A Statement of Principles of Ethical Conduct
for Neuropsychopharmacologic Research in Human Subjects

INTRODUCTION

The purpose of this Statement of Principles (Statement) is to serve as an ethical guide for neuropsychophar­macologic research with human subjects, when such research is performed by a member of the American College of Neuropsychopharmacology (ACNP). As utilized in this Statement, neuropsychopharmacologic research is defined as the evaluation of the effects of synthetic compounds or natural products employed as investigational agents that affect the brain and/or the peripheral nervous system, and therefore affect behavioral and mental functions. While the principles provided herein may be relevant to other areas of research with human subjects, this Statement is not designed to function as a guide for research outside the scope of the field of neuropsychopharmacology, nor is this Statement intended to replace or override applicable federal and state laws governing research with human subjects.

In promulgating this Statement, the ACNP is providing its members with a set of guidelines for meeting current ethical issues regarding human subject research. Accordingly, the Statement should not be used in a retrospective manner for the evaluation of research conducted prior to its adoption. As a living document, the Statement will evolve over time, as additional data, clinical experience, and ethical and legal guidelines emerge in the area of human subject research.

BACKGROUND

Medical research is designed to generate new knowledge and to thus improve human welfare. However, such research cannot and should not be conducted in a vacuum. Rather, medical research relies upon a partnership between the subject, the researcher, and society, with the aim of advancing the understanding and the treatment of disease. For example, neuropsychopharmacologic research has led to the discovery and development of new drugs for patients with severe psychiatric and neurological illnesses. Such patients were once considered untreatable and relegated to institutions for protracted periods of time. With the development of new pharmacotherapies, many of these treated patients, once deemed to be treatment-refractory, have been able to return to their families and communities, often as productive members of society. Other groups of patients have derived benefit from such therapies by an avoidance of, or minimization in the duration of, inpatient psychiatric hospitalization.

STATEMENT OF PURPOSE AND ISSUES TO BE ADDRESSED

These dramatic and beneficial advances to society notwithstanding, clinical research often entails certain risks. The principles set forth in this Statement are designed to reconcile the tension between the need to advance knowledge for the benefit of society as a whole, with the obligation to protect individual subjects by ensuring that research is conducted in an ethically informed and regulated manner. To aid ACNP members in this effort, this Statement addresses the following issues:

A. Ensuring appropriateness of the study and its design;

B. Minimizing risk to the subject while maximizing benefit, either to the subject and/or to the population of patients suffering from a given psychiatric or neuropsychiatric illness;

C. Ensuring informed consent, with particular attention to the special challenges represented by subjects who may have limited decision-making capacity; and

D. Ensuring confidentiality.

A. ENSURING APPROPRIATENESS OF THE STUDY

1. Qualifications and Responsibilities of the Principal Investigator

Before assuming full responsibility for conducting neuropsychopharmacologic research studies with human subjects, the Principal Investigator (Investigator or PI) shall have had adequate training and experience to conduct the proposed research study. Trainees or fellows involved in conducting or participating in a study should receive appropriate supervision, mentoring, and consultation. Under some circumstances, it may be appropriate for trainees or fellows to be involved in the planning and execution of pilot studies. Such roles may be assumed by trainees or fellows with supervision by the Investigator as necessary and appropriate, and subject to the approval of the facility’s Institutional Review Board (IRB). The ACNP deems research undertaken by an Investigator unqualified to conduct a proposed study to be unethical.

Commentary

The Investigator’s prior experience in neuropsychopharmacologic research with human subjects shall be given weight in assessing his or her competence to conduct such studies. Prior expertise and demonstrated competency are particularly critical in studies involving more than minimal risk. The adequacy and quality of the Investigator’s experience relevant to the proposed research should be confirmed and documented by the facility’s IRB or its equivalent in areas where the work to be conducted is external to or not affiliated with an academic facility. If the IRB does not deem itself to be qualified to carry out the function of assessing the Investigator’s competence to conduct the proposed study, a specially designated Scientific Review Board may be needed to perform such an evaluation.

2. Responsibilities of the Investigator

General Responsibilities

The Investigator engaged in neuropsychopharmacologic research with human subjects should take precautions to preserve the autonomy, rights, and safety of all subjects. It is acknowledged that studies differ in their purposes and goals, and thus may entail different degrees of risk or perceived risk. For example, the development of new therapies is often perceived by the public as entailing more risk than a project focused on documenting the nature and course of a given psychiatric illness. Thus, the degree of precaution taken by the Investigator must correspond to the degree of anticipated risk to the participant, whether actual or perceived.

