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

1. The Ethical Conduct of Clinical Research Involving ChildrenInstitute of Medicine, National Academy of Sciences, 2004 Robert M. Nelson, M.D., Ph.D. Associate Professor of Anesthesia and Pediatrics The Children’s Hospital of Philadelphia University of Pennsylvania FDA Pediatric Advisory Subcommittee, June 9, 2004

2. Arthur Beaudet, MD Russell Chesney, MD F. Sessions Cole, III, MD Deborah Dokken, MPA Celia Fisher, PhD Angela Holder, JD, LLM Marilyn Field, PhD Study Director Loretta Kopelman, PhD Susan Kornetsky, MPH, CIP Robert Nelson, MD, PhD David Poplack, MD Bonnie Ramsey, MD Diane Scott-Jones, PhD Stephen Spielberg, MD, PhD Alan Fleischman, MD Expert Adviser Study CommitteeRichard Behrman, JD, MD, Chair

3. Study Process 5 Committee meetings between January 2003 and November 2003 Public meetings with professional societies, advocacy groups, and parents and adolescents Outside review: Dec 2003 - Feb 2004 Public release: March 25, 2004

4. Facing a Dilemma • “Those who care about and for children currently face a dilemma. We want children to benefit from the dramatic and accelerating rate of progress in medical care that is fueled by scientific research. At the same time, we do not want to place any children at risk of being harmed by participating in such research, even though their very involvement may be essential to improving the overall medical care of children. …The concern is how best to balance these potentially conflicting objectives.” Preface, Ethical Conduct of Clinical Research Involving Children (IOM 2004)

5. The Charge to the IOM • Review regulations, reports, research; recommend desirable practices in clinical research with children • Specific topics were: • appropriateness of regulations for children of various ages • interpretation of regulatory criteria for approving research • processes for securing parents' and children's agreement to child's participation in research • expectations and comprehension of children and parents about participating in research • appropriateness of payment for child's research participation • compliance with and enforcement of federal regulations • unique roles and responsibilities of IRBs Best Pharmaceuticals for Children Act of 2002 (P.L. 107-109)

6. Three Broad Themes - 1 • Well-designed and well-executed clinical research involving children is essential to improve the health of future children-and future adults-in the United States and worldwide. Ethical Conduct of Clinical Research Involving Children (IOM 2004)

7. Three Broad Themes - 2 • A robust system for protecting human research participants in general is a necessary foundation for protecting child research participants in particular. Ethical Conduct of Clinical Research Involving Children (IOM 2004)

8. Three Broad Themes - 3 • Effective implementation of policies to protect child participants in research requires appropriate expertise in child health at all stages in the design, review, and conduct of such research. Ethical Conduct of Clinical Research Involving Children (IOM 2004)

9. Summary Statement • The federal regulations…for child participants are, in general, appropriate for children of different ages. • The problems with the regulations relate to • insufficient government guidance about their interpretation and implementation • shortfalls in data about implementation and compliance • variability in investigator and IRB interpretations of the criteria for approving research involving children. • Some criteria include inherently subjective elements that would not be substantially and predictably clarified by revising the regulations. Ethical Conduct of Clinical Research Involving Children (IOM 2004)

10. Selected Recommendations • Interpretation and Application of Regulations (Subpart D) • Parental Permission and Child Assent • Payments (subjects, investigators) • Regulatory Compliance • Responsible Conduct of Research (i.e., System Improvements

11. Definition: Minimal Risk • the probability and magnitude of harm or discomfort anticipated in the research are not greater ... than those ordinarily encountered in daily life or ... [in] routine physical or psychological examinations or tests. 45 CFR §46.102(i)

12. Interpretation of Minimal Risk • In evaluating potential harms or discomfort posed by a research protocol that includes children… • interpret minimal risk in relation to the normal experiences of average, healthy, normal children • focus on equivalence of potential harms or discomfort anticipated in research with harms or discomfort that average, healthy, normal children may encounter in daily lives or experience in routine physical or psychological examinations or tests • consider risk of harms or discomfort in relation to ages of children to be studied • assess duration, probability and magnitude of potential harms or discomfort in determining level of risk Recommendation 4.1 (IOM, 2004)

13. Minor Increase Over Minimal Risk In evaluating risks of research involving children with a disorder or condition but no prospect of direct benefit • Interpret minor increase over minimal risk to mean slight increase in potential for harm beyond minimal risk (as defined in relation to normal, healthy children) Recomendation 4.2 (IOM, 2004)

