Industry Approach to Diversity in Clinical Trials: Design and Implementation

1. Industry Approach to Diversity in Clinical Trials: Design and Implementation Gregory P. Geba, M.D., M.P.H Vice President Head, Resp/Derm & Infectious Diseases Therapeutic Area US Clinical Development and Medical Affairs Novartis Pharmaceuticals Corporation The Pyramid Club Philadelphia, October 6, 2006

2. Diversity: definitions

3. Diversity: definitions Gender Race Age Ethnicity Tradition/cultural Language Socio-economic Environment Religion Politics

4. Industry perspective:Why is diversity of patient selection important? Patient characteristics are often associated with markers of disease prevalence and severity and influence how an individual absorbs, metabolizes, and ultimately responds to medications designed to treat that disease

5. FDA guidance on diversity: Striking a balance Recognition of differences in patient populations Vs.Expediting access to important new drugs for the treatment of disease

6. FDA guidance on diversity: The regulations 1988:"Final Demographic Rule on Investigational New Drug Applications (NDAs)" required that analyses of effectiveness and safety data for important demographic subgroups, including gender and racial subgroups, be submitted to NDAs and that enrollment of subjects into clinical studies for drug and biological products be tabulated by important demographic subgroups in investigational new drug (IND) annual reports, i.e., age group, gender, and race. 1993:"Guideline for the Study and Evaluation of Gender Differences in Clinical Evaluation of Drugs” 21 CFR 314.50; revised. 1997:Further revisions, increasing attention to the incorporation of women and minorities in the design and implementation of clinical trials. Form: Subgroup analyses need to be presented to provide insight into efficacy and safety Refs: http://www.fda.gov/cder/reports/race_ethnicity/race_ethnicity_report.htm; Toigo, etal. Participation of Racial/Ethnic Groups in Clinical Trials  and Race-Related Labeling; http://www.fda.gov/cder/guidance/5656fnl.pdf

7. FDA guidance on diversity: 2005 2005: “Guidance for Industry: Collection of race and ethnicity data in clinical trials”. Provided more specific guidance about the categorization of race and ethnic groups and the need for sub-group analyses to be included in the NDA and safety reports to assess response across racial and ethnic groups. A two question format (minimal choices) was recommended: For race: For ethnicity: • American Indian or Alaska Native Hispanic or Latino • Asian Non-Hispanic or Latino • Black or African American • Native Hawaiian or Other Pacific Islander • White http://www.fda.gov/cder/guidance/5656fnl.pdf

8. To balance speed to market and need for additional data, FDA will use the approach of phase 4 commitments to understand efficacy and safety in smaller populations

9. Ex-US jurisdictions: approach As the population becomes more diverse and as understanding of potential differences is greater:EU: Guidelines ethnic/racial diversity in clinical trial populations beginning to developJapan: Mandates trails be conducted in Japanese ethnicity exposed to Japanese diet

10. Implementation:Incorporating diversity in design of clinical trials Main goal:Study patients who mimic the population of those likely to be treated with the new medicine

11. Focus therefore must be on BOTH the patient populations and physicians that care for and have access to them

12. Finding the patients A difficult task • Although patients with a disease/condition may be numerous, their connection to capable researchers at sites that can care for them may not be. • Standard approach: Academic groups and pharmaceutical companies have attempted to identify patients through patient records or via investigator databases. • New approach: Identifying where the patients are geographically, and connecting them to established, or facilitate development of new investigators that can care for them and participate in clinical trials.

13. “Conventional” Strategies for Maximizing Minority Accrual Developing a detailed recruitment plan will facilitate minority accrual to include: • Definition of target population • Hire and train recruitment staff that represent the target population • Consider potential barriers and develop plans to address them • Test recruitment strategies Ref: http://www.dfhcc.harvard.edu/minority_initiatives/index.asp

14. Strategies for Maximizing Minority Accrual: Approaches 1.-Definition of the target population • Understand medical, epidemiological and sociological basis of disease • Obtain information on health beliefs and behaviors relevant to participation in clinical trials • Know the community • Seek collaboration from leaders in the target community, involving community groups that have the trust of the target population (religious and social organizations, education institutions, medical institutions, athletic groups.

15. Strategies for Maximizing Minority Accrual 2.-Hire and train diverse recruitment staff: • Recruit study staff from the target populations. • Ensure that recruitment staff have cultural competency skills. • Include investigators or staff on your research team that have an understanding of the target populations.

16. Strategies for Maximizing Minority Accrual 3.-Recognize potential barriers/develop strategies to address: • Sociocultural barriers • Language barriers • Cultural beliefs or myths about a specific disease • Economic barriers • Cost of participation; transportation • Lack of insurance • Individual barriers • Denial or underestimation of risk vulnerability • Lack of time, child care

17. Strategies for Maximizing Minority Accrual • Barriers in regard to the study design • Complex and technical forms • Complicated study procedures • Frequent visits to health care setting • Utilize focus groups and key informant interviews to identify and understand potential barriers and seek solutions. • Hire bilingual staff and/or utilize medical interpreters. • Especially relevant for Hispanic and Asian populations • Ensure that translated materials are both linguistically and culturally appropriate. • E.g. WOMAC: 3 versions

18. Help the patient find the trial:Clinical trial registries Facilitate public access to information concerning:Real-time existence and contact information about on-going clinical trialsDisseminating clinical trial results for the main trial endpointshttp://www.clinicaltrials.govhttp://www.phrma.org

19. NVS approaches to diverse patient population recruitment

20. Protocol reviews and sign-off Carefully constructed protocol committees comprised of clinical, statistical, epidemiological, health economics staff supplemented by clinical trial managers, study coordinators, investigators, patient representatives…..Which reviews initial protocol concept, and later the full protocol via dedicated focused meetings. Focus: Appropriateness of study/design, study population to be recruited, protection of patient safety.Sign-off required to proceed.