Individual Responsibility

Each Investigator shall ascertain and respect the ethical standards and currently acceptable procedures in conducting neuropsychopharmacologic research studies with human subjects. This includes behavior in accord with the ethical guidelines contained in this Statement, which entail respect for human subjects and concern for their dignity, welfare, and individual rights. Further, all associates, employees, or students who assist an ACNP Investigator are bound by these principles as well. The following sets forth the major individual ethical responsibilities of the Investigator:

a. The Investigator shall take precautions to ensure that all persons who assist in the research study are made aware of the principles contained in this Statement.

b. The ethical responsibilities set forth by this Statement shall be applicable when the Investigator makes the initial decision to undertake a human neuropsycho-pharmacologic study, and shall continue through the conclusion of the project and publication of all reports based on the study, as well as throughout all subsequent efforts to protect such privileged or confidential material pertaining to study subjects as may occur.

c. The Investigator shall be diligent in becoming familiar with regulations relevant to the proposed research, and shall comply with such regulations. Federal regulations pursuant to clinical research and confidentiality are set forth in Sections 45 and 42 of the Code of Federal Regulations (CFR), respectively. Other sources of regulations and research guidelines include, but are not limited to, Food and Drug Administration (FDA) regulations, the National Advisory Council on Drug Abuse Recommended Guidelines for the Administration of Drugs to Human Subjects, regulations promulgated by the Office for the Protection from Research Risk (OPRR), state laws, promulgation of guidelines by the Investigator^TMs internal or local IRB, and published literature on bioethical perspectives relative to human subject research.

d. The Investigator has an obligation to disclose to future participants the source of funding and the identity of any entity sponsoring the research. The Investigator is also obliged to inform participants of the existence of any personal financial interest that he or she may have in the project, e.g., the existence of financial arrangements between the Investigator and an industrial sponsor, such as a pharmaceutical company, including financial incentives for the recruitment of participants

3. Review by the IRB

An Investigator shall undertake a neuropsychopharmacologic study involving human subjects only after the approval of an appropriate, qualified reviewing body, and shall obtain subsequent approval from such body for modification to the protocol. Some types of projects, e.g., those involving multi-site collaborations, may require documented review by several IRBs to assure adequate protection of human subjects. In such cases, the Investigator shall ensure that all of the appropriate review has been obtained before the work commences. Periodic review by the IRB of continuing studies, at least annually, is required. Finally, research reports submitted for publication shall include a clear statement that IRB approval for the protocol was obtained.

Commentary

The United States Department of Health and Human Services (DHHS) requires the establishment of intra-institutional IRBs to review and approve research with human subjects.¹ Guidelines on this subject were published by the Department of Health, Education and Welfare (HEW) in 1971, and the guidelines were codified into federal regulation by the National Research Act (Pub.L.93-348) of 1974, which established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (NCPHSBBR). ^{2,3 I}n 1981 the FDA published regulations on the protection of human subjects that included standards for IRBs for clinical investigation and a compendium of research activities that such boards may review.^4,5,6 The most recent FDA regulations, which were issued in 1994,⁷ give IRBs the primary responsibility for protecting the rights and welfare of research subjects.

It is the opinion of the ACNP that an Investigator who is not affiliated with an institution that has an IRB shall not undertake a neuropsychopharmacologic research study unless it is initially approved and reviewed (on at least an annual basis) by an appropriately constituted independent review body. Independent review in this context refers to a group of individuals, who are comprised of persons who have no real or apparent conflict of interest, and who participate in an independent examination of the study in terms of determining whether the research should be conducted.

In the event that the HHS abandons, or substantially restricts, its requirements for local IRBs, this Statement requires the approval and review of ACNP-related research studies by appropriate review bodies, since it is held that all neuropsychopharmacologic research, regardless of funding source, must be subject to periodic and meaningful review.

The ACNP further holds that Investigators have the responsibility to serve on an IRB, or its equivalent, when requested, in order to ensure adequacy of the peer review process. Additional members of an IRB should include members of the lay public, as recommended and set forth by Federal regulations. While the IRB has the role of serving as the primary protector of the rights of participants, through such procedures as the review of the informed consent process, clinical procedures, and research design, Investigators, and by association, members of the research team bear the responsibility for the implementation of the protection of research subjects following IRB review and approval. IRBs should exercise special vigilance in the review of protocols involving individuals with questionable capacity in accordance with 45 CFR 46.11(b).[a] The area of informed consent related to individuals of questionable capacity is addressed in greater detail elsewhere in these guidelines.

