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Vulnerable Subject Populations

Requirements When Children are Research Participants

Children are considered a vulnerable research population because their intellectual and emotional capacities are limited and therefore, they are legally incompetent to give valid informed consent. Investigators interested in enrolling children are required to complete Appendix D when completing the electronic IRB Application or when requesting a modification to an IRB-approved study. Research involving children can be approved by the IRB if it satisfies the following requirements of federal regulations:

When reviewing research involving children as subjects, the IRB considers the risks and discomforts inherent in the proposed research and assesses their justification in light of the expected benefits to the child-subject or to society as a whole.

Federal Regulations regarding "Children" (both 45 CFR 46 and 21 CFR 50) state, "'Children' are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted." Thus, who qualifies as a "child" depends on local laws for consent. In California, 18 is the usual age when people can consent to treatments or procedures, but there are important exceptions, such as when seeking medical care related to the prevention or treatment of pregnancy (see below for further clarifications).

NOTE: Researchers interested in enrolling children are required to complete Appendix D when completing the electronic IRB Application or when requesting a modification to an IRB-approved study.

Permitted Categories for Research with Children

Federal regulations classify permissible research involving children into four categories based on degree of risk and type of individual subjects. These categories are described in relation to "minimal risk":

  1. Research not involving greater than minimal risk (45 CFR 46.404 and 21 CFR 50.51)
    1. Permission from at least one parent/guardian required
    2. Assent of the child (if child is 7 years of age or older) required
    3. Expedited level of review necessary

  2. Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects (45 CFR 46.405 and 21 CFR 50.52):
    • The risks must be justified by the anticipated benefits; and
    • The risk to benefit ratio must be at least the as favorable as alternative treatments or approaches.
    1. Permission from at least one parent/guardian required
    2. Assent of the child (if child is 7 years of age or older) required
    3. Full Committee review necessary

  3. Research that involves more than minimal risk and presents the prospect of no direct benefit to individual subjects, but generalizable knowledge (societal benefit) (45 CFR 46.406 and 21 CFR 50.53):
    • The risks represent a small increase over minimal risk;
    • The interventions or procedures are commensurate with those associated with the subjects' actual or expected medical, dental, psychological, social or education situations; and
    • The interventions or procedures are likely to yield generalizable information about the subjects' disorder, condition, situation, which is of vital importance to understand or ameliorate.
    1. Permission from both parents/guardians required*
    2. Assent of the child (if child is 7 years of age or older) required
    3. Full Committee review necessary

  4. Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children (45 CFR 46.407 and 21 CFR 50.54):
    1. Permission from both parents/guardians required*
    2. Assent of the child (if child is 7 years of age or older) required
    3. Full Committee review necessary
    4. Post IRB concurrence, requires submission to the Secretary of the US Department of Health and Human Services who after consultation with panel of experts and following an opportunity for public review and comment must either approve or deny approval of the study.
    5. This type of study is very rarely approved.

Parental Permission

Because children cannot legally provide consent for research on their own behalf, permission by at least one parent or legal guardian is required prior to enrollment of a minor in a research study.

  1. Research involving no more than minimal risk requires permission from at least one parent (or guardian).
  2. Research that involves more than minimal risk but presents the prospect of direct benefit to individual subjects requires permission from at least one parent (or guardian).
  3. Research that involves more than minimal risk and presents the prospect of no direct benefit to individual subjects, but generalizable knowledge (societal benefit) requires permission from both parents.*
  4. Research that presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children, does NOT provide direct benefit to the subject or societal (indirect) benefit requires permission from both parents.*

NOTE: If there are two parents available to give permission but they disagree about allowing their child to participate in the study, the child should not be enrolled unless that disagreement can be resolved. This policy applies to all permissible categories of research involving children.

*Unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child. If these circumstances are present, the researcher should document this in the subject's research record.

