Opportunities and Challenges for Enrichment of the Diversity Pipeline

1. Opportunities and Challenges for Enrichment of the Diversity Pipeline James R. Gavin III, MD, PhD Clinical Professor of Medicine Emory University School of Medicine President & CEO MicroIslet, Inc.

2. Focus on the diversity issue as it relates to the conduct of clinical trials and clinical research----confronting the challenges and opportunities of enhancing the diversity of both patients and PIs………_ anything less will not drive the improvement in outcomes needed!

3. Minority Representation in Clinical Trials of Recently Approved Drugs • No comprehensive data available! • Current estimates average substantially less <5% in pivotal trials supporting drug safety and efficacy • Trend persists although African Americans are disproportionately affected by most major disease categories • Further shifts in the demographics will make this an increasing rather than decreasing problem

4. Racial/Ethnic Differences in Disease • Clinical trials have demonstrated racial & ethnic differences in the pharmacokinetics of certain drugs • These differences can also determine the biologic course of certain diseases in the face of active treatment programs • These are underestimated contributors to differences in outcomes Johnson JA. Influence of race or ethnicity on pharmacokinetics of certain drugs. J Pharm Sci. 1997;86:1328-33 Kalow W. Interethnic variation of drug metabolism. Trends Pharmacol Sci. 1991;12:102-107

5. Why is Diversity Important in HTN? • This 1998 study revealed conclusive data that pretreatment plasma renin activity is not a reliable indicator of anti-hypertensive response to therapy with an ACE inhibitor in AA patients. Weir MR, et. al. Renin status does no predict the anti-hypertensive response to ACE inhibition in AA’s. Trandolapril Multicenter Study Group. J Hum Hypertens. 1998;12:189-94

6. Why is Diversity Important in Bipolar Disease? • A 1995 study revealed that African Americans may require lower dosages of lithium carbonate in the treatment of bipolar disease. • Their data showed that higher plasma concentrations of lithium in AA subjects vs. C led to an increased incidence of adverse effects to the therapy. Strickland TL, et.al. Comparison of lithium ratio between African-American and Caucasian bipolar patients. Biol Psych. 1995;37:325-330.

7. Genetics and the Case for Diversity • Genetic polymorphisms in metabolic enzymes, receptor expression and drug transport • There are marked polymorphisms between whites, blacks & Asians in adrenergic receptors • Marked differences in CYP450 (CY2D6) responsible for metabolizing β-blockers, tricyclics & codiene • Genetics accounts for up to 95% of drug disposition and effect (Kalow W, et. al. 1998 Pharmacogenetics) • Differences in expression of CYP2C9 responsible for Warfarin metabolism (11% of W vs. 3% of AA)

8. There is clear evidence for diverse behavior of diseases across ethnic groups, often driven by documented biological differences……. Thus, we need the benefit of broader participation of diverse groups in clinical research to evaluate treatment boundaries and natural histories, but there are challenges beyond biology------

9. Historical Challenges to Diversity • Pre-& Post-Civil War medical experiments • AA grave robbery for medical schools • 1932 US Public Health Service Syphilis Study • 1944 Illinois prisoners given malaria • 1970 Willowbrook experiments • 1970’s Mexican Am. Women BCP experiments

10. Understanding the Breach of Trust • Cultural mistrust between AA’s and white’s pre-dates the Syphilis Study • AA mistrust of government institutions • The negative impact of segregation • A two tiered system within healthcare institutions • Lack of access to culturally sensitive healthcare providers

11. Barriers to African American Patient Participation in Clinical Trials • Distrust of medical research • Lower inclusion of AA physicians in clinical research • Lack of MD recommendation • Less access to healthcare • Socioeconomic obstacles • Perceived & actual patient compliance issues • Oversight by sponsors (never saw need)

12. FDA Ethnicity Guidelines • Sponsors required to present analysis of data on demographic subgroups • 2001 Clinical Studies of Labeling • 2000 Content & Format of Adverse Rxns • 1999 Population Pharmacokinetics • 1998 FDA demographic rule • 1993 Refusal to File Option

13. Barriers to African-American MD Participation in Clinical Trials • Lack of clinical trials experience • Provider compliance issues • Researcher’s beliefs and biases • Lower MD/patient ratios • Lack of information about clinical research • Concern about loss of patients • Lack of financial (& other) resources

14. The pipeline for enrichment of the diversity in the Patient population is directly linked to the pipeline of Providers________ A strategic focus on increasing the representation of underrepresented minority investigators must be embraced as the rate-limiting step in assuring the required diversity in clinical research/ clinical trials

15. The Connection Between PI & Patient • Minority MD’s are more likely to care for minority patients. • Minority MD’s provide a disproportionate amount of care to minorities, poor & medicaid recipients Gray B, et al. Patient-physician pairing: Does racial and ethnic congruity influence selection of a regular physician? J Comm Health 1997;22(4): 247-59. Saha S, et al. Do patients choose physicians of their own race? Health Aff (Millwood) 2000;19(4): 76-83. Komaroumy M, et al. The role of Black and Hispanic physicians in providing healthcare for underserved populations. N Engl J Med 1996; 334(20): 1305-10

16. Minority physicians tend to care for minority patients

17. Minority physicians tend to care for minority patients

18. Most minority physicians are naïve investigators • Total Physicians By Race/Ethnicity- 2004 • (total physicians = 884,974) • Race/EthnicityNumberPercentage • White 421,659 47.8 • Black 20,653 2.3 • Hispanic 27,935 3.2 (38,500 per us Census Bureau) • Asian 73,152 8.3 • American Native/ • Alaska Native 504 .06 • Other 20,011 2.3 • Unknown 321,060 36 • Note: At year-end 2004, the AMA had race/ethnicity data for over three fifths of all physicians in the US. • Source: Physician Characteristics and Distribution in the US, 2006 Edition. American Medical Association. No accurate estimate of minority investigators • There is significant opportunity for Novartis

19. Most minority physicians are open to clinical research Evidence of Demand • National Medical Association • 3 year project to determine member interest level and develop best model to offer as a member benefit • Resulted in Project IMPACT: Increasing Minority Participation and Awareness of Clinical trials • Association of Black Cardiologists • Newly opened 40,000 sq.ft. research center in Atlanta • First annual (?) investigator training session held at new center • Pfizer - “Investigator Training Program” • Fully developed curriculum covering 5 modules • Full-time staff committed to training • AstraZeneca • Early efforts of creating regional lists of minority physicians • Decentralized within medical organization • Novartis - “Multicultural Diversity Initiatives” • Strategies for more effective engagement of PIs and patients • Full-time staff committed to program development & training

20. Building on Success—it can be done! • AAASPS (the AA Anti-platelet Stroke Prevention Study) • DASH (Dietary Approaches to Stop Hypertension Collaborative Research Group) • BCPT (Breast Cancer Prevention Trial) • AAHPC (AA Hereditary Prostate Cancer Study) • BHN (The Black Health Network, Inc.) • AHEFT (no patients lost to follow up) How can successful models be achieved?

21. Utilizing Cultural Intermediaries • Bridge trust through use of experienced, culturally sensitive entities • Utilize minority PI’s • Utilize organizations that can bond with the sites and maintain continual support throughout a trial • Support PI development programs for underrepresented groups, then use them! • Use organizations that can illicit support from trusted cultural icons to foster community support

22. Develop Culturally Sensitive Strategies • Use minority “key” opinion leaders • Consult with cultural intermediaries during protocol development • Recruit more high level minorities within your organization • Foster relationships with minority medical institutions • Develop culturally sensitive marketing materials to support clinical trials (use minority consultants)

23. Enrichment of the Diversity Pipeline will require a recognition of the real differences between the social, cultural, economic, and relational dynamics of urban vs. less urban populations Strategies for success will demand careful tailoring (and rigorous assessment), since “one size will definitely not fit all”

24. Minority patients and their physicians’ offices are located in and around urban centers • 52%: proportion of blacks who live in the central city of a metropolitan area (Congressional Black Caucus) • ~50%: proportion the nation’s Dominicans who live in NYC (US Census) • ~50%: proportion of the nation’s Cubans residing in Miami-Dade County, Fla. (US Census) • 4.6 million Hispanics live in Los Angeles County, CA (US Census) • These demographics compel the design of an “urban strategy” to help fix the pipeline

25. Barriers to Recruitment and Retention: A Pipeline Problem • Fear and mistrust • Variability of health priorities • Negative experiences with the health care system • Differences in health beliefs • Economic issues- study requirements interfered with work and family • Complexity of study procedures- record keeping too complicated Green BL et al. Ethnicity and Disease. 2000 10(1): 76-86. Janson SL. Et al Control Clin Trials 2001; 22:236S-243S

26. Sub-optimal outcomes in Clinical Studies: A “no-win” strategy for all • Poor patient recruitment is the number one reason that trials fail or are delayed • Some reasons for poor enrollment • Investigators over-estimating enrollment • Diminished patient interest • Wrong time of year • Protocol requirements to burdensome • Competing trials • Laboratory values / clinical endpoints not reflective of population

27. Snapshots of Selected Industry Trends • Clinical Development costs are increasing • Average $897 million per trial (Tufts) • Longer trial time and increased trial size • Increased protocol complexity • More procedures performed per subject • Increased inclusion/exclusion criteria • Rising recruitment and retention costs • Increased number of trials per NDA • Pharma/Biotech slow to embrace technological advances • Increased industry focus on minority patient drug effects • BiDil (Nitromed) • Phase III Sickle Cell (Icagen/JNJ)

28. Sponsor Initiated Strategies to Improve Recruitment and Retention—Approaches to “fix” the Pipeline • Cultural Intermediaries • Minority Investigators • Bridge to the Community • Well established and respected • Existing ties to social networks • Church • Social clubs • Considered as community ICONs and Spokespersons • Minority physicians treat minority patients

29. The “Culturally-Centered” Approach to fix the Pipeline: Sponsor-Initiated Strategies to Improve Recruitment and Retention Establish ongoing relationships with Cultural Intermediaries • Physician organizations • National Medical Association • Association of Black Cardiologist • International Society of Hypertension in Blacks • Historically Black Colleges/Institutions • Morehouse • Howard • Community Based Organizations • NAACP • Congress of National Black Churches • Black Health Network • Total Lifestyle Change, Inc

30. Sponsor-Initiated Strategies to Improve Recruitment • Use Cultural Intermediaries for: • Educational Program Development & Delivery • Culturally sensitive promotional materials • Low-literacy education materials that explain disease process and clinical trial requirements • Recruitment videotapes that explain clinical trial along with patient testimonials • Targeted messages tailored to the social, cultural and economic concerns of the target population

31. Sponsor-Initiated Strategies to Improve Recruitment • Use Cultural Intermediaries for: • Community Strategies • Public presentations to community groups. Focus on support groups for the disease state being investigated. Presentations should preferably be done by principal investigator (if he/she represents target population) • Community-based screening in high prevalence disease states • Provide free non-trial services or health-related information • Organize a community advisory committee

32. Sponsor Initiated Strategies to Improve Recruitment • Use Cultural Intermediaries for: • Communication strategies • Culturally sensitive television and radio promotion • Community Outreach • Health fairs • Work-site programs • Churches • Community centers • Schools

33. Sponsor-Initiated Strategies to Improve Recruitment • Use Cultural Intermediaries for: • Communication Techniques • Newsletters, “campaign” buttons, posters, billboards, door-to-door canvassing, bus advertisement, grocery stores • Bulk mailings***

34. Sponsor-Initiated Areas of Improvement • Patient surveys found clinical trial participants would like: • More information about the trial prior to its commencement • More information about the trial while it was in progress • More education about “my” disease state • Post-trial follow-up and continued communication (newsletters)

35. Sponsor Initiated Strategies to Improve Recruitment and Retention—Approaches to “fix” the Pipeline • Cultural Intermediaries • Minority Investigators • Bridge to the Community • Well established and respected • Existing ties to social networks • Church • Social clubs • Considered as community ICONs and Spokespersons • Minority physicians treat minority patients

36. DEVELOPMENT OF AN APPROACH TO “FIX” THE PIPELINE: PROPOSED ROLE FOR “INDUSTRY CHAMPION” • Commission a thorough study of the issue surrounding minority clinical investigators with the goal of proving a null hypothesis • Work with a company/group that can develop recommendations and execute • Identify senior level champion(s) internally

37. Components of the Null Hypothesis • Mitigating the financial and execution risk to physicians and sponsor will speed market adoption • Provide shared services to multiple practices in a geographic cluster • More “hands-on” involvement may be needed initially • Centralized patient scheduling and supply management • “Virtual” nurse coordinator at multiple sites • Query handling • Investigator training and certification • Lock-in relationship with investigators with long term (5 years) Site Management Organization (SMO) - like contract via a third party

38. Strategies/Reflections for “Curing” the Diversity Pipeline Problem • Invest in minority investigators over time • Expecting quick fixes will only disappoint • Showing sustained interest in this community will garner support • Engaging community early in the process will be more successful (protocol development stage versus protocol rescue) • Resist requirement for exclusivity • Physicians do not want to feel beholden to one company • i.e. high prescribers who prescribe a small percentage of competing drugs to “keep companies honest’ • Often difficult for one pharma/biotech company to generate enough income to sustain a practice’s increased overhead • 1/2 - 1 FTE • Additional office space and equipment • Increase use of supplies, faxes, etc • Risk of losing perceived objectivity in your clinical research • Physicians may be open to “preferred position” versus exclusive

39. Components of the Null Hypothesis • Many minority practices will require financial assistance to expand into clinical trials (element of the “urban” strategy) • While open to new financial opportunity, patient demographics cause minority physicians to be reluctant or unable to invest in upfront costs of trials • Traditional organizations are not always the best sources of new minority investigators • National Medical Association membership <10,000 • National Hispanic Medical Association membership <1000 • Association of American Indian Physicians membership <100 • Real need is to develop a framework to identify practices with the potential to deliver patients

40. Cluster/Shared Services Model Investigator Investigator Investigator Protocol development and review Investigator Investigator Pre-screened and trained investigator sites Centralized and virtual services within minority populated MSA Community advertising and outreach for patient recruitment Maintain contact with the investigator sites for support Use of software at sites to enhance patient ID Direct onsite support Investigator training on protocol and therapeutic area. Query handling and resolution Participation in investigator meetings

41. What Lessons have we Learned? • A single historical event is not responsible for the lack of trust in the AA community • The physician-patient relationship is critical • Building protocols for Clinical Trials should be based on a “foundation” of diversity • Use the success of others to increase minority participation in clinical trials • Steering committees and advisory boards must be more inclusive and diverse • Change starts at the top!!!---the pipeline is fixable