and any compensation for psychological and/or physical harm should be clearly, accurately and fully documented in reports to the review committee, the patients' medical records, and in any papers submitted for publication.
L. If, during the research, the patient wishes to be removed from the protocol, his/her wishes should be immediately respected. If the patient requires any psychological or medical attention, it should be immediately provided. If the physician/researcher or scientific researcher, an independent physician, a surrogate or a monitor have determined that the patient should be removed from the protocol, or if the amount of risk involved increases to more than minimum risk, the patient should be immediately removed from the protocol, and appropriate psychological and medical care should be immediately administered.
M. If patients who have been participating in the research drop out or are dropped out of the protocol, every effort should be made to locate the patients, and provide any needed psychological or medical care, or compensation for any psychological or physical harm incurred during their participation in the research, or for psychological or physical harm which is a latent result of participating in the research.
N. All occurrences of dropouts, and the location, condition and psychological and medical treatment of those who dropped out should be clearly, accurately and fully documented in reports to the review committee, the patients' medical records, and in any papers submitted for publication.
O. It is encouraged that a National Ethics Advisory Authority be created to address the issues and formulate special guidelines concerning clinical research with persons with mental illness, especially those with severe chronic illnesses such as schizophrenia.

(Issues graciously submitted by commentators on the first draft of the Declaration of Baltimore:)

AA. Many of these concepts have been displaced by U.S. federal regulations.
BB. The authors of the Nuremberg Code made it very clear that they were not talking about the types of research that are of interest to the Declaration of Baltimore.
CC. A clear and precise definition of what patients are to be included in the phrase "persons with neurological conditions" is needed.
DD. Published research asserts that not all or the majority of mentally ill patients are cognitively impaired.
EE. Careful distinctions have to be drawn between persons with mental disorders who may have the capacity to consent and those who cannot. Entirely different regulations need to be drafted for these two groups.
FF. It does not seem appropriate to require that experiments be based on "sound animal experimentation".
GG. Requiring that "the interests of science and society should never take precedence over considerations related to the well-being of the subject", or that clinical research may be conducted "only if there is some direct benefit to the patient, and "only when certain moral, ethical and legal standards are met" is: irrational; would preclude most clinical research from taking place; would rule out all research in the field of epidemiology, all studies in pathogenesis and all Phase I drug testing; would discriminate against mentally ill patients who are competent to participate in the informed consent process; would discriminate against all mentally ill persons as a "class" of persons, and leave them as "therapeutic orphans"; denies them the right of altruism toward society; deprives them of asserting their rights to be involved in research.
HH. Language following that of the National Commission - especially that referring to research involving children - should be considered in drafting guidelines for the use of persons with mental illness in neurobiological research.
II. To require a competency review in cases where there are no questions of incompetence and particularly when the research presents no more than minimal risk is unduly burdensome.
JJ. To require that informed consent be obtained by a non-research doctor makes no sense; would be a very cumbersome policy; is not required by U.S. federal regulations or by the recommendations of the National Commission; should be required, if all, only whenever any reasonable doubts can be raised about competence and the investigator still believes that the subject is competent to consent.
KK. Does responsibility for obtaining proper informed and proxy consent rest with the investigator if he/she is a Ph.D.-only investigator (i.e., is not a physician or psychiatrist)?
LL. Requiring that proxy consent can be valid only if there is direct benefit to the individual patient is too restrictive; the roles of proxy consent need to be carefully spelled out.
MM. Monitoring is a good idea only if research involves more than minimal risk and is not for the direct benefit of the patient; needs further discussion as to what intervals are specified, and for which studies; the language of the National Commission should be used.
NN. Does responsibility for the health and welfare of the subject always rest with a medically qualified persons and never on the subject of the research - even if the patient is competent? Does this responsibility also fall on investigators who are not physicians - e.g., who are Ph.D.'s only? Investigators who are Ph.D.'s only should also be allowed to do research in this field.
OO. Does the inclusion of members who are "experienced with and concerned for the best interests and welfare of the patients with mental illness" on the review committee mean that every medical disorder studied would have to have such representative members? Such a requirement would cripple the work of the IRB in a typical university medical center; is gratuitous to demand that kind of background.
PP. By what means do we educate members of IRB's and investigators about research using persons with mental illness in neurological research?
QQ. The value of a National Ethics Authority is questionable.

Endnotes

1 For purposes of clarity and uniformity, the relevant sections of the first draft of the Declaration of Baltimore have been set within the context of the most recent CIOMS 1993 international guidelines on the use of human subjects in research. Copies of those guidelines will be provided to all participants of the Conference. [Back]

2 International Ethical Guidelines for Biomedical Research Involving Human Subjects, prepared by the Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO) (Geneva: 1993). Appreciation is expressed to Robert J. Levine, M.D., for distribution of this document to us. Dr. Levine was the co-chairman of the CIOMS Steering Committee which helped to draft these Guidelines, and of the Conference on Ethics and Research on Human Subjects - International Guidelines. [Back]

3 World Medical Association Declaration of Helsinki, adopted by the 18th World Medical Assembly (Helsinki, Finland: June 1964); and amended by the 29th World Medical Assembly (Tokyo, Japan: October 1975), the 35th World Medical Assembly (Venice, Italy: October 1983), and the 41st World Medical Assembly (Hong Kong, China: September 1989). [Back]

4 Persons with mental illnesses and behavioral disorders have been declared to belong to a "vulnerable group" by the National Commission, the President's Commission, the Declaration(s) of Helsinki, and the CIOMS Guidelines. [Back]

5 Relevant sections of the CIOMS document have been selected, and attempts have been made to list them in context as much as possible in this short draft. Most of these sections are so listed in affirmation of the relevant principles or guidelines. Some have been listed which are not automatically affirmed, and which may require further discussion and refinement. [Back]

1, 2,