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THE COMMITTEE ON HUMAN RESEARCH

UCSF GUIDANCE ON RESEARCH TOPICS AND ISSUES

Vulnerable Subject Populations – Children and Minors in Research
(Revised December 2004, November 2006, February, March 2008)

•	What Comes First – Brief Overview
•	“Children” and “Minors”
•	Rationale for Inclusion of Children in Research
•	Permitted Categories for Research with Children
	•	Assessing Risk: Research vs. Standard of Care
	•	Table of Permitted Categories for Research with Children
	•	Discussion of Permitted Categories Examples
	•	Summary Table on 45 CFR 46, Subpart D: Additional DHHS Protections for Children Involved as Subjects in Research
•	Consent Process and Documentation
	•	Permission from Parents and Assent from Children
	•	Table of “One vs. Both Parents” Permission Requirements
	•	Table of CHR Consent Guidelines for Children by Age Group
	•	Discussion of CHR Consent Guidelines for Children
	•	Exceptions to CHR Consent Guidelines for Children
		•	When One Parent’s Permission Is Sufficient
		•	When Parents Disagree
		•	Waiver of Child’s Assent
		•	Waiver of Parental Permission
	•	Documentation of Permission and Assent
•	Legal Exceptions Permitting Certain Minors to Consent
•	Special Recruitment Considerations
	•	Minimizing Pressure to Participate
	•	Miscellaneous Arrangements
	•	Payment and Reimbursement
•	Difficult Issues
	•	Discovery and Disclosure of Sensitive Information
	•	Enrolling Children in Long-Term Studies
•	Research Involving Children in Educational Settings
•	Glossary
•	Definitions
•	Useful Links and References

What Comes First – Brief Overview

When planning a study that will involve children, the principal investigator (PI) should first consider four main issues:
1. What is the rationale for including children? What unique outcomes, benefits, and risks will come from studying children? Does the study address a condition that particularly affects children?
2. How is the study risk level determined? What are the relevant regulations?
3. How are study procedures different from standard of care for the subjects?
4. What are consent (permission and assent) requirements for the study? Will permission from one or both parents be needed?

Special considerations apply when research involves subjects who are minors (in California, under 18 years of age). Such research is important to obtain accurate data and develop optimal therapies for children. At the same time, children are inherently more vulnerable than adults, and require a higher level of protection.

Federal regulations for research with adult subjects (Title 45-Code of Federal Regulations (CFR)-Part 46) serve as a starting point. Additional special considerations for children are outlined in 45 CFR 46, Subpart D (and 21 CFR 50 for FDA-regulated research) and interpreted by UCSF’s Institutional Review Board (IRB)—the Committee on Human Research (CHR)—as described below.

Research involving children that will be conducted in whole or in part at the Veterans Affairs Medical Center requires VA approval from Washington DC before children may be enrolled. See Working with the VA for more information.

The purpose of these guidelines is to assist investigators in applying for CHR approval to conduct studies involving children.

"Children" and "Minors"

For clarity, these guidelines use the following terminology:

• “Children” are people who have not reached the legal age to consent for treatment or procedures involved in the research. In California , the legal age is usually 18, but there are important exceptions (explained below). Researchers working in other states or countries must learn about local laws governing the legal age of consent for the treatment or procedures involved in the research.
• “Minors” are people under 18 years of age. Because in California some people under 18 years of age can consent for themselves to some research procedures, not all “minors” meet the federal criteria for being “children.”

Both common speech and California law use the terms “children” and “minors” inconsistently. In the great majority of cases people who are “minors” under California law are also “children” under the federal human research regulations. Nevertheless, occasionally the difference is significant, and these guidelines attempt to use the terms consistently as described above.

Researchers working in othere states or countries should consult with their local collaborators and describe to the CHR how their plans to enroll children or minors will comply with local laws and regulations. Researchers may also call the CHR office for help in framing a query to UCSF legal counsel.

Federal Regulations Regarding “Children:” Federal regulations (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.” In other words, who qualifies as a “child” depends on local laws for consent (and not necessarily on local definitions of the word “child”). In California , 18 is the usual age at which 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 (but see below for limitations).

