Camila Flaksberg Chevis Undergraduate medical student from UNICAMP Campinas - Brazil

1. Ethical issues including children in prospective population-based cohort studies – an undergraduate medical student perspective Camila FlaksbergChevis Undergraduate medical studentfrom UNICAMP Campinas - Brazil

2. Background • Large prospective pediatric cohort studies are being created to help untangle the interactions between genes and environment that underlie common and complex diseases • These studies raise the concern of guaranteeing long-term contact with the families involved • In most cases, the children involved are healthy and growing up during the ongoing study • These features contribute to the scientific value of cohort studies and are the sources of legal and ethical concerns

3. Background • The overall ethical issues raise questions concerning the patient, their family and siblings • There is little consensus regarding these issues in the current literature • Pivotal motivation: a postgraduate thesis using 10.000 Guthrie cards from newborn screening to analyze the prevalence of the R337H P53 mutation in normal babies and correlate with adrenal cortical tumors patients

4. Objective • To review the literature data focusing on ethical aspects concerning: • Newborn screening for genes related to childhood cancer • Use of newborn biobank specimens for future research • Children’s participation in prospective cohort studies • Communication of diagnosis to the family and siblings

5. Methods • A selected review from the literature using the key words: newborn screening, biobank, ethical issues, genetic counseling, parental consent, assent, communication of results • Articles concerning adults patients were excluded.

6. Literature data • 39 articles were selected: • 19 complete discussions about ethical issues on involving children in prospective studies • 11 discussions about the ethical issues involved on the Newborn Screening Programs, storage and further use of the Guthrie cards • 3 guidelines reviews: 2 concerning biological sample collection form minors and one about reporting genetic results • 1 recommendation from Newborn Screening Task Force • 1 Federal Regulation from USA (45 CFR 46) about parental consent • 4 cohort studies involving children

7. Discussion 1) Biobank storage and use of neonatal blood samples for research Current practices among US newborn screening programs: • In 74.5% of programs, parents are notified but not asked for consent before collection of the sample • 19.6% neither notify parents nor obtain consent before screening • 70.6% of programs retain residual blood samples • 49.0% of programs aggregate data for research. In 16.0% of these, the data are publicly available (Mandl et al, Pediatrics, 2002)

8. Biobank storage and use of neonatal blood samples for research Blood spots collected in screening could be used to provide epidemiological information about genetic predisposition to late onset disorders; care must be taken to ensure that such testing remains anonymous (WHO, 1995; cited by Norgaard-Pedersen B, SimonsenH. 1999, ActaPaediatrSuppl )

9. Biobank storage and use of neonatal blood samples for research The Newborn Screening Task Force supported the permission for the use of anonymized samples from Newborn Screening Program for research and recommended that Newborn Screening Programs should establish a formal policy for the storage of residual bloodspots (American Academy of Pediatrics. 2000, Pediatrics)

10. Anonymization • Anonymizationof genetic information does not completely mask identity • Researchers could identify individuals within anonymizeddata sets having a small amount of identified genetic information for reference, using a specific genotyping method (Homer N, et al. 2008, PLoS Genet )

11. Informed consent • Stored newborn blood spots may be used subsequently for research without consent only if samples are anonymous • (Danish Council of Ethics, 1993; cited by Norgaard-Pedersen B, SimonsenH. 1999, ActaPaediatrSuppl ) • A USA Federal Regulation (45 CFR 46) allow newborn screening samples to be used in research without informed parental consent if the samples are anonymized • (Protection of Human Subjects § 46.101(b)(4), 45 CFR 46 (2009))

12. Discussion 2)The involvement of children in prospective studies concerning their growth and development Analysis of six birth cohort studies in North America and Europe (Ries, MN.2010, BMC Med Ethics) • All studies required initial consent from the mother but the breadth of consent varied across the six studies • Although almost all studies hadn’t established an assent policy, in practice,adolescents were often asked for consent in different moments of life

