Regenerative medicine in clinical trials by Derek Brown

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An Introduction to Clinical Trials in Regenerative Medicine David Smith, M.D. Principal and Chief Medical Officer Integrium Clinical Research

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Outline • Clinical and Regulatory Challenges of Regenerative Medicine Trials • Patient Recruitment and Milestone Challenges • Costs of Regenerative versus Traditional trials

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Who is in charge at the FDA? • Center for Biologics Evaluation and Research • Office of Cell, Tissue and Gene Therapy • Potential Review Pathways – Biologics Regulations • IND – Investigational New Drug • BLA- Biologics License Application

– Device Regulations • IDE- Investigational Device Exemption • PMA- Premarketing Application • HDE- Humanitarian Device Exemption

– Combination products • Office of Combination Products) • Previous intercenter agreements and precedents • Device + Cells in conjunction with CDRH

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Regenerative Medicine Trials-Phase 1 Phase 1 • It is imperative to establish a rationale for the first-in-human trial • Cell and gene therapy product trials are conducted in the disease population, not in healthy volunteers – Ascertain recommendations for later clinical trial design – Initial safe starting dose, dose escalation scheme, target organ/tissue toxicity, eligibility criteria, clinical monitoring

• Comply with regulations – 21 CFR 312.23 (a)(8) Pharmacology and Toxicology Information – 21 CFR 58 GLP compliance

Implications • Normal Volunteer Phase1 mills replaced by hospital settings delivering first in man treatment by medical specialists adapting usual procedures • Local IRBs / Safety Review Boards / Recruitment / Staff Training • 5-10 times $ increase in cost and time Copyright © Integrium, LLC

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Regenerative Medicine Trials – Later Phases Site Selection • Sites: enthusiastic; few experienced; over-committed • We strive to incorporate non-academic sites • Central IRBs • Additional Review Requirements – NIH RAC Public hearing – Appendix M – Institutional Biosafety Committees

• You will need to provide additional training for specialized and adapted procedures for delivery • There is a need for Ancillary Facilities – Product reception, storage, preparation Copyright © Integrium, LLC

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Gene Therapy meets Stem Cell Therapy

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Factors Impacting Site Selection & Performance SITE Patient Acquisition ED /ICU/CCU/Clinic

Sponsor Site CRO

PROTOCOL Factor / Impact SOC encouraged ↑↑

Pharmacy

Strict SOC requirements ↓

Product Delivery

Placebo /Sham ↓

Imaging

Acute Care Unaffected ↑↑ Xtra Imaging Required ↓ Radiation Exposure ↓ Prolonged Hospital Stay ↓ Repeat Invasive Procedures ↓ Novel Therapy ↑

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Regenerative Medicine Trials – Later Phases Implications • Longer trials: FPS to LPLV • Modified delivery procedures not covered by SOC • Long term follow-up – Imaging – Tests – Outcomes

• 5-10 X traditional costs – $25-$100 K per patient

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Driving Patient Recruitment- Setting Expectations •

Randomization is a relatively infrequent event over a lengthy enrollment period – Sites randomize a patient every few months – Screen failures approach 90% – “Repeating first patient” syndrome – “lessons learned” lost between successive patients

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Track, Monitor and Compensate Activities Filling The Funnel – Keeps sponsor and site more regularly engaged“What are you doing to find patients?” – Minimizes protocol knowledge loss between randomized patients – Involve study coordinator’s colleagues – Provides the best gauge of site interest and ability to fulfill enrollment quota

All Diseased Patients Those Eligible Consented Screened Randomized

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Determining Efficacy Could be quite elementary… • What was absent or malfunctioning now present and functioning • Surrogate endpoints might be acceptable

…or quite confounding • Assessing the efficacy of a single treatment added to “standard of care” – Benefits sustained over the long term – An improvement over SOC when SOC intensifies with time; Sham arm? – Outcomes benefits v. surrogate endpoints • • • •

Improvements in Quality of Life Reduced need “for standard of care” Reduced utilization of medical resources Distinguish from confounding outcomes – All Cause Mortality; All Cause Hospitalizations

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Monitoring or Conducting Safety • Will Traditional Outcomes efficacy trump all? – Rethink statistical models

• Monitoring in vivo cell fate – Migration (where to they go?) – Survival (how long do they exist?) – Phenotype (do they behave?)

