Innovative Systems for Delivery of Drugs and Biologics DrugEluting Stents Current Approach to Review

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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

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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
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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
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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

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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
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Regulatory Review Team for DES
Expertise required
Mechanical Performance Testing Regimes
Animal Experimentation Evaluation
Clinical Trial Design Methodology
Chemistry Drug Substance Carrier(s)
Pharmacokinetics / Pharmacodynamics
Manufacturing

• CDRH CDER SUCCESS

DHHS/FDA/CDRH
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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

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Approval of Devices, Drugs Biologics
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Comparison of Device Drug Development
DHHS/FDA/CDRH
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Information to Support DES Applications
Refer to CDER Guidance, Content Format of
INDs for Phase 1 Studies of Drugs www.fd
a.gov/cder/guidance/phase1.pdf
Refer to CDRH Guidance, Interventional
Cardiology Devices Intravascular Stents
www.fda.gov/cdrh/ode/846.pdf
DHHS/FDA/CDRH
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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

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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
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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

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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
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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
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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

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Questions? Talk to us!

• Coronary DES
• Ashley Boam, Branch Chief (aab_at_cdrh.fda.gov)
• Joni Foy, Ph.D., Lead Reviewer (jrf_at_cdrh.fda.gov)
  
  
• Peripheral DES
• Elisa Harvey, DVM, Branch Chief
  (edh_at_cdrh.fda.gov)
  
• Jennifer Goode, Lead Reviewer (jlg_at_cdrh.fda.gov)