03n-0203-ts00010-Boam

Innovative Systems for Delivery of Drugs and BiologicsDrug-Eluting Stents Current Approach to Review : 

Innovative Systems for Delivery of Drugs and BiologicsDrug-Eluting Stents Current Approach to Review Ashley B. Boam, MSBE Division of Cardiovascular Devices Office of Device Evaluation Center for Devices and Radiological Health

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 & Delivery System Carrier(s) Drug Components

DES and the Regulatory Process : 

DES and the Regulatory Process Stent Platform & Delivery System [CRDH Review] Pharmacologic Agent (‘Drug’) [CDER Review] Carrier (e.g., Polymer) [CDRH Review] Drug Eluting Stent DHHS/FDA/CDRH Three Component System

Overview of Review “Challenges” for DES : 

Overview of Review “Challenges” for DES Regulatory jurisdiction Inspectional authority & site readiness Disparity in statutory & regulatory requirements between CDRH & CDER Appropriate leveraging of information from INDs, NDAs, DMFs, MAFs, etc. Appropriate pre-clinical testing & clinical trial design Post-market studies and surveillance

Regulatory Jurisdiction : 

Regulatory Jurisdiction Combination Products (21 CFR Part 3) CDRH lead center with CDER consultation http://www.fda.gov/oc/combination/updates.html Divisions involved include… Cardiovascular Devices (ODE/CDRH) Cardio-Renal Drug Products (OND/CDER) New Drug Chemistry I (OPS/CDER) Pharmaceutical Evaluation I (OCP/CDER) Mechanics & Materials (OST/CDRH) Submissions: IDEs & PMAs DHHS/FDA/CDRH

Regulatory Review Team for DES : 

Regulatory Review Team for DES CDRH + 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

Inspectional Authority and Site Readiness : 

Inspectional Authority and Site Readiness Inspections conducted by CDRH with CDER/ONDC participation Validations should be complete prior to inspection Subsequent manufacturing changes may require reinspection

Approval of Devices, Drugs & Biologics : 

Approval of Devices, Drugs & Biologics

Comparison of Device & Drug Development : 

Comparison of Device & Drug Development DHHS/FDA/CDRH

Information to Support DES Applications : 

Information to Support DES Applications * 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

Approved vs. UnstudiedDrug Substances : 

Approved vs. UnstudiedDrug Substances Potential Sources for Safety Data (Phase 1 IND) Approved drug – NDA Drug under IND investigation “Unstudied” – New Molecular Entity (NME) Analog of Approved Drug is an NME Necessary Categories of Safety Information Chemistry, Manufacturing & Controls (CMC) Systemic Pre-clinical Pharmacology/Toxicity Systemic Clinical Exposure Potentially Influences Clinical Trial Design

Preclinical Testing Objectives : 

Preclinical Testing Objectives Characterization of finished, sterilized product to be studied is essential Coating/drug loading characteristics – drug and carrier content, uniformity, abrasion resistance (if coating), particulate In vitro/ in vivo elution Methods and initial specifications for stability testing Adequate animal studies needed to assess safety prior to human studies DHHS/FDA/CDRH

Common Preclinical Testing Deficiencies : 

Common Preclinical Testing Deficiencies Inadequate Stent Platform Testing Fatigue and corrosion testing Inadequate Analysis of Surface Modifications Coating integrity/durability Drug content/uniformity Incomplete In vitro Pharmacokinetics Methodology and IVIVC, if possible CMC Issues Inadequately Addressed Stability/shelf life

Common Animal Study Deficiencies : 

Common Animal Study Deficiencies Inadequate Reports to Assess Safety Lack evaluation of doses intended for clinical evaluation &/or overdosage at appropriate time points Lack evaluation of serial sections of myocardium Lack description of arterial histopathology Lack necropsy reports (especially important for unexpected deaths) DHHS/FDA/CDRH

Clinical Evaluation of DES : 

Clinical Evaluation of DES Reasonable Assurance of Safety and Effectiveness Clinical Study Needs to Be Designed for Both Objectives Usual Standard of Evidence is RCT Study Endpoints for Coronary DES Primary – Clinically Meaningful Use of surrogate and/or co-primary endpoints? Non-inferiority trial - appropriate delta Use of Independent Core Labs, CEC & Active DSMB DHHS/FDA/CDRH

DES Post-Market : 

DES Post-Market TPLC is critical for DES! 5 year follow-up of all patient cohorts (feasibility, pivotal, any supportive) Additional data collection post-market to gain further understanding of rates of drug-related adverse events Approval for new indications, new study populations through IDE Adverse events are reported through MDR reports to CDRH, data shared with CDER

Questions? Talk to us! : 

Questions? Talk to us! Coronary DES Ashley Boam, Branch Chief (aab@cdrh.fda.gov) Joni Foy, Ph.D., Lead Reviewer (jrf@cdrh.fda.gov) Peripheral DES Elisa Harvey, DVM, Branch Chief (edh@cdrh.fda.gov) Jennifer Goode, Lead Reviewer (jlg@cdrh.fda.gov)