• Sophisticated imaging – not widely available – associated with risk and cost

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Costs versus Traditional Trials A Regenerative Medicine Trial ≈ An Outcomes Trial • Site capabilities shortage – Multiple specialists; Division of PI responsibilities

• Modified procedures v. usual and customary – Facilities, equipment, training

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More protracted Regulatory Reviews & Contracting Patient Recruitment Activities Offering therapy to those allocated Sham Long term follow-up – Imaging & tests – Covering therapy related complications

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Where we find ourselves… • Regenerative Medicine therapies have the potential to repair and even correct diseased tissue • Tantalizing niche applications have moved into the clinical setting • Developing iPSCs capable of replacing diseased tissue at our direction has yet to be attained

A great start…a way to go…but we must respond to the challenge…

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About Integrium • Integrium is a full service clinical research firm that specializes in the strategy, study design, and execution of Proof of Concept clinical trials. •

Integrium was founded in 1998 by clinical research thought leaders who had a vision of building a CRO based on therapeutic focus and excellence. These individuals continue to lead the company today.

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Integrium’s Client Base consists of specialty, small, mid-size, and large biopharmaceutical companies.

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Regenerative Medicine Experience • Gene, stem cell, Gene-Stem Cell, growth factor and tissue trial experience • Post MI, Heart Failure • Diabetes Mellitus • Wound healing

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Scientific Leadership David H.G. Smith, M.D. • •

Chief Medical Officer and Founding Partner. Extensively involved in clinical research in the cardiovascular and metabolic areas – – – –

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Chronic and acute conditions Large international, multicenter clinical trial programs Advisory boards Feasibility reviews on planned trials

Special interests in the study of the renin-angiotensin system, disorders of arterial compliance and endothelial dysfunction, 24-hour ambulatory blood pressure monitoring and the general pharmacotherapy of cardiovascular and metabolic disorders. Authored numerous journal articles, abstracts, and book chapters; formally presented at many scientific meetings. Medical degree from the University of Witwatersrand in Johannesburg, South Africa; Completed training in internal medicine and cardiovascular disease at the Veterans Affairs Medical Center, Long Beach, California and at the University of California, Irvine Member of several specialty organizations; designated as a Specialist in Clinical Hypertension.

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Scientific Leadership – Joel M. Neutel, M.D. • •

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Medical Director and Founding Partner Director of Research of the Orange County Research Center in Tustin, California and at the Memorial Research Medical Clinic in Long Beach, California. – Principal Investigator on hundreds of trials in the cardiovascular, metabolic, and other therapeutic areas. – Phase 1 – 4 Supports and advises the biopharmaceutical industry on clinical development programs, and strategic planning and market positioning Medical degree from the University of Witwatersrand in Johannesburg, South Africa; completed his internship and residency in internal medicine at the Veterans Administration Medical Center in Long Beach and University of California, Irvine Authored numerous abstracts, journal articles and book chapters.

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Global Clinical Research Services CLINICAL OPERATIONS Phases I-IV Study Design Protocol Development Investigator Identification / Recruitment Project Leadership Site Monitoring Site Management Patient Recruitment Staffing Solutions

RESEARCH SITE | CORE LAB SERVICES Clinical Pharmacology Unit Phase I - IV Unit Ambulatory Blood Pressure Monitoring

DATA MANAGEMENT | BIOSTASTICS CRF Design CRF Production Database Design / Setup Data Entry / EDC Data Validation / Cleaning Database Transfers Statistical Analysis Plans SAS Programming Statistical Analysis

MEDICAL SAFETY Serious Adverse Event Management Medical Monitoring Medical Coding Database Reconciliation Coding of Adverse Events and Concomitant Medications DSMB Management Endpoint Adjudication Lab Safety Review

QUALITY ASSURANCE Quality Assurance Consulting Quality Assurance Auditing Records Management Document Archiving Quality Systems Regulatory Authority Inspections / Preparations / Management

REGULATORY SERVICES Regulatory Strategy Consulting Strategic Drug Development Consulting Regulatory Submissions Medical Writing

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At Integrium, the whole world is our laboratory Integrium offices:  Southern California  NY/NJ Metro Area  Johannesburg, South Africa Partnerships with regional CROs:  Europe  Central America  South America  Australia  India Copyright © Integrium, LLC

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Integrium works with:  Major biopharmaceuticals companies including 12 of the top 20 firms  Mid-sized biopharmaceutical companies  Development-phase and specialty biopharmaceutical companies  Pharma spinoff companies  Generic pharmaceutical Companies  University Research Teams Copyright © Integrium, LLC

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Integrium studies include:           

PK/PD First-in-man Dose-ranging Thorough QT/QTc Bioavailability Bioequivalence Drug interactions Food-effect Proof-of-concept Renal impairment In vivo/In vitro correlation

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Integrium is affiliated with the Orange County Research Center  

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52-bed clinical pharmacology unit Located in a diverse, metropolitan population center with 24 nearby colleges and universities Extensive database of patients and healthy volunteers Dedicated, in-house recruiters Experienced clinicians, coordinators and nurses AHA, ACLS certified

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