Model for Diversity in Clinical Trials: Academic Perspective

1. Model for Diversity in Clinical Trials: Academic Perspective Shiriki Kumanyika, PhD, MPH Center for Clinical Epidemiology and Biostatistics Depts of Biostatistics and Epidemiology and Pediatrics (Nutrition) Graduate Program in Public Health Studies NCMHD EXPORT Center for Inner City Health

2. Overview • Review and Rationale of Policy • Recent Up-Dates & Implications • Implementation

3. NIH Policy on Inclusion of Women & Minorities in Clinical Research • Why does NIH have this policy? • Mandated by Congress, 1993 PL 103-43 • Ethical principal of justice and importance of balancing research burdens and benefits • Amended 2001 http://grants.nih.gov/grants/funding/women_min/women_min.htm

4. NIH Revitalization ActPublic Law PL 103-43 • Women and Minorities must be included in all clinical research studies • Women and Minorities must be included in Phase III clinical trials in numbers adequate for valid analysis • Cost is NOT allowed as an acceptable reason for exclusion • NIH to support outreach efforts to recruit and retain women, minorities, and their subpopulations in clinical studies

5. WOMEN AND HEALTH RESEARCH: ETHICALANDLEGALISSUESOFINCLUDINGWOMENINCLINICALSTUDIES VOLUME 1 (Report) Anna C. Mastroianni, Ruth Faden, and Daniel Federman, Editors National Academy of Sciences, 1994 Volume 2 (Workshop and Commissioned Papers)

6. Conflict of two policy positions • Protectionism • Human subjects abuses of the 1950’s and 1960’s • Adverse outcomes in children of women who had taken certain drugs • Mid-70’s regulations to protect against fetal injury

7. Conflict of two policy positions • Access • 1980’s challenges from women’s health groups and AIDS activists that policies were overprotective and overly exclusive • 1990 GAO report--failure to implement 1986 policy on inclusion of women in clinical studies • NIH Revitalization act of 1993 included provision on inclusion of women and members of diverse racial and ethnic groups

8. Paradigm ShiftReframing of Issues • Exclusion to Inclusion • Justice—equal distribution of the benefits of biomedical research • Scientific Issues • Social and Ethical Issues • Legal Considerations • Practical Issues

9. Recommendations • The committee supports the efforts of NIH to establish a registry of clinical studies and recommends that such a registry include information on the participation of women and men and on the racial and ethnic composition of participants in such studies, as well as the research questions addressed, that such information be reasonably accessible to investigators and the public, and that the scope of the studies included in the registry be comprehensive.

10. Recommendations • The committee recommends that NIH work with other federal agencies and departments that conduct clinical research to ensure reporting of all federally funded clinical studies. • The committee further recommends that representatives of NIH initiate discussions with FDA concerning the feasibility of including privately funded studies in such a registry.

11. Recommendations • …ensure that scientific advances in medicine and public health fairly benefit all people, regardless of gender, race, ethnicity, or age. • …justice may require a policy of preferential treatment toward these specific areas in order to remedy a past injustice and to avoid perpetuating that injustice. • Volunteers …should be offered the opportunity to participate without regard to gender, race, ethnicity, or age. Women and men should be enrolled …in a manner that ensures that research yields scientifically generalizable results applicable to both genders.

12. Scientific Considerations • When do responses of men and women differ significantly? • Biological • Psychosocial • Trade-offs between heterogeneity and homogeneity in clinical trials • Argument for exclusion is actually an argument for inclusion

13. Recommendations • Gender differences in drug response should be studied • Investigators should be alert to possible gender issues and design studies accordingly • Investigators should avoid exclusions based on demographic characteristics • Investigators should demonstrate reasonable review of relevant evidence

14. Social and Ethical Considerations • Unconscious biases • influence topics selected • how topics are operationalized • study design • data collection method • participants chosen for inclusion • Male bias and male norm

15. Recommendations • Educational efforts to increase awareness of gender bias… • Continued efforts to encourage women of all racial and ethnic groups to become scientific researchers and assume positions of authority within the scientific hierarchy

16. Conduct research on barriers to participation among women, racial and ethnic groups and the poor • Train initial review groups (IRGs) • Tailor study designs and recruitment and retention efforts • Achieve clarity in informed consent

17. Committee on Understanding the Biology of Sex and Gender Differences Institute of Medicine National Academy of Sciences, 2001

