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Innovative Systems for Delivery of Drugs and Biologics Drug-Eluting Stents Current Approach to Review

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

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Innovative Systems for Delivery of Drugs and Biologics Drug-Eluting Stents Current Approach to Review

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  1. 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

  2. What is a Drug-Eluting Stent (DES)? Example:Cordis’ Cypher™ Sirolimus-Eluting Coronary Stent Components • Stent Platform & Delivery System • Carrier(s) • Drug DHHS/FDA/CDRH

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

  4. 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. 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. Expertise required… Regulatory Review Team for DES Mechanical Performance & Testing Regimes Animal Experimentation & Evaluation Clinical Trial Design & Methodology Chemistry [Drug Substance & Carrier(s)] CDRH + CDER = SUCCESS Pharmacokinetics / Pharmacodynamics Manufacturing 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. Approval of Devices, Drugs & Biologics

  9. Comparison of Device & Drug Development DHHS/FDA/CDRH

  10. 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

  11. 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

  12. 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. 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. 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)

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