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.