Experiences of Children Enrolled in Pediatric Oncology Research: Implications for Assent

1. Experiences of Children Enrolled in Pediatric Oncology Research: Implications for Assent Yoram Unguru, MD, MS, MA The Herman & Walter Samuelson Children’s Hospital at Sinai Division of Pediatric Hematology/Oncology Johns Hopkins University - Berman Institute of Bioethics

2. DISCLOSURES • None

3. "The good parent does not just nurture to a point of maturation: he is expected to inhibit self-destructive impulses; he is expected to substitute his superior judgment for the short vision of the child; he is expected to use education, persuasion, seduction, and even force and coercion when necessary in the service of producing a healthy and independent adult." Gaylin W. Competence: No longer all or none.  In: Gaylin W and Macklin R eds. Who speaks for the Child: The problems of proxy consent. New York: Plenum Press; 1982, 31.

4. BACKGROUND • Research is a cornerstone of modern medicine • Research agenda is the sine qua non of pediatric cancer • Cancer clinical research trials • Children >>>>> Adults

5. BACKGROUND • Pediatric clinical trials are complex * • Therapeutic misconception

6. WHY IS ASSENT AN IMPORTANT TOPIC? • Birth of assent • History of assent • National Commission + Belmont Report • American Academy of Pediatrics

7. BELMONT • “Because the subject's ability to understand is a function of intelligence, rationality, maturity and language, it is necessary to adapt the presentation of the information to the subject's capacities.” • “Investigators are responsible for ascertaining that the subject has comprehended the information.” • National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, DC: US Government Printing Office.

8. AAP • “[Make] a clinical assessment of [the] patient’s understanding of the situation and the factors influencing how he or she is responding, including whether there is inappropriate pressure to accept testing or therapy.” • Committee on Bioethics, American Academy of Pediatrics. Informed consent, parental permission, and assent in pediatric practice. Pediatrics 1995;95:314-317.

9. BACKGROUND • Subpart D of 45 CFR 46 governs pediatric research (1983) • Assent • “A child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent” • IRBs • “shall determine that adequate provisions are made for soliciting the assent of the children, when in the judgment of the IRB the children are capable of providing assent”

10. PROBLEMS • Vague and unclear • Problems with CFR definition of assent • No specific age limit • Onus is on IRB • Flexible, yet fail to enumerate what is required with too little guidance as to what constitutes a meaningful concept of assent • Kimberely, et al. Variation in Standards of Research Compensation and Child Assent Practices: A Comparison of 69 Institutional Review Board-Approved Informed Permission and Assent Forms for 3 Multicenter Pediatric Clinical Trials. Pediatrics 2006;117:1706-1711. • Whittle, et al. Institutional Review Board Practices Regarding Assent in Pediatric Research. Pediatrics 2004;113:1747-1752.

11. MORE PROBLEMS • Assent in 2009 • No consensus • Government, Prof associations, Assent community • Definition • Age • Participants • Conflict resolution • Assent vs consent • Disclosure • Children’s desires • Assessment • Decision-making model

12. ASSENT  CONSENT • Children’s Views on Their Involvement in Clinical Research • Chappuy H, et al. Ped Blood & Cancer 2008;50:1043-1046 • “To examine the level of children’s understanding of informed consent in clinical trials & factors that may influence these processes” • “Determine children’s understanding of 9 items required in the informed consent document”*

13. ASSENT IN 2009 ASSENT IN 2007

15. BACKGROUND • Components of valid assent • Determine children’s understanding • Preferences for involvement • Children & the therapeutic misconception

16. METHODS • Sample • 7-18 year olds with cancer who have assented to therapeutic clinical trials • Survey instrument (QuAs) • Closed-ended • Open-ended

17. METHODS • Eligibility criteria • Sixty-two children • Documented malignancy • Age 7-18 years • Assented to a COG / PBTC research protocol

18. METHODS • Study Procedure • Semi-structured, private, face-to-face, audio-recorded interviews • Respondents were given a questionnaire identical to the one used by the investigator • Questions were read aloud & children responded orally • Prompts were included to assure understanding • Interviews were transcribed verbatim & verified against the audiotape

19. Research Familiarity Knowledge Awareness Understanding Appreciation Decision-making Decisional priority Types of decisions Role in decision to enroll Preferences / Perceptions Suggestions CHILDREN’S UNDERSTANDING & PREFERENCES for RESEARCH INVOLVEMENT