Important Note: Only people who are “children” under the federal regulations are covered by the additional protections described in Subpart D of 45 CFR 46 and 21 CFR 50 (for example, the requirement for permission of one or two parents in addition to assent from the “child.”)

California Law and “Minors:” For research conducted in California , people considered minors or children by California law usually also are considered “children” in the applicable Federal regulations. California law uses both terms to refer to people who are under 18 years of age. For example, California Family Code 6500 defines “minor” as “an individual who is under 18 years of age” and CFC 3402 says a “child” is “an individual who has not attained 18 years of age.” For clarity, these guidelines use “child” for people who meet the federal definition and “minor” for those who are under 18.

“Minors” Who Are Not “Children:” In California , certain people under 18 years of age are legally able to consent for treatments or procedures involved in research. In the terms used in these guidelines, they are minors but not children.

For example, California Family Code 6925 says, “A minor may consent to medical care related to the prevention or treatment of pregnancy.” The minors in a study involving prevention of pregnancy are of legal age to consent to the treatment or procedures involved in the study. Therefore they are not “children” as defined in federal regulations. They can sign their own consent form as if they were adults, and parental permission is not required.

Other examples of people under 18 able to consent to treatment or procedures in California include self-sufficient minors and emancipated minors.

Additional information is provided below in the section titled Legal Exceptions Permitting Certain Minors to Consent.

For definitions of other terms see Definitions near the end of this guideline.

Rationale for Inclusion of Children in Research

As in any human research application, the choice of subject population must be explained. The investigator should analyze what is unique to children in formulating this rationale, as well as in assessing the risks and benefits of the study (see below).

APPLICATION NOTE: The rationale for including children in the study should be described in Part 2-C, Study Background of the CHR application and also the background section of the consent form.

Permitted Categories for Research with Children

Assessing Risk: Research vs. Standard of Care

Federal regulations classify permissible research involving children into four categories, based on degree of risk and type of prospective benefit. These categories are described in relation to “minimal risk.”

	Minimal risk is defined as “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.” [45 CFR 46.102 21 CFR 50.3].
	For an excellent discussion of issues involved in making this assessment, see J. Sugarman’s article, “Determining the Appropriateness of Including Children in Clinical Research,” JAMA 2004; 291(4):494-496.
	Greater than minimal risk is a term used in defining Category 2 [45 CFR 46.405 21 CFR 50.52] and Category 3 [45 CFR 46.406 21 CFR 50.53]. The regulations do not provide any further definition of this term (except for specifying “a minor increase over minimal risk” in regards to Category 3 only). Thus, the protocol should clearly describe the study risks so that the CHR can determine into which category the study fits.
	IMPORTANT NOTE: When assessing risk/benefit level, keep in mind that what constitutes "daily life" or a "routine test” may not be constant over childhood, among children of the same age, or before and after the occurrence of a disease or condition.

Standard of Care: A vital part of the risk/benefit assessment is clarifying what would be standard of care for the subject group(s) and how the research procedures differ from that standard of care. The application should clearly convey this distinction. The consent/assent forms need only discuss in detail procedures (and their risks) that are being done specifically for purposes of the study.

Table of Permitted Categories for Research with Children
The following information is from the US Code of Federal Regulations (CFR) regarding the four permitted categories of research with minors. For complete requirements, see Summary Table on Subpart D, 45 CFR 46 and 21 CFR 50 - Additional DHHS Protections for Children Involved as Subjects in Research

Note: Click on word "Example" below for further discussion in each category

Discussion of Permitted Categories Examples
See here

Summary Table on Subpart D, 45 CFR 46 and 21 CFR 50 - Additional DHHS Protections for Children Involved as Subjects in Research

Consent Process and Documentation

IMPORTANT NOTE: Within this document, “consent” may be used as a generic term for parental “permission” and child’s “assent.”

In research with children, considerations regarding consent—both process and documentation—become more complex than with adult subjects.