If an Investigator is a member of an IRB considering his or her own project, the Investigator should not participate in the review of that project, and if the Investigator does not recuse him or herself from the review of the project, such action should be taken by the IRB.

B. STUDY DESIGN: MINIMIZING RISK AND MAXIMIZING KNOWLEDGE

1. General Considerations

a. As set forth above, gains expected from research shall be weighed against the reasonably- anticipated risks involved. At the time the research is undertaken, and throughout its performance, there should exist a scientific basis for a reasonable belief that the project will ultimately produce knowledge that will be of benefit to future patients.

b. The Investigator has an obligation to minimize, as much as possible, all physical and mental discomfort and to explain in advance to the subject the nature of any anticipated or reasonably foreseeable such discomfort. When it appears that a research study may have resulted in undesired or averse consequences for the subject that cannot be managed within the protocol (e.g., toxicity, exacerbation of symptomatology, or significant clinical worsening), the Investigator shall make every reasonable attempt to define the problem, inform the subject, and assure adequate follow‘up treatment to remove, correct, or relieve such consequences. All clinically significant adverse effects deemed to be related to participation in the research protocol must be promptly reported to the IRB, and to other entities as required by law or regulation (e.g., the FDA). In the event that adverse experiences are encountered by a disproportionate number of subjects than what would be reasonably anticipated in terms of risks, the PI should give serious consideration to a reevaluation of the design of the protocol.

c. The Investigator shall not use a procedure, if such procedure is likely to cause disabling or lasting harm to subjects, or if the reasonably anticipated benefits to a subject are outweighed by reasonably foreseeable risks or disadvantages.

Commentary

Patients who are subjects in treatment studies should be monitored closely and in an ongoing fashion, so that fluctuations in clinical status can be tracked to ensure that any clinically significant change is detected in a timely fashion. Determining whether a clinically significant deterioration has occurred often requires repeated observation and assessment to ensure that the research subject is not exposed to undue risk. Subjects evidencing clinical deterioration, other than that which can be expected as a natural course of the disease (e.g., Alzheimer’s disease), of a magnitude that exceeds a manageable increase in symptomatology, should be removed from the protocol and treated as expeditiously as possible, with such therapy as determined by the subjects’ needs, clinical status, and where feasible, the participant’s stated preference.

2. Study Design and Methodology

A neuropsychopharmacologic research study with human subjects shall be designed and conducted in accordance with generally accepted scientific principles and must reasonably anticipate increasing knowledge. Expert understanding of experimental design and statistical analysis of data are essential. The following examples are some of the many items that must be considered when preparing a research protocol:

a. Subjects should only be included if they appear suitable to test the specific hypotheses proposed in the research (e.g., accuracy of diagnosis at issue, absence of exclusion criteria).

b. Studies should be planned so that the number of subjects included is the minimal number consistent with the statistical requirements necessary to assure that subsequent conclusions will be viewed as scientifically valid.

c. Related to the above, the Investigator should have access to appropriate statistical expertise to assure that the results of the experiment will be considered meaningful to the scientific community.

d. In those research designs utilizing symptomatic patients as subjects, random assignment to treatment may be required. In evaluating new drugs or treatments for this population, care must be taken in the selection of an appropriate control group for the experimental design.

e. The DHHS regulations on research involving children permit IRBs to approve research presenting no more than minimal risk as long as requirements for parental/legal guardian permission and child assent are satisfied.⁸ If a study presents more than minimal risk and offers no prospect of direct benefit to child subjects, criteria for IRB approval include: (i) a finding that the research presents a minor increase over minimal risk; (ii) a finding that the intervention or procedure presents experiences that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; and (iii) a finding that the study is likely to produce generalizable and vitally important information on the subjects’ condition.⁸Clearly, such safeguards are in place for research study with children, because of the cognitive and decision making limitations of the subjects, including their inability to fully understand or comprehend the procedures and implications of the research study and their sometimes incompletely developed ability to clearly communicate their feelings and responses to the Investigator.[b] Children may also be included as normal control subjects in comparison studies, but the considerations cited above should be assessed. In general, research studies of medications in children shall not be undertaken unless, where it is feasible, prior studies in adults have indicated the medication is safe under the conditions to be employed. However, there are certain conditions in which the age of onset is in childhood, and where both productive research and efficacious treatment may depend upon the study of the early phases of the illness. Additionally, there are certain other conditions, which are manifested differently in children than in adults, and where the treatment would thus be distinctly different (e.g., ADHD). In these and other cases where an adult model or preliminary trial would be clinically and scientifically inappropriate, the research should be undertaken with strict adherence to federal regulations and internal IRB guidelines. Additional information related to the utilization of children as research participants may be found in the Informed Consent section of this Statement.

