Children in Research

Overview

Research involving children as subjects requires compliance with the Common Rule at 45 CFR 46, Subpart A as well as compliance with 45 CFR 46, Subpart D, Additional Protections for Children Involved as Subjects in Research.  For research that is FDA regulated, investigators must comply with the regulations at 21 CFR 50, Subpart D.

Studies conducted or supported by NIH and/or which involve the use of the Clinical and Translational Research Center (CTRC) must be compliant with the NIH guidelines that require including children when conducting clinical research, unless there is a strong scientific and/or ethical reason for their exclusion.  

Investigators who are considering using child subjects should ask themselves if the proposed research is directly important to the health and well-being of the children, if it will answer a question affecting the health or welfare of children, or whether the study objectives can be met by using adult subjects.  When children will be enrolled, the IRB will consider if the study methods are appropriate and assure that informed consent and assent are being obtained in a manner that is appropriate.  

Definitions

Assent: Affirmative agreement by the child to participate in the research. Note, mere failure to object should not, absent affirmative agreement, be construed as assent.

Children: persons who have not attained the legal age of consent.  In the Commonwealth of Pennsylvania, the legal age of consent is recognized as age 18, with some exceptions.  

Legal Guardian: Person authorized under state law to consent on behalf of the child for general medical care

Minimal risk: 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

Parent: a child’s biological or legally adoptive parent

Permission: Agreement of parent or legal guardian to allow the child to participate in the research

Categories of Child Research

The University of Pittsburgh IRB can choose to approve research that fits into the following categories.  The categories should be considered exclusive of one another and not considered to be in order of ascending risk or decreased acceptability of the research procedures:

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

  • Some examples of minimal risk procedures include obtaining small blood samples, urinalysis, EEGs, minor dietary changes, non-invasive swabbing, and some standard psychological tests.  Studies involving children that are determined to be minimal risk may be eligible for expedited review.  It is important to remember that minimal risk is based on the daily lives of healthy children.  Procedures that are deemed minimal risk in a healthy population may not be deemed minimal risk when considered in a population suffering from a disease or condition.
  • The IRB will determine if the permission of one parent/legal guardian is sufficient for participation in the research approved under this category.

Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects (45 CFR 46.405, 21 CFR 50.52)

  • The risk is justified by the anticipated benefit to the subjects; and
  • The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches
    While many are familiar with determining the prospect of direct benefit, this category extends benefit to studies that include a monitoring procedure that is likely to contribute to the subject's well-being.  Any benefit of monitoring must be an objective of the study and cannot be incidental. The IRB may consider dietary and exercise regimens, psychosocial interventions, (i.e. coping skills, problem solving skills, anger management strategies) or other interventions that contribute to and/or improve the subject’s ongoing well-being to satisfy this category. The determination will weigh the potential contribution to the subject’s well-being against the probability and magnitude of the risks of the intervention.
  • The IRB will determine if the permission of one parent/legal guardian is sufficient for participation in the research approved under this category or if both parents’ permission is necessary.

Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition (45 CFR 46.406, 21 CFR 50.53)

  • The risk represents a minor increase over minimal risk;
  • The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; and
  • The intervention or procedure is likely to yield generalizable knowledge about the subjects' disorder or condition which is of vital importance for the understanding or amelioration of the subjects' disorder or condition
  • Both parents must provide permission for the child to participate in research approved under this category.

In all three cases, the IRB must find that adequate provisions are made for soliciting the permission of parents or guardians and assent of the children as necessary.

If, in reviewing the research, the IRB finds that it cannot approve it under any of the above categories but agrees that the research meets the criteria for IRB approval under the Common Rule and is worthwhile, the IRB can classify the research under the following category and require further review by a panel of experts:

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, 21 CFR 50.54)

  • The research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health and welfare of children;
  • The research will be conducted in accordance with sound ethical principles; and
  • Adequate provisions are made for soliciting assent of the children and permission of their parents or guardians.
  • Both parents must provide permission for the child to participate in research approved under this category.

When the research is federally supported or conducted or subject to FDA regulations, the IRB will contact Department of Health and Human Services (DHHS) to convene the panel of experts.  If the research is not federally supported, conducted or subject to FDA regulations, the IRB will convene the panel of experts, with the majority not being affiliated with the IRB.  The IRB will assist the investigator in addressing any correctable issues prior to the expert panel review and will manage all submissions and correspondence to the expert panel.  

