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

2. DHHS/FDA/CDRH 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

3. DHHS/FDA/CDRH 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

4. DHHS/FDA/CDRH 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

5. DHHS/FDA/CDRH 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

6. 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

7. 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

8. DHHS/FDA/CDRH Approval of Devices, Drugs & Biologics CDRHCDERCBER Approval to begin Clinical Evaluation IDE Investigational Device Exemption IND Investigational New Drug IND Permission to begin Marketing PMA (Class III Devices) NDA New Drug Application BLA Biologic License Application Permission to Market a Modified Product PMA Supplement NDA or Efficacy/Manufacturing Supplement (for approved drug) New License Application, Efficacy or Manufacturing Supplement Other Pathways to Marketing 510(k) PreMarket Clearance ANDA Abbreviated NDA N/A Generic drug bioequivalent to approved drug

9. DHHS/FDA/CDRH Comparison of Device & Drug Development DHHS/FDA/CDRH Developmental Feature DeviceDrug Rate of technology change FastSlow Ease of in vitro assessment HighLow Reimbursement during clinical trials FrequentRare Influence of MD technique on results HighLow Ability to visualize performance after use HighLow Definition of “Orphan” (# of patients) 4,000200,000 # of full scale studies usually required 12 # of regulatory classes 31

10. DHHS/FDA/CDRH 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 Drug ± Carrier(s) Stent Platform * ApprovedUnapproved Approved12 Unstudied * 34

11. DHHS/FDA/CDRH Approved vs. Unstudied Drug 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

12. DHHS/FDA/CDRH 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

13. 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

14. DHHS/FDA/CDRH 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

15. 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

16. 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

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