21. Critical challenges • Optimal placement of trials: Identifying the right investigators (both existing investigators and potentially new investigators) in the right geographic areas with the right population of patients appropriate to the trial of interest. • Work force management – optimize placement of our own staff.

22. Finding the patients: a new NVS approach As an adjunct to traditional measures:Develop new a tool to determine where patients with particular disease and demographic characteristics are situated.

23. Finding the patient: GeoDART3T Using a customer master database providing source information Step 1:Integrated HCP customer information Across multiple transactional systems (Point Solutions) • SONIC (SciOps CRM Solution) • IMPACT (Novartis Clinical Trials) • Master Investigator Database (MIDB) • Speaker Central • MediCus (Medical Inquiry System) Step 2: Integrate 3rd Party information: • Demographics from US Census • Disease prevalence from Market Scan Creating a Web-based tool providing robust reporting and analytics capabilities

24. Benefits Immediate • Improved performance: streamlined investigator selection process; assisted in identifying geographic areas with the targeted population; more efficient placement and use of resources • Shared and integrated data: access to broad range of data available to the 5 US CD & MA areas that interact with investigators, patients and clinical data • Improved recruitment efficiency: GeoDAR3T offer a unique ability to enhance investigator recruitment and geographic coverage • Potential future benefits • Other data sources can be integrated into system to further expand recruitment capabilities

25. What does the name “GeoDAR3T” mean? GEOcoded Dataset Application for Research Recruitment Report Targeting

26. What goes into GeoDAR3T: US Census Demographics HCP Medical Inquiry Data Novartis Investigator Data 3RD Party FDA 1572 Data 3RD Party Disease Data Novartis CRM Data

27. What comes out of GeoDAR3T: Summary Reports With the ability to Drill Down to underlying details:

28. What comes out of GeoDAR3T: Results can be displayed in a variety of graphical formats

29. What comes out of GeoDAR3T: Geo-based results (such as Disease Prevalence by MSA CODE) can also be plotted on a MAP with drill-down capabilities.

30. We can identify the patientsBUT have we identified qualified investigators needed to implement the trial?

31. Step 1: Master Investigator DatabaseEstablished investigatorsKnown patient populationsExperienced in NVS clinical trials Finding the investigator:

32. Finding researchers new to a specific company Experienced investigators-Develop relationships with minority professional organizations exemplified by: National Medical Association HAAMA -Obtain names and contact numbers of interested parties via referrals from already registered investigators

33. Step 2: New Investigator Training Program October, 2006

34. Rationale for Program • The anticipated trial work in the US projected to continue to escalate over the next 5 years • Needed additional investigators beyond the currently available pool in order to meet that increased expectation • Most investigators [approximately 75%] new to research never file a second 1572 (perseverance rate is low) • Need diverse investigators to enroll diverse patients into our clinical trials to meet public health informational and regulatory requirements

35. Find and train interested clinicians new to pharma research -Requires a). A process whereby the patients are identified b). An understanding of the capabilities of physicians who are co-localized c). Establishing a link that can be leveraged between interested MDs and pockets of disease burden Finding the researchers

36. Novartis approach to new investigator development 1). Leverage local “FOCUS” teams of CRA, SciOps and clinical personnel (FOCUS teams) who know the patient distribution and physicians in the local area2). Establish a relationship with interested investigators via direct meetings/contact3). Offer an intensive clinical research training session before the official investigator meeting to train in the fundamentals of clinical research (NEXT)

37. NEXT training topics (1) • Following major topics discussed: • Purpose of the training • The process of patient selection • Specific training in clinical research fundamentals, via slide presentation, hands on examination of documents and video presentations

38. NEXT training topics (2) 250 slide/video presentation, reviewing, in a single Intensive session prior to the investigator meeting: -Ethics in clinical research -Phases and objectives of clinical trials -Life cycle management -Review protocol development -Review roles and responsibilities of clinical trial staff -IRB, Informed consent -Study start-up activities, investigator meeting -Source documentation, record retention -Publication policy

39. NEXT (3) Assures that new investigators brought into clinical trials understand and are fully trained in the principles of clinical research, good clinical practices and the details of the protocol to maximize likelihood of success and interest and ability to continue as NVS clinical investigators

40. Final points

41. Academics and Industry:How can we best work together? Relationship challenges:1). Academic IRBs (local vs. central)2). Clinical vs. basic science research focus of academia3). Regulatory environment4). Intellectual property issues5). University overhead/Indirect costs6). Time limitations of academic clinicians dedicated to care of diverse populations

42. How can we best work together? Relationship benefits:1). Partnering with academic thought leaders2). Gaining access to the most needy patients often urban settings, who then have access to cutting-edge medicines3). Identifying and enrolling most diverse patient populations4). Working with investigators of diverse backgrounds

43. Thank you!

44. AcknowledgmentsDr. Eric FloydVP, Regulatory Head, RDIDonna Long NEXT program coordinatorLuAnn Silvestro GeoDart coordinator