Investigators are cautioned not to view deference to an expert panel as a tacit disapproval of the research.  On the contrary, the IRB chooses this category because it agrees that the research is meritorious.  If the investigator is aware prior to submission to the IRB that the research will require this review, the IRB should be notified through askirb@pitt.edu so that the expert panel can be prepared.

The panel may make any of the following determinations:

  • The research satisfies the criteria under §46.407 and may move forward with Pitt IRB approval in the future
  • The research is approvable under §46.404, §46.405 or §46.406
  • The research does not present a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health and welfare of children and does not fit any of the other categories and therefore cannot be approved.

Parental Permission for Participation

§46.404

Minimal Risk

One or both parents’ permission, as determined by the IRB

§46.405

Greater than minimal risk with prospect of direct benefit

One or both parents’ permission, as determined by the IRB

§46.406

Greater than minimal risk, without prospect of direct benefit, likely to yield general knowledge about the subject’s disease or condition                          

Both parents’ permission required by regulation, when reasonably available

§46.407

Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children

Both parents’ permission required by regulation, when reasonably available

In order to approve research involving children, the IRB must determine that adequate provisions are made for soliciting assent of the children and permission of their parents or legal guardian.      

Because children are often recruited from clinic visits, both parents may not be with the child when the research consent process takes place.  It is up to the investigator to determine if the absent parent is reasonably available.  Generally speaking, a parent that is unknown, incarcerated, uninvolved in the child’s life, deceased, or deployed may be considered “not reasonably available.”  However, context and circumstances need to be very carefully considered.  When attempts are made to contact a parent, the attempts need to be documented in detail, as should the entire consent process.  

Additionally, a parent may have sole legal responsibility for the child.  In such cases, permission from that parent is sufficient for participation but the parent must provide documented proof of the custody arrangements.  A more comprehensive discussion of this concept is given in the Not Reasonably Available Guidance document.

Determining Who Can Provide Permission

Sometimes the most difficult part of obtaining permission is determining who is legally authorized to provide it for a particular child.  Situations may arise where a grandparent or other relative is raising the child and has physical custody but, may not be the child’s court-established legal guardian. Therefore, a copy of the court order naming her or him as the child’s legal guardian with the ability to consent for the child’s medical care must be provided to the study team and filed with the consent form. Courts will often award physical custody to a guardian, but will not extinguish the legal rights of the parents to consent for their child.

If you need assistance in determining whether the court order provided is sufficient, contact the IRB Director of Regulatory Affairs at askirb@pitt.edu for review of the court order prior to obtaining parental permission to insure the individual is authorized.  

While a particular caregiver may not be able to provide the legal permission for the child to participate, it may be appropriate for them to participate in the consent process along with the child and the parent.  Familial relationships should be considered and respected during recruitment, the consent process and throughout the conduct of the research.  


*When in doubt as to whether the provided court order is appropriate, contact the IRB Director of Regulatory Affairs at askirb@pitt.edu for review of the court order prior to obtaining parental permission to insure the individual is authorized. 

Child Assent

Assent is the affirmative agreement of the child to participate in the research.  It is important to note that a child’s mere failure to object does not constitute assent.  While it is the responsibility of the IRB to evaluate the research and determine if assent will be obtained from none, some or all of the child subjects, the investigator must provide adequate information for the IRB to make that decision.  The IRB will take the age, maturity, and psychological state of the children involved into account when making this determination.  This judgment may be made for all children to be involved in given research study, or for each child, as the IRB deems appropriate.

When the IRB determines that assent will be obtained, it is up to the investigator to determine the manner in which it is obtained and to describe the assent process in their IRB application.  Assent may be obtained with the child’s written signature or verbally. The investigator must include the procedures and forms that will be used during the assent process in their IRB application. The assent process must include an explanation of the research procedures using words and visual aids that are appropriate to the child's age, experience, maturity, and condition. In addition, the explanation must include a discussion of any discomforts and inconveniences the child may experience upon participation.

The assent process may be documented in a number of ways. For instance:

  • If the child participant will provide a written signature as part of the assent process this can be accomplished utilizing a separate assent form or through the inclusion of additional signature lines within the document parents will provide parental permission on.
  • If the child participant will provide verbal assent, the study team should document the child’s verbal assent in the research record to include the date and time verbal assent was obtained, any questions or concerns the child expressed during the process, the resolution of those questions and concerns and who obtained the verbal assent from the child.