Waiver of Parental Permission

For some expedited research studies the IRB may waive the requirement to obtain written parental permission. See Waiver of Written (Signed) Informed Consent for more information.

In certain cases, research may be designed for conditions or for a subject population for which parental permission for inclusion in research is not a reasonable requirement to protect the subjects (e.g., neglected or abused children).

  1. For non-FDA regulated studies, the IRB may waive the requirement to obtain parent(s)/guardian(s) permission provided "an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and provided further that the waiver is not inconsistent with Federal, State, or local laws."
  2. For FDA regulated studies, parent(s)/guardian(s) permission cannot be waived for FDA-regulated clinical investigations; FDA regulations lack the provision for wavier of parental permission.

Child Assent

Federal regulation and state statute require that minors assent to participate in research.

Written Assent Requirements

Assent forms should be written at the appropriate educational and maturity level of the youngest prospective subject in the age range.

Assent Elements

An assent form should contain date and signature lines for the child, a witness, and an investigator. The assent form should cover the following points:

A sample Assent Form is available. Please note: the sample is not meant to serve as a template. Assent forms must be tailored to the reading and comprehension level(s) of the subject populations to be enrolled and will vary widely from study to study.

Waiver of Assent

Assent of the child is not a necessary condition for proceeding with the research under the following conditions:

  1. The capability of some or all of the children is so limited that they cannot reasonably be consulted; or
  2. The IRB determines that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well being of the children and is available only in the context of the research.
    1. Under such circumstances, a child's dissent which should normally be respected may be overruled by the child's parents at the IRB's discretion.
  3. Finally, even where the IRB determines that the child participants are capable of assenting, the IRB may still waive the assent requirement under circumstances in which consent may be waived for adults in accordance with 45 CFR 46.116(d) regarding waiver or alteration of informed consent.

Wards of the State

Children who are wards of the state or any other agency can be involved in research that is:

  1. no more than minimal risk with permission from a guardian;
  2. more than minimal risk but presents the prospect of direct benefit to individual subjects with permission from a guardian;
  3. more than minimal risk and presents the prospect of no direct benefit to individual subjects, but generalizable knowledge (societal benefit) ONLY if the research is
    • related to their status as wards, or
    • conducted in schools camps, hospitals, institutions, or similar settings in which the majority of children involved are not wards.
    The IRB must require appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis.
  4. Research not otherwise approvable that presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children, but does NOT provide direct benefit to the subject or societal (indirect) benefit. The research cannot be approved unless the criteria in #3 are met and HHS Secretary approval is granted.

When Parental Permission is not needed

In California, certain people under 18 years of age are legally able to consent for certain treatments or procedures. For those procedures, these minors do not fit the federal definition of "children." The IRB may determine that these individuals may consent for themselves to participate in research involving those treatments or procedures. The following information provides examples of circumstances under which California law combined with federal regulations permits individuals under 18 to enroll in research without permission from parent(s) or guardian(s).

  1. Minors may consent for themselves to medical care related to the prevention or treatment of pregnancy, but not necessarily to sterilization or abortion [California Family Code (CFC) Section 6925; Health and Safety Code Section 123450 for abortion].
  2. Minors 12 years of age or older have the legal right to consent on their own behalf, for:
    • mental health treatment or counseling on an outpatient basis or residential shelter services (in limited circumstances) [CFC Section 6924]
    • medical care related to the diagnosis or treatment of infectious, contagious or communicable diseases that are required to be reported to the local health officer or a related sexually transmitted diseases [CFC Section 6926]
    • medical care related to the diagnosis or treatment of the condition and collection of medical evidence with regard to alleged rape or sexual assault [CFC Section 6927].
    • medical care and counseling related to the diagnosis and treatment of a alcohol or drug-related problem [CFC Section 6929]
  3. Self-sufficient minors who are:
    1. 15 years of age or older;
    2. living separate from their parents/guardians; and
    3. managing their own financial affairs have the legal right to consent on their own behalf to medical or dental care [CFC 6922].
  4. Emancipated minors, those who are:
    1. married or divorced
    2. on active duty in the U.S. armed forces or
    3. emancipated by a court
    4. have the legal right to consent on their own behalf to medical, dental, or mental health treatment. They also have extensive other rights to enter into legal and business arrangements, and so can consent to be included in other research (e.g., interviews, surveys) [CFC 7000-7143].