f. Adults with limited decisional capacity may be subjects in neuropsychopharmacological research if the IRB deems the study and consent procedures appropriate and in accordance with applicable regulations and guidelines. For research protocols that present greater than minimal risk, an IRB should strongly consider recommending the use of an independent qualified professional in conjunction with the assessment of the PI, so as to provide an additional safeguard in the assessment of a potential subject’s capacity to provide informed consent.

g. In addition to interviewing the potential research subject, or where appropriate, the legal guardian of the child potential subject, the determination of whether the individual is suitable as a research subject should include a record review, and, as clinically indicated, consultation with treating physicians, other mental health professionals and staff who know the patient, as well as relevant family members and significant others (subject to the consent of the patient, or guardian, as appropriate).

Commentary

Many of the ethical problems addressed in this section of the document have been given thoughtful, detailed consideration in the four following sources: Ethical Principles in the Conduct of Research with Human Participants;¹¹ Ethical Principles of Psychologists;¹²Ethical Issues in Mental Health Research in Children and Adolescents;¹³ Ethics in Psychiatric Research: A Resource for Human Subjects Protection.¹⁴

3. Specific Designs: Placebo, Medication Discontinuation, and Challenge

Studies

Challenge, placebo and controlled medication discontinuation studies, common in biomedical research, should be governed by standardized safeguards. Such safeguards include those that: (1) minimize foreseeable risk (e.g., careful screening, operationalized stopping rules, available method for reversing adverse effects); and (2) optimize consent procedures by assessing subjects individually and not solely on the basis of diagnosis. For example, an optimized consent procedure might include: (a) a one‘page simple language description; (b) a questionnaire to verify the subject^TMs understanding of the study (e.g., identity of the test substance, possible adverse effects, ability to drop out at any point); (c) an opportunity for the subject to ask questions or discuss concerns with a knowledgeable person who is not on the research team; and (d) with the participant^‘s permission, an opportunity for the participant to review the proposed study with family members and significant others.

As additional safeguards, standardized procedures for selecting subjects, monitoring behavior, terminating drug use, and providing information on the availability of other modalities should be developed. Testing of alcohol and other abusable substances should follow the guidelines for such testing published by NIDA and NIAAA. Promulgating such safeguards as they are developed will provide additional guidance to ACNP members, promote consistency in research procedures, and improve communication with the lay public and the media.

a. Pharmacologically Inert Substances (Placebo Studies)

The Investigator who proposes to use a placebo as part of the study shall define the necessity and provide ethical justification for such use, as it relates to the specific illness under study, or to the particular research problem. The use of placebos must be reviewed by the local IRB or qualified review body.

The use of a placebo in all subjects, but in particular those who are severely ill, such as very disturbed and/or severely deteriorated chronic schizophrenic patients presenting with gross thought disorders and hallucinations, should be carefully considered by the Investigator. Such review should examine whether a standard treatment to compare the medication to be tested exists, and, if so, whether use of such a standard treatment would be preferable to the use of a placebo. Consideration should also be given to the implementation of a crossover methodology if the treatment proves to be beneficial. The ethical decision by an IRB to allow a placebo or a “no drug” control group to be included in a research study should be based on the available medical knowledge concerning the relative foreseeable risk and the informed consent of the patient or patient surrogate.”¹⁵ On the other hand, the use of a placebo can be critical to the experiment, such that any results obtained without its use would not be meaningful. In such cases, and subject to IRB review and approval, use of a placebo would not only be scientifically but also ethically appropriate.

b. Medication Discontinuation Studies

The discontinuation of treatment (or substitution of placebo for active treatment) is commonly encountered in medical practice. Thus, patients often discontinue their medications without consultations, or against the advice of, their treating physician. In the course of therapy, a specific treatment may be halted by a physician with the agreement of the patient, in order to determine whether further medication is required or a new treatment initiated.

