Federal Regulations require that special consideration be given to protecting the welfare of particularly vulnerable participants, such as children, pregnant women, prisoners, mentally disabled or handicapped persons, or economically or educationally disadvantaged persons. In general, special regulations allow approval of research that is of minimal risk or that will benefit the subjects directly.
Children
The IRB assesses each study that includes minors based on DHHS requirements for involving children as subjects in research. Four categories of research involving children may be approved, based upon the degree of risk and benefit to individual subjects:
1. Research that does not involve greater than minimal risk. (45 CFR 46.404 and 21 CFR 50.51)
2. Research that involves greater than minimal risk but presents the prospect of direct benefit to the individual subjects may be approved only if:
· The risk is justified by the anticipated benefit to the subjects; and
· The relation of the anticipated benefit to the risk is a least as favorable to the subjects as that presented by available alternative approaches. (45 CFR 46.405 and 21 CFR 50.52)
3. Research that involves greater than minimal risk and no prospect of direct benefit to individual subjects, only if:
· The risk represents a minor increase over minimal risk, and
· The interventions or procedures presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social or educational situations, and
· The intervention or procedure is likely to yield generalizable knowledge about the subject’s disorder or condition, which is of vital importance for the understanding or amelioration of the subject’s disorder or condition. (45 CFR 46.406 and 21 CFR 50.53)
4. Research that is otherwise not approvable but which presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children may be approved only if:
· The IRB finds that the research presents a reasonable opportunity to further the understanding, prevention or alleviation of a serious problem affecting the health or welfare of children; and
· The Secretary of DHHS and the Commissioner of Food and Drugs, if applicable, after consultation with a panel of experts in pertinent disciplines, and following opportunity for public review and comments, has determined either:
a) That the research in fact satisfies the above requirements of this section, or
b) The research presents a reasonable opportunity to further the understanding, prevention or alleviation of a serious problem affecting the health or welfare of children, and it will be conducted in accordance with sound ethical principles. (45 CFR 46.407 and 21 CFR 50.54)
FDA regulations further stipulate that adequate provision must be made for soliciting the assent of children and the permission of their parents or guardians, as set forth below, in all of the above categories of research involving children.
Children’s Assent: Although minors do not have the legal capacity to consent to participate in research, children and adolescents should be asked for their agreement to be in a research study whenever they are capable of giving their assent. In determining whether children are capable of assenting, the IRB shall take into consideration the ages, maturity and psychological state of the children involved. (See Appendix 9 for Model Assent form) The FDA defines specific criteria for waiver of the assent requirements. (See 21 CFR 50.55d, 1-4)
Parental Consent: In all cases involving minors, including when minors are asked to assent to be in a study, parental consent must be obtained. When research meets category (1) or (2) above, the IRB may determine that consent of one parent is sufficient. Where the research meets category (3) or (4) above, the consent of both parents must be obtained unless one parent is deceased, unknown, incapacitated or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child.
Pregnant Women, Fetuses and In Vitro Fertilizations (45 CFR 46, Subpart B)
Pregnant woman or fetuses may be involved as a subject in a research activity if all of the following conditions are met:
a) Where scientifically appropriate, preclinical studies including studies on pregnant animals and clinical studies including nonpregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses;
b) The risk to the fetus is caused solely by interventions or procedures that hold out benefit for the woman or fetus; or if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is development of important biomedical knowledge which cannot be obtained by any other means; Any risk is the least possible for achieving the objectives of the research;
c) If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when the risk to the fetus is not greater than minimal and the purpose of the research is development of important biomedical knowledge which cannot be obtained by any other means, the woman’s consent is obtained;
d) If the research holds out the prospect of direct benefit solely to the fetus then the consent of the pregnant woman and the father is obtained, except if he is unable to consent because of the unavailability, incompetence or temporary incapacity or the pregnancy resulted from rape or incest.
e) Each individual providing consent under paragraphs (4) and (5) of this section is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate;
f) For children defined in §46.402(a) who are pregnant, assent and permission are obtained in accord with the provisions of subpart D;
g) No inducements, monetary or otherwise will be offered to terminate the pregnancy;
h) Individuals engaged in the research will have no part in any decisions as to the timing, method or procedures used to terminate the pregnancy;
i) Individuals engaged in the research will have no part in determining the viability of a neonate.
Additional limitations and restrictions on activities directed toward fetuses in utero and fetuses ex utero are outlined in § 46.205-207.
Prisoners (45 CFR 46 Subpart C)
Federal regulations provide additional protections pertaining to biomedical and behavioral research involving prisoners as subjects. Prisoners may be involved in research only if the research involves solely one of the following:
a) Study of the possible causes, effects and process of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;
b) Study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;
c) Research on conditions particularly affecting prisoners as a class provided that the study may proceed only after the DHHS Secretary has consulted with appropriate experts, and published notice of the intent to approve such research;
d) Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subjects.
Additional regulations pertaining to the inclusion of prisoners as subjects are found in 45 CFR 46, Subpart C.
Incapacitated Subjects
- When a subject does not have the capacity to give informed consent, federal regulations state that the investigator must obtain written permission from a legally authorized representative prior to enrolling the subject in a research study. Incapacitated subjects may include unconscious subjects, subjects with decisional (cognitive or emotional) impairment, persons with Alzheimer’s Disease, subjects with diagnosed psychoses and those institutionalized as mentally disabled. Special considerations must be provided for the protection of these populations and the investigator must provide in the protocol written justification for including such subjects.
