The Ethical Conduct of Clinical Research Involving Children Institute of Medicine

1. The Ethical Conduct of Clinical Research Involving Children Institute of Medicine National Academy of Sciences 2004

2. IOM/Academies Reports • Ethical Conduct of Clinical Research Involving Children (2004) • Responsible Research (2003) • Protecting Participants and Facilitating Social and Behavioral Sciences Research (2003) View or purchase at www.nap.edu

3. CONTEXT FOR IOM STUDY • Incentives for pediatric research • 1997 FDA “pediatric exclusivity” • 1998 NIH “inclusion of children” policy • 2002 Best Pharmaceuticals for Children • 2003 Pediatric Research Equity Act • 1997 to 2001: Estimated tripling of children participating in clinical trials • Underscores importance of research protections for children

4. CHARGE TO IOM COMMITTEE • Consider definition of minimal risk for purposes of approving research involving children • Assess appropriateness of regulations for children of different ages • Evaluate regulatory compliance • Consider IRB roles, responsibilities

5. CHARGE (cont’d) • Examine comprehension of parents and children of child’s research participation • Examine process for obtaining parental permission and child assent to research participation • Examine appropriateness of payments to parents or children

6. REGULATORY FRAMEWORK • Common Rule (Subpart A): basic regulations to protect human research participants; developed by DHHS; now applies to 17 agencies • Subpart D: protections for children; also adopted by Dept of Education, CIA, and SSA but not, e.g., HUD, EPA, etc. • FDA: similar but separate regulations

7. REGULATORY FRAMEWORK • Some research that can be approved for adults cannot be approved for children • If research with children involves more than minimal risk, it must (in brief summary) • involve only slightly more risk AND children with disorder/condition AND vitally important have potential for direct benefit OR • knowledge about the disorder/condition OR • be approved by DHHS or FDA (rarely)

8. DEFINITION: Minimal Risk Definition in Subpart A: probability and magnitude of harm or discomfort anticipated in research are not greater . . . than those ordinarily encountered in daily life or . . . [in] routine physical or psychological examinations or tests.

9. DEFINITION: Minimal Risk • Interpretation: What is minimal risk is same for healthy and ill children • It is not acceptable to approve higher risk in research because children to be studied research face higher risk in their daily lives (e.g., unsafe homes) or in their medical care (e.g., painful tests or treatments)

10. APPROPRIATENESS OF REGULATIONS: Recommendations • All research with children should occur under umbrella of formal human research participants program that incorporates the protections of Subpart D. • FDA rules should be consistent with other DHHS rules allowing waiver of parental permission when • Permission not in child’s best interests • Other safeguards in place

11. COMPLIANCE WITH REGULATIONS: Findings • Lack of data—especially on research involving children—make systematic evaluation impossible. • Considerable evidence of inconsistency in interpretation. • Some evidence of inattention to certain aspects of regulations.

12. COMPLIANCE WITH REGULATIONS: Recommendations • Need for more explicit federal guidance to investigators and IRBs to encourage consistency and compliance with Subpart D • Guidance should be easily located on federal & IRB web sites • OHRP, FDA should collect more data to guide education, QI, enforcement

13. COMPREHENSION OF RESEARCH:Findings • Adults—as parents and in their own right—often misunderstand research • Therapeutic misconception: believing purpose of clinical research is to treat rather than gain knowledge • Written information is too complex • Focus is too often on forms not communication

14. COMPREHENSION OF RESEARCH: Findings • Even young children can understand basic information about what will happen in research. • Older adolescents similar to adults in many aspects of understanding. • Education and discussion usually increase understanding.

15. PERMISSION AND ASSENT:Basics Instead of informed consent— • Parents provide permission and • Children, when appropriate, provide their assent (or dissent)

16. Assent is not informed consent Seeking assent is respectful. My daughter will be nine years old and she needs some kind of input in what’s going on. She’s presently in a study and I need for her to be able to understand what she’s getting herself into . . . She’s at the point where she asks a lot of questions. Andrell Vaughn, parent, 2003

17. PERMISSION AND ASSENT: Recommendations • Focus on process not forms It has to be very interactive process. After I was asked this entire list of questions, I began to question my own first response. Just giving a kid a piece of paper--no matter how comprehensible--is not effective. I think the kid needs to be prompted with questions. Sarah, research participant at age 13

18. PERMISSION AND ASSENT: Recommendations • Provide details in protocol on how permission and assent will be sought. • Try to provide written information at 6th grade reading level. • Devise ongoing process for families facing serious, acute illness.

19. Permission as ongoing process There is never enough time in those situations to make an “informed decision.” We signed [the form] because that’s what you do. It’s always at the worst time to be reading this type of material . . . Parents aren’t in control nor is the child. Joseph Lilly, parent, 2003

20. PAYMENTS TO PARENTS OR CHILDREN • Concern: some payments may distort parent’s or child’s decisions and lead to choices that are not in the child’s best interests. • Findings: limited data but evidence of considerable variability in practices • Findings: lack of explicit IRB policies and guidance for investigators

21. PAYMENTS TO PARENTS OR CHILDREN: Recommendations • IRBs should adopt explicit policies on acceptable payment practices. • To equalize access to research participation, IRBs, agencies, sponsors should encourage investigators to accommodate parental work and family commitments.

22. PAYMENTS TO PARENTS OR CHILDREN: Recommendations • Okay: reasonable reimbursement for expenses of being in research • Okay: tokens of appreciation • Scrutinize carefully: payments for child’s time and inconvenience for research w/o prospect of benefit • Never okay: payments to parent or child for increased research risk