In clinical research, treatment may be discontinued for research purposes only with the informed consent of the subject. Rationales for controlled discontinuation include but are not limited to the following: (1) to gain a more complete understanding of the diagnosis or optimal treatments of a patient population; (2) to establish or clarify a diagnosis in a particular patient; (3) to establish the need for continued treatment in general, as well as to ascertain whether continued or long-term treatment, in particular after a first clinical episode, is essential for the individual or the particular diagnostic group. This may be particularly relevant when long-term drug therapy may provoke side effects; (4) to confirm remission in a patient without active symptoms; (5) to evaluate the efficacy (or lack thereof) of multiple medications when such are prescribed, and, to determine whether selective discontinuation of one or more agents to simplify the therapeutic regimen is indicated (e.g., selective monotherapy); and (6) to optimize treatment for incomplete responders and refractory patients.

c. Challenge or Symptom Provocation (Unmasking) Studies

Challenge studies have been crucial in providing a scientific foundation for substantial diagnostic and therapeutic advances in various areas of medicine. Advancements in the understanding of the cause, and in designing new treatments, of psychiatric disorders also require the use of the challenge paradigm. While such studies do not have a therapeutic intent per se, their ultimate purpose is to develop new diagnostic or treatment approaches. The need for a standardized documentation of safeguards should be built into any challenge study. Such safeguards should address at least two issues: (1) minimization of risk (e.g., careful screening of subjects, magnitude of the challenge, operationalized stopping rules, available method for identifying and reversing adverse effects with adequate follow-up after the challenge study to evaluate for residual or delayed adverse effects, such as increased risk of relapse or resistance to treatment); and (2) optimizing consent procedures. In the case of the latter, consent forms must contain an explicit statement about the lack of therapeutic intent or individual benefit of the challenge study. In the case of the former, a crucial issue to challenge studies as well as discontinuation studies and placebo studies has to do with the identification of endpoints of the study and corresponding guidelines on how and when medication (if indicated) will be introduced or reintroduced.¹⁶ That is to say, Investigators must set forth in their protocols specific details as to when and how active intervention will occur.¹⁶ It is deemed to be unethical and clinically inappropriate to wait until a full-blown relapse of the illness occurs prior to initiating such intervention.

C. INFORMED CONSENT

1. The Requirement of Informed Consent

Informed consent, as used in the context of this Statement, is the agreement obtained from a subject (or from a legally authorized representative) to participate in a neuropsychopharmacologic research study. Informed consent is an essential component of clinical studies across the entire spectrum of biomedical research. The purpose of informed consent is to allow potential subjects to rationally judge the risks involved in an experimental protocol. Researchers should appropriately explain both the foreseeable risks of the study and the degree to which current knowledge limits a precise estimate of future risks. Investigators should scrupulously adhere to the principle that subjects should also be provided timely notification when new information becomes available that relates to the risks associated with continued participation in the study.

If a subject lacks capacity to consent, the Investigator shall obtain permission from a person legally authorized to give consent on behalf of the subject, or shall initiate or recommend that appropriate legal action be taken, such as pursuit of a legal guardian, should the subject not have an appropriate surrogate to provide such consent, or should the laws of the jurisdiction not permit surrogate decision making without either the appointment of a legal guardian or an Order of Court. The PI and his or her IRB should be familiar with the requirements for surrogate decision making related to research participation as such exist in the jurisdiction where the research is to be conducted. It is the position of the ACNP that decisional capacity, regardless of diagnosis, must be considered for every potential research subject, as part of the informed consent process.

When an Investigator is recruiting subjects for a clinical research subject, it is not ethically appropriate for him or her to approach his or her own patient for participation. Rather, it is preferred and strongly recommended by most IRBs and supported by the ACNP that a clinician who is independent to the study be the individual who presents the study and invites the potentially eligible patient of the Investigator to consider participation in it. The PI/primary clinician may subsequently discuss the study with the patient after the initial contact has been made by an independent third party. Should such discussion occur, to avoid the appearance of coercion, the PI/primary clinician should make explicitly clear to the patient that non-participation in the study will not negatively affect or jeopardize the patient^TMs future care or treatment by the PI/primary clinician.

