Chapter 13: Vulnerable Subject Populations

In certain cases, parental permission is not a reasonable requirement to protect subjects (neglected or abused children); more detailed examples are given below. The IRB will consider requests for waiver of parental permission on a case-by-case basis. For FDA regulated research a waiver may be granted for expedited review/minimal risk research. For non-FDA-regulated studies, the IRB may waive parental/guardian 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 law” (45 CFR 46.408). Additionally, Public Demonstration Projects may obtain a waiver of parental permission if the IRB finds that all criteria below are satisfied:

• The research is to be conducted by or subject to the approval of state or local government officials, and
• The research is designed to study, evaluate or otherwise examine: (i) public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs, and
• The research could not practicably be carried out without the waiver or alteration, and
• The research is not FDA-regulated.

Examples where parental permission may be waived:

• Research on child abuse or neglect, or research that is reasonably likely to elicit information identifying child abuse or neglect, where there is serious doubt as to whether the parents’ interests reflect the child’s interests [45 CFR 46.408(c)].
  • The Federal Regulations specifically refer to “research on neglected or abused children” as an instance where “parental or guardian permission is not a reasonable requirement to protect the subjects,” the IRB would be likely to waive parental permission in such a case, provided the other requirements of the regulations [45 CFR 46.408(c)] are met.
• Research on people under age 18 who are in circumstances where they are clearly outside of parental influence or control.
  • Researchers also should be aware that some people under 18 who are living independently may not fit the federal definition of “children” and are able to consent for themselves without a waiver of parental permission. See California Exceptions Permitting Certain Minors to Consent below.

Waiver of Child Assent

In certain cases, the IRB may waive the requirement to obtain children’s assent, for example:

• The capability of some or all of the children is so limited that they cannot reasonably be consulted, or
• 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 (45 CFR 46.408, 21 CFR 50.55)

Assent may not be required but should always be sought.

The parents’ right to make medical decisions for their child may come into conflict with the child’s right to give or withhold assent. In this situation, assent may not be mandatory, though it always should be sought.

If the child is considered capable of being involved in the informational process, a simple verbal explanation of what will happen to him/her and the opportunity for questions and discussion should always be provided. Even if the requirement for assent is waived, it is always preferable to seek the child’s assent if possible. There must be documentation on the parental permission form or in the study records that the child was appropriately informed about the study.

NOTE: Parental Permission for children’s enrollment cannot be waived for FDA- regulated studies except for the use of an FDA test article meeting the emergency exception or a study involves no more that minimal risk, and meets the criteria set forth in the following guidance: “IRB Waiver or Alteration of Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to Human Subjects”

Waiver or Alteration of Informed Consent in Studies Involving No More than Minimal Risk

The IRB may approve a consent procedure that does not include, or that alters, some or all of the elements of informed consent set forth in 21 CFR 50.25, or may waive the requirement to obtain informed consent or assent if the following is found and documented:

1. The clinical investigation involves no more than minimal risk (as defined in 21 CFR 50.3(k) or 56.102(i)) to the subjects;
2. The waiver or alteration will not adversely affect the rights and welfare of the subjects;
3. The clinical investigation could not practicably be carried out without the waiver or alteration; and
4. Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

Please see the guidance document for more information: “IRB Waiver or Alteration of Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to Human Subjects”

Children under Guardian Care

In California, a guardian normally has the same authority with respect to the child as a parent having legal custody, except as limited by statute or court order (the legal document establishing the guardianship). This includes the authority to consent on behalf of the child to general medical care.

For research that involves medical care, however, a guardian’s authority to consent or require is restricted, in the absence of an affirmative court order, in the following circumstances:

• By the terms of any letters of guardianship issued by a court (a certified copy of which should be obtained and placed in the medical record)
• For surgery on a child 14 years or older, unless:
  • The child also consents;
  • The guardian obtains a court order, or
  • The guardian has determined based on medical advice that an emergency exists in which the child faces loss of life or serious bodily injury if the surgery is not performed.
• From administering an “experimental drug” (defined in Health & Safety Code Section 111515; FDA investigational drug), unless a 7 years or older child also consents, and the drug is related to maintaining or improving health or obtaining information about a pathological condition of the child
• From authorizing electro-convulsive treatment (defined in Welfare & Institutions Code Section 5325)
• From admitting the child to a “mental health treatment facility” [defined in Probate Code 2356(a)] without the child’s consent
• From authorizing antipsychotic drugs except under certain circumstances
• From authorizing an elective procedure performed primarily for the purpose of rendering the child sterile (not treatment which secondarily results in sterilization)
• From authorizing psychosurgery under any circumstances

For additional information regarding informed consent considerations, refer to “Informed Consent for Children Not in Parental Custody” below.