14. Interpretation of Condition • The term condition should be interpreted as referring to a specific (or a set of specific) physical, psychological, neurodevelopmental, or social characteristic(s) that an established body of scientific evidence or clinical knowledge has shown to negatively affect children's health and well-being or to increase their risk of developing a health problem in the future. Recommendation 4.3 (IOM, 2004)

15. FDA Ethics Working Group Consensus Statement • “In general, pediatric studies should be conducted in subjects who may benefit from participation in the trial. Usually this implies the subject has or is susceptible to the disease under study. The Advisory Subcommittee utilized a broad definition of potential benefit. For example, any child has the potential to benefit from a treatment for otitis media.” FDA Pediatric Advisory Subcommittee, September 15, 1999

16. Need for Federal Guidance • SACHRP should… develop additional consensus descriptions of interventions that present minimal risk or no more than a minor increase over minimal risk • OHRP and FDA should cooperate to develop and disseminate guidance and examples… to clarify important regulatory concepts and definitions (including minimal risk, minor increase over minimal risk, condition, and prospect of direct benefit) Recommendation 4.5 (IOM, 2004)

17. Component Analysis of Risk • IRBs should assess the potential harms and benefits of each intervention or procedure in a pediatric protocol to determine whether each conforms to the regulatory criteria for approving research involving children. When some procedures present the prospect of direct benefit and others do not, the potential benefits from one component of the research should not be held to offset or justify the risks presented by another. Recommendation 4.6 (IOM, 2004)

18. Choice of Control Group • “For research involving children and a placebo control group to be approved by an IRB under federal regulations, either • (1) the balance of potential harms and benefits for children in the placebo control arm must be as favorable as those for children receiving the active, standard treatment or • (2) the potential harms to which children in the placebo control arm would be exposed are no more than minimal or involve only a minor increase over minimal risk.” Ethical Conduct of Clinical Research Involving Children (IOM 2004)

19. ICH: Choice of Control Group Placebo controls may be used if… • No serious harm of withholding effective treatment (or) … • Serious harm: “death or irreversible morbidity” • Effective treatment has severe toxicity • Voluntary and informed consent required • Noncoercive setting and patients fully informed ICH E-10 Section 2.1.3 Ethical Issues (July 2000)

20. Selected Recommendations • Interpretation and Application of Regulations (Subpart D) • Parental Permission and Child Assent • Payments (subjects, investigators) • Regulatory Compliance • Responsible Conduct of Research (i.e., System Improvements

21. Waiving Parental Permission • IRBs should consider waiving parental permission for adolescent research participation when research… • is important to adolescent health and well-being and cannot reasonably or practically be carried out without waiver or • involves treatments that state laws permit adolescents to receive without parental permission and evidence exists that adolescents capable of understanding and • appropriate safeguards included to protect interests of adolescent consistent with risk presented by research Recommendation 5.4 (IOM, 2004)

22. Harmonization of FDA and HHS Regulations • FDA should adopt policies consistent with federal regulations at 45 CFR 46.408(c) that allow IRBs with appropriate expertise to waive requirements for parental permission in research, provided that additional, appropriate safeguards are in place to protect the child's or the adolescent's welfare. Recommendation 5.5 (IOM, 2004)

23. Selected Recommendations • Interpretation and Application of Regulations (Subpart D) • Parental Permission and Child Assent • Payments (subjects, investigators) • Regulatory Compliance • Responsible Conduct of Research (i.e., System Improvements

24. Compensation for Injury • Research organizations and sponsors should pay the medical and rehabilitation costs for children injured as a direct result of research participation, without regard to fault. Consent and permission documents should disclose to parents (and adolescents, if appropriate) the child's right to compensation and the mechanisms for seeking such compensation. Recommendation 6.3 (IOM, 2004)

25. Investigator Payments • Investigators and their staffs may appropriately be reimbursed for the costs associated with conducting research. Payments in the form of finder's fees or bonuses for enrolling a specific number of children or adolescents are unethical and should not be permitted. Recommendation 6.4 (IOM, 2004)