Link to examples of signature lines that may be need to be included in consent forms

Waiver or Alteration of Parental Permission

The IRB may waive the requirements for obtaining parental or legal guardian permission under the two following provisions:

  1. 45 CFR 46 116.(d) – The IRB may approve a consent procedure which does not include, or which alters or waives the requirements to obtain informed consent provided the IRB finds and documents that

(a) The research involves no more than minimal risk to the subjects;

(b) The waiver or alteration will not adversely affect the rights and welfare of the subjects;

(c) The research could not practicably be carried out without the waiver or alteration; and

(d) Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

Examples of when the use of a waiver under this provision would be appropriate include:

  • When the investigator will not be interacting or intervening with the parent/legal guardian or subject for research purposes (e.g. retrospective specimen or document research).
  • When the investigator will be interacting or intervening with the child subject, obtaining the child’s assent to participate but, will not be obtaining the permission of the parent/legal guardian (e.g. smoking cessation research, drug/alcohol abuse research, research about gender identity or sexual orientation).

Examples of when the use of an alteration under this provision would be appropriate include:

  • When the study will employ an opt-out mechanism for parental/legal guardian permission. This is most commonly seen in research being conducted in schools or after-school programs. In this scenario, the parents/legal guardians are provided with all pertinent information regarding the research study their child is being recruited into.  However, rather than requesting parental/legal guardian signature affirming the parent/legal guardian’s permission for enrollment, the investigator requests that the parent/legal guardian sign and return the document if they do not want their child to participate in the study.

2. 45 CFR 46.408(c) - The IRB determines that a research protocol is designed to study conditions in children or a participant population for which parental/legal guardian permission is not a reasonable requirement to protect the participants and the following 2 additional criteria are also met:

(a) an appropriate mechanism is in place to protect the children, and
(b) the waiver is not inconsistent with federal, state, or local law (45 CFR 46.408(c)).

The choice of an appropriate substitute mechanism (for example, appointing a child advocate or an assent monitor) for protecting children participating in research would depend on the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and the child’s age, maturity, status, and condition.

Examples of when the use of a waiver under this provision would be appropriate include:

  • When the investigator will be interacting or intervening with the child subject, obtaining the child’s assent to participate but, will not be obtaining the permission of the parent/legal guardian because parental/legal guardian consent provides no additional protection or could reduce protection of the child (e.g. research with neglected or abused children).

*Note, the IRB may waive the requirement for obtaining parental/legal guardian permission under 45 CFR 46.408(c) even if the research involves more than minimal risk to the child subjects. If the study team would like to request a waiver of parental/legal guardian permission for a Greater than Minimal risk study under this provision, please consult with the IRB prior to submission your IRB application, by emailing askirb@pitt.edu.

Investigators can request the waiver of parental/legal guardian permission in item 4.7 of OSIRIS.  With the exception noted above, all research procedures covered under a waiver or alteration of parental/legal guardian permission must be minimal risk.

An investigator must justify the following criteria:

(a) The research involves no more than minimal risk to the subjects;

(b) The waiver or alteration will not adversely affect the rights and welfare of the subjects;

(c) The research could not practicably be carried out without the waiver or alteration; and

(d) Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

When justifying the criteria for waiver, investigators should remember that they are being asked how the waiver will affect the child who will be the subject of the research, not the parent/legal guardian.  Note that waivers of parental/legal guardian permission cannot be granted in FDA regulated studies.  

Waiver to Document Parental/Legal Guardian Permission

A waiver to document parental/legal guardian permission can be useful in situations where the research will take place over the phone or in situations where parental permission is required but the parent/legal guardian is not in the physical company of the child who is being enrolled.  Under a waiver to document, the full consent process still takes place but no signature is obtained.  Investigators should document in the research record when and how the consent process took place and that affirmative agreement was given.  

The request for a waiver to document must be reviewed and approved prior to use.  Investigators can request the waiver to document in OSIRIS 4.6 and will be required to justify that one of the following apply. Any scripts or information sheets used in lieu of a consent form must still incorporate the elements of informed consent as set forth in 45 CFR 46.116.

All research procedures covered under the waiver to document must be minimal risk:

1.    The only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality [45 CFR 46.117(c)(1)]; or
2.    The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context [45 CFR 46.117(c)(2)].
 

