Innovative Systems for Delivery Innovative Systems for Delivery of Drugs and Biologicsof Drugs and Biologics

Drug-Eluting Stents Drug-Eluting Stents Current Approach to ReviewCurrent Approach to Review

Ashley B. Boam, MSBEAshley B. Boam, MSBEDivision of Cardiovascular DevicesDivision of Cardiovascular Devices

Office of Device EvaluationOffice of Device EvaluationCenter for Devices and Radiological HealthCenter for Devices and Radiological Health

DHHS/FDA/CDRH

What is a Drug-Eluting Stent (DES)?What is a Drug-Eluting Stent (DES)?

DHHS/FDA/CDRH

Example: Cordis’ Cypher™ Sirolimus-Eluting Coronary Stent

Stent Platform & Stent Platform & Delivery SystemDelivery SystemCarrier(s)Carrier(s)DrugDrug

Components

DHHS/FDA/CDRH

DES and the Regulatory ProcessDES and the Regulatory Process

Stent Platform & Delivery System[CRDH Review]

PharmacologicAgent (‘Drug’)

[CDER Review]

Carrier (e.g., Polymer)[CDRH Review]

DrugElutingStent

DHHS/FDA/CDRH

Three Component System

DHHS/FDA/CDRH

Overview of Review “Challenges” for Overview of Review “Challenges” for DESDES

Regulatory jurisdictionRegulatory jurisdiction

Inspectional authority & site readinessInspectional authority & site readiness

Disparity in statutory & regulatory Disparity in statutory & regulatory requirements requirements between CDRH & CDERbetween CDRH & CDER

Appropriate leveraging of information from Appropriate leveraging of information from INDs, NDAs, DMFs, MAFs, etc.INDs, NDAs, DMFs, MAFs, etc.

Appropriate pre-clinical testing & clinical trial Appropriate pre-clinical testing & clinical trial designdesign

Post-market studies and surveillance Post-market studies and surveillance

DHHS/FDA/CDRH

Regulatory JurisdictionRegulatory Jurisdiction

Combination Products (21 CFR Part 3)Combination Products (21 CFR Part 3)

CDRH lead center with CDER consultationCDRH lead center with CDER consultationhttp://www.fda.gov/oc/combination/updates.htmlhttp://www.fda.gov/oc/combination/updates.html

Divisions involved include…Divisions involved include…– Cardiovascular Devices (ODE/CDRH)Cardiovascular Devices (ODE/CDRH)– Cardio-Renal Drug Products (OND/CDER)Cardio-Renal Drug Products (OND/CDER)– New Drug Chemistry I (OPS/CDER)New Drug Chemistry I (OPS/CDER)– Pharmaceutical Evaluation I (OCP/CDER)Pharmaceutical Evaluation I (OCP/CDER)– Mechanics & Materials (OST/CDRH)Mechanics & Materials (OST/CDRH)

Submissions: IDEs & PMAsSubmissions: IDEs & PMAs

DHHS/FDA/CDRH

Regulatory Review Team for DESRegulatory Review Team for DES

CDRH + CDER = SUCCESSCDRH + CDER = SUCCESS

Expertise required…Mechanical Performance

& Testing Regimes

Chemistry [Drug Substance & Carrier(s)]

Manufacturing

Animal Experimentation & Evaluation Clinical Trial Design

& Methodology

Pharmacokinetics / Pharmacodynamics

DHHS/FDA/CDRH

DHHS/FDA/CDRH

Inspectional Authority and Inspectional Authority and Site ReadinessSite Readiness

Inspections conducted by CDRH with Inspections conducted by CDRH with CDER/ONDC participationCDER/ONDC participation

Validations should be complete prior to Validations should be complete prior to inspectioninspection

Subsequent manufacturing changes may Subsequent manufacturing changes may require reinspectionrequire reinspection

DHHS/FDA/CDRH

Approval of Devices, Drugs & BiologicsApproval of Devices, Drugs & BiologicsCDRHCDRH CDERCDER CBERCBER