Children under the Jurisdiction of Dependency Court / Court Appointee

Parental permission and consent for a child’s participation in research is not required when the juvenile dependency court has explicitly removed the individual parents’ power to make such a decision. In cases where the parent has lost parental rights, the IRB can accept consent from whomever the court appoints as authorized under applicable state or local law to consent on behalf of a child to general medical care.

If the research involves children who are wards of the state, investigators should contact the Office of Compliance. Research involving greater than minimal risk and the prospect of participant direct benefit to wards may be approved by the IRB. Research which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children may be approved only if:

• There is a court appointed advocate for each child who:
  • May be the same individual for all of the children
  • Has the background and experience to act in (and agrees to act in) the best interest of the child for the duration of the research, and
  • Is not associated in any way with the research (except as an advocate), the investigators, or any guardian association

Additionally, for research involving medical care for wards of a court, often an order from the judge is required, in addition to permission from the person charged with the care of the child.

Before waiving the parental consent requirement, the IRB should require a court order that clearly and specifically provides that the children may participate in research without parental consent. According to California Welfare and Institutions Code Section 361 (a) there is no limitation of parents’ right to consent to research that was not “necessary to protect the child.”

Informed Consent for Children Not in Parental Custody

Investigators are required to obtain a court order permitting the participation of the individual subjects/class subjects in the research without parental consent, and are required to follow the procedure in Los Angeles County Superior Court Rule Chapter 7 (if research and the children are within Los Angeles County) or other applicable court procedures.

The investigators are required to obtain the assent of subjects unless the IRB determines that assent should not be obtained in accordance with federal human subjects regulations.

California Exceptions Permitting Certain Minors to Consent

In California, minors (those under 18 years of age) generally may not consent to medical care or treatment, or research involving medical care or treatment, without a parent or legally authorized representative (LAR). Federal regulations when interpreted with California legal exceptions allow minors to consent as adults to research or treatment.

The following categories of minors are permitted to consent as adults to research or treatment:

• • Emancipated minors in California have the legal right to consent on their own behalf to medical, dental, or mental health treatment. They also have extensive rights to enter into legal and business arrangements, or participation in research (Section 7000-7143):Emancipated minors may be:
    • married or divorced, or
    • on active duty in the U.S. armed forces
    • emancipated by a court
  • Self-Sufficient minors:
    • 15 years of age or older, and
    • living separate from their parents/guardians, and
    • managing their own financial affairs
    • may consent to the minor’s own medical or dental care (Section 6922)

• Minors, 12 years or older, seeking care for:
  • Prevention or treatment of pregnancy
  • Out-patient mental health treatment or counseling, excluding drugs
  • Care related to the diagnosis or treatment of reportable infectious, contagious, or communicable/sexually transmitted diseases
  • Care provided to the victims of sexual assault or rape
  • Medical care and counseling relating to the diagnosis and treatment of drug or alcohol abuse (only if treating physician deems and documents that parental involvement is inappropriate), excluding narcotic replacement drugs.

With IRB approval, for the above categories a minor must provide consent and sign the consent form just as an adult would, unless the IRB approves a waiver or alteration of the usual consent standards for adults. The IRB requires that any investigator that is not familiar with these laws and proposes to enroll a minor without parental permission to contact the IRB staff for further guidance. The IRB always retains the option to exclude minors that may otherwise consent in light of risks or the nature of the trial.

Researchers enrolling 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 because they are too young, they are considered “children” by federal regulations. If they can consent for the treatments or procedures, they are not “children” by federal regulations (therefore if they are not “children” 45CFR46 subpart D does not apply).

Managing Disclosure of Sensitive Information

In the course of research investigators may explore such topics as STDs, use of illegal substance or HIV status. The investigator may be required to disclose sensitive information during the course of a study. 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 cases, it may be appropriate for the PI to seek an NIH Certificate of Confidentiality (refer to Section 10.4 – Certificate of Confidentiality).

Also visit http://grants.nih.gov/grants/policy/coc/background.htm for information as to whether a certificate is applicable for a particular study.

Mandatory Reporting

Discovery of child abuse initiates certain ethical and legal obligations. In most cases, the same reporting expectations pertain in research settings as in clinical settings. University researchers may be health professionals or other “mandated reporters” under the California Child Abuse and Neglect Reporting Act (California Penal Code 11164- 11174.3). Even if the mandated reporter status is not clear, the investigator can make a voluntary report to the appropriate agency. Please refer to the following USC policy for details and guidance: http://policy.usc.edu/mandated-reporters/. See also USC policy on Protecting Minors at: https://policy.usc.edu/protecting-minors/

If an investigator 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 (not anticipated given the study design or subject population), the PI should contact the Los Angeles County Department of Children and Family Services (800) 540-4000 and the Office of Compliance.

