Vulnerable Populations

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":

Research not involving greater than minimal risk (45 CFR 46.404 and 21 CFR 50.51)

• Permission from at least one parent/guardian required
• Assent of the child (if child is 7 years of age or older) required
• Expedited level of review necessary

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):

• Permission from at least one parent/guardian required
• Assent of the child (if child is 7 years of age or older) required
• Full Committee review necessary
• 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.

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):

• Permission from both parents/guardians required*
• Assent of the child (if child is 7 years of age or older) required
• Full Committee review necessary
• 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.

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):

• Permission from both parents/guardians required*
• Assent of the child (if child is 7 years of age or older) required
• Full Committee review necessary
• 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.
• This type of study is very rarely approved.

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.

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).

• 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."
• 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.

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

• Assent is defined as a minor's affirmative agreement to participate in research.
• In most cases, this must be documented in writing if the subjects are at least seven years old.
• The IRB has authority to require assent from children younger than seven if they are likely to comprehend and appreciate what it would mean to volunteer to participate in a given protocol.

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

• Techniques such as the use of larger type, simple schema, and pictures may help boost a child's understanding of the text.
• Depending on the age range of the minors to be involved, the Lead Researcher may be required to develop 2 different assent forms at different reading comprehension levels (e.g., one assent form written for young children ages 7-12 years old, and one assent form written for minors ages 13-17 years old).
• Alternatively, for children 13-17 years of age, the researcher may develop a joint assent/permission consent form and obtain the signatures of the minor and parent(s) or guardian(s) on one document.

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:

• what the study is about,
• why the child is eligible to participate for the study,
• what procedures will be performed,
• potential risks and discomforts to the child,
• potential benefits to the child and society,
• for non-therapeutic research, a statement that the child can choose whether to participate and may withdraw at any time without negative consequences,
• an invitation to ask questions any time, and
• names and phone numbers of whom to contact with questions.

A sample Assent Form is available on the IRB Forms page. 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.

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.
   • 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.

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.

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 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:
   • 15 years of age or older;
   • living separate from their parents/guardians; and
   • managing their own financial affairs have the legal right to consent on their own behalf to medical or dental care [CFC 6922].
   • Emancipated minors, those who are:
     • married or divorced
     • on active duty in the U.S. armed forces or
     • emancipated by a court
     • 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.

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.

• Confidentiality: Researchers need to consider how they will handle such situations should they arise. The permission and/or assent form should describe plans for disclosure—or non-disclosure—of such information to parents, legal authorities, and the subjects themselves. In some situations, it may be appropriate to obtain a NIH Certificate of Confidentiality (see https://grants.nih.gov/grants/policy/coc/background.htm for information as to whether this is applicable for a particular study).
• NOTE: Effective April 17. 2006 if HIV testing is conducted as part of research, HIV positive test results are to be reported by name to the local heath department who then sends the information to the California Department of Health Services, Office of AIDS HIV/AIDS Case Registry. The reporting of positive HIV status by name should be explained in the Confidentiality section of the parental permission document.
• Child Abuse Reporting: Ethical and legal obligations apply whenever child abuse is discovered. Researchers should be aware that, in most cases, the same reporting expectations pertain in research settings as in clinical settings. UCI researchers may fall into a category of health professionals or others listed as "mandated reporters" under the California Child Abuse and Neglect Reporting Act (11164-11174.4). Even if the mandated reporter status is not clear, the researcher can make a voluntary report to the appropriate agency.
  • If a researcher is planning a study that is designed or likely to elicit information about sexual or physical abuse of a child, the application and consent/assent forms must indicate how discovery of such information will be handled.
  • If such information is discovered unexpectedly (i.e., not anticipated given the study design or subject population), the LR should seek advice from his/her department chair or dean or from the Director of the UCI Research Protections, who may refer the question to UC Legal Counsel.

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.