Research Ethics Consultation

1. Research Ethics Consultation Joachim Hallmayer

2. History of research ethics consultation • Clinical ethics consultation in place for over two decades • Informal consultation common • Fairly new service--proposed at Stanford in 2003 and piloted 2005-2008 • Small # • Largely focused on genetics/genomics (NHGRI funded)

3. Covers wide range of activities • Assist in research design (e.g., how to deal with incidental findings) • Help researchers draft responses to funding agency with particular questions • Advise on ethical literature on a topic • Long term examination of a difficult and controversial topic that requires extensive research (e.g., minimal genome, placing human neurons into mice)

4. Need for Consultation • Offers advice on topics and issues not covered by IRB and other bodies • Advise on bench research (non-human subjects) • Large social questions • Collaborative work on research design, often part of grants • Can help provide expertise • Methods of community engagement in research • Knowledge of social science, ethics or legal literature

5. How useful? McCormick et al., PLoS One 2009

6. How useful? • 51% said research ethics consultation would be moderately, very or extremely useful • 60% of human subjects researchers • 47% of non-human subjects researchers McCormick et al., PLoS One 2009

7. Stanford IRB • Ensure compliance with all regulatory requirements • Follow all ORI, OHRP, NIH, HHS, and FDA guidance (shadow regulations) • Beyond regs and shadow regs, rely on investigators to meet ethical standards

8. Time-lag between ethics and regs • New issues identified • New consensus emerges on issue • E.g., incidental findings, returning results • Current model--IRB assumes that investigators are staying up to date on research ethics issues • PI’s assume IRB approval means most key issues addressed (except possibly larger social issues) • Research ethics consultation fills this gap

9. Common Issues • Incidental findings (Ehlers-Danlos Syndrome type IV found in “healthy” sample) • Returning research results • Tissue banking/DNA • Research in less developed nations • Methods of engaging communities in research • Stem Cell Clinical Trials • Race/indigenous peoples/ethnic groups/gender • Research with broad social acceptability issues • Pediatric Research—meaning of “minimal risk”, “prospect of direct benefit” • Pediatric Research—early phase “first in class” trials

14. Case: Reporting Research Results • Study of autism in twins to investigate genetic contributions to the disease • First large study • Psychological and behavioral assessments carried out (not by MDs or licensed clinical psychologists) • Genetic analysis to look for Fragile X, zygosity,

15. Assessments conducted • Autism Diagnostic Observation Schedule (ADOS) • Stanford-Binet Intelligence Scales, Fifth Edition • PPVT-III (for receptive language) • Delis-Kaplan Executive Function System (D-KEFS) • NEPSY Tower Test • Smarties test • Eyes test • Plus tests administered through parents • Autism Diagnostic Interview, Revised (ADI-R) • Vineland Adaptive Behavior Scales (VABS) • Repetitive Behavior Scale, Revised (RBS-R) • Social Reciprocity Scale (SRS)

16. Questions that need to be addressed identified • What needs to be reported to families? • In which form should families be notified of results? Specifically • Do cognitive tests need to be reported to parents? • Should ADI & ADOS results be given to parents? • Should we only report on the affected children? • Should learning disabilities or behavior issues observed during assessment (but not specifically obtained for the purposes of the study) be reported to parents? • What should be done in cases where research/test results differ from parents knowledge? (i.e. if a “typical”child has a low IQ score or scores indicate a diagnosis of autism?) • What information do we give regarding Fragile X or zygosity results?

17. Ethical Issues • 1. Benefit/risk to subjects and families • how can reporting results harm or help families? Results of assessments conducted in the CATS study can: a) affect families’ ability to obtain services for children that require a diagnosis of autism, b) have previously-unrecognized clinical implications (e.g., apparently positive test for Fragile X), c) have reproductive implications, and d) affect parents and childrens’ perception of themselves (and may be disruptive if CATS assessments are discordant with previously obtained tests). • 2. Researcher obligations – • to what extent are the researchers obliged to provide research results to subjects? • 3. Researcher-subject relationship – • will withholding research results disincent prospective subjects from enrolling, or damage existing researcher-subject relationships? • 4. Justice – • do lower-income families participate in this research to gain access to assessments that they would ordinarily not be able to obtain, and would withholding results discourage these families from participating or put these families at a disadvantage in obtaining medical information or services for autistic children?

18. Emerging consensus about returning genetics research results • None of the research results meet criteria for category 1--that is, researchers not obligated to provide research results (the results were not indicative of an immediately life-threatening serious condition for which effective intervention or preventive measures exist)

19. Emerging consensus about returning genetics research results • Assessment results do meet Category 2 • Permissible to return results, not obligatory • Need to use different methods to return results • Ongoing assessment to determine if cases arise that rise to level where returning results obligatory

20. Recommendation 1 • Parents given the option of providing the name of a primary care or other health care provider, to whom preliminary, positive Fragile X test results would be released after confirmation • Parents should be informed in forms and process that the test is conducted for research purposes, and not by a laboratory certified to provide results of clinical tests. • If a positive test result ensues, the identified health care provider obtains another DNA sample for testing by a CLIA-approved • Consent should also include cautions about implications for insurance, employment or adoption.

21. Recommendations • Recommendation 2: The researchers are not obligated to offer the results of zygosity testing (because it does not offer significant clinical benefit) but it would be permissible to offer these results. • Recommendation 3: The researchers are not obligated to offer the results of ADOS and ADI-R tests but that it would be permissible to offer these results. • Recommendation 4: IQ tests test results should be offered in ranges based on clinical utility, such as “normal”, “below normal” and “above normal”, where the normal range was defined based on clinical criteria.

22. Recommendations • Recommendation 5: Test results from methods that have not been established as clinically valid or reliable should not be offered • Recommendation 6: Obtain a certificate of confidentiality from NIH • Recommendation 7: In the informed consent process and forms: • allow parents to opt out of receiving each and all results • inform parents that if researchers do not contact them, this doesn’t mean that all tests gave negative results

23. Recommendations • Recommendation 8: If a child was considered “normal” at enrollment, but one of the study’s assessments indicated an abnormal test result that is clinically relevant, these results should be reviewed by a psychologist [clinically licensed?] and should be offered to the parents. • Recommendation 9: If a child was considered autistic at enrollment, but one of the study’s assessments indicated non-autism or non-ASD, this results should be offered to the parents and not given to health care providers. • Recommendation 10: Learning disabilities or behavioral issues not specifically assessed for the study but observed during the assessment should be verified by the research team and only offered to parents if the observations are reliable and valid and interventions exist.

24. Thanks to David Magnus, PhD Mildred Cho, PhD Stanford University