Federal regulations do not provide many specifics. They do include parental permission requirements (see Table of Permitted Categories for Research Involving Children above and Table of “One vs. Both Parents” Permission Requirements below). They also charge that “adequate provisions [be] made for soliciting the assent of the children, when in the judgment of the IRB the children are capable of providing assent...[taking] into account the ages, maturity, and psychological state of the children involved” [45 CFR 46.408].

In general, the CHR interprets these regulations according to the Table of CHR Consent Guidelines for Children by Age Group shown below.

Permission from Parents and Assent from Children

For parents or guardians, the term used is permission. In most cases, permission from one or both parents/guardians must be obtained for their child/ward to participate in a research study. Circumstances in which parental permission may be unnecessary or inappropriate are discussed below under Waiver of Parental Permission.

For children/subjects, the term used is assent. Typically, children do not have the legal capacity to consent to participate in research, but children should be involved in the process if they are able to assent (i.e., capable of having a study explained to them and/or reading a simple form about it, and giving verbal or written agreement if they decide to participate in the study.) Circumstances in which a child's assent may be unnecessary or inappropriate are discussed below under Waiver of Child’s Assent.

Table of “One vs. Both Parents” Permission Requirements
(See above “Table of Permitted Categories for Research with Children” for details)

Table of CHR Consent Guidelines for Children by Age Group

The CHR sample consent and assent forms can be adapted for use in most studies, using these guidelines as a basis.

See “Exceptions to CHR Consent Guidelines for Children” for situations where the above requirements or guidelines may be excepted.

APPLICATION NOTE: The CHR relies on the expertise of principal investigators in determining the capability of particular child subject groups and individuals to assent. The PI assumes primary responsibility for making such determinations, both in preparing the CHR application and in carrying out the study upon approval.

Discussion of CHR Consent Guidelines for Children

• Children up to 7 years old: In most cases, children this young will not be able to participate in the assent process, and only a permission form for the parents or legal guardians will be needed.

CONSENT/ASSENT NOTES:

1. This parental permission form should be based on the CHR sample consent forms, referring to the subject throughout as “your child.”

2. The signature line of this form should be preceded by an explanatory statement such as:

“The person being considered for this study is unable to consent for herself/himself because s/he is a child. By signing this form, you are giving permission for your child or ward to participate in the study.”

3. In certain cases, the investigator may deem a child in this age range capable of being involved in the assent process. If so, the PI should make sure the child is given a simple verbal explanation of what will happen to him/her, and that there is documentation on the parental permission form or in the study records that this was done.

• Children 7 to 12 years old: In most cases, children this age will be able to participate in the assent process, using a simplified assent form. A separate, more detailed permission form will be needed for the parents or guardians.

CONSENT/ASSENT NOTES:

1. A very simple assent form is needed here, based on the CHR sample assent form #1 or #2, referring to the subject throughout as “you.” The child should sign the form if possible. If not, the form or study records must still document that verbal assent was obtained.

2. The separate consent/permission form for the parents or guardians should be based on the CHR sample consent forms, referring to the subject throughout as “your child.”

3. The signature line of the parent’s or guardian’s form should be preceded by an explanatory statement such as:

“The person being considered for this study is unable to consent for herself/himself because s/he is a child. By signing this form, you are giving permission for your child or ward to participate in the study.”

• Adolescents 13 to 17 years old: In most cases, adolescents should be fully informed about a study and give assent to their own participation in the research. There are two ways this assent can be documented.

	•	Adolescent Consent Documentation-Option A:
		Option A is usually preferred.
		One form is written for the adolescent subject and the parents or guardians.

CONSENT/ASSENT NOTES:

1. This assent/consent form should use clear, straightforward language (eighth-grade reading level).

2. It should be based on the CHR sample consent forms, referring to the adolescent subject throughout as “you.” Both the adolescent and the parents or guardians are asked to sign this form, with a signature line for the adolescent first.

3. The signature line for parental consent/permission should follow, preceded by an explanatory statement such as:

“The person being considered for this study is legally unable to consent for herself/himself because s/he is a child. By signing this form, you are giving permission for your child or ward to participate in the study.”

