What provisions would you recommend when conducting research with vulnerable populations?

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. Investigator's interested in enrolling children are required to address specific additional questions when completing the electronic IRB Application or when requesting an amendment to an IRB-approved study. 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).

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":

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.

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).

• 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.

Child Assent

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.

Written Assent Requirements

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.

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:

• 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 OR Applications & 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.

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.
   • 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 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.

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.

• 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.

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 amendment to an IRB-approved study.

Definition of a Prisoner (45 CFR 46.303 (HHS – Subpart C)

“Prisoner” means any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing (45 CFR 46.303(c)).

Individuals are prisoners if they are in any kind of penal institution, such as a prison, jail, or juvenile offender facility, and their ability to leave the institution is restricted. Prisoners may be convicted felons or may be untried persons who are detained pending judicial action, for example, arraignment or trial.

Prisoner Examples

• Individuals who are detained in a residential facility for court-ordered substance abuse treatment as a form of sentencing or alternative to incarceration
• Individuals with psychiatric illnesses who have been committed involuntarily to an institution as an alternative to a criminal prosecution or incarceration
• Parolees who are detained in a treatment center as a condition of parole
•  

Non-Prisoner Examples:

• Individuals who are receiving non-residential court-ordered substance abuse treatment and are residing in the community
• Individuals who have been voluntarily admitted to an institution for treatment of a psychiatric illness, or who have been civilly committed to non-penal institutions for treatment because their illness makes them a danger to themselves or others
• Persons living in the community and sentenced to community-supervised monitoring, including parolees
• Probationers and individuals wearing monitoring devices, however, situations of this kind frequently require an analysis of the particular circumstances of the planned subject population. Institutions may consult with OHRP when questions arise about research involving these populations.
•  

For research involving prisoners, the definition of minimal risk is as follows:

“Minimal risk” as it relates to prisoners is defined as 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 (45 CFR 46.303(d)).

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:

• Studies of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects.
• Studies 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.
• Research on conditions particularly affecting prisoners as a class (e.g., vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) provided that the study may proceed only after consultation with, and approval by the HHS Secretary.
• Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject. In cases in which those studies require the assignment of prisoners in a manner consistent with protocols approved by the IRB to control groups which may not benefit from the research, the study may proceed only after consultation with, and approval by the HHS Secretary.
• Studies of epidemiologic research that describe the prevalence or incidence of a disease by identifying all cases or studies of the potential risk factor associations for a disease, where prisoners are not the particular focus of the research.
•  

Further Reading

• Waiver of certain provisions for epidemiologic research involving prisoners as subjects - June 20, 2003, Federal Register Notice. In addition, visit the robust OHRP FAQ page on this topic.
• UCI HRPP Policy # 37 - Prisoners as Research Participants
• California Penal Code Sections 3501-3523

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 amendment 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

• Fetus means the product of conception from implantation until delivery.
• Neonate means a newborn.
• Pregnancy encompasses the period of time from implantation until delivery. A woman shall be assumed to be pregnant if she exhibits any of the pertinent presumptive signs of pregnancy, such as missed menses, until the results of a pregnancy test are negative or until delivery.
• Viable, as it pertains to the neonate, means being able, after delivery, to survive (given the benefit of available medical therapy) to the point of independently maintaining heartbeat and respiration. If a neonate is viable then it may be included in research only to the extent permitted and in accordance with the requirements for research involving children.

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

• Preclinical studies have been conducted, including studies on pregnant animals; clinical studies, that include nonpregnant women and provide data for assessing potential risks to pregnant women and fetuses
• Risk to the fetus is caused solely by interventions or procedures that hold the prospect of direct benefit for the woman or the fetus or,
• If no benefit, the risk to the fetus is not greater than minimal and the research develops important biomedical knowledge not obtainable by any other means.
• Any risk is the least possible for achieving the objectives of the research.
• Individuals engaged in the research will have no part in: 1) any decisions as to the timing, method, or procedures used to terminate a pregnancy, and 2) determining the viability of the fetus at the termination of the pregnancy; and
• No inducements, monetary or otherwise, will be offered to terminate the pregnancy.

Consent Signature Requirements

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

• the prospect of direct benefit to the pregnant woman, or
• 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 but risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means;

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 onlyDirect benefit to mother and fetusDirect benefit to fetus onlyNo direct benefit or societal benefits onlyRisk is more than minimalMother's consentMother's consentMother and father's consentNOT APPROVABLE BY IRBRisk is no more than minimalMother's consentMother's consentMother and father'sconsentNOT APPROVABLE BY IRB

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. 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 IRB Application, or by requesting an amendment 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 Privacy and Student 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 address additional consideration as part of the IRB review process in Kuali Research (KR) Protocols.

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 that the IRB allow for the use of surrogate consent.

How can we protect vulnerable participants in research?

Why is it important to include vulnerable populations in research?

Can vulnerable populations be used in research?

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