Approval to begin Clinical EvaluationApproval to begin Clinical Evaluation

IDEIDEInvestigational Device Investigational Device

ExemptionExemption

INDINDInvestigational New DrugInvestigational New Drug

INDINDInvestigational New DrugInvestigational New Drug

Permission to begin MarketingPermission to begin Marketing

PMAPMA(Class III Devices)(Class III Devices)

NDANDANew Drug ApplicationNew Drug Application

BLABLABiologic License ApplicationBiologic License Application

Permission to Market a Modified ProductPermission to Market a Modified Product

PMA SupplementPMA Supplement NDA or NDA or Efficacy/Manufacturing Efficacy/Manufacturing

Supplement (for approved Supplement (for approved drug)drug)

New License Application, New License Application, Efficacy or Manufacturing Efficacy or Manufacturing

SupplementSupplement

Other Pathways to MarketingOther Pathways to Marketing

510(k)510(k)PreMarket ClearancePreMarket Clearance

ANDAANDAAbbreviated NDAAbbreviated NDA

N/AN/A

Generic drug bioequivalent Generic drug bioequivalent to approved drugto approved drug

DHHS/FDA/CDRH

Comparison of Device & Drug DevelopmentComparison of Device & Drug Development

DHHS/FDA/CDRH

Developmental FeatureDevelopmental Feature DeviceDevice DrugDrug

Rate of technology changeRate of technology change FastFast SlowSlow

Ease of Ease of in vitroin vitro assessment assessment HighHigh LowLow

Reimbursement during clinical trialsReimbursement during clinical trials FrequentFrequent RareRare

Influence of MD technique on resultsInfluence of MD technique on results HighHigh LowLow

Ability to visualize performance after useAbility to visualize performance after use High High LowLow

Definition of “Orphan” (# of patients)Definition of “Orphan” (# of patients) 4,0004,000 200,000200,000

# of full scale studies usually required# of full scale studies usually required 11 22

# of regulatory classes# of regulatory classes 33 11

DHHS/FDA/CDRH

Information to Support DES Information to Support DES ApplicationsApplications

* Refer to CDER Guidance, “Content & Format of INDs for Phase 1 Studies of Drugs…”; www.fda.gov/cder/guidance/phase1.pdf

* Refer to CDRH Guidance, “…Interventional Cardiology Devices: …Intravascular Stents”; www.fda.gov/cdrh/ode/846.pdf

DHHS/FDA/CDRH

Drug Drug ± ± Carrier(s)Carrier(s)

Stent Platform Stent Platform **

ApprovedApproved UnapprovedUnapproved

ApprovedApproved 11 22

Unstudied *Unstudied * 33 44

DHHS/FDA/CDRH

Approved vs. UnstudiedApproved vs. UnstudiedDrug SubstancesDrug Substances

Potential Sources for Safety Data (Phase 1 IND)Potential Sources for Safety Data (Phase 1 IND)– Approved drug – NDA Approved drug – NDA – Drug under IND investigationDrug under IND investigation– ““Unstudied” – New Molecular Entity (NME)Unstudied” – New Molecular Entity (NME)

Analog of Approved Drug is an NMEAnalog of Approved Drug is an NME

Necessary Categories of Safety Information Necessary Categories of Safety Information – Chemistry, Manufacturing & Controls (CMC)Chemistry, Manufacturing & Controls (CMC)– Systemic Pre-clinical Pharmacology/ToxicitySystemic Pre-clinical Pharmacology/Toxicity– Systemic Clinical ExposureSystemic Clinical Exposure

Potentially Influences Clinical Trial DesignPotentially Influences Clinical Trial Design

DHHS/FDA/CDRH

Preclinical Testing ObjectivesPreclinical Testing Objectives

Characterization of finished, sterilized product to Characterization of finished, sterilized product to be studied is essentialbe studied is essential– Coating/drug loading characteristics – drug and Coating/drug loading characteristics – drug and

carrier content, uniformity, abrasion resistance (if carrier content, uniformity, abrasion resistance (if coating), particulatecoating), particulate

