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Robert T. McNally, Ph.D.CEO – Cell Dynamics, LLC
Regulation of Tissue EngineeredProducts by the FDA
Pre-clinical trials, Safety, Efficacy, Clinical end-points
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GLOSSARY OF TERMS
• Pre-clinical Trials– Normally, animal trials designed to mimic the human
condition the tissue engineered product is designed tocorrect
• Safety– DO NO HARM– Toxicology - Non-clinical safety study– Sometimes determined in pre-clinical trial– Definitely part of human (clinical) trials
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GLOSSARY OF TERMS
• Efficacy– Does it function for the intended purpose?– Does it function better than current clinical products?
• Clinical End-points– What is measurable to supply a statistically relevant
observation to support safety and/or efficacy?
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Bioengineering Approach to
Product Development
Design
IdeaPrototype
Animal
ModelFunctional
Product
Human Clinicals
PHASE I, II, III
Product Release
PHASE IVScale up Production
Final FDASubmission
FDASubmission
IDE & IND
Next modelor design
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Design Idea
• R&D• Do not harm• Improvement over current products• Can it be manufactured?• End user friendly• Will someone pay?• FDA approvable?
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Prototype Animal
• Toxicology• Safety & efficacy• Failure mode analysis• Small vs. large animal• Determine method of use
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Functional Product
• cGmp• Control of:
– Facility– Equipment (validation)– Personnel– Raw materials (audit)– Production– Storage– Documents– Final Product
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Human Clinicals
• Safety & efficacy• Determine endpoints• Clinical protocols
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Human ClinicalsPhase I, II, III
• Scale up production
• Final FDA Submission
• Gather Data
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Product ReleasePhase IV
• Monitor for failure• Determine failure modes• Complications• Complaints• Generate performance statistics• Suggest next generation product
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TISSUE ENGINEERINGCONSTRUCT
Vascular Graft, Skin Sub, Valve Whatever?
Device
Prosthetic
IDE
Biologic
Likely Choice
IND
Drug
Not Likely
IND
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REGULATORY APPROVAL OFNEW DRUGS/BIOLOGICS
InitialToxicityStudies IND PLA Marketing
Phase IV StudiesClinical TrialsPhase I, II, III
Initial Phase IProtocol
Pharmacology StudiesPharmacokinetic Studies
Chronic Toxicity StudiesCarcinogenicitySpecial Toxicity StudiesDrug Metabolism
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TISSUE ENGINEEREDPRODUCTS AND THE FDA
• Tissues Regulated by the FDA• Human Tissue as a Biologic• 21 CFR / 1270 / 1271 Part C/210/211/820• Proposed Legislation 1271• FDA Proposed Regulatory Guidelines
–Combinational Products
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REGULATEDTISSUES AND CELLS
• Blood• Human Breast Milk• Reproductive Cells• Bone Marrow• Human Heart Valves• Bone, Cornea, Vessels, Connective Tissue• ?? Engineered and Cultured Tissues ??
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FDA NEW APPROACH February 28, 1997
• “Proposed Approach to the Regulation ofCellular and Tissue-based Products”–Tiered system of regulation–Provides firm structure to regulations–Reduces restrictions on new technology
development–Technology representing higher level of risk
concerns receive greater level of review
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TIERED SYSTEMOF REGULATION
• Areas of Concern– Transmission of Communicable Disease– Processing
• Minimal vs. more-than-minimal– Clinical Safety
• Non-homologous use of cells/tissues• Non-tissue components in product• Metabolic function of cells/tissues
– Promotion and Labeling– Facility / Product Registration
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TISSUE/CELL PROCESSING
• Minimal Manipulation vs. More-than-MinimalManipulation– Alteration of biologic or functional characteristics of
tissue or cell• Less than Minimal Manipulation
– Follow “GTPs” with no S&E Submission• More-than-Minimal Manipulation
– Follow GMPs with controls to address S&E concerns
*Safety and Efficacy
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CLINICAL SAFETYIND or IDE for Safety/Effectiveness Data, if...
