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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. 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!
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