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)?

Example: Cordis Cypher Sirolimus-Eluting Coronary Stent

Components
Stent Platform &
Delivery System
Carrier(s)
Drug

DHHS/FDA/CDRH

DES and the Regulatory Process

Three Component System
Stent Platform & Delivery System
[CRDH Review]

Pharmacologic
Agent (Drug)
[CDER Review]

Drug
Eluting
Stent

Carrier (e.g., Polymer)

[CDRH Review]

DHHS/FDA/CDRH

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
DHHS/FDA/CDRH

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
Mechanical Performance
& Testing Regimes
Animal Experimentation
& Evaluation
Chemistry
[Drug Substance & Carrier(s)]

Clinical Trial Design

& Methodology
Pharmacokinetics /
Pharmacodynamics

Manufacturing

CDRH + CDER = SUCCESS

DHHS/FDA/CDRH

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

DHHS/FDA/CDRH

Approval of Devices, Drugs & Biologics

CDRH

CDER

CBER

Approval to begin Clinical Evaluation

IDE
Investigational Device
Exemption

IND
Investigational New Drug

IND
Investigational New Drug

Permission to begin Marketing

PMA
(Class III Devices)

NDA
New Drug Application

BLA
Biologic License Application

Permission to Market a Modified Product

PMA Supplement

NDA or
Efficacy/Manufacturing
Supplement (for approved
drug)

New License Application,

Efficacy or Manufacturing
Supplement

Other Pathways to Marketing

510(k)
PreMarket Clearance

ANDA
Abbreviated NDA

N/A

Generic drug bioequivalent

to approved drug
DHHS/FDA/CDRH

Comparison of Device & Drug Development

Developmental Feature

Device

Drug

Rate of technology change

Fast

Slow

Ease of in vitro assessment

High

Low

Frequent

Rare

Influence of MD technique on results

High

Low

Ability to visualize performance after use

High

Low

Definition of Orphan (# of patients)

4,000

200,000

# of full scale studies usually required

# of regulatory classes

Reimbursement during clinical trials

DHHS/FDA/CDRH

Information to Support DES

Applications
Drug
Carrier(s)
Approved
Unstudied *

Stent Platform *
Approved
Unapproved
1
3

2
4

* 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
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

DHHS/FDA/CDRH

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
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
DHHS/FDA/CDRH

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

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
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
DHHS/FDA/CDRH

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)
DHHS/FDA/CDRH