Informed consent should be an active and ongoing process, be non-coercive in practice as well as appearance, and, accordingly should be reconsidered, as appropriate, throughout the course of the study. The basic elements of informed consent are:

a. An explanation of the procedures to be followed, including an identification of those aspects of the study that are experimental.

b. A description of the reasonably foreseeable attendant discomforts and risks and a statement of the uncertainty of the anticipated risks due to the inherent nature of the research process.

c. A clarification that treatment in clinical research is different than what is available in open treatment, and related to this distinction, a disclosure of appropriate and available alternate procedures and treatments that might be advantageous for the subject.

d. An opportunity to ask questions or discuss concerns with a knowledgeable person who is not on the research team.

e. In studies involving the use of placebo medication, redisclosure of such use to the subject, including the likelihood of use, as well as a discussion of the rationale for such use.

f. In studies involving medication discontinuation, a disclosure of the projected duration of such discontinuation and the specific risks associated with discontinuation.

g. In studies involving a randomized assignment as part of the study design, an explanation, in lay terms, of the probability that the subject may be placed in one or another treatment group and the rationale for same.

h. An explanation that the subject may withdraw consent and discontinue participation in the study at any time without penalty or other negative repercussions. Related to this, the assurance that should there be a need for a referral for further medical services at the time of such withdrawal and upon the request of the subject for such a referral, that such referral will be provided for the subject.

i. A statement that the Investigator will inform the subject of any significant new information arising from the study or other ongoing experiments that may bear on the subject^TMs choice to remain in the study.

j. A statement that the Investigator will provide, upon a subject^TMs request, a review of the results of the study, as clinically appropriate to the mental status of the subject at the time of such request. If such request is denied or the information requested is shared only in part, the rationale for such action will be communicated to the subject.

Current FDA regulations for the protection of human subjects require that the subject be informed that the FDA may inspect their research records. Thus, the subject should be informed about the extent to which confidentiality of the subject^TMs research records can be maintained. Please refer to the Confidentiality section of these guidelines for additional treatment of this important subject.

2. Subjects Who Lack the Capacity to Consent

a. When a patient is deemed incapable of comprehending the consent process, either by reason of developmental level or decisional capacity, consent must be obtained from someone legally authorized to provide it on behalf of the proposed subject. Where permitted by law, individuals with impaired capacity may have a family member or other legally authorized representative serve as surrogate for research decisions, with this role documented during the consent process. The aforementioned elements of informed consent are to be applied to surrogates before a surrogate may provide permission for an individual to participate in a study. As the study progresses, the Investigator must keep the surrogate informed of any major changes in the research protocol or significant side effects.

b. If a subject is deemed capable of exercising some judgment concerning the nature of the research study and his or her participation in it, the Investigator shall obtain the assent of the subject in addition to the informed consent of a legally authorized surrogate. Supplemental guidelines for research involving mentally disabled institutionalized individuals were published in the Federal Register in 1978.¹⁷ While such proposed regulations were not made into law, they serve as instructive guidelines in this difficult area. More recently, the National Bioethics Advisory Commission (NBAC) requested papers addressing research involving persons with mental disorders that may affect decision making capacity, and these were published in May, 1999. While this work was not promulgated with the force of legal regulations, it offers extensive guidance for potential subjects, their physicians, clinical investigators, IRBs and other policymaking bodies such as the ACNP and is recommended as a valuable resource in the complex and controversial area of conducting research with decisionally-impaired individuals.⁸

c. Parental consent is required by federal regulation when children under the age of eighteen are the intended subject group in general as well as neuropsychopharmacologic experiments. However, the parent or court – appointed proxy has no moral right to give consent for a child to participate in an experiment that will provide no specific etiologic, diagnostic, or therapeutic benefit of the disease presented by the child, except in those cases where there are no reasonably foreseeable risks as defined above. Consent cannot be furnished for a child^TMs participation in a study unless the study is related to the child^TMs illness, or if only a minor increment over minimal risk is expected. Exceptions to this policy can only be approved by the Secretary of the DHHS. When the subject is a child who has reached the age of some discretion, and is otherwise competent (without having attained the chronological age to be able to provide independent informed consent for research participation), the Investigator must obtain the subject’s assent in addition to the informed consent of the legally authorized guardian.¹⁰

Commentary

Subjects unable to give informed consent pose special problems. While limited decision making capacity should not preclude an individual from participating in research, additional scrutiny by the IRBs and Investigators is warranted for research involving this population. Thus, the Investigator assumes additional ethical responsibilities with respect to a to the patient-subject who may be unable to make rational judgments concerning participation or withdrawal from the study.¹⁸