13. Assentandconsent • Researchers must develop procedures for seeking assent and consent from individual participants as they mature and become capable of expressing their own preferences and making autonomous choices(Ries, NM. 2007, Health Law Journal) • Four reasons why assent is important (Diekema, DS. 2003, Am J Bioethics): • giving children the opportunity to assent to research treats them with dignity and respect • benefits children’s development as autonomous individuals • the process of obtaining assent from children reminds parents and researchers that children are persons with interests • seeking consent sets an example for children to treat others with respect

14. Assentandconsent • Empirical studies suggest that psychosocial maturity to understand the nature of research activities and the rights of research subjects develops by age 7 to 10, and by age 14 to 16 an adolescent’s capacity is generally the same as an adult’s (Ries, NM. 2007, Health Law Journal) • The acquisition of the ability to understand and decidedepends on the age, mental abilities of children and also on the nature of the study (Singh M, Madhusudan. 2012, J Postgrad Med EduRes)

15. Guidelines and Position Papers • A systematic review of guidelines and position papers (Hens et al. 2009, Journal of Human Genetics ) revealed that: • All documents mentioned the need of special requirements when samples originate from children, including specific consentand assent • It is reasonable to recontact minors and give them the opportunity to withdraw their data, although the guidelines reviewed remain vague regarding what’s the criterion for when to do it

16. The degree of risk and benefit • In research involving children, the degree of risk and benefit is critical in determining if their participation, based on parental consent, is ethically acceptable. Indeed, it is debatable whether a parent can permit their child to participate in research involving anything more than minimal or low risk where the research is of no direct benefit to the child • This raises the problem of identifying the type and magnitude of risk to which a child is exposed (Ries, NM. 2007, Health Law Journal)

17. Discussion 3) Communicatingresultstothechild, familyand siblings Focus groups were asked about some concerns of including children in large cohort studies, including returning research results (Kaufman et al. 2008, Am J Med Genet ) • The majority of the focus groups members agreed that some or all of the study results pertaining to children should be provided to their parents • Some people felt that they would only like to receive personal results from the study when the result had some clinical utility • Some participants questioned whether individual genetic results related to late-onset diseases should be returned to children at all

18. Communicatingresultstothechild, familyand siblings • International Ethics Guidelines agree that results should be returned to research participants only if they meet the requirements of scientific validity, clinical significance and benefit, such as prevention or treatment measures • Results should not be offered without an effective mechanism to provide immediate support (Knoppers BM et al. 2006, Eur J Hum Genet)

19. Communicatingresultstothechild, familyand siblings • As children mature and researchers provide opportunities for them to give assent/consent to continuing participation, should them give the child options for receiving information about themselves, including information taken in infancy and early childhood? How?

20. Conclusions • Every study involving children require a clear and complete informed consent from parents • Before the beginning of the study, specific policies regarding the possibility of getting the child’s consent at determinate time should be discussed • Every study must consider before returning resultsthe existing information about having a disease-susceptibility gene, including risk, age of onset, health implications, morbidity, mortality and availability of proven therapeutic or preventive interventions

21. Conclusions • More discussion and international standards are required on ethical issues involved in genetic research in order to homogenize studies’ practices and permit the most proper protection of children, parents and families involved, minimizing any potential risks • Meanwhile each study should report its own approaches and assure that everything is precisely exposed in paper and directly to the subjects Nothing should remain implicit.

22. Future challenges • What is “minimum/low risk”? What are the “risks” that parents can allow their children to be exposed during a study? • When is the moment to ask for children assent? • Age? Mental ability? • Should children have access to information about themselves? When? How?

23. Future challenges • What are the responsibilities after returning results? • Therapeutic and psychological support • Follow up: To whom it concern? • How to deal with relatives after returning results? • Reproductive implications

24. Thankyou for theopportunity email: ca_chevis@hotmail.com