NOTE: The California Family Code includes more restrictions and exceptions than can be summarized here. Researchers considering enrolling subjects based on the above examples should consult the relevant sections of the law.

Researchers enrolling research participants in other states or countries must comply with local law. In all cases, if the prospective subjects cannot legally consent for the treatments or procedures involved in the study, they are considered "children” by federal regulations. Conversely, if they can consent for the treatments or procedures, they are NOT "children” by federal regulations.

Difficult Issues/Sensitive Matters involving Children

Discovery and Disclosure of Sensitive Information
In the course of research with children, especially adolescents, researchers may discover sensitive information about subjects that is not related to the study itself. For example, such information as sexual activity, STDs, use of illegal substances, and child abuse.

Enrolling Children in Long-Term Studies

Long-term research studies may involve subjects who are children at the time of enrollment but reach the age of consenting for themselves (in California, usually 18 years old) while study procedures or follow-up are still ongoing. UCI IRB will consider on a protocol-by-protocol basis whether obtaining new consent from such subjects is required.

If there is continued interaction with subjects who were first enrolled as children, "re-consenting" when a subject's legal status changes will usually be required. If the only continuing study procedures are follow-up activities such as review of records or examination of biological specimens, the original consent may suffice.

Prisoners as Subjects

Prisoners are considered a vulnerable research population because the very fact of incarceration may make it difficult for them to give truly voluntary informed consent. Investigators interested in enrolling prisoners as research subjects must complete Appendix C when completing the electronic IRB Application or when requesting a modification to an IRB-approved study.

For research involving prisoners, the definition of minimal risk requires reference to physical or psychological harm, as opposed to harm or discomfort, to risks normally encountered in the daily lives, or routine medical, dental or psychological examination of healthy persons.

Definition of Minimal Risk in Prisoner Research 45 CFR 46.303(d) Definition of Minimal Risk in 45 CFR part 46, subpart A, 45 CFR 46.102(i)
"Minimal risk" is the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons. "Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

Important Note: The criteria for involving prisoners in research apply whenever any human subject in a research protocol becomes a prisoner at any time during a study. If a subject becomes a prisoner after enrollment in research, the investigator must notify the IRB right away. See also FAQs about Prisoner Research.

To protect this study population, federal regulations stipulate that the only studies that may use prisoners are those with an independent and valid reason for involving them. Specifically:

Further reading: Waiver of certain provisions for epidemiologic research involving prisoners as subjects-June 20, 2003, Federal Register Notice.

Pregnant Women, Fetuses and Neonates

While pregnant women may be involved in several categories of research, studies involving the human fetus raise special concerns. Research involving pregnant women, fetuses and human in vitro fertilization are subject to special federal regulations that guide IRB deliberations on such studies. Investigators interested in studying pregnant women, fetuses and/or neonates are required to complete Appendix B when completing the electronic IRB Application or when requesting a modification to an IRB-approved study.

Additional protections are in place for all research involving pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates.

Definitions:

Research studies involving pregnant women or fetuses can be approved by the IRB if the following requirements of federal regulations are satisfied:

Consent Signature Requirements

The mother's consent is required when the research holds:

Consent from the mother *and* father is required (unless the father is absent, incompetent, unknown or the pregnancy resulted from rape/incest) when the research holds out the prospect of direct benefit solely to the fetus.