• Adolescent Consent Documentation-Option B:
Option B is reserved for studies where Option A is not feasible or appropriate. This option can be used for studies with a very complex protocol and/or involving adolescent subjects whose medical condition demands a simpler form than the adult’s form, even when the adult’s form is written at an eighth-grade level (e.g., see Sample Assent Form #3)

A simplified assent form is written for the adolescents. A separate, more detailed permission form is written for the parents or guardians.

CONSENT/ASSENT NOTES:

1. This adolescent assent form should be simpler than the adult consent form for the same study. (Note that assent forms written for 7-12 year olds are often too simple for adolescents, but can be expanded upon or adapted as appropriate).

2. It should be based on CHR Sample Assent Form #2 or #3, referring to the subject throughout as “you.” Only the adolescent is asked to sign this form.

3. The separate consent/permission form for the parents or guardians should be based on the CHR sample consent forms, referring to the subject throughout as “your child.”

4. The signature line of parent’s or guardian’s form should be preceded by an explanatory statement such as:

“The person being considered for this study is legally unable to consent for herself/himself because s/he is a child. By signing this form, you are giving permission for your child or ward to participate in the study.”

Exceptions to CHR Consent Guidelines for Children

The CHR uses the above guidelines as a basis in reviewing research involving children. But questions may arise related to specific studies or subject groups. The following provides clarification regarding some of the most common issues.

(See “Table of Permitted Categories for Research with Children,” “Table of ‘One vs. Both Parents’ Permission Requirements,” and “Table of CHR Consent Guidelines for Children by Age Group,” above, for requirements and guidelines to which the exceptions below apply.)

When One Parent’s Permission Is Sufficient
For research that falls into risk-benefit Category 1 [45 CFR 46.404 21 CFR 50.51] or 2 [45 CFR 46.405 21 CFR 50.52], the CHR may determine that permission from only one parent is sufficient. The CHR will find that permission of one parent is sufficient unless the nature of the study seems likely to provoke disagreements about participation among two parents, in which case permission from two parents may be required unless one parent is deceased, unknown, incompetent, not reasonably available, or does not have legal responsibility for the custody of the minor. Research that falls into Category 3 [45 CFR 46.406 21 CFR 50.53] or 4 [45 CFR 46.407 21 CFR 50.54] requires permission from both parents, unless one parent is deceased, unknown, incompetent, not reasonably available, or does not have legal responsibility for the custody of the child [45 CFR 46.406 or 407, 21 CFR 50.55(e)].

When there is only one living parent or guardian or one parent has sole custody after a divorce, the PI may determine that single-parent or single-guardian permission is sufficient.

When Parents Disagree
If there are two parents available to give permission but they disagree about allowing their child to participate in the study, the child may not be enrolled unless that disagreement can be resolved. (Note that this applies to all permissible categories. I.e., even if only one parent’s signature is required, when both parents are involved in the decision, they must agree for the child to be enrolled).

Waiver of Child’s Assent
In certain cases, the CHR may consider waiving 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].

Here 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.

APPLICATION NOTE: In such cases, the PI may propose a waiver of child’s assent under 45 CFR 46.408(a) 21 CFR 50.55 or 45 CFR 46.116 21 CFR 50.20 in the CHR application and Minors Supplement.

The CHR’s decision about waiver of assent will depend on the specifics of the study. For example, approval of waiver would be likely for a trial of primary induction therapy for a new malignancy, where there is a real prospect of direct benefit to subjects. But in a “last-ditch” recurrent brain tumor study, where direct benefit is not probable, approval of waiver would be less likely—the CHR would want to ensure that the child could refuse if he/she did not want to participate.

CONSENT/ASSENT NOTES:
• 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.

Waiver of Parental Permission
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). More detailed examples are given below. [45 CFR 46.408]

PARENTAL PERMISSION FOR CHILDREN’S ENROLLMENT CANNOT BE WAIVED FOR FDA-REGULATED STUDIES. Subpart 21 CFR 50 (the FDA version of the “Common Rule”) lacks the provision for waiver of parental permission, because the FDA says it does not oversee studies for which such a waiver is appropriate. Researchers who need to study FDA-regulated articles in selected groups of adolescents should consider the section below titled Legal Exceptions Permitting Certain Minors to Consent.