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 (18 years old, in California) while study procedures or follow-up are still ongoing. The IRB will consider on a study-by-study 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.

Research Involving Children in Educational Settings

Parental permission is usually a prerequisite to the recruitment of human research participants who are children. Unless the IRB has waived parental or guardian permission, such permission is required prior to seeking assent from a child to participate in research. Parental consent constitutes only half of the consent process. Assent, the agreement of a child to participate in research, is the second component of the informed consent procedure for children.

Researchers must be aware of district policy of the school in which they intend to do research. District policy dictates who gives permission and what kind of research can be conducted. For the participation of individual children in research only a parent or a legally authorized representative (LAR) may grant permission to approach the child to participate in research.

If the study will be conducted during school hours, an equivalent alternative activity should be offered for students who do not wish to participate.

Additionally, according to California Education Code 51513, generally speaking, no test, questionnaire, survey, or examination containing any questions about the pupil’s personal beliefs or practices in sex, family life, morality, and religion, or any questions about the pupil’s parents’ or guardians’ beliefs and practices in sex, family life, morality, and religion, shall be administered to any pupil in kindergarten or grades 1 to 12, inclusive, unless the parent or guardian of the pupil is notified in writing of any of these procedures.

FERPA Rules and Research with Education Records

The Family Educational Rights and Privacy Act (FERPA) (34 CFR 99) sets limits on the conditions under which education records can be accessed for research purposes.

Education records are generally defined in FERPA as personally identifiable information regarding a student in a K-12 or higher education setting that receives federal funding.

It is the holder of the records (e.g., a school authority, university registrar) –not the researcher – who carries the legal responsibility for abiding by FERPA. Therefore, it is the holder of the records–not the researcher – who is in violation of FERPA if education records are released inappropriately or illegally.

It is not the responsibility of the IRB to ensure that researchers access personally identifiable student level data in compliance with FERPA. It is up to the researcher to ensure that the personally identifiable information from an education record will not be disclosed to any other party without prior consent of the parent or eligible student. If a researcher improperly discloses personally identifiable information from an education record, the researcher may not be allowed to access information from education records for five years (34 CFR 99.33(e)). Please see FERPA for more information: https://www2.ed.gov/policy/fund/guid/humansub/overview.html

FERPA requires that the holder of the records ensure written consent is obtained from a parent or eligible student in order to release personally identifiable student information. The holder of the record only obtains consent from parents and eligible students under limited circumstances (see the Directory Information Policy exception below).

There are exceptions to FERPA that might also enable a researcher to access personally identifiable student information without obtaining consent from the parent or eligible student. The holder of the record may release the records to the researcher under the following conditions:

• The researcher is conducting studies for or on behalf of the school or district (34 CFR 99.31(a)(6))
• The information is identified by the school within its Directory Information policy (34 CFR 99.31(a)(11)) (see each school’s Directory Information Policy for more information).

Consent is not required if the information requested for release is not personally identifiable (therefore has been stripped of any identifying information).

Individuals who are employed by schools or universities in one role (e.g., teacher, administrator, superintendent, academic advisor) and who are conducting research as part of their graduate level coursework (e.g., master’s thesis or dissertation) must abide by FERPA when seeking to access personally identifiable student information. In other words, for the purposes of accessing student information as a researcher, they must ensure that they seek parent or eligible student consent or that they are able to access the information as the result of one of the aforementioned exceptions. They may not use their access through their employment in order to obtain personally identifiable information.

PPRA Role in Research Supported by Department of Education

USC Office of Compliance and outside legal counsel have determined that there is no IRB role in applying the Protection of Pupil Rights Amendment (PPRA) to human subjects research. Complying with PPRA is the responsibility of the school system/district (per internal communication dated 3/20/14).

It is the responsibility of the researcher/school that research funded by the Department of Education complies with additional protections under the Protection of Pupil Rights Amendment (PPRA) (34 CFR Part 98).

Schools and contractors must obtain prior written parental consent before minor students are required to participate in any survey, analysis, or evaluation funded by the Department of Education.

Research Supported by the Department of Defense (DOD)

Research supported by or in collaboration with the Department of Defense (DOD) is subject to additional regulations. The DOD has adopted 45 CFR 46, Subpart D with the following modification:

• The DOD does not apply Subpart D to active duty personnel under the age of 18 as it considers all active duty military to be adults with legal capacity to participate in DOD supported research.

Because incarceration affects a person’s ability to make a truly voluntary decision whether or not to participate in a research project, state and federal regulations provide additional safeguards for the protection of prisoners in research. If research is supported by or conducted in collaboration with the Department of Defense (DOD), refer to the end of this section for additional DOD regulations.

