CTSA Implementation at the University of Pennsylvania Carl June, M.D. Professor of Pathology and Lab...
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Transcript of CTSA Implementation at the University of Pennsylvania Carl June, M.D. Professor of Pathology and Lab...
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
Institute for Translational Medicine and Therapeutics: Governance
Executive OversightExecutive Oversight
Operational OversightCommittee
Operational OversightCommittee
DirectorITMAT and CTSA
DirectorITMAT and CTSA
Internal Advisory BoardInternal Advisory BoardExternal Advisory BoardExternal Advisory Board
Associate DirectorsAssociate Directors
CentersCenters
CoresCores
Programs: PINBPrograms: PINB
Education and TrainingEducation and Training
OutreachOutreach
Implementation of CTSA: View from the Trenches
• Transitioning from GCRCs– UPenn and CHOP consolidation of two independent
GCRCs to a single CTRC (Clinical and Translational Research Center) in 2006
– Impressions to date:• Consolidation and staffing efficiencies realized
• Broader expertise for protocol review
• Unanticipated benefit: people talk to each other!
• Implement CTSA-funded “Program in Novel Biotherapeutics”
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
Development Clinical
HIC BRSOBRSO, CVPFCVPF CVPFCVPF, CCMT,HIC
TRP, IME
Quality Control/ Quality Assurance
UPenn CTSA Program in Novel Biotherapeutics
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
EmergingBiologics Research
EmergingBiologics Research
Cell & Gene Therapies
Examples
Neuroblastoma Vaccine + T Cell Boost PilotNeuroblastoma Vaccine + T Cell Boost Pilot(PI: Stephan Grupp, MD, PhD)(PI: Stephan Grupp, MD, PhD)
cisplatin/VP-16
VCR/Adr/CTX
Ifos/VP-16
carbo/VP-16
VCR/Adr/CTX
surgery
XRT
Induction
High dose therapy with stem cell rescue
collectstem cells
infusestem cells
infusestem cells
Costimulated T cell expansion
Cellular Therapy
collectT cells
infuseT cells
Carbo/VP-16Cytoxan
Melphalan/TBI
d+2d+12d+90
1o immune assessments:• CD4 at d+60• Prevnar and flu vaccine
d+12 and d+60
cisplatin/VP-16
VCR/Adr/CTX
Ifos/VP-16
carbo/VP-16
VCR/Adr/CTX
surgery
XRT
Induction
High dose therapy with stem cell rescue
collectstem cells
infusestem cells
infusestem cells
Costimulated T cell expansion
Cellular Therapy
collectT cells
infuseT cells
Carbo/VP-16Cytoxan
Melphalan/TBI
d+2d+12d+90
1o immune assessments:• CD4 at d+60• Prevnar and flu vaccine
d+12 and d+60
Example from ongoing trialUPenn CTSA Program in Novel Biotherapeutics
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.
Example of success
UPenn CTSA Program in Novel Biotherapeutics
NCRR Reporter, July 2007
Impact for neuroblastoma trial
UPenn CTSA Program in Novel Biotherapeutics
• Neuroblastoma is a rare pediatric tumor: orphan disease indication
• Initial NCI funded phase I trial carried out at Children’s Hospital of Philadelphia. Traditional funding mechanisms would not support the next step: a multi-institutional phase I/II study
• CTSA infrastructure manages IND (held at UPenn), recruited additional trial site at Dana Farber Cancer Inst., and monitors/audits trial at CHOP and DFCI.
• Required 3-way indemnification agreement between CHOP, UPenn and DFCI….SOPs, etc.
• Benefit: cuts enrollment from 8 months to 4 months, and potentially enables efficacy trials, if justified
UPenn CTSA Program in Novel Biotherapeutics
– Educational mission
» Training junior faculty for translational careers
– Barriers for junior faculty in engaged translational research: the pace of research is slower, and academic promotion can be difficult
– Education in human subjects research
» Regulatory approval pathway is more complex than for most other clinical research
Regulatory complexity: Pilot test of lentiviral engineered T cells for
refractory leukemia
UPenn CTSA Program in Novel Biotherapeutics
– Issues:
» Scalability: GMP manufacturing for biologics
» Outreach: interinstitutional agreements to facilitate phase II trials: a gap in traditional translational mechanisms
» Risks of biologics and gene therapy: perceived and real. What if something goes wrong….
Human Subjects Research: Biologics and Gene Therapies
Biologic trial: • first in humanCD28 antibody • healthy volunteers
London, UKMarch 2006
NEJM 2006: 355: 1018
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
When Things Go Wrong:Lessons Learned and Issues Raised
• TeGenero antibody trial in UK subject selection: normal volunteers for first in human multiple subject enrollment at first dose cohort scientific rationale and peer review flawed
• Gene therapy trial in Chicago
Cause of death: disseminated histoplasmosis and retroperitoneal bleeding / hematoma Death was unexpected: more than 100 patients had been enrolled on the trial Trial design: toxic ity assignment and causality. How distinguish AAV intra-articular TNF blockade from systemic Humira (adalimumab, anti-TNF) therapy?
• Issues raised and Lessons learned Patient selection / eligibility and exclusion criteria
Informed consent process: Primary care physic ian should not enroll patients on phase I safety studies Trial design flaws Peer review was suboptimal High profile of perceived risk: indemnification of academic investigators
© 2002-2007 Trustees of the University of Pennsylvania
Environmental Health & Radiation
Safety
Office of Regulatory
Affairs
University
IRB
Human ResearchAdvisory
Committee
Conflict of Interest Standing
Committee
BiosafetyCommittee
RadiationSafety
Committee
Human Subjects Research Oversight at UPennHuman Subjects Research Oversight at UPenn
Office of HumanResearch
ResearchCompliance
& QI
ResearchEducation &
Training
ResearchOperations
School of Medicine
Office of ResearchCompliance &
Integrity
ScientificMisconduct
Investigation
PrivacyProtection
FinancialCompliance
Institutional OfficialsFor Human Subject Protections
Vice Provost forResearch
Executive Vice Dean & CSO
- A “two office” model
© 2002-2007 Trustees of the University of Pennsylvania
Additional Oversight for Gene Therapy Research Additional Oversight for Gene Therapy Research
FDAOffice of Biotechnology
ActivitiesRAC
Office ofRegulatory Affairs
IRB
Environmental Health &Radiation Safety
Biosafety Committee
Office of Human Research
Monitoring & Auditing
Research ReviewSubcommittee
Vice ProvostHuman Research
Advisory Committee
Federal OversightHuman Subject Protections
University OversightHuman Subject Protections
Final decision permitting gene therapy research to be conducted at Penn
OHRP
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.
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.