For non-FDA-regulated studies, the CHR 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]

APPLICATION NOTE: In such cases, the PI may propose a waiver of parental consent/permission under 45 CFR 46.408(c) or 45 CFR 46.116 in the CHR application and Minors Supplement.

The CHR will consider all other requests for waiver of parental permission on a protocol-by-protocol basis.

Examples where parental permission MAY be waived

APPLICATION NOTE: Investigators should address all such consent concerns for research with minors, including arguments for waiver of standard consent procedures, in the CHR Application, Part 8- Consent Process and Inclusion of Minors Supplement, lower boxes.

Documentation of Permission and Assent

Signed parental permission forms should be retained with the study records.

Informing and obtaining assent from children who are deemed capable may be documented in one of several ways (upon approval by the CHR):

1.	Assent form signed by child (e.g., see Adolescent Assent-Option B, Sample Assent Form #3) is retained with the study records.
2.	Assent form signed by person conducting the assent discussion (PI or other study staff member) is retained with the study records.
3.	Certification of discussion/assent signed by person conducting the assent discussion (PI or other study staff member) is:
	•	appended to parental permission form; or
	•	retained separately with the study records.

Legal 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 legal guardian’s consent. However, federal regulations, when interpreted with California legal exceptions, permit some minors to consent to research as follows:

• Emancipated minors
• Self-Sufficient minors
• Care related to the prevention or treatment of pregnancy
• Minors, 12 years or older, seeking care for:
  1. Out-patient mental health treatment or counseling, excluding drugs
  2. Care related to the diagnosis or treatment of reportable infectious, contagious, or communicable/sexually transmitted diseases
  3. Care provided to the victims of sexual assault or rape
  4. 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. ¹

The CHR carefully evaluates all studies targeting subjects under 18 to ensure they are properly protected. With CHR approval, for the above categories a minor should provide consent and sign the consent form just as an adult would, unless the CHR approves a waiver or alteration of the usual consent standards for adults.

While the CHR is not legally required to apply the special protections of Subpart D for children set forth in 45 CFR 46 and 21 CFR 50 for research involving the categories of minors above, the CHR may apply special protections depending on the specific research study.

Further, in certain cases, the CHR may determine that certain groups of minors that otherwise may legally consent should be excluded from a research study in light of potential risks or due to the investigational nature of the trial (e.g., phase I or phase II trials of investigational new drugs or devices).

Finally, even if the CHR approves minor consent for the specific study, the principal investigator must also ensure that any individual minor possesses the mental capacity to understand the risks, benefits and the consequences of the decision to participate in research.

The following information provides greater detail regarding circumstances under which California law combined with Federal regulations permits minors who can consent to medical care and treatment under California state law to enroll in research without permission from a parent or guardian.

Important Note: UCSF researchers enrolling research participants in other states or countries should take care to 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. Researchers working in other states or countries should consult with their local collaborators about applicable laws and regulations. Researchers may also call the CHR office for help in framing a query to UCSF legal counsel.

Examples of Legal Exceptions Permitting Certain Minors to Consent:

Important Note: The California Family Code includes more restrictions and exceptions than can be summarized here. Researchers considering enrolling subjects based on the following examples should consult the relevant sections of the law. Researchers working in other states or countries should consult with their local collaborators and describe to the CHR how their plans to enroll children or minors will comply with laws and regulations. Researchers may also call the CHR office for help in framing a query to UCSF legal counsel.

Under Provisions of the California Family Code:

Special Recruitment Considerations

Minimizing Pressure to Participate

When children are asked to do something by parents, doctors, teachers, or other adult authorities, they often feel implicit pressure to agree. Similar issues with social or peer pressure (e.g., for studies in educational settings) may also arise in recruiting children to participate in research.

APPLICATION NOTE: Investigators should describe how they plan to minimize implicit pressure to participate (CHR Application, Part 7-Recruitment, Section B). As with all consent and assent forms, the freedom to decline participation should be made clear.