2. Federal regulations define legally authorized representative as an “individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in the research.” [45 CFR 46.102(c) & 21 CFR 50.3(l)]
- Pennsylvania law requires a physician to obtain informed consent from a patient or the patient’s authorized representative prior to certain procedures, including administration of an experimental medication, use of an experimental device or use of an approved medication or device in an experimental manner.
4. In Pennsylvania, clearly designated legal representatives include guardians (natural or court appointed) or persons acting under a durable power of attorney (DPOA) authorizing medical decisions. Although no statues address the issue, there is some case law in a non-research context, which supports substituted consent by a close family member when a patient lacks capacity to make medical decisions. In certain limited circumstances, the IRB may allow consent by next-of-kin (family representative).
- If a potential research subject lacks the capacity to understand the consent process, substituted consent may be used in specific IRB-approved circumstances.
- The IRB will evaluate the relative risk versus benefit for each request to use substituted consent. If subjects can get the same therapy outside of the research setting, being in a research study may pose more risk because:
· the study seeks to resolve a research question rather than provide individual therapy (therapeutic misconception).
· there may be additional monitoring needed for the study (i.e. labs, procedures, tests, etc.)
· the study requires data collection and confidentiality risks.
What is substituted consent?
Substituted consent is consent given by someone other than the subject of the research study; it is consent by a surrogate. The investigator must request approval from the IRB to use substituted consent for each individual protocol, where applicable.
Who may give substituted consent?
The following lists the persons who may give substituted consent.
· Parents acting as natural guardians of a minor (governed by pertinent regulations - See Section P, Special Populations)
· Agent under durable power of attorney authorized to make health care decisions for procedures involved in the research (DPOA) or mental health power of attorney authorized to consent to research.
· Agent under Mental health Declaration authorized to consent to research (Note that Mental Health Declarations may be used to consent only if an agent is appointed in the Declaration.)
· Court appointed legal guardian, with specific court order authorizing research participation
· Next-of-kin (family representative)
Responsibilities
1. The IRB will
· evaluate that the risks of enrollment in the protocol are reasonable in relation to the potential direct benefits and determine if substituted consent is appropriate.
· review the use of substituted consent (parents, guardian, DPOA or family representative) for each protocol where subjects without capacity to consent will be enrolled
· as deemed necessary, require additional safeguards to the consent process for subjects with diminished capacity, such as monitoring or auditing the substituted consent process.
2. The Investigator will:
· request approval to use surrogate consent by completing and submitting to the IRB the Application for Surrogate Consent (Appendix 11).
· provide the IRB with justification for the use of substituted consent.
· ensure that the appropriate medical and/or psychiatric determination is made that the subject lacks capacity to understand the research and is unable to give effective informed consent per IRB requirements.
· inquire about the existence of Powers of Attorney or guardianships particularly for subjects with a history of mental incapacity such as mental retardation or dementia and review existing Powers of Attorney to determine if it can be used to provide substituted consent before the use of family representative consent.
· inform the surrogate of their role in the consent process.
· review the consent document with the surrogate and provide information about the research study, the risks and benefits, alternatives to the research and the surrogate’s ability to stop the subject’s participation in the research. The surrogate will receive a copy of the consent document.
· obtain the assent of subjects who may understand some of the process but who are not capable of fully and effectively consenting to participate in the research.
· obtain the consent of the subject to continue in the study if the subject becomes capable of understanding the nature, risks, benefits of and alternatives to the research study and is able to provided effective informed consent.
· notify the IRB office within 2 business days of each time substituted consent is used.
3. The surrogate will:
· act in accordance with the wishes of the subject, or, if unknown, act on what the surrogate believes the subject would have wanted in view of the subject’s preferences, goals, values and beliefs and the subject’s medical condition.
4. All actions take will be in the best interest of the subject.
5. No substituted consent will be used where a subject objects.
How is lack of capacity determined?
1. Two physicians on the medical staff must make the determination that the subject lacks the capacity to understand the nature, risks and benefits of and alternatives to research and provide effective informed consent. One physician may be the investigator and the
other physician must not be related to the study or be in the same medical practice group as the investigator.
2. Both physicians must document in the subject’s medical record the basis for the lack of capacity. In addition, the investigator must document the reason for lack of capacity on the consent form.
Use of Consent by a Family Representative
Approval for consent by family member will only be granted when none of the other representatives listed above exist and when the following conditions are met:
a) The subject has a condition which is a significant threat to the health of that individual, and
b) The research demonstrates a meaningful chance of direct benefit to the subject over what they could receive outside the research setting. If there is a standard therapy it does not work well, and
c) The risks do not outweigh this potential direct benefit, and
d) The time delay in appointing a legal guardian would compromise patient care.
The family representative may consent in the following hierarchy:
a) Spouse
b) Adult children (in chronological order if another is present)
c) Parents
d) Adult Siblings
Where there is disagreement among family members, if consensus cannot be reached, the subject may not be enrolled in the research by family representative consent. {See Section F, Informed Consent]
Illiterate Subjects
Subjects who are unable to read should not be excluded from research on the grounds of illiteracy. If a subject is unable to read or if a legally authorized representative is unable to read, the short form of consent may be utilized or the written consent form and any other written information to be provided to subjects must be read and explained to the subject or the subject’s legally authorized representative. In both instances an impartial witness, unrelated to the study, should be present during the entire informed consent discussion and sign the appropriate consent documents. [See Section F, Informed Consent].
If the subject is capable, he should sign the consent form or, if incapable, should indicate orally that he consents to participate in the research. By signing the consent form, the witness attests that the information in the consent form and other written material was accurately explained and apparently understood by the subject or the subject’s legally authorized representative.
[See additional information on Documentation of Consent and Alternative to Written Signature in Section F, Informed Consent]
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