– In vitroIn vitro/ / in vivoin vivo elution elution

– Methods and initial specifications for stability testingMethods and initial specifications for stability testing

Adequate animal studies needed to assess Adequate animal studies needed to assess safety prior to human studiessafety prior to human studies

DHHS/FDA/CDRH

DHHS/FDA/CDRH

Common Preclinical Testing Common Preclinical Testing DeficienciesDeficiencies

Inadequate Stent Platform TestingInadequate Stent Platform Testing– Fatigue and corrosion testingFatigue and corrosion testing

Inadequate Analysis of Surface ModificationsInadequate Analysis of Surface Modifications– Coating integrity/durabilityCoating integrity/durability

– Drug content/uniformityDrug content/uniformity

Incomplete Incomplete In vitroIn vitro Pharmacokinetics Pharmacokinetics– Methodology and IVIVC, if possibleMethodology and IVIVC, if possible

CMC Issues Inadequately AddressedCMC Issues Inadequately Addressed– Stability/shelf lifeStability/shelf life

DHHS/FDA/CDRH

Common Animal Study DeficienciesCommon Animal Study Deficiencies

Inadequate Reports to Assess SafetyInadequate Reports to Assess Safety

– Lack evaluation of Lack evaluation of doses intended for doses intended for clinical clinical evaluationevaluation &/or &/or overdosageoverdosage at appropriate time points at appropriate time points

– Lack evaluation of serial sections of myocardium Lack evaluation of serial sections of myocardium

– Lack description of arterial histopathology Lack description of arterial histopathology

– Lack necropsy reports Lack necropsy reports (especially important for unexpected deaths)(especially important for unexpected deaths)

DHHS/FDA/CDRH

DHHS/FDA/CDRH

Clinical Evaluation of DESClinical Evaluation of DES

Reasonable Assurance of Reasonable Assurance of SafetySafety and and EffectivenessEffectiveness

Clinical Study Needs to Be Designed for Both Clinical Study Needs to Be Designed for Both ObjectivesObjectives

Usual Standard of Evidence is RCTUsual Standard of Evidence is RCT

Study Endpoints for Coronary DESStudy Endpoints for Coronary DES– Primary – Clinically MeaningfulPrimary – Clinically Meaningful

– Use of surrogate and/or co-primary endpoints? Use of surrogate and/or co-primary endpoints?

– Non-inferiority trial - appropriate deltaNon-inferiority trial - appropriate delta

Use of Independent Core Labs, CEC & Active Use of Independent Core Labs, CEC & Active DSMBDSMB

DHHS/FDA/CDRH

DHHS/FDA/CDRH

DES Post-MarketDES Post-Market

TPLC is critical for DES!TPLC is critical for DES!

5 year follow-up of all patient cohorts 5 year follow-up of all patient cohorts (feasibility, pivotal, any supportive)(feasibility, pivotal, any supportive)

Additional data collection post-market to gain Additional data collection post-market to gain further understanding of rates of drug-related further understanding of rates of drug-related adverse eventsadverse events

Approval for new indications, new study Approval for new indications, new study populations through IDEpopulations through IDE

Adverse events are reported through MDR Adverse events are reported through MDR – reports to CDRH, data shared with CDERreports to CDRH, data shared with CDER

DHHS/FDA/CDRH

Questions? Talk to us!Questions? Talk to us!

Coronary DESCoronary DES

– Ashley Boam, Branch ChiefAshley Boam, Branch Chief ( (aab@cdrh.fda.govaab@cdrh.fda.gov))

– Joni Foy, Ph.D., Lead ReviewerJoni Foy, Ph.D., Lead Reviewer ( (jrf@cdrh.fda.govjrf@cdrh.fda.gov) )

Peripheral DESPeripheral DES

– Elisa Harvey, DVM, Branch ChiefElisa Harvey, DVM, Branch Chief ( (edh@cdrh.fda.govedh@cdrh.fda.gov))

– Jennifer Goode, Lead ReviewerJennifer Goode, Lead Reviewer ( (jlg@cdrh.fda.govjlg@cdrh.fda.gov) )