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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

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model for diversity in clinical trials academic perspective

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

  • Review and Rationale of Policy
  • Recent Up-Dates & Implications
  • Implementation
nih policy on inclusion of women minorities in clinical research
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

nih revitalization act public law pl 103 43
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


VOLUME 1 (Report)

Anna C. Mastroianni, Ruth Faden, and Daniel Federman, Editors

National Academy of Sciences, 1994

Volume 2

(Workshop and Commissioned Papers)

conflict of two policy positions
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
conflict of two policy positions7
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
paradigm shift reframing of issues
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
  • 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.
  • 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.
  • …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.
scientific considerations
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
  • 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
social and ethical considerations
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
  • 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
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

Committee on Understanding the Biology of Sex and Gender Differences

Institute of Medicine

National Academy of Sciences, 2001

health implications of sex differences
Health implications of sex differences
  • Etiology
  • Diagnosis
  • Treatment
  • 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

diseases conditions with greater impact on women
Migraine with aura

Carpal tunnel syndrome

Raynaud’s disease


Gallbladder disease

Irritable bowel syndrome

Interstitial cystitis


Multiple sclerosis

Rhematoid arthritis

Lupus erythematosus

Autoimmune diseases


Diseases/Conditions with greater impact on women

January 2003

updates to inclusion policy
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
nih definition of clinical research
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;

nih definition of clinical research continued
NIH Definition of Clinical Research (continued)

(2)  Epidemiologic and behavioral studies;

(3)  Outcomes research and health services


instructions in phs 398
Instructions in PHS 398
  • Best source of information for investigators
instructions in phs 39826
Instructions in PHS 398
  • Section E: Human Subjects Research
    • Inclusion of Women
    • Inclusion of Minorities
  • Failure to include = Return Application Prior to Review
instructions in phs 39827
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
  • Study question
  • Study design and sample size
    • Diversity only (compliance)
    • Referenced to affected population (science)
    • Subgroup differences (science)
    • Ethnic minority group only?
    • Exclusion criteria
exclusion criteria bias and relevance
Exclusion Criteria: Bias and Relevance
  • Goal
    • Internal validity and relevance
  • Potential for enrollment
    • Willing participants
  • Potential for adherence
    • ‘good’ participants
    • predictable result
exclusion criteria bias and relevance 2
Exclusion Criteria: Bias and Relevance (2)
  • e.g., high body mass index
    • Relevance
    • Feasibility
  • Comorbidities
eligibility issues
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

reaching and retaining the population
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
perceived participant benefits
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

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

  • 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
  • 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
  • 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
determinants of retention
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
  • 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