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Regulatory Challenges for
Bioabsorbable Stent Approval
Ashley Boam, MSBE for:
Andrew Farb, M.D.
Interventional Cardiology Devices Branch
Division of Cardiovascular Devices
U.S. FDA/CDRH
BIOABSORBABLE STENT SYMPOSIUM
CRT 2010
Washington, DC
February 22, 2010
DHHS/FDA
DISCLOSURES
Ashley Boam
I have no real or apparent conflicts of
interest to report.
Novel DES in
Development or Trials
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New drugs
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Degradable polymers
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DES with biologics
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Programmable stent lengths

Dedicated bifurcation DES

Bioabsorbable stents (BAS)
DHHS/FDA
Characterization of
Biodegradable Stents (BAS)
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Questions that guide testing:
– What are the expected advantages of the
BAS?
– What is the mechanism of biodegradation?
– What are the degradation products and
what are their biologic activities?
– How does the proposed BAS balance the
need for mechanical integrity with the ability
to degrade over time?
DHHS/FDA
Preclinical Testing Objectives

Complete characterization of the finished
sterilized product
– Coating/drug loading characteristics – drug
and carrier content, coating integrity
– In vitro/in vivo elution of both coating and
stent substrate
– Methods and specifications to allow stability
testing

Adequate bench & animal studies to
assess safety prior to human trials
DHHS/FDA
BAS Preclinical Evaluation
Bench Testing


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Standard tests such as stent and coating
durability no longer as relevant
Still need to test the mechanical properties
in a physiologically relevant environment
Need to conduct mechanical tests at multiple
time points to fully characterize the impact
of degradation on mechanical integrity
Characterize degradation products
How to assess “particulