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Building better clinical trials : A perspective from a cell therapy trialist (and dean)

This presentation by Robert D. Simari, M.D. discusses the importance of inclusiveness in early clinical trials and the impact of diversity on the generalizability and financial outcomes of these trials. It highlights the need for representation of diverse populations in order to improve the development of novel cardiovascular therapeutics.

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Building better clinical trials : A perspective from a cell therapy trialist (and dean)

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  1. Building better clinical trials: A perspective from a cell therapy trialist (and dean) PRESENTED BY ROBERT D. SIMARI, M.D.

  2. 2 year f/up: 1 cardiac death in BMC group 0 deaths in PL group JAMA 2013, Circ Res 2018

  3. f/up: 0 deaths in BMC group 1 noncardiac death in PL group JAMA 2102

  4. Are the outcomes representative of the population? • One year mortality in elderly community population- 20% • Three year all cause mortality- HORIZONS AMI- 5-7% • BAMI powered for 12% two year mortality Setoguchi JACC 2008, Stone Lancet 2011, Ng EHJ ACC 2014

  5. How representative was the population studied? • TIME: 17% female, 86%-white • Late TIME: 11% female, 96%-white

  6. Hypothesis: Development of novel CV therapeutics has been inhibited by lack of inclusiveness in early clinical trials

  7. We are an increasingly diverse country

  8. We are an increasingly diverse country: Year when whites become minority

  9. We are an increasingly older country

  10. Socioeconomic position • Race, ethnicity • Social support • Culture and language • Access to care • Residential environment Havranek, Circ 2015

  11. Economic Burden of Health Disparities in US Potential reduction of direct medical care expenditures if disparities were eliminated Potential reduction of indirect costs associated with illness and premature death due to disparities Percent excess direct medical care expenses for AA, Asians and Hispanics $230 billion USD $1trillion USD 31% LaViest, Econoimic Burden of Health Inequities 2009

  12. Racial disparities and outcomes: Survival following Acute MI • Cohort study using PREMIER and TRIUMPH databases (6402 pts) • 5year mortality rate for blacks was 28.9% and 18.0% for white pts (HR=1.72, p<0.001) • Blacks and whites differed significantly in most characteristics. • Propensity analysis was performed. • “The higher the prevalence of characteristics associated with being a black patient the higher the 5-year mortality, but no differences were observed between black patients and white patients with similar characteristics.” Graham, JAMA Network Open 2018

  13. Neighborhoods impact CHD risk CHD Incidence/1000 person-years Personal income Diez Roux NEJM 2001

  14. Diversity of participants in clinical trials in the U.S. • The NIH Revitalization Act of 1993 mandated the appropriate inclusion of minorities in all NIH-funded research. • FDA guidance expects sponsors to enroll study participants who reflect the demographics of clinically relevant populations for their product with regard to age, sex, race and ethnicity. • FDA concludes that current clinical trial populations do not reflect the true demographics and disease prevalence in the US.

  15. Diversity of participants in clinical trials • Race/ethnicity rarely included in cardiovascular cohort studies (Ranganathan 2006) • Outcomes rarely reported by sex, race or ethnicity (Geller, J Women’s Health 2011) • Three studies have shown an equal willingness of minorities to participate in clinical trial (Katz JNMA2007, Wendler PLOS Med 2005, Langford Cancer 2014)

  16. Knepper, MacLeod Nature 2018

  17. Document diversity (race, ethnicity) • Design global studies for a global population • Regulators should support trials that home in on special populations • Address social barriers to participation • Work towards personalized (genomic) characterization rather than race and ethnicity. Knepper, MacLeod Nature 2018

  18. % European contribution to African-American Communities Marsha and Abebe, Human Genomics 2015

  19. Ancestry proportions of Mexicans and Puerto Ricans Marsha and Abebe, Human Genomics 2015

  20. Use ancestry (biogeographical ancestry) to describe actual genetic variation. Use race to describe health disparities in societies characterized by racial categories Use ethnicity to describe traditions, lifestyle, diet and values. Marsha and Abebe, Human Genomics 2015

  21. Diversity of participants in early phase clinical trials • Over-representation of minorites in Phase 1 studies • The business of PK/PD clinical trial units • The “mild torture economy” • Elliot, Abadie NEJM 2008 • Under-representation in Phase 2/3 clinical trials of cell therapies • Cochrane analysis suggests >80% male; race and ethnicity largely not presented • Commitment of time • Limited to major medical centers

  22. Why is diversity of participants in clinical trials important? • Required by NIH/FDA • Ethics of inclusiveness- justice • Generalizability of outcomes • Differences in drug response/metabolism • FINANCIAL BENEFITS

  23. The financial imperatives of inclusion Greater generalizability of results creates a larger likelihood of broad acceptance and third party coverage = recoup investment sooner.

  24. The financial imperatives of inclusion • A more inclusive study population will generally = a higher risk population • Higher risk = more events • More events = more power • More power means less likely to miss therapeutic outcome= less $ wasted on negative trials

  25. If performance of inclusive studies is beneficial financially, how might that impact conduct of clinical trials? Sponsors should be more willing to utilize resources with the goal of performing inclusive studies. And we need to convince them do so while providing innovative new methods.

  26. Designing trials specifically for diverse populations: SENECA trial StEm cell iNjEction in Cancer survivors A Phase I, First-in-Human, Multicenter, Randomized, Double-Blinded, Placebo Controlled Study of the Safety and Efficacy of Allogeneic Mesenchymal Stem Cells in Cancer Survivors with Anthracycline-Induced Cardiomyopathy

  27. Publication of 6M & 12M results Dec 2019/Jan 2020 Design paper published in Am Heart J July 2018

  28. SENECA Subjects

  29. SENECA Subjects • Cancer dx 18.5 yrs ago (avg) • Anthracycline was largely Doxirubicin(91%) • Avg AIC exposure 328.8 mg/m2 (n=22) • Most had radiation (>70%) but only small number included left chest (8.5%) • AIC dx 8.5 yrs ago (avg) • Screening LVEF 33% (avg) • More class NYHA 2 (83%) than class 3 (17%) • More than half w/ cardiac devices (54%)

  30. 2. Designing trials specifically to include diverse populations Dr. Christie Befort -KUMC

  31. BMI 30-45 kg/m2 Age 20-75 years PCP clearance Primary Outcome: Weight change at 2 years Secondary Outcomes: Quality of life, metabolic syndrome, implementation process measures Dr. Christie Befort -KUMC

  32. RE-POWER Clinical sites

  33. Patient-centered engagement principles Shared vision and mission Informal, everyone on first name basis Hard work acknowledged and celebrated Input on budget and payments Sharing of experiences across providers and patients Patients are experts in communication, consenting, and retention

  34. 3. Models of community engagement RAND-led panel utilized modified Delphi Panel approach of translational research and community leaders nationwide to rank ethical principles of community-engaged research. Proximal goals: Studies that are culturally appropriate, scientifically valid, grounded in trust, transparent, beneficial to community and action oriented. Ultimate goal: Studies that are community driven and based on equal partnerships. Khodyakov, Transl Res 2016

  35. Potential value of social media for targeting diverse populations for clinical trials • Practical concerns include brevity and capacity to target. • Ethical concerns over privacy and enticement Caplan, Friesen PLOS Biol 2017 Use of internet including Google ads, patient groups, etc.

  36. 4. Train a diverse population of investigators Duncan, AATS 2016

  37. 4. Train a diverse population of investigators Duncan, AATS 2016

  38. 4. Train a diverse population of investigators Duncan, AATS 2016

  39. 4. Train a diverse population of investigators Pre-matriculation Diversity Post Bac KUMC Educational Experience

  40. 4. Train a diverse population of investigators • KUSOM Rural Health Scholars Program • Accepts students with rural backgrounds as college sophomores Since 1997 Accepted=249 Current undergrad=35 Entered SOM= 193 Current SOM=53 Current GME=53 In practice=73 61 in KS Majority in rural/urban underseved areas

  41. We need more diversity in clinical trial participants • It is the right thing to do. • It is more cost effective. • Because it is cost effective, we need to not be ashamed to use novel and resource-intensive approaches. • We will not succeed without a more diverse team of investigators

  42. Thanks LemMoye’- UTSPH Matt Moreno-MS4

  43. Thank you

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