Promises and Perils of Translational Research at Academic Health Centers: The CCHMC Model

1. Promises and Perils of Translational Research at Academic Health Centers: The CCHMC Model Timothy P. Cripe, MD, PhD Faculty Cross-Talk October 5, 2006

2. Public Mandate It is no longer good enough to cure a mouse.

3. Translational research is… “...moving a basic discovery into early clinical trials.” Promises • J Kaiser, in • “Translational Research: A Cure for Medicine’s Ailments?” • Science 311:1852, 31 Mar 2006

4. Discovery Development Delivery

5. Discovery Delivery Development Is it safe? Does it work? Can we make it better?

6. Laboratory Clinic Bench Bedside Petri Dish Patient Translational Research is a Two-Way Bridge

7. Analogy compliments of S. Davies

8. Peril #1: Time and Money

9. Preclinical: 3-5 yrs, $3-5 million Manufacturing: 1-2 yrs, $1-2 million IND: 3-6 months, $0.5-1 million Phase I: 1-2 yrs, $1-3 million Phase II: 2-3 yrs, $3-6 million Phase III: 3-4 yrs, $10-20 million FDA: 1-3 yrs, $2-4 million Time and Money Source: http://www.wistechnology.com/article.php?id=377

10. 15-20 years Direct costs: $403 million Add in marketing: $802 million Some estimates up to $1.7 billion Pharmaceutical Drug Development: Saganesque “…billions and billions…” From: DeMasi et al., J Health Economics 22:151, 2003

11. “…does anybody truly believe that academic translational research centers will be as efficient, let alone competitive, at developing drugs as pharma?” “…investing in translational research is akin to building a bridge to nowhere.” • J Erickson, in • Commentary: “Translational Research and Drug Development” • Science 312:997, 19 May 2006

12. Is AHC Translational Research Successful? Nature, Cell, Science, JBC, JCI, J Exp Med From: Contopoulos-Ioannidis et al., Am J Med 114:477, 2003

13. Of those identified over 5 year period: 1 in 4 led to published randomized trial 1 in 6 validated in positive trial <1 in 10 entered routine clinical use Only 1 deemed to have major impact (ACE inhibitors) 20 Year Follow-up of Promising Basic Science Technology From: Contopoulos-Ioannidis et al., Am J Med 114:477, 2003

14. From: Contopoulos-Ioannidis et al., Am J Med 114:477, 2003

15. Peril #2: Regulatory Hurdles

16. Extensive pre-clinical (laboratory) research precedes clinical trials History has shown that safeguards are necessary to protect people in clinical trials Safeguards are extensive Enormous effort, time, costs underlie trials Human Subject Research

17. cGMP IRB TOX SAC RAC IBC IND Regulatory Steps in Translational Research IRB Laboratory Clinic

18. Levels of Burden: Sponsor vs. Investigator • No IND • Fulfill PI level obligations (GCP) • Company-held IND • Fulfill PI level obligations (GCP) • Investigator-held, cross-referenced IND • Fulfill PI and Sponsor obligations (GCP) • Investigator-held IND • Manufacture product (GMP) • Conduct non-clinical studies (GLP) • Fulfill PI and Sponsor obligations (GCP) (Be the pharmaceutical company)

19. Peril #3: Academic Metrics

20. Training Extended Requires scientist-clinician mentoring Typically has been “on the job” Funding Especially for orphan diseases, childhood diseases! Slow results (may take years for 1 trial) Regulatory burdens Fragmented infrastructure Traditional metrics of success inadequate Publications Grants Patient revenues Hurdles for Patient-Oriented Translational Clinical Researchers From: Nathan DG, J Clin Invest 115:795, 2005

21. 2001: Initial preclinical data ExampleHSV Oncolysis for Cancer UV-Mutant HSV Mutant HSV

22. 2001: Clinical trial concept proposed 2001-2004: More animal efficacy/safety 2004-2006: Regulatory/funding hurdles Local GCRC SAC, IBC, Radiation, IRB National NGVL, NIH RAC, FDA IND ExampleHSV Oncolysis for Cancer

23. My IND: 1 year and counting

24. AHCs are birthplaces of ideas Lionshare of basic science research Unburdened by company constraints Tantalizing translational data needed to engage industry AHCs can promote agendas with low market value Orphan diseases Pediatric diseases Why should AHCs Conduct Translational Research?

25. CCHMC TRI NIH CTSA What’s an Institution to do? • Enhance scientific and clinical interactions • Build scientific infrastructure through grants program • Build clinical operations to facilitate complex and multidisciplinary translational and clinical trials • Provide support for complex regulatory help/oversight

26. Founded in 2001 Supported by clinical revenues Two-tiered mission To stimulate translational research via grants (financial support) Pre-clinical and early phase clinical trials Includes collection/analysis of biological samples To create infrastructure (regulatory support) New cores Workshops for clinical/research interactions Education Annual symposium Faculty scholar Masters program for fellows Translational Research Trials Office CCHMC Translational Research Initiative (TRI): Cripe et al. Acad Med 80:1012, 2005

27. Translational research projects 31 projects 30 investigators 21 divisions/departments $2.475 million Cores 3 cores Fanconi anemia cell repository Human milk bank Mouse genotoxicity $250,000 Workshops/symposia/retreats 13 $39,000 TRI Projects Funded 2001-2004

28. 44 manuscripts 18 extramural grants Total direct costs: $27,691,304 7 patents 12 clinical trials launched Results: First Four Years(30 Investigators given $2,475,000)

29. 11 INDs (plus 2 in development) 48 IRB-approved protocols 15 Therapeutic 33 Biologic/specimen collection Utilized by 8 CCHMC divisions Normal donor program for lab research Blood (124) G-CSF mobilized peripheral blood stem cells (86) Bone marrow (173) Umbilical cord blood (380) TRTO Office: First Five Years

30. 2001 TRTO Human Resources Personnel Funding 100% Institutional Grants 2 staff

31. Personnel Funding 46% 54% Institutional Grants 2006 TRTO Human Resources 8 staff

32. In conclusion…

33. TranslationalResearch:MissionImpossible?

34. Proceed cautiously, hang in there

35. Pre-clinical testing is essential

36. Usually testing in multiple species is required

37. Other ideas may also work

38. When it comes to getting water to the fire…