20. FAMILIARITY & KNOWLEDGE of RESEARCH • Research term • Study • Research • Protocol • Experimental • Trial • Enrollment • Randomization • Consent • Assent • Knowledge of research • Familiarity + being told about different ways to tx illness

21. AWARENESS of RESEARCH • Know tx is considered clinical research • Main reason for study participation is to improve care for future children with cancer • One reason for study participation is to determine effect(s) of tx(s) • Prior to starting tx, signed name to a form • Know that signing name means agreed to participate in a study • Read form • Child / Parent received copy of signed form

22. UNDERSTANDING of RESEARCH • One reason my doctor is giving me the medicines (s)he is, is to compare (figure out) the effects (good & bad) of 2 or more different ways of treating other children who have the same type of illness as mine to see which is better • The treatment I get/got as part of the clinical research was chosen randomly (by chance, like flipping a coin) from 2 or more options • Compared to other treatment for my illness, my study does not have more risks or discomforts (bad things) associated with it • It is proven that the medicines I am getting are the best treatment for my type of illness • By being part of the study, I am helping my doctor learn about my illness & ways to help kids who will get sick like me in the future • I can withdraw (not be part of) from the study anytime my parents or I decide to withdraw

23. APPRECIATION of RESEARCH • Why did you decide to participate in a clinical research study? • My parents told me to • My doctor told me to • My parents & doctor told me to • To get better • To help other children • To help my doctor learn more about illness

24. DECISION-MAKING • Decisional priority • Children’s overall involvement in decisions • Types of decisions • Major or minor • Role in decision to enroll • Very large, Large, Little, Very little, None • Preferences / Perceptions • Info, peer discussions, inclusion in decisions • Suggestions • For improving their role in decision-making

26. RESULTS • Children • Unaware their treatment is clinical research • Limited understanding of research * • Do not understand MD’s explanation * • Personal gain + Altruism * • Pressured to enroll * • Exclusion versus inclusion * • Reluctant to discuss decision-making * • Types of decisions – Minor • Want to make decisions • Desire parental + MD role * • Interested in research

27. Children’s Familiarity with Research Terminology,Research Knowledge, & Elements Comprising Awareness of Research Enrollment (n = 37)

28. RESULTS • HD & GCT greater knowledge (mean=7.6) than “others” (mean=5.0) • HD, CNS, leukemia higher mean understanding (7.8, 7.5, 6.8) than “others” (mean 6.0) • Controlling for age, neither remained sig, p=0.38, p=0.22 • Knowledge, awareness, understanding, & appreciation of research were not significantly associated with gender, protocol phase or type, months since diagnosis, or ongoing versus completed treatment • HD, GCT, leukemia significantly greater awareness(mean=5.5) & appreciation (mean=2.2) than “others” (mean 3.6 & 1.0) • Remained significant when controlling for age, p=0.019, p<0.001

29. CHILDREN’S SUGGESTIONS for IMPROVEMENT • “Talk to me (too)” • No “medicalese” • “Don’t assume” • Be honest / truthful • More choices / details • “Don’t focus on my age” • Offer advice

30. DISCUSSION • Irrespective of age, children with HD, GCT, & leukemia had sig greater awareness & appreciation of research (p=0.019, p<0.001) • ?Outcome-related • ?Altruism • Decisional priority + Pressure to enroll

31. LIMITATIONS • Single investigator-single institution, pilot study • Responses may not reflect actual beliefs, but what children think investigators want them to say • Interviews occurred after children had assented to research enrollment • Findings reflect reports of children only

32. IMPLICATIONS • Clinical trials • Gold standard in pediatric heme/onc • Improve understanding • Greater decision-making role • When appropriate

33. Present me with more choices for treatment in the • beginning. [Things like] Facts & previous outcomes from • treatments they've given. I know decisions sometimes are • needed in a short amount of time, but sometimes you need a • little time to think about what's going to happen - at least • just ask. Just because I am deemed a child because I'm less • than 18, I don't think I should be treated like a full child • when it comes to my health . . . I need doctors' advice, but • sometimes I want to decide & not be written off & treated • like a child because I'm under 18 • 17 year-old

34. LET ASSENT OUT ITS CAGE