Miscellaneous Arrangements

In designing studies involving children, investigators should consider any special arrangements for participation, such as scheduling, parking, and food, and discuss them with parents if appropriate. Though such information is not required, it could be helpful to parents in deciding about or planning for study participation.

Examples of special study arrangements to consider

•	If the subject is to receive a series of procedures or tests, can these be coordinated with school and/or work schedules?
•	Are there siblings who will need childcare or other provisions made?
•	What about transportation and/or parking permits for the facility where the research is being conducted?
•	Will subjects or their family members need snacks or meals during the study?

Payment and Reimbursement

Ethics and regulations: Ethical considerations regarding payment of subjects who participate in studies become even more complex when the research involves children. The regulations offer no specific guidance in this regard; IRBs have varying perspectives and policies. The CHR neither encourages nor prohibits payment of children in research studies, but considers such proposals on a case-by-case basis.

General guidelines: When evaluating this issue, the CHR will apply its usual guidelines for Payment of Research Subjects. The CHR will also look closely at certain factors such as age, health, socioeconomic and cultural backgrounds of the subjects to ensure that proposed payment does not constitute undue inducement to participate.

Amounts and recipients of payment: At present, $20-$25 (or the equivalent in tokens of appreciation) per subject visit is commonly offered as payment for studies involving children at UCSF. In most cases, the CHR recommends that payment for study participation be made directly to the subject or to both child and parent(s) at the same time, rather than to the parent(s) alone.

Reimbursement: The CHR considers reimbursement separately from payment, and recommends that study subjects or their families be reimbursed for expenses related to research (e.g., parking, travel, meals) whenever possible.

CONSENT/ASSENT NOTES

•	Types, amounts and schedules of payment or reimbursement should be described in the appropriate section of the consent form.
•	If subjects need to keep receipts in order to be reimbursed, this should be clearly stated.
•	The form should note whether subjects who begin but do not finish a study will be paid on a pro-rated basis.

Difficult Issues

Discovery and Disclosure of Sensitive Information

In the course of research with minors, especially adolescents, investigators may discover sensitive information about subjects that is not related to the study itself.
Examples of such information include sexual activity, STDs, use of illegal substances, HIV status, cancer, and child abuse.

Confidentiality: Investigators 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 cases, it may be appropriate for the PI to seek an NIH Certificate of Confidentiality (see http://grants.nih.gov/grants/policy/coc/background.htm for information as to whether this is applicable for a particular study).

• As with all UCSF consent forms, complete confidentiality should never be promised. See CHR sample consent forms for recommended wording.

Child Abuse Reporting: Ethical and legal obligations apply whenever child abuse is discovered. Investigators should be aware that, in most cases, the same reporting expectations pertain in research settings as in clinical settings. University researchers may fall into a category of health professionals or others listed as “mandated reporters” under the California Child Abuse and Neglect Reporting Act (California Penal Code 11164-11174.4). Even if the mandated reporter status is not clear, the investigator can make a voluntary report to the appropriate agency.

• 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 (i.e., not anticipated given the study design or subject population), the PI should seek advice from his/her department chair or dean or from the director of the UCSF HRPP, 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. The CHR 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.

APPLICATION NOTE: If relevant, the above issue should be addressed in the CHR application.

Research Involving Children in Educational Settings

When planning studies involving children in educational settings, investigators should consider the following issues:

Obtaining support of educational community: The first step for investigators is to obtain support from the educational community of their target school/subject group. This may include contacting school district officials, the local PTA, and/or the principal of a particular school.

School officials and/or teachers may approve recruitment for a study, but they do not have authority to give permission for participation of individual children in research—only a parent or guardian, with the child’s assent, can do so.

Active vs. implied consent: The CHR is unlikely to approve use of “implied consent” (e.g., a child brings home information about participating in a study at school, and absence of response is considered agreement.) In most cases, obtaining “active consent” via permission and assent procedures appropriate for the subject group(s) is required.

Special recruitment considerations: Particular attention should be paid to recruitment issues such as scheduling, payment, and minimizing pressure to participate, discussed in the section above.

