Ethical Considerations for Pediatric Clinical Trials

1. Ethical Considerations for Pediatric Clinical Trials William K. Sietsema, PhD Vice President, Regulatory Consulting & Submissions, Kendle International Inc. and Adjunct Professor of Pharmaceutical Sciences, University of Cincinnati College of Pharmacy

2. Topics to be Covered • Concept that children deserve special protection • Assent • Parental permission • Principles of the Belmont Report • Concept of exploitation • Beneficiaries of research: adults versus children • Sequencing adult and pediatric studies • Use of placebo control groups • IRB categories of risk • Investigator payments in pediatric studies • Improving IRB review of pediatric studies • Minimizing distress

3. Children Deserve Special Protection “Social justice requires that distinction be drawn between classes of subjects that ought, and ought not, to participate in any particular kind of research, based on the ability of members of that class to bear burdens and on the appropriateness of placing further burdens on already burdened persons. Thus, it can be considered a matter of social justice that there is an order of preference in the selection of classes of subjects (e.g., adults before children)…” * The Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The National Commission for the Protection Of Human Subjects of Biomedical and Behavioral Research. April 18, 1979

4. But Children Deserve Research, too “Children are both vulnerable subjects in need of protection from research risks and a neglected class that needs better access to the benefits of research”* US Government agrees to need for research as evidenced by passing of: • PREA • BPCA *Eric Kodish, MD, Rainbow Center for Pediatric Ethics

5. Assent • “…a child’s affirmative agreement to participate in a clinical investigation. Mere failure to object may not, absent affirmative agreement, be construed as assent” [21 CFR 50.3(n)] • Only required when IRB judges that the children involved are capable of assenting • IRB takes into account in making that determination: • Age • Maturity • Psychological state • Determination can be made for all children in a trial or individually • IRB determines whether and how assent is documented 21 CFR 50.55

6. When Assent is Not Required • Capability of the subjects to understand is limited • Generally, below the age of 7 • Intervention holds out prospect of direct benefit and is only available in the clinical trial • Parental permission is still required 21 CFR 50.55 and Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations. Committee on Drugs. American Academy of Pediatrics. Pediatrics 95:286-294 (1995)

7. When Assent May be Waived by IRB • The investigation is considered minimal risk • The waiver will not adversely affect the rights and welfare of the subjects • The investigation could not be conducted without the waiver • When appropriate, subjects will be provided with additional pertinent information after participation • Consent is still required 21 CFR 50.55

8. Basis of Assent, Belmont Report “Special provision may need to be made when comprehension is severely limited --- for example, by conditions of immaturity or mental disability. Each class of subjects that one might consider as incompetent (e.g., infants and young children…) should be considered on its own terms. Even for these persons, however, respect requires giving them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections of these subjects to involvement should be honored, unless the research entails providing them a therapy unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to protect the subjects from harm.” * The Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The National Commission for the Protection Of Human Subjects of Biomedical and Behavioral Research. April 18, 1979

9. Benefits of Assent to Child • Assent reminds us that children should be treated with dignity and respect • Permitting children a shared role in decision making benefits their development as autonomous individuals • Requirement of assent serves to remind parents and investigators that children are persons with interests and not mere vessels for the purpose of research • An assent requirement offers school-age children the opportunity to learn the meaning of respect for others Diekema DK. Taking Children Seriously: What’s so Important about Assent? American Journal of Bioethics 3(4):25-26 (2003)

10. Parental Consent • For research subjects under the age of 18 in the US • In the US, permission must generally be obtained from both parents • Exceptions for one parent if: • Other parent is deceased • Other parent is unknown • Other parent is incompetent • Other parent not reasonably available • Only one parent has legal custody • IRB may allow permission from only one parent for investigations of minimal risk or where there is prospect for direct benefit 21 CFR 50.55; also see Diekema DS. Conducting Ethical Research in Pediatric Emergency Medicine. Clinical Pediatric Emergency Medicine 4:273-284 (2003)