Consent Decision Chart for Pregnant Women and Fetuses

Direct benefit to mother only Direct benefit to mother and fetus Direct benefit to fetus only No direct benefit or societal benefits only
Risk is more than minimal Mother's consent Mother's consent Mother and father's consent NOT APPROVABLE BY IRB
Risk is no more than minimal Mother's consent Mother's consent Mother and father'sconsent Mother's consent

Investigators proposing to conduct research using neonates (viable, uncertain viability, or nonviable) or research using the placenta, dead fetuses or fetal material, or pregnant women, fetus and neonate research not otherwise described above, are encouraged to consult with the Research Protections staff for additional guidance prior to submitting an IRB application.

Students, Employees, or Faculty as Research Subjects

UCI students and employees that are asked to volunteer as human subjects in a researcher's study may feel some pressure to agree to participate, especially if the requesting researcher is their supervisor or instructor, or someone who might be in a position to influence their future. Students and employees may volunteer to participate out of a belief that doing so will place them in good favor with faculty (e.g., that participating will result in receiving better grades, recommendations, employment, or the like), or that failure to participate will negatively affect their relationship with the investigator or faculty generally (i.e., by seeming "uncooperative").

IRB Policy

  1. 1. To protect against even the appearance of coercion or undue influence, when UCI investigators wish to recruit UCI students (undergraduate, graduate, and medical students), staff (administrative, clerical, nursing, lab, "house" staff, etc.), or faculty as human subjects, they must first request approval for inclusion of one or more of these populations on the electronic IRB Application, or by requesting a modification to an IRB- approved study.
  2. Researchers who include students and subordinates in research are urged to exercise great caution to avoid even the appearance of pressuring or coercing potential subjects into enrollment or continued participation. In addition, researchers should guard against the potential for compromised objectivity and/or confidentiality when including students or subordinates in a study.

Additional Guidelines for the Recruitment of Students

  1. The Lead Researcher must provide assurance in the protocol narrative that a student's experimental results, performance, or any confidential data will not be given to whomever is grading the student, except for stating whether the student participated or not unless the approved study design provides for this.
  2. It is unacceptable to require participation in research for course credit. However, instructors who wish to involve students in simulations of human experimentation and course-assigned data collection for educational purposes only (as opposed to research purposes) may require such participation as part of the class requirements.
  3. UCI students may earn extra course credit through the Social Science Lab if an instructor includes this option in the course syllabus. When students participate in research studies for extra class credit, they must be provided alternative ways to earn extra credit that require equal or less time and effort. The IRB may require the investigator to include the available alternatives to participation in the informed consent document.
  4. Researchers interested in accessing student records for research purposes are directed to the UCI Registrar website on Confidentiality of Students Records. The disclosure of information from student records is governed in large measure by the Federal Family Educational Rights and Privacy Act of 1974, by the State of California Education Code, and by University policy and procedures implementing these laws. Generally, documentation of informed consent is required to access private student information.

Cognitively Impaired Research Subjects

All adults (including those with cognitive impairments) are presumed competent to consent unless legally judged to be incompetent. Cognitively impaired persons are considered a vulnerable research population because their mental disability may compromise their capacity to make a reasoned decision about participation in a study. Investigators interested in studying individuals with cognitive impairment are required to complete Appendix E when completing the electronic IRB Application or when requesting a modification to an IRB-approved study.

People with Alzheimer's disease, dementia, mental illness and developmental disabilities may be considered cognitively impaired and may not be able to provide informed consent for participation in research. In certain circumstances, when it is determined that a potential research participant is cognitively impaired, federal regulations and state statute permit researchers to obtain consent from a legally-authorized representative (surrogate consent).

To have the option to obtain consent from a subject's legally-authorized representative, the investigator must request the use of surrogate consent by completing Appendix E and the IRB must specifically approve the request, usually at a convened IRB meeting. When consent will be obtained from a legally-authorized representative (surrogate), the IRB usually will require that the assent of the subject be obtained. Assent is defined as affirmative agreement to participate in research. Failure to object does not qualify as assent. For information, see Assessing Decision-Making Capacity and use of surrogate consent.