3. Consent of Involuntarily Committed Persons, Prison Inmates and Other Vulnerable Populations

a. If potential research subjects are involuntarily institutionalized in a psychiatric facility or subject to some legal restraint within the criminal justice system, Investigators should take special precautions to ensure the subject has an opportunity to obtain complete information about the research study, including the right to refuse participation, or to withdraw from the study at any time, without penalty. Such precautions are essential to avoid the appearance of coercion in vulnerable populations. Federal regulations also require the explicit justification of the choice of prisoners as subjects for clinical study.¹⁹

b. When an Investigator proposes to study individuals who are involuntarily institutionalized, who are under some legal restraint, or whose personal circumstances are such that their need for volunteer compensation or course accreditation (e.g., students) may unduly influence their decision making or judgment, the final approval concerning the general research study and the ability of subjects to provide informed consent shall reside with the ap­propriate qualified reviewing body. In such circumstances, the Investigator also assumes additional ethical responsibilities and should weigh carefully whether a subject^TMs decision to consent is rational and non-coerced, given the potential risks and benefits to the individual.

c. Documentation of appropriate informed consent must be maintained for every clinical research study. The use of forms that incorporate the ten elements listed above and that are signed by the Investigator and the subject is the current standard procedure. An alternative procedure involves the use of an individual not involved in the research study. In this case, such an individual assists the subject by explaining the risks and benefits of the research and certifies that informed consent has in fact been obtained. In most cases such an individual may facilitate the explanation of risks and benefits in a more appropriate manner for the subject or for the person giving consent on his or her behalf.

d. The authority of a person to provide informed consent on behalf of one who lacks capacity varies across the United States. Some states may require informed consent from the closest living relative; others may insist on approval from a Court of law. As previously stated, It is the Investigator’s responsibility as well as the IRB of the jurisdiction to be familiar with the appropriate person or entity that must be consulted concerning consent in their particular locale.

Commentary

This principle is not intended to exclude from research all persons who may be vulnerable to undue influence, but rather to best protect the interests of those persons, who by reason of developmental level or other reasons, have immature or impaired decision making capability. Thus, decisions related to the participation of vulnerable subjects must be made by an appropriate IRB and implemented by the responsible Investigator on a protocol-by-protocol and case-by-case basis.

4. Explanation to Subjects

a. Information about the goals of the study and the potential benefits arising from it, as well as such foreseeable side effects of the proposed therapies to be used in the research should be given to the subject and/or the person who consents to the subject^TMs participation.

b. After the data are collected, the Investigator should provide a review of the nature and results of the study to those subjects who request such information, to include, as appropriate, a disclosure or debriefing of what agent the patient received during the study period, when such a study involved the use of placebo controlled or two cell/no placebo conditions. When scientific or humane values justify delaying or withholding information, the Investigator incurs a special responsibility to take reasonable precautions that this action does not incur adverse consequences for the subject.

c. After termination of studies involving those who lack the capacity to consent, such as young children, the Investigator shall reveal, upon request, important and pertinent results to the person/surrogate who provided consent for the subject.

5. Subject’s Right to Decline Participation and Right to Withdraw

The Investigator must respect the freedom of the subject, or in the case of those who lack capacity to consent, the person legally authorized to act on the patient’s behalf, to decline to participate in a research study or to discontinue participation at any time without penalty or other negative repercussions pursuant to their medical care.

Reviewing Body

The IRB and the individual Investigator are responsible for ensuring that the research protocol protects the subject’s freedom to participate and withdraw. The IRB shall determine whether or not the research procedures protect the subject from deceit or any type of undue influence.

Commentary

In all clinical studies the subject may withdraw from the research project at any time. However, patient-subjects unable to provide informed consent pose particular problems. The Investigator assumes additional ethical responsibilities when the subject, because of lack of capacity, demonstrates an inability to make or communicate rational judgments concerning withdrawal from the study. These additional responsibilities require exceptionally careful attention to a patient-subject’s rejection of a particular experimental treatment or desire to withdraw.

Regardless of the research subject’s mental state, the Investigator may be uniquely able to anticipate adverse consequences from the continuation of an experiment. Study participation may alter the subject’s judgment such that he or she may no longer be a good judge of the appropriateness of continuing to participate. It is the Investigator’s responsibility to withdraw the subject from the study if such a situation appears imminent. This responsibility includes subjects receiving either active drug or placebo.

D. CONFIDENTIALITY

The Investigator is responsible for maintaining the confidentiality of information and for not improperly releasing or giving access to information pertaining to subjects in the study. This responsibility includes not only information specifically protected by law, which may not apply to all subjects, but also that which affects the privacy and dignity of subjects. When there is likelihood that others may obtain access to information from research records, the Investigator, in obtaining informed consent, shall explain this possibility to the subject (or in the case of those lacking mental capacity, the person who provides consent on behalf of the subject). Such situations, e.g., the mandatory reporting of child abuse, should be communicated to the participant and included in the consent form. Similarly, the consent form should specifically address the issue of storage of data obtained in the course of the research and who will have access to such data. This is particularly crucial when data is electronically stored.