11. Basis of Parental Consent, Belmont Report “…not every human being is capable of self-determination. The capacity for self-determination matures during an individual's life… Respect for the immature and the incapacitated may require protecting them as they mature or while they are incapacitated.” * The Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The National Commission for the Protection Of Human Subjects of Biomedical and Behavioral Research. April 18, 1979

12. Basis of Parental Consent,25 Years After Belmont Report Dr. Schwetz: As another vulnerable group, do you think it is appropriate for us today to be encouraging that research will be done in children so that we have drugs that have data that would allow their safe use in children? Dr. Height: I certainly do, but I also think this is all the more reason why we need to be conscious of the importance of having surrogates who are responsible, people who help make responsible decisions for children. I think this is where we lie with children, a need to make sure of those who are speaking for them are responsibly informed. * From an interview of Dr. Dorothy I. Height, Belmont Oral History Project, June 30, 2004

13. Waiver of Parental Consent • 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 • Special considerations needed for emancipated minors, “mature minors”, and parents under the age of 18 and vary by state Ethical Conduct of Clinical Research Involving Children, Recommendation 5.4 (IOM 2004) and Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations. American Academy of Pediatrics. Pediatrics 95:286-294 (1995)

14. Concept of Exploitation • Are children being exploited in some international settings? • When trials are being conducted in one location because they could not be conducted elsewhere? • When there is no intention to make the therapy available to the population in which the test is being conducted? • When trial might be considered unethical in another country? Silverman HJ, Luce JM, Lanken PN, et al. Recommendations for informed consent forms for critical care clinical trials. Critical Care Medicine 33(4):867-882 (2005).

15. Example of Proposed SurfaxinTM Trial • Treatment of Respiratory Distress Syndrome in premature infants • Cost of treatment in US is $2000+ • Probable death if untreated • Company wanted to conduct placebo-controlled trial in ~325 infants • Could not conduct in US because treatment is generally available and parents would not consent to placebo controlled trial • Trial planned in Latin America, where treatment unaffordable • Following public debate, company agreed not to conduct trial • However, Temple of US FDA defended design on basis that without trial, none of the infants would be treated and even placebo-treated infants would receive better care London AJ. Justice and the Human Development Approach to International Research. Hastings Center Report. January-February 2005

16. Beneficiaries of Research,Adult versus Pediatric • Primarily children, for a drug intended for treating pediatric diseases (e.g. otitis media) • Primarily adults, for a drug intended for treating adult diseases (e.g. hypertension) • Both adults and children, for a drug generally useful for adult and pediatric diseases (e.g. dysmenorrhea)

17. Sequence of Adult and PediatricStudies in Clinical Development • Where intervention may benefit primarily adults or both adults and children, conduct pivotal studies in adults first • Subsequent studies in children only need to establish optimal dose level so placebo may be avoided • This approach not an option if intervention primarily benefits children or if pediatric studies must be first ICH Guidance E11 Clinical Investigation of Medicinal Products in the Paediatric Population

18. Use of Least Vulnerable Population • Don’t use institutionalized children to study intervention in a disease prevalent in non-institutionalized subjects • But use of institutionalized children may be appropriate if disease primarily affects those children and the intervention cannot be studied any other way ICH Guidance E11 Clinical Investigation of Medicinal Products in the Paediatric Population

19. Need for Placebo Controls • Placebo should be avoided in pediatric studies wherever possible • Not at the expense of good science • Poorly controlled study risks not learning from a study and undermines potential benefits • Easier to avoid placebo if adults used to prove efficacy • Placebo controls absolutely unacceptable where risk to the subjects may be mortality or irreversible morbidity • Alternative designs may substitute for placebo control in some circumstances: • Add-on design with SOC as background • Randomized withdrawal designs to minimize time on placebo

20. More on Placebo Controls • Under federal regulations, for an IRB to approve research involving children and an untreated placebo control, requires either: (1) Balance of potential harms and benefits in placebo arm must be as favorable as those for active treatment, or (2) Potential harms in placebo arm are no more than minimal or involve only a minor increase over minimal risk From: Ethical Conduct of Clinical Research Involving Children (IOM 2004)