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

Glossary

CHR: Committee on Human Research (UCSF’s IRB)

DHHS: (U.S.) Department of Health and Human Services

FDA: (U.S.) Food and Drug Administration

HRPP: Human Research Protection Program (UCSF)

IRB: Institutional Review Board, mandated by federal regulations

NIH: (U.S.) National Institutes of Health

OPRR: (U.S.) Office for Protection from Research Risks

PI: Principal Investigator (of a research study)

Definitions

The following definitions are from the Code of Federal Regulations on Protection of Human Subjects (45 CFR Part 46.402).

Assent: A child's affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent.

Child: Person who has not attained the legal age for consent to research treatments or procedures, under the applicable law of the jurisdiction in which the research will be conducted. [In California , this legal age is usually 18 years old, but as noted above, some people under the age of 18 may be able to consent for themselves in some circumstances.]

Guardian: An individual who is authorized under applicable state or local law to consent on behalf of a child to general medical care. [In California, a guardian may be a parent, a legally appointed guardian, a guardian ad litem as appointed by a court (this is an individual who may have no relationship to the minor who is appointed by the court to protect and represent the interests of the minor before the court), or others as consistent with an order of a court having jurisdiction over the minor. For wards of a court, usually an order from the judge is required in addition to permission from the person charged with care of the child.]

Minor: See “Child.” [Federal human research regulations refer to “children.” California laws use both “minor” and “child” to refer to people under 18. The CHR guidelines use the federal definition for “child” and use “minor” to refer to people under 18, whether or not they meet the federal definition of “child”]

Parent: A child's biological or adoptive parent.

Permission: The agreement of parent(s) or guardian(s) to the participation of their child or ward in research.

Useful Links and References

U.S. Department of Health and Human Services (DHHS), Code of Federal Regulations, Title 45 Public Welfare, DHHS, National Institutes of Health, Office for Protection from Research Risks, Part 46, Protection of Human Subjects. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.

U.S. Department of Health and Human Services, Office for Human Research Protections, Special Protections for Children as Research Participants. http://www.hhs.gov/ohrp/children/index.html.

National Institutes of Health (NIH) Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects
http://grants1.nih.gov/grants/guide/notice-files/not98-024.html.

U.S. Food and Drug Administration (FDA): Guidance for Institutional Review Boards and Clinical Investigators http://www.fda.gov/oc/ohrt/irbs/default.htm ; Office of Pediatric Therapeutics http://www.fda.gov/oc/opt/default.htm ; Pediatric Advisory Committee (PAC) http://www.fda.gov/oc/advisory/OCPedsCharter.html.

Institute of Medicine, The Ethical Conduct of Clinical Research Involving Children (2004). http://www.nap.edu/books/0309091810/html.

U.S. Department of Health and Human Services, Office for Protection from Research Risks, Institutional Review Board Guidebook, Chap. 6, C. Children and Minors. http://www.med.umich.edu/irbmed/OPRR-IRBguidebook/chapter6.htm.

Sugarman J. Determining the appropriateness of including children in clinical research. JAMA 2004; 291(4):494-496.

Kodish E, Eder M, Noo R, Ruccione K, Lange B, Angiolillo A, Pentz R, Zyzanski S, Siminoff L, Drotar D. Communication of randomization in childhood leukemia trials. JAMA 2004; 291(4): 470-475.

Wendler D, Rackoff JE, Emanuel EJ. The ethics of paying for children’s participation in research. J Pediatrics 2002; 141(2):166-171.

Dorn L, Susman E, Fletcher J. Informed consent in children and adolescents: age, maturation and psychological state. J Adolesc Health 1995; 16:185-190.

University of California, Los Angeles IRB web site: http://www.oprs.ucla.edu/human/DEFAULT.htm.

University of California, San Diego IRB web site: http://irb.ucsd.edu/.

University of Minnesota IRB web site: http://www.irb.umn.edu/.

¹ Unless the principal investigator obtains a Certificate of Confidentiality, the minor’s parents or legal guardians may obtain medical information relating to the minor’s drug or alcohol abuse care even if the minor objects.