26. Payment to Investigators • Payment to clinical investigators or their institutions should be reasonable and based on work performed by the investigator and the investigator’s staff, not on any other considerations. • When enrollment is particularly challenging, reasonable additional payments may be made to compensate the clinical investigator or institution for time and effort spent on extra recruiting efforts to enroll appropriate research participants. Pharma: Principles For Conduct Of Clinical Trials (2002)

27. Investigator Payments • Secret payments to treating physicians and principal investigators for recruitment…[is] illegal conduct. • No law prohibits payments to doctors for recruiting study subjects, but jury would find practice wrong. • "Even in the absence of an express statutory prohibition on finders' fees, they're problematic." • Sponsors should be able to explain the process they used in deciding how much to pay an investigator, based on anticipated expenses and overhead. James G. Sheehan, Assoc U.S. Attorney, Eastern District PA, 12-11-2003

28. Selected Recommendations • Interpretation and Application of Regulations (Subpart D) • Parental Permission and Child Assent • Payments (subjects, investigators) • Regulatory Compliance • Responsible Conduct of Research (i.e., System Improvements

29. Need for Data • To identify what guidance, education, or other steps are needed to protect child participants in research, DHHS should develop and implement plan for gathering and reporting data on • research involving children, with categorization of studies by relevant section of regulations, and • implementation of regulations governing research involving children, including OHRP and FDA data on inquiries, investigations, and sanctions Recommendation 7.1 (IOM, 2004)

30. Selected Recommendations • Interpretation and Application of Regulations (Subpart D) • Parental Permission and Child Assent • Payments (subjects, investigators) • Regulatory Compliance • Responsible Conduct of Research (i.e., System Improvements

31. Closing the Gaps • Federal law should require that all clinical research involving infants, children and adolescents be conducted under the oversight of a formal program for protecting human participants in research. Recommendation 8.1 (IOM, 2004)

32. Research Revitalization Act of 2004 • Provides statutory authority and requires OHRP to issue unified rule by Jan. 1, 2007 • If OHRP misses Jan 2007 deadline, the “Common Rule“ would apply to all research involving human participants, regardless of the funding source. • Require all “greater than minimal risk” research with human participants gain approval from an accredited IRB, effective Jan. 1, 2008. Sen. Edward M. Kennedy (D-Mass.)

33. Need for IRB Expertise • IRBs reviewing pediatric protocols should have adequate expertise in child health care and research. • at least three individuals with such expertise present (and voting) when pediatric research protocol is reviewed • among them, these individuals should have expertise in • pediatric clinical care and research • psychosocial aspects of child and adolescent health care and research • ethics of research involving children. • When appropriate, IRBs should consult with other child health experts and with parents, children, adolescents, and community members who can provide relevant family or community perspectives Recommendation 8.3 (IOM, 2004)

34. Need for Expertise (cont.) • “This committee…advises that standing pediatric advisory committees and pediatric IRBs include at least one nonscientist, unaffiliated member who can represent explicitly the perspectives of parents and children.” Ethical Conduct of Clinical Research Involving Children (IOM 2004)

35. Multicenter Studies • The federal government, research institutions, research sponsors, and groups of institutional review boards should continue to test and evaluate means to improve the efficiency as well as the quality and consistency of reviews of multicenter studies, including those involving infants, children, and adolescents. Recommendation 8.5 (IOM, 2004)

36. Guidance • OHRP, FDA, NIH, and other agencies with relevant responsibilities that include research involving children should each provide comprehensive, consistent, periodically updated guidance to investigators, IRBs, and others on the interpretation and application of federal regulations for the protection of child participants in research. Recommendation 8.6 (IOM, 2004)

37. 21 CFR 50.54; 45 CFR 46.407 OHRP and FDA should • establish an open and publicly accessible process for reviewing research protocols referred by IRBs under 45 CFR 46.407 and 21 CFR 50.54 • create a standing panel that would meet as needed to consider such proposals • provide detailed guidance on interpretation of federal regulations governing research involving children to reduce unnecessary referrals of protocols Recommendation 8.7 (IOM, 2004)

38. Selected Recommendations • Interpretation and Application of Regulations (Subpart D) • Parental Permission and Child Assent • Payments (subjects, investigators) • Regulatory Compliance • Responsible Conduct of Research (i.e., System Improvements

39. Three Broad Themes • Clinical research is essential to improve the health of future children. • Robust system is necessary for protecting child research participants. • Effective protection requires expertise in child health at all stages in the design, review, and conduct of such research.