1. CTSA Implementation at the University of Pennsylvania Carl June, M.D. Professor of Pathology and Lab Medicine Director of Translational Research Institute for Translational Medicine and Therapeutics University of Pennsylvania Secretary’s Advisory Committee on Human Subject Protections October 30, 2007

2. Institute for Translational Medicine and Therapeutics: Governance Executive Oversight Operational Oversight Committee Operational Oversight Committee Director ITMAT and CTSA Director ITMAT and CTSA Internal Advisory Board External Advisory Board Associate Directors Centers Cores Programs: PINB Education and Training Outreach

4. Delivery of novel biotherapeutics Basic research Synergistic interactions between lab and clinic Material, Reagent & Process Develop. Validation & Scale- up GMP Manufacture Assay Develop. & Assessment Phase I Clinical Develop. Existing Infrastructure to be expanded New CTSA initiatives Facilitating Translational Research By Addressing Potential Bottlenecks Pre-clinical Operations Regulatory Expertise Operations/ Management/ Admin Clinical Informatics / Data management Training/ Mentorship DevelopmentClinical HICBRSOBRSO, CVPFCVPF CVPF, CCMT,H IC TRP, IME Quality Control/ Quality Assurance

5. UPenn CTSA Program in Novel Biotherapeutics –Rationale: »Address bottlenecks for translation »Promote ‘first in human’ trials »Manufacturing of biologics in academia »Orphan indications and customized therapies may require combination with other agents. »Lack of industry support: academic networks required to advance clinical development to enable handoff to industry –Metrics of successful translation »Open protocols »Physician and Institution Sponsored INDs

6. Emerging Biologics Research Cell & Gene Therapies Examples

7. Neuroblastoma Vaccine + T Cell Boost Pilot (PI: Stephan Grupp, MD, PhD)

8. Example from ongoing trial NCRR Reporter, July 2007 Physician-scientist Stephan Grupp at the Children’s Hospital of Philadelphia is testing a new therapy for neuroblastoma, a common and deadly cancer among children. Using resources provided through the CTSA at the University of Pennsylvania, Grupp was able to enlist the help of a collaborating institution to complete his study more rapidly.

9. Example of success NCRR Reporter, July 2007

10. Impact for neuroblastoma trial

11. UPenn CTSA Program in Novel Biotherapeutics

12. Regulatory complexity: Pilot test of lentiviral engineered T cells for refractory leukemia

13. UPenn CTSA Program in Novel Biotherapeutics

14. Biologic trial: first in human CD28 antibody healthy volunteers London, UK March 2006 NEJM 2006: 355: 1018

15. AAV Gene Therapy Protocol for Arthritis Feb. 12, 2007: Jolee Mohr of rural Taylorville, Illinois, signs 15-page consent form Feb. 26: Mohr receives a first injection of genetically engineered viruses into her right knee. July 2: She receives a second injection. July 12: She is admitted to Springfield hospital. July 20-24: Targeted Genetics notifies FDA of Mohr's illness. The study is suspended. Mohr dies. Sept. 17: The National Institutes of Health's OBA/RAC advisory committee meeting Washington Post, August 2007

16. When Things Go Wrong: Lessons Learned and Issues Raised

17. © 2002-2007 Trustees of the University of Pennsylvania Environmental Health & Radiation Safety Office of Regulatory Affairs University IRB Human Research Advisory Committee Conflict of Interest Standing Committee Biosafety Committee Radiation Safety Committee Human Subjects Research Oversight at UPenn Office of Human Research Compliance & QI Research Education & Training Research Operations School of Medicine Office of Research Compliance & Integrity Scientific Misconduct Investigation Privacy Protection Financial Compliance Institutional Officials For Human Subject Protections Vice Provost for Research Executive Vice Dean & CSO - A “two office” model

18. © 2002-2007 Trustees of the University of Pennsylvania Additional Oversight for Gene Therapy Research FDA Office of Biotechnology Activities RAC Office of Regulatory Affairs IRB Environmental Health & Radiation Safety Biosafety Committee Office of Human Research Monitoring & Auditing Research Review Subcommittee Vice Provost Human Research Advisory Committee Federal Oversight Human Subject Protections University Oversight Human Subject Protections Final decision permitting gene therapy research to be conducted at Penn OHRP

19. Evolving Human Subjects Issues at Academic Centers - I The CTSA should foster translational development and testing of biologics and targeted therapeutics, focusing on areas that are underserved by large pharma. However, first in human trials, biologics, and gene therapies may be inherently unpredictable. Emerging ‘cottage industry’ of lawsuits has given cause for some institutions to abandon translational medicine. Federal protection and indemnification of institutions and investigators involved in compliant human subjects research is not sufficient. Biologics and targeted therapeutics often involve INDs/IDEs at CTSAs. This raises additional issues of indemnification. Additional challenges arise when private, state and federal institutions collaborate.

20. Evolving Human Subjects Issues at Academic Centers - II Expertise of IRB and scientific review is critical to prevent or minimize SAEs. Local IRBs may not have the expertise for first in human trials, orphan indications, etc. Long and complex regulatory approval for biologic trials is a barrier to entry for junior faculty. When things go wrong: how can the informed consent process be improved to protect patient, institution and investigator? –Written testing, and/or videotape of ICD process? –Centralized IRB at CTSA for complex protocols? Funding issues: CTSA support is currently inadequate to support the necessary infrastructure for landscape of translational pilot trials that are on the horizon.