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FDA Regulation of Cell FDA Regulation of Cell TherapyTherapy

Celia M.Witten, Ph.D., M.D.Celia M.Witten, Ph.D., M.D.Director, Office of Cellular, Tissue, and Gene Director, Office of Cellular, Tissue, and Gene

TherapiesTherapiesThird Annual HD Clinical Research SymposiumThird Annual HD Clinical Research Symposium

November 21, 2009November 21, 2009Baltimore, Maryland Baltimore, Maryland

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OutlineOutline

OCTGTOCTGTEarly Clinical DevelopmentEarly Clinical DevelopmentFDA Outreach/Policy DevelopmentFDA Outreach/Policy DevelopmentFDA Critical Path ResearchFDA Critical Path Research

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OrganizationOrganization CBER (Center for Biologics Evaluation and Research): vaccines, CBER (Center for Biologics Evaluation and Research): vaccines,

blood and blood products, human tissue/tissue products for blood and blood products, human tissue/tissue products for transplantation, cells, gene therapytransplantation, cells, gene therapy Office of Cellular, Tissue, and Gene TherapiesOffice of Cellular, Tissue, and Gene Therapies Office of Vaccines Research and ReviewOffice of Vaccines Research and Review Office of Blood Research and ReviewOffice of Blood Research and Review

CDER (Center for Drug Evaluation and Research): drugs, some CDER (Center for Drug Evaluation and Research): drugs, some biological productsbiological products

CDRH (Center for Devices and Radiological Health): devices for CDRH (Center for Devices and Radiological Health): devices for treatment, implants, diagnostic devicestreatment, implants, diagnostic devices

CVMCVM CFSANCFSAN NCTRNCTR

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Office of Cellular, Tissue, and Gene TherapiesCelia M.Witten, Ph.D, M.D.

Stephanie Simek, Ph.D., Office Deputy DirectorRichard McFarland, Ph.D, M.D. Associate Director for Policy

Suzanne Epstein, Ph.D., Associate Director for ResearchPatrick Riggins, Ph.D., Director RPM

Division of Cellular and Gene TherapiesRaj Puri, Ph.D., M.D., Director

Division of Human TissuesEllen Lazarus, M.D., Director

Division of Clinical Evaluation and Pharmacology/ToxicologyVacant

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Organization Cont’dOrganization Cont’d Office of Cellular, Tissue, and Gene Therapies, Celia

M.Witten, Ph.D, M.D. Stephanie Simek, Ph.D., Office Deputy Director Richard McFarland, Ph.D, M.D. Associate Director for Policy Suzanne Epstein, Ph.D., Associate Director for Research Patrick Riggins, Ph.D., Director RPM Division of Cellular and Gene Therapies Raj Puri, Ph.D., M.D.,

Director Division of Human Tissues Ellen Lazarus, M.D., Director Division of Clinical Evaluation and Pharmacology/Toxicology

Vacant

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OCTGT ProductsOCTGT Products

Cellular therapies Cellular therapies Tumor vaccines and immunotherapyTumor vaccines and immunotherapy Gene therapiesGene therapies Tissue and tissue based productsTissue and tissue based products Xenotransplantation productsXenotransplantation products Combination products Combination products Devices used for cells/tissuesDevices used for cells/tissues Donor screening tests (for use with cadaveric Donor screening tests (for use with cadaveric

blood samples)blood samples)

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Cells: Examples of Cells: Examples of Indications/SourcesIndications/Sources

Pancreatic islets for diabetesPancreatic islets for diabetes Stem and skeletal muscle progenitor cells for Stem and skeletal muscle progenitor cells for

ischemic cardiac ischemic cardiac Hematopoietic reconstitution in treatment of Hematopoietic reconstitution in treatment of

malignanciesmalignancies Stem cells for metabolic storage diseasesStem cells for metabolic storage diseases Stem cells for CNS indications (Parkinson’s Stem cells for CNS indications (Parkinson’s

disease)disease) Expanded autologous cartilage for joint repairExpanded autologous cartilage for joint repair