Research involving prisoners is never exempt from IRB review. Any study that recruits prisoners that does not qualify for expedited review must be reviewed at a fully convened IRB meeting with a prisoner representative present for the discussion and vote of that study protocol. The IRB Chair and/or IRB Associate Directors, and/or IRB Staff ensure a prisoner representative and/or consultant will be present at the meeting.

Apart from their membership on the IRB, the majority of the IRB members (exclusive of prisoner representative) shall have no association with the prison(s) involved in the research being reviewed. If research activities under the jurisdiction of the USC IRB involve prisoners held outside of the state of California, the investigator is responsible for identifying and ensuring compliance with the laws of that state.

Additional PI Responsibilities

Under 28 CFR 512 the Federal Bureau of Prisons places special restrictions on research that takes place in the Bureau of Prisons. The regulations specify additional requirements that must be addressed by the PI to obtain approval for Bureau of Prison based research.

The California Department of Corrections and Rehabilitation (CDCR), Title 15, (California Code of Regulations) requires that research that takes place in the department facilities be submitted by the PI to the departments research advisory committee for review and approval.

It is the investigator’s responsibility to identify and meet these requirements.

Federal Regulations Permit 5 Categories of Research with Prisoners (45 CFR 46.306)

The 5 permitted categories are:

1. 1. 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
   2. 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
   3. Research on conditions particularly affecting prisoners as a class (for example, 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 the Secretary of HHS (through OHRP) has consulted with appropriate experts, including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of their intent to approve such research
   4. 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 the Secretary (through OHRP) has consulted with appropriate experts including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of his intent to approve such research
   5. Waiving the applicability of 45 CFR 46.305(a)(1) and 45 CFR 46.306(a)(2) for certain research conducted or supported by HHS. This is referred to as the Epidemiology Waiver. In specific, for HHS conducted or supported research involving epidemiologic studies: (1) In which the sole purposes are (i) To describe the prevalence or incidence of a disease by identifying all cases, or (ii) To study potential risk factor associations for a disease, and (2) Where the Institution responsible for the conduct of the research certifies to OHRP, acting on behalf of the Secretary, that the IRB approved the research and fulfilled its duties under 45 CFR 46.305(a)(2)-(7) and determined and documented that (i) The research presents no more than minimal risk and no more than inconvenience to the prisoner-subjects, and (ii) Prisoners are not a particular focus of the research. (For more information, refer to: http://www.gpo.gov/fdsys/pkg/FR-2003-06- 20/html/03-15580.htm)

The informed consent form must include additional information for potential subjects regarding the fact that participation or non-participation will have no effect on their duration of incarceration or terms of parole. The IRB must determine whether assent is a requirement for research pertaining to prisoners that are children.

IRB Considerations for Prisoner Subjects (45 CFR 46.305)

When a prisoner is a subject, in addition to the usual criteria for approval, the IRB must find:

1. 1. The research under review represents one of the categories of research permissible under 45 CFR 46.306(a)(2).
   2. Any possible advantages accruing to the prisoner through their participation in the research, when compared to the general living conditions, medical care, quality of food, amenities and opportunity for earnings in the prison, are not of such a magnitude that their ability to weigh the risks of the research against the value of such advantages in the limited choice environment of the prison is impaired
   3. The risks involved in the research are commensurate with risks that would be accepted by non-prisoner volunteers
   4. Procedures for the selection of subjects within the prison are fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners. Unless the PI provides to the IRB justification in writing for following some other procedures, control subjects must be selected randomly from the group of available prisoners who meet the characteristics needed for that particular research project
   5. The consent information is presented in language which is understandable to the subject population
   6. Adequate assurance exists that parole boards will not take into account a prisoner’s participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on their parole
   7. Where the IRB finds there may be a need for follow-up examination or care of subjects after the end of their participation, adequate provision has been made for such examination or care, taking into account the varying lengths of individual prisoners’ sentences. Subjects must be adequately informed of this fact.

If the research is conducted or supported by HHS, the University must certify to the HHS Secretary (through OHRP) that the IRB has approved the research under the HHS regulations for research that involves prisoners as participants. Additionally, the HHS Secretary (through OHRP) must determine that the research meets one of the approvable categories before the research can be initiated. This determination is known as the “OHRP Prisoner Research Certification”.

Helpful Links

• OHRP Guidance on the Involvement of Prisoners in Research:
  http://www.hhs.gov/ohrp/policy/prisoner.html
• OHRP Frequently Asked Questions – Prisoner Research:
  http://answers.hhs.gov/ohrp/categories/1568

Definitions Related to Prisoners as Research Subjects