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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 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

Components

  • Stent Platform & Delivery System

  • Carrier(s)

  • Drug

DHHS/FDA/CDRH


Des and the regulatory process
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


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

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


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




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 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

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 ([email protected])

    • Joni Foy, Ph.D., Lead Reviewer ([email protected])

  • Peripheral DES

    • Elisa Harvey, DVM, Branch Chief ([email protected])

    • Jennifer Goode, Lead Reviewer ([email protected])


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