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

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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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Innovative systems for delivery of drugs and biologics drug 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)?

Example:Cordis’ Cypher™ Sirolimus-Eluting Coronary Stent


  • Stent Platform & Delivery System

  • Carrier(s)

  • Drug


Des and the regulatory process

DES and the Regulatory Process

Three Component System

Stent Platform & Delivery System

[CRDH Review]





Agent (‘Drug’)

[CDER Review]

Carrier (e.g., Polymer)

[CDRH Review]


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

  • 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


Regulatory review team for des

Expertise required…

Regulatory Review Team for DES

Mechanical Performance

& Testing Regimes

Animal Experimentation

& Evaluation

Clinical Trial Design

& Methodology


[Drug Substance & Carrier(s)]


Pharmacokinetics /




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


Information to support des applications

Information to Support DES Applications

* Refer to CDER Guidance, “Content & Format of INDs for Phase 1

Studies of Drugs…”;

* Refer to CDRH Guidance, “…Interventional Cardiology Devices:

…Intravascular Stents”;


Approved vs unstudied drug 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


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)


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


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 (

    • Joni Foy, Ph.D., Lead Reviewer (

  • Peripheral DES

    • Elisa Harvey, DVM, Branch Chief (

    • Jennifer Goode, Lead Reviewer (

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