• More-than-minimal Manipulation– Alteration of biologic and functional character
• Non-homologous Use– Does not replace an analogous structural function
• Combination with a Non-tissue Component• Tissue/Cell Used for Metabolic Purpose
– Except reproductive or autologous tissue
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• Concept– Vascular Graft
• Design Review (Testing/Efficacy/End-points)– Xenograft Collagen & Mammalian Cells
• Prototype (Design Lock)– 5mm x 10cm
• In-vitro Feasibility– Hemodynamics
• In-vivo Feasibility– 3 Animals Carotid
STEPS IN PRODUCTDEVELOPMENT
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PRECLINICAL TESTING
• Selection of Animal Species– Rat
• Large #• M&F
• Mode of Delivery– Dog
• More likely to mimic human delivery• Immunogenicity - Probably a Big Issue with
Tissue Engineering Constructs– Measurement of antibodies
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• Analysis of Raw Materials/Supplies– Purity, Identity, Strength, Sterility, Stability
• CMC (Validation/Viral Assay Development)– ID By-products and Interaction of All Components
• Documentation Process– SOP/cGMP/GLP
• Toxicology– Acute, Subacute/Subchronic, Chronic
• Pre-clinical Testing (Animal Efficacy/Safety)– Define Human Protocol/End-points
STEPS IN PRODUCTDEVELOPMENT
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PRODUCT DETAIL
• Product– List of all components– Manufacturing and packaging– Limits to identify, strength, quality, purity– Stability
• Labeling– Pharmacology and toxicology– Previous human experience
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PRODUCT DETAIL
• CMC– Chemistry Manufacturing and Control– Assure proper identification of quality, purity, and
strength of product– Product made from impure components, chemical
structures which are toxic, and chemical instability– Poorly characterized cell bank– Starting with source of supply, is it consistent and work
towards current product?– How is it made? Identity, strength, quality, purity
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SAFETY PHARMACOLOGY
• Effects on Cardiovascular,Respiratory, Central Nervous System,Renal System, etc.
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TOXICOKINETICS ANDPHARMACOKINETICS (ADME)
• Absorption• Distribution
– Labeled studies• Metabolism
– Sophisticated detection method chromatographic• Execution• Immunotoxicity• Reproduction performance• Genotixicity• Carcinogenicity• Local Tolerance
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NON-CLINICAL SAFETY• General Purpose is to Evaluate Negative Effects of
Large Dosing a Product in Small Animal Modelsand to Help Determine the Limits to Safety of theProduct (e.g., How Much Can be Used Before theProduct Induces a Negative Effect?).
• Safety Pharmacology - Effect on Vital Function(e.g., CV, Central Nervous System, or RespiratorySystem).
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GENERAL CONSIDERATIONS
Duration of Phase of Duration of Animal Human Exposure Clinical Trial Toxicity Studies
1-3 Days I, II, III, PLA 2 Species; 2 WeeksUp to 2 Weeks I 2 Species; 2 Weeks
II 2 Species, Up to 4 WeeksIII, PLA 2 Species; Up to 3 Months
Up to 3 Months I, II 2 Species; 4 WeeksIII 2 Species; 3 MonthsPLA 2 Species; Up to 6 Months
6 Months to Unlimited I, II 2 Species; 3 MonthsIII 2 Species; 6 Months or LongerPLA 2 Species; 12 Months (Non-rodent)
18 Months (Rodent)
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• Human Protocol– Phase I
• Not Applicable for A/V Shunt– Phase II
• Safety/Efficacy• 3 Sites x 10 Patients on Dialysis• Develop Statistics for Phase III
– Phase III• Efficacy• 10 Sites x 30 Patients on Dialysis
STEPS IN PRODUCTDEVELOPMENT
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CLINICAL TRIAL EXAMPLE• Vascular Graft A/V Shunt for Kidney Dialysis Versus PTFE
– Safety (Do No Harm)• Prions Test: Blood Test• Microbiology Test: Blood Test• No Aneurysm Test: Doppler• Occlusion Test: Doppler
– Efficacy (Functional Parameters)• Flow Test: Doppler• # of Punctures Test: Measurement
– End-points (Label Claims)• Immunogenic Test: Blood Test• Flow Test: Doppler• Patency Test: Doppler• Hematoma Test: Measurement
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CLINICAL TRIAL EXAMPLE
• Skin Graft Versus Porcine Patch for BurnPatients with >50% Burn
– Safety (Do No Harm)
– Efficacy (Functional Parameters)
– End-points (Label Claims)
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• Phase I: Healthy Volunteer (10-50 pts)–Single dose–Dose escalation–Repeated dose
GENERAL CONSIDERATIONSFOR HUMAN CLINICAL TRIALS
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• Phase II: Small Scale(3 Hospitals Doing 10 Procedures for the Indicated Condition)
–Objectives:• Work on surgical technique• Refine end-points• Reassured about doing NO HARM (Safety)• Helps define the statistical difference between the
control group and experimental product to determinethe number of patients required for Phase III
GENERAL CONSIDERATIONS FORHUMAN CLINICAL TRIALS
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GENERAL CONSIDERATIONSFOR HUMAN CLINICAL TRIALS• Phase III: Large Scale Statistically
Relevant Studies(Typically 10 Sites Doing 20 or More Patients per Site)
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• Product License Application/FDA Submission• Approval (3-5 Years After Initial Concept)• Post-Marketing Surveillance
STEPS IN PRODUCTDEVELOPMENT
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DRUG DEVELOPMENTIN THE UNITED STATES
AverageTime Required
(?) 3.5 years 6 years 2 years
Laboratory
Synthesis
Preclinical(Animal)
Pharmacology
Toxicology
DiscoveryPLA
Manifested
PLAApproval
PLASubmissionIND
Filing
ClinicalIND
Phase 1 Phase 3Phase 3Phase 2(Cont.)
Phase 4