21. IRB Categories of Risk • Minimal risk (21 CFR 50.51) • Greater than minimal risk with prospect of direct benefit to subjects (21 CFR 50.52) • Greater than minimal risk without prospect of direct benefit to subjects (21 CFR 50.53) • Not otherwise approvable but present opportunity to understand, prevent, or alleviate a serious health problem affecting children (21 CFR 50.54)

22. Minimal Risk Category • Assent required • Permission (consent) of parents or guardians required

23. Greater than Minimal Risk withProspect of Direct Benefit • IRB must find: • Risks are justified by anticipated benefits to the subjects • Relation of anticipated benefit to risk is at least as favorable as that from available alternative approaches • Adequate provisions are made for assent and consent

24. Greater than Minimal Risk with No Prospect of Direct Benefit • IRB must find: • Risk represents a minor increase over minimal risk • Intervention or procedure presents experiences reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations • Intervention or procedure likely to yield generalizable knowledge about condition that is of vital importance to understanding or ameliorating condition • Adequate provisions are made for assent and consent (both parents)

25. Not Otherwise Approvable but May Address Serious Health Problem • May proceed only if: • IRB finds that the research will address a serious health problem affecting children • FDA commissioner, after consultation with experts and following public review: • Agrees with IRB that the research will address a serious health problem affecting children • The investigation will be conducted according to sound ethical principles • That adequate provisions are made for assent and consent (both parents)

26. Ethics of Investigator Payments • Investigators and their staffs appropriately reimbursed for costs of conducting research • Finder's fees or bonuses for enrolling a specific number of children are unethical and should not be permitted. From: Ethical Conduct of Clinical Research Involving Children, Recommendation 6.4 (IOM 2004)

27. Improving Pediatric Expertise of IRBs • IRBs reviewing pediatric studies should have expertise in child health care and research • At least 3 members with pediatric expertise should be present (and voting) when a pediatric research protocol is reviewed and 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 child health experts, parents, children, adolescents, and community members who can provide relevant perspectives • IRBs should include at least one nonscientist, unaffiliated member who can represent explicitly the perspectives of parents and children From: Ethical Conduct of Clinical Research Involving Children, Recommendation 6.4 (IOM 2004)

28. Minimizing Distress • Studies designed by personnel experienced with children • Use of appropriate formulations and routes of administration • Studies designed for pediatric populations, don’t copy adult • Use personnel skilled in pediatric procedures • Physical setting - furniture, activities, toys, food appropriate for age • Use familiar environment where participants normally receive care • Topical anesthesia for placing catheters • Catheters instead of repeated venipunctures • Piggybacking sample collections • If child becomes upset by procedure, researchers should accept this as a valid refusal ICH Guidance E11 Clinical Investigation of Medicinal Products in the Paediatric Population and MRC Ethics Guide. Medical Research Involving Children. 2004. Medical Research Council. London, UK.

29. Summary – From ICH E11 • Vulnerable, requiring special measures to shield from undue risk • Studies properly designed to insure quality and interpretability • Participants expected to benefit except under special circumstances • IRBs approving pediatric research have members knowledgeable in pediatric ethical, clinical, and psychosocial issues • Recruitment free from inducements to parents or children • Compensation to parents/children limited to subsistence and must be approved by IRB • Assent from participant if capable and permission from parents • Use of least vulnerable population in which research can be conducted • Minimize distress by actions and environment ICH Guidance E11 Clinical Investigation of Medicinal Products in the Paediatric Population

30. Acknowledgements I am grateful for contributions from and discussions with the following: • Albert R. Jonsen, PhD, Professor Emeritus of Ethics in Medicine, School of Medicine, University of Washington, Consultant and Lecturer in Bioethics • Douglas S. Diekema, MD, MPH, Department of Pediatrics, Children’s Hospital and Medical Center, Seattle • Enrique Eduardo Rivas-Merelles, Director Regional de Desarrollo Clinico Sanofi Pasteur Mexico