REFERENCES

1. Reatig, N. Federal regulations affecting psychopharmacology research in the United States. In Burroughs, G.D. and Werry, J.D. (eds.) Advances in Human Psychopharmacology, Vol. 2. Greenwich, CT: JAI Press Inc., 265-314, 1981.
2. Department of Health, Education and Welfare. The Institutional Guide to DHEW Policy on Protection of Human Subjects. DHEW Pub. No. 72‘102, December 1, 1971.
3. Department of Health, Education and Welfare, Office of the Secretary. Protection of Human Subjects. Amending Subtitle A of Title 45 of the Code of Federal Regulations by adding Part 46. Federal Register 39(105): 18916, May 30, 1974.
4. Department of Health, Education and Welfare, Office of the Secretary. Protection of Human Subjects: Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research: Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Federal Register 44(76): 23192, April 18, 1979.
5. Department of Health and Human Services, Office of the Secretary. Protection of Human Subjects. Title 45 of the Code of Federal Regulations, Sub-Part 46. OPRR Reports, Revised June 18, 1991, Reprinted March 15, 1994.
6. Department of Health and Human Services, Food and Drug Administration. Protection of Human Subjects. Title 21 of the Code of Federal Regulations. Federal Register 46(17), January 27, 1981.
7. Department of Health and Human Services, Food and Drug Administration. Protection of Human Subjects. Title 21 of the Code of Federal Regulations, Parts 50 and 56. April 1, 1994 Edition.
8. National Bioethics Advisory Commission. Research Involving Persons with Mental Disorders that May Affect Decisionmaking Capacity Volume II.Rockville, MD: NBAC, May, 1999.
9. Department of Health, Education and Welfare, Office of the Secretary. Research involving children. Report and recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Federal Register 43(9): 2084, January 13, 1978.
10. Department of Health and Human Services, Office of the Secretary. Additional protections for children involved as subjects in research. Federal Register 48(46): 9814, March 8, 1983.
11. Ad Hoc Committee on Ethical Standards in Psychological Research. Ethical Principles in the Conduct of Research with Human Participants. Washington, DC: American Psychological Association, 1973.
12. American Psychological Association. Ethical Principles of Psychologists and Code of Conduct. American Psychologist 47(12): 1597-1611, 1992.
13. Hoagwood, K, Jensen, P.S., and Fisher, C.B. (Eds). Ethical Issues in Mental Health Research in Children and Adolescents. Mahway, NJ: Lawrence Earlbaum Associates, 1996.
14. Pincus, H.A., Lieberman, J.A., and Ferris, S. (Eds). Ethics in Psychiatric Research: A Resource Manual for Human Subjects Protection. Washington, DC: American Psychiatric Association, 1999.
15. Bishop, M.P., and Gallant, D.M. Observation of placebo response in chronic schizophrenic patients. Archives of General Psychiatry 14:497‘503, 1966.
16. Hall, L.L. Medication discontinuation and symptom provocation in research: A consumer and family perspective (Commentary). Biological Psychiatry46:1017-1020, 1999.
17. Department of Health, Education and Welfare, Office of the Secretary. Protection of Human Subjects: Proposed regulations involving those institutionalized as mentally disabled. Federal Register 43(223): 53950, November 17, 1978.
18. Gallant, D.M. Psychopharmacologic research in severely chronic schizophrenic inpatients. Psychopharmacology Bulletin 6(4): 4-12, 1970.
19. Department of Health, Education and Welfare, Office of the Secretary. Additional protections pertaining to biomedical and behavioral research involving prisoners as subjects. Federal Register 43(222): 11341, November 16, 1978.

[a] When some or all of the subjects are likely to be vulnerable to coercion or undue influence, including those with cognitive limitations, the IRB must be sure that additional safeguards have been included in the study to protect the rights and welfare of these subjects {45 CFR 46.111(b); 21 CFR 56.111(b)}.

b The report and recommendations by the NCPHSBBR on research involving children were published in the Federal Register in 1978.⁹ In 1983, additional protections for children involved as subjects in research, including requirements for permission by parents or guardians, were prescribed in the Federal Register.¹⁰ These protections remain particularly important, since in 1998, NIH mandated that children, defned as persons less than 21 years, be included in all federally funded research studies.