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Early Clinical DevelopmentEarly Clinical Development

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[Some] Questions that Should be Asked[Some] Questions that Should be Asked

What cell type(s) will be used?What cell type(s) will be used? What is the source of the cell(s)?What is the source of the cell(s)? How many cells are needed?How many cells are needed? Are the cells implanted alone?...with a scaffold?Are the cells implanted alone?...with a scaffold? Are the cells modified?...now a ‘gene therapy’?Are the cells modified?...now a ‘gene therapy’? What is the proposed therapeutic action?What is the proposed therapeutic action? What is/are the biologically relevant animal What is/are the biologically relevant animal

species for your product ? species for your product ? Are there potentially relevant animals models of Are there potentially relevant animals models of

disease/injury that can be used?disease/injury that can be used?

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[Some] More Questions…[Some] More Questions…What is the optimal method/route to What is the optimal method/route to

deliver the product?deliver the product?What is the optimal timing for product What is the optimal timing for product

administration relative to the onset of administration relative to the onset of disease/ injury? disease/ injury?

What happens to the cells What happens to the cells in vivoin vivo following following delivery?delivery?

Will repeat administration be needed? Will repeat administration be needed? What is the risk/benefit ratio for the What is the risk/benefit ratio for the

intended patient population?intended patient population?

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Developing a Cell-Based productDeveloping a Cell-Based product

Source ControlsSource ControlsManufacturing Process controlsManufacturing Process controls

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Product Safety and EfficacyProduct Safety and Efficacy

Safety Issues:Safety Issues:Sterility (bacterial, fungal, mycoplasma)Sterility (bacterial, fungal, mycoplasma)PurityPurity IdentityIdentitySegregation and trackingSegregation and tracking

Efficacy Issues:Efficacy Issues:PotencyPotencyStabilityStability

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Cell Therapy Product Cell Therapy Product CharacterizationCharacterization

Morphologic evaluationMorphologic evaluationUnique biochemical markersUnique biochemical markersGene and protein expression analysisGene and protein expression analysisCellular impurities profileCellular impurities profileBiologic activity/PotencyBiologic activity/Potency Identity: HLA, other unique markerIdentity: HLA, other unique marker

Preclinical Expectations for Early Preclinical Expectations for Early Phase Clinical TrialsPhase Clinical Trials

Proof-of-concept [POC] Proof-of-concept [POC] Potential mechanism of action [neuroprotective, Potential mechanism of action [neuroprotective,

neoangiogenesis, tolerance induction, etc…]neoangiogenesis, tolerance induction, etc…] Establish pharmacologically effective dose(s)Establish pharmacologically effective dose(s) Optimize ROA/dosing regimenOptimize ROA/dosing regimen Rationale for species/model selection for further testingRationale for species/model selection for further testing

Safety of conducting clinical trial – risk/benefitSafety of conducting clinical trial – risk/benefit Dosing schemeDosing scheme Potential target tissue(s) of toxicity/activityPotential target tissue(s) of toxicity/activity Parameters to monitor clinicallyParameters to monitor clinically Eligible patient populationEligible patient population

Clinically relevant product and study designClinically relevant product and study design

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Preclinical Study Design(s)Preclinical Study Design(s) Biologically relevant animal species/modelBiologically relevant animal species/model Appropriate controls and multiple dose levels of productAppropriate controls and multiple dose levels of product DosingDosing regimen – mimic clinical regimen – mimic clinical ‘‘Standard’ toxicology endpointsStandard’ toxicology endpoints

Mortality, clinical observations, body weights, appetiteMortality, clinical observations, body weights, appetite Hematology and coagulationHematology and coagulation Serum chemistrySerum chemistry Pathology – target & nontarget tissuesPathology – target & nontarget tissues

Other endpointsOther endpoints Cell fate [trafficking, survival, differentiation, etc…]Cell fate [trafficking, survival, differentiation, etc…] Functional outcome, PK/PDFunctional outcome, PK/PD Product-dependent [carcinogenicity/tumorigenicity, immunogenicity, Product-dependent [carcinogenicity/tumorigenicity, immunogenicity,

etc…]etc…] Disease-dependent [cardiac, neurological, etc…]Disease-dependent [cardiac, neurological, etc…]

Sufficient study durationSufficient study duration Endpoints measured at multiple intervalsEndpoints measured at multiple intervals

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Investigational StudiesInvestigational Studies Study must be Study must be reasonably safereasonably safe

Risk vs.benefits Risk vs.benefits First-time-in-humans--most attention of allFirst-time-in-humans--most attention of all Consider other trials, indications, similar products, riskds of Consider other trials, indications, similar products, riskds of

procedure;procedure; Assess drug exposure; duration of therapy; number of patients Assess drug exposure; duration of therapy; number of patients

exposed; stopping rules and expected/acceptable toxicity; exposed; stopping rules and expected/acceptable toxicity; potential benefits; type of patients treated; minimization of potential benefits; type of patients treated; minimization of risks to subjects; plans for later phases; supporting animal risks to subjects; plans for later phases; supporting animal data, clinical data, data, clinical data, in vitroin vitro data, manufacturing issues (e.g., data, manufacturing issues (e.g., product sterility, lot release data, etc.)product sterility, lot release data, etc.)

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Objectives of Phase 1 Studies for Objectives of Phase 1 Studies for Traditional Drug DevelopmentTraditional Drug Development

Safety/tolerabilitySafety/tolerabilityPharmacokineticsPharmacokineticsDose selection (MTD)Dose selection (MTD)

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Objectives of Early Phase Studies Objectives of Early Phase Studies for Cell/Gene Therapies may also for Cell/Gene Therapies may also

include information to inform:include information to inform:Product characterizationProduct characterizationProduct delivery/dosing/safetyProduct delivery/dosing/safetyProof of concept/mechanism of actionProof of concept/mechanism of actionPatient selection (include biomarkers)Patient selection (include biomarkers)Assessment parameters for toxicityAssessment parameters for toxicityEffectiveness parameters (early surrogates Effectiveness parameters (early surrogates

and modeling of relationships)and modeling of relationships)Timing of assessmentsTiming of assessmentsDuration of observationDuration of observation

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Huntington’s Disease: Challenges Huntington’s Disease: Challenges for Cell Therapyfor Cell Therapy

Relatively small patient populationRelatively small patient populationDefining the therapeutic product/targetDefining the therapeutic product/targetEarly evidence from animal modelsEarly evidence from animal modelsDelivery modalitiesDelivery modalitiesDuration of observation/availability of early Duration of observation/availability of early

measures measures

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Examples from Other FieldsExamples from Other Fields

CardiologyCardiologyPancreatic IsletsPancreatic Islets

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Rosenzweig, A. Cardiac Cell Therapy-Mixed Results from Mixed Rosenzweig, A. Cardiac Cell Therapy-Mixed Results from Mixed Cells (Editorial). N Eng J Med 2006;355: 1274-1277.Cells (Editorial). N Eng J Med 2006;355: 1274-1277.

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Product AdministrationProduct Administration Site of Injection Site of Injection

Method to Determine the Sites of InjectionMethod to Determine the Sites of Injection Method to Match the Actual and Planned SitesMethod to Match the Actual and Planned Sites Method to Record the Location of InjectionMethod to Record the Location of Injection

ProductProduct ConcentrationConcentration VolumeVolume RateRate

Administration Administration # Injections (total and per wall)# Injections (total and per wall) # Balloon Inflations, Duration# Balloon Inflations, Duration

DeliveryDelivery Hand deliveryHand delivery Device Device

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Pancreatic IsletsPancreatic Islets

Mechanism of action understoodMechanism of action understoodCan follow metabolic activity with clinical Can follow metabolic activity with clinical

measuresmeasuresTechnical issues identifiedTechnical issues identified

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Outreach/Meetings/Policy Outreach/Meetings/Policy Development Development

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FDA and MeetingsFDA and Meetings

Product specific confidential inquiries Product specific confidential inquiries during pre-IND (IDE), IND (IDE) processduring pre-IND (IDE), IND (IDE) process

Scientific meetingsScientific meetingsAdvisory Committee Discussions Advisory Committee Discussions WorkshopsWorkshopsLiaison MeetingsLiaison Meetings

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Early FDA InteractionEarly FDA Interaction Informal: Pre-pre IND discussion Informal: Pre-pre IND discussion

(Generally CMC and Preclinical topics)(Generally CMC and Preclinical topics)PreIND/Type B: Formal meeting (Discuss PreIND/Type B: Formal meeting (Discuss

product development activities prior to product development activities prior to submission of an Investigational New Drug submission of an Investigational New Drug (IND) application(IND) application

Contact: Contact: Patrick S. Riggins, Ph.D., Patrick S. Riggins, Ph.D., Branch Chief Branch Chief Regulatory Management StaffRegulatory Management Staff Office of Cellular Tissue and Gene TherapiesOffice of Cellular Tissue and Gene Therapies Center for Biologics Evaluation and ResearchCenter for Biologics Evaluation and Research Food and Drug AdministrationFood and Drug Administration 1401 Rockville Pike, Rockville Maryland 208521401 Rockville Pike, Rockville Maryland 20852 301-827-5366 (phone) 301-827-9796 (fax)301-827-5366 (phone) 301-827-9796 (fax)

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Recent Meetings/WorkshopsRecent Meetings/Workshops

Sponsored or co-sponsored by FDA onSponsored or co-sponsored by FDA onscientific/regulatory topics:scientific/regulatory topics:

FDA/NIAID Workshop: Animal Models for the Treatment of FDA/NIAID Workshop: Animal Models for the Treatment of Acute Radiation Syndrome — September 27, 2008Acute Radiation Syndrome — September 27, 2008

FDA/NIH/CIBMTR/ASBMT Workshop: Clinical Trials FDA/NIH/CIBMTR/ASBMT Workshop: Clinical Trials Endpoints for Acute Graft-Versus-Host Disease After Endpoints for Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation — Allogeneic Hematopoietic Stem Cell Transplantation — March 13, 2009March 13, 2009

FDA/NCI Workshop: Therapeutic Cancer VaccinesFDA/NCI Workshop: Therapeutic Cancer VaccinesConsiderations for Early Phase Clinical Trials Based on Considerations for Early Phase Clinical Trials Based on Lessons Learned from Phase IIILessons Learned from Phase III — October 27, 2009— October 27, 2009

NIH/JDRF/FDA Workshop: Next Generation Beta-Cell NIH/JDRF/FDA Workshop: Next Generation Beta-Cell Transplantation — November 9, 2009Transplantation — November 9, 2009

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Recent Advisory Committee Recent Advisory Committee MeetingsMeetings

April 10-11 2008:April 10-11 2008: Cellular Therapies Derived from Human Embryonic Stem Cells Scientific Cellular Therapies Derived from Human Embryonic Stem Cells Scientific

Considerations for Pre-Clinical Safety TestingConsiderations for Pre-Clinical Safety Testing Response to September 2005 Review of OCTGT Research ProgramResponse to September 2005 Review of OCTGT Research Program FDA Somatic Cell Therapy LetterFDA Somatic Cell Therapy Letter Update: OCTGT Guidance Development ProgramUpdate: OCTGT Guidance Development Program

May 14-15 2009: May 14-15 2009: The potential for The potential for Chlamydia trachomatisChlamydia trachomatis and and Neisseria gonorrheaNeisseria gonorrhea

transmission by certain human cells, tissues, and cellular and tissue-transmission by certain human cells, tissues, and cellular and tissue-based products (HCT/Ps) based products (HCT/Ps)

Animal models for porcine xenotransplantation products intended to Animal models for porcine xenotransplantation products intended to treat Type 1 diabetes or acute liver failure treat Type 1 diabetes or acute liver failure

Clinical issues related to the FDA draft guidance “Preparation of IDEs Clinical issues related to the FDA draft guidance “Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage.”and INDs for Products Intended to Repair or Replace Knee Cartilage.”

October 9 2009: Isolagen Therapy for moderate to severe October 9 2009: Isolagen Therapy for moderate to severe nasolabial fold wrinklesnasolabial fold wrinkles

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Safety of Cell Therapies Derived Safety of Cell Therapies Derived from Human Embryonic Stem Cellsfrom Human Embryonic Stem Cells

April 10, 2008April 10, 2008

Safety ConcernsSafety ConcernsProduct CharacterizationProduct CharacterizationTrial DesignTrial Design

Contributions from Contributions from Advisory Committee MeetingsAdvisory Committee MeetingsReviewer Experience/Interactions with Reviewer Experience/Interactions with

StakeholdersStakeholders

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Safety ConcernsSafety Concerns Stem cells and inappropriate differentiationStem cells and inappropriate differentiation

TeratomaTeratoma Ectopic tissue Ectopic tissue Currently concerns restrict direct use of hESCCurrently concerns restrict direct use of hESC

Persistence of Undifferentiated CellsPersistence of Undifferentiated Cells Likely to be present in ESC-derived productsLikely to be present in ESC-derived products Proliferation, migrationProliferation, migration

Anatomic location and constraintsAnatomic location and constraints Enclosed space (eg IC vs. IV administration)Enclosed space (eg IC vs. IV administration)

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Preclinical StudiesPreclinical Studies Reflect the proposed clinical indication as closely Reflect the proposed clinical indication as closely

as possibleas possible Detect site-dependent toxicitiesDetect site-dependent toxicities Provide evidence to support therapeutic rationaleProvide evidence to support therapeutic rationale Considerations for choice of Animal Models Considerations for choice of Animal Models

Immunosuppressed/immunodeficient animals Immunosuppressed/immunodeficient animals Site of administration Site of administration Absolute number of cells, percentage in the final productAbsolute number of cells, percentage in the final product Number of animals for statistically valid evaluation of Number of animals for statistically valid evaluation of

potentially rare adverse events potentially rare adverse events Duration of studyDuration of study Appropriate monitoringAppropriate monitoring

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Product CharacterizationProduct Characterization

Establish sensitive analytical methods to detect cells with Establish sensitive analytical methods to detect cells with undesired characteristicsundesired characteristics Minimize undifferentiated stem cells Minimize undifferentiated stem cells

Identify characteristics capable of reliably predicting Identify characteristics capable of reliably predicting safety and anticipating clinical effectivenesssafety and anticipating clinical effectiveness in-process and lot release testingin-process and lot release testing

Ensure that products are as safe as possible Ensure that products are as safe as possible current limitations in scientific knowledge current limitations in scientific knowledge

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Clinical Trial DesignClinical Trial DesignRationaleRationale

Contrast established risk (teratoma) vs. Contrast established risk (teratoma) vs. intended clinical benefit (little experience)intended clinical benefit (little experience)

For first in man studies, justified by For first in man studies, justified by particularly strong preclinical proof-of particularly strong preclinical proof-of conceptconcept

Appropriate trial designAppropriate trial designDoses/dose escalationDoses/dose escalationPatient monitoringPatient monitoringFollow-upFollow-up

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Major ConsiderationsMajor Considerations

Stronger than usual proof of concept evidence Stronger than usual proof of concept evidence may be requiredmay be required

The dose of cells administered to humans The dose of cells administered to humans should be below the minimum number of cells should be below the minimum number of cells observed to form tumors in animal modelsobserved to form tumors in animal models

First in man clinical applications should be First in man clinical applications should be picked carefully due to inherent riskspicked carefully due to inherent risks

Long term follow up recommended due to Long term follow up recommended due to perceived risk perceived risk

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2009 Guidance Documents2009 Guidance Documents Draft Guidance for Industry: Clinical Considerations for Draft Guidance for Industry: Clinical Considerations for

Therapeutic Cancer Vaccines 9/2009Therapeutic Cancer Vaccines 9/2009 Guidance for Industry: Considerations for Allogeneic Guidance for Industry: Considerations for Allogeneic

Pancreatic Islet Cell Products 9/2009Pancreatic Islet Cell Products 9/2009 Draft Guidance for Industry: Somatic Cell Therapy for Cardiac Draft Guidance for Industry: Somatic Cell Therapy for Cardiac

Disease 3/2009Disease 3/2009 Draft Guidance for Industry: Use of Serological Tests to Draft Guidance for Industry: Use of Serological Tests to

Reduce the Risk of Transmission of Trypanosoma cruzi Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components for Infection in Whole Blood and Blood Components for Transfusion and Human Cells, Tissues, and Cellular and Transfusion and Human Cells, Tissues, and Cellular and Tissue-Based Products 3/2009Tissue-Based Products 3/2009

Guidance for Industry: Current Good Tissue Practice (CGTP) Guidance for Industry: Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 1/2009(HCT/Ps) 1/2009

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Outreach/CollaborationsOutreach/Collaborations Government organizationsGovernment organizations

MATESMATES NINDSNINDS NCINCI CDCCDC NISTNIST NHLBINHLBI

Liaison meetingsLiaison meetings ISCTISCT AATBAATB

Standards organizationsStandards organizations ASTMASTM AAMIAAMI ISOISO

Research collaborationsResearch collaborations NCTRNCTR NISTNIST NIHNIH CDCCDC Academic InstitutionsAcademic Institutions

International activitiesInternational activities WHOWHO ICHICH EUEU

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Science in Research and Review: Science in Research and Review: Critical Path InitiativeCritical Path Initiative

Bring scientific advances to medical product Bring scientific advances to medical product development process (simulation models, development process (simulation models, validated biomarkers, new clinical trial designs)validated biomarkers, new clinical trial designs)

Stimulate development of applicable research Stimulate development of applicable research programs in critical path scientific areas, aim to programs in critical path scientific areas, aim to develop techniques that address challenges develop techniques that address challenges encountered during product developmentencountered during product development

Regulatory guidance/practice and standards to Regulatory guidance/practice and standards to reflect best available science, integrate FDA reflect best available science, integrate FDA involvementinvolvement

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Research Program AreasResearch Program Areas VirologyVirology

Retroviruses, adeno, herpes, PERVRetroviruses, adeno, herpes, PERV ImmunologyImmunology

Host-vector interactions, transplant rejectionHost-vector interactions, transplant rejection Cell biologyCell biology

Control of differentiation in animal models, stem cell biologyControl of differentiation in animal models, stem cell biology Cancer biologyCancer biology

Molecular biomarkers, animal modelsMolecular biomarkers, animal models BiotechnologyBiotechnology

Microarray, flow cytometryMicroarray, flow cytometry Tissue safetyTissue safety

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Contact InformationContact Information

Celia Witten, PH.D., M.D.Celia Witten, PH.D., M.D.Office Director, OCTGTOffice Director, OCTGTCBER/FDA CBER/FDA 1401 Rockville Pike (HFM 70)1401 Rockville Pike (HFM 70)Rockville, MD 20852-1448Rockville, MD 20852-1448witten@cber.fda.govwitten@cber.fda.gov301-827-5102301-827-5102