18. Health implications of sex differences • Etiology • Diagnosis • Treatment

19. QUESTIONS • What do we know, and what can we learn about biological sex differences? • Do sex differences matter to health? • In what ways does sex affect health, especially beyond the reproductive system? • How can the study of sex improve women’s health? Institute of Medicine

20. Migraine with aura Carpal tunnel syndrome Raynaud’s disease Esophagitis Gallbladder disease Irritable bowel syndrome Interstitial cystitis Fibromyalgia Multiple sclerosis Rhematoid arthritis Lupus erythematosus Autoimmune diseases Obesity Diseases/Conditions with greater impact on women

21. January 2003 orwh.od.nih.gov/pubs/SMR_Final.pdf

22. Updates to Inclusion Policy • NIH Definition of Clinical Research • New OMB Standards for Data on Ethnicity and Race • Further Clarification about Phase III Clinical Trials

23. NIH Definition of Clinical Research • Patient-oriented research. Research conducted with human subjects … for which an investigator (or colleague) directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. Patient-oriented research includes: (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, and (d) development of new technologies;

24. NIH Definition of Clinical Research (continued) (2)  Epidemiologic and behavioral studies; (3)  Outcomes research and health services research.

25. Instructions in PHS 398 • Best source of information for investigators • http://grants.nih.gov/grants/funding/phs398/phs398.html

26. Instructions in PHS 398 • Section E: Human Subjects Research • Inclusion of Women • Inclusion of Minorities • Failure to include = Return Application Prior to Review

27. Instructions in PHS 398 • Inclusion of Women and Minorities Sections must include: • Subject Selection Criteria & Rationale • Rationale for Any Exclusions • Enrollment dates (start and end) • Outreach Plans for Recruitment • Proposed Composition Using New Tables

28. Implementation • Study question • Study design and sample size • Diversity only (compliance) • Referenced to affected population (science) • Subgroup differences (science) • Ethnic minority group only? • Exclusion criteria

29. Exclusion Criteria: Bias and Relevance • Goal • Internal validity and relevance • Potential for enrollment • Willing participants • Potential for adherence • ‘good’ participants • predictable result

30. Exclusion Criteria: Bias and Relevance (2) • e.g., high body mass index • Relevance • Feasibility • Comorbidities

31. Eligibility Issues • Assessed 235 consecutively diagnosed patients at the Howard University Hospital and Cancer Center (165 women and 70 men) for eligible for cancer treatment trials • 8% were eligible; 60% of those eligible enrolled (n=12) • Disease characteristics excluded patients from the prostate and breast trials Adams-Campbell et al, J Clin Ocol 2004;22:730-734

32. Reaching and retaining the population • Reasons for participation • Feasibility of participation • Outreach • Distrust • Respect/relationships • Literacy • Socioeconomic Status • Demographic differences in subgroups recruited and retained

33. Perceived participant benefits • Tangible outcome of intervention and control conditions (willingness to accept randomization) • Otherwise unavailable or inaccessible services • Curiosity or desire for knowledge • Altruism • Group interactions • Relationship with counselor or case manager • Study incentives

34. Recruitment Annual Review of Public Health 2006;27:1-28

35. Findings • Mass mailing may work for middle and higher SES African Americans • Personal contact may be critical for lower SES, obese populations • Population based sampling will not yield sufficient numbers of minority participants for subgroup analyses • Reactive or passive strategies work best when eligibility is broad; proactive approaches are needed when eligibility is rare

36. Findings • Eligibility constraints may limit recruitment • Community involvement may be more important for retention than for recruitment of African Americans and Latinos • Effectiveness of cultural adaptations, including ethnic matches of staff, is unclear • Community ties may be more important than ethnicity of recruiters

38. Recommendations • Subject compensation for burden • Cultural/linguistic differences • Large geographical areas • Compensate recruiter burden • Competitive salaries for recruiters • Recognize need for recruiters’ community engagement • Value staff; involve in leadership • Involve recruiters in study design • Recognize ‘fall out’ from pressure on faculty

39. Determinants of Retention • Type of benefit • Participation requirements • Logistics • Initial selectivity • Strict inclusion hurdles yield a more narrow group of participants who may be easier to retain • Retention activities

40. Summary • Current guidelines reflect major paradigm shift • NIH hard line on implementation • Some scientific issues are now incorporated into compliance • Creates cost and logistical issues • Effort and resources needed for recruitment and retention may be underestimated