Children who turn 18 during the course of the study

Children who turn 18 during the course of the study must consent on their own behalf to continue to participate in the research.  This can be accomplished in two ways:  

  • Have the subject sign a new adult version of the consent form
  • Incorporate a “Consent for Continued Participation” section into the original child consent form and have the subject sign this section when they turn 18.

Recruitment Procedures

The age, maturity and psychological state of the children as well as the research topic should be considered when determining whether recruitment efforts should be targeted towards the parent/legal guardian or the child.

For instance, for research involving adolescents it may be appropriate to approach the child subjects first to ascertain their interest prior to approaching the parent/legal guardian.  This ensures that adolescents have time to consider whether they’d like to participate in the study without undue influence from the parent/legal guardian.  If the adolescent agrees that they’d like to move forward, the discussion can then open up to include the parent/legal guardian and obtain parental/legal guardian permission.

For research involving younger children or children with developmental delays, recruitment efforts should be targeted towards the parent/legal guardian. For example, recruitment materials should use language such as “your child” (e.g. Has your child been diagnosed with ADHD? S/he may be eligible to participate in a research study being conducted at the University of Pittsburgh).

Regardless of whether recruitment materials will target the parent/legal guardian or children, advertisements for research involving children are not permitted to contain the dollar amount of compensation to be provided for participation. The advertisement may merely state that compensation for time and travel will be provided.

Enrolling persons under the age of 18 who are not children

The definition of a child is someone who has not reached the age of consent for treatments or procedures involved in the research under the applicable jurisdiction.  A person who does not meet the definition of a child for a research study would not fall under the requirements of 45 CFR 46, Subpart D. 

If it is determined that they do not meet the definition of children, the subjects may be able to consent on their own behalf, requiring no parental permission or waivers, if the research is about any of the following topics:

  • psychiatric conditions
  • sexually transmitted diseases
  • contraception
  • pregnancy

This is not an all-inclusive list and each of these topics must be carefully considered within the context of the research that is being conducted.  In order for a teen to provide consent on their own behalf, all of the research procedures must be procedures that the teen could consent for under Pennsylvania law outside of the research context.

OSIRIS

Section 3, Human Subjects – Question 3.5 addresses the participation of children.  An affirmative answer to question 3.5 triggers a series of questions for justification for the inclusion of children as subjects.  Be prepared to choose and justify a risk category.

Section 4, Subject Recruitment and Informed Consent – Question 4.12 addresses the process that will be used to inform subjects and their parents about the research study.  This section needs to include:

  • how the investigator will determine who is eligible to provide parental/legal guardian permission
  • how the investigators will approach the parent(s) or legal guardian
  • the process of obtaining parental/legal guardian permission
  • how and when the assent process will take place, if applicable
  • how and when the consent to continued participation will take place, if applicable

Other Considerations

Research Involving Wards of the State: Special considerations must be made for research involving wards of the state.  When wards are to be included in research approved under 45 CFR 46.406 and 45 CFR 46.407 or 21 CFR 50.53 and 21 CFR 50.54 the research must be related to their status as wards or conducted in settings (e.g. camps, schools) where the majority of children enrolled are not wards.  Advocates must be appointed for subjects enrolled under these conditions.  

Research Involving Student Records: research of this type may be subject to the Family Educational Rights and Privacy Act (FERPA).  Investigators should refer to the FERPA guidance when using children’s education records.

Online Research Involving Children: Investigators conducting online research with children under the age of 13 must comply with the Children’s Online Privacy Protection Rule (COPPA).  This rule was designed to place parents in control over what information is collected from their children online.

Child Clearances: All research staff interacting with children must have Pennsylvania Department of Public Welfare Child Abuse History Clearance; Pennsylvania State Police Criminal Record Check; and FBI Criminal Background Check prior to their performance of any research procedures

Maintenance of Research Records: Records for research involving children must be kept until the youngest subjects of the research turn 23 years old.

Additional Information

Code of Federal Regulations Part 46, Protection of Human Subjects, Subpart D
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd

Code of Federal Regulations Part 21, Protection of Human Subjects, Subpart D (FDA)
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50

National Institutes of Health Inclusion of Children as Participants in Research Involving Human Subjects
http://grants.nih.gov/grants/funding/children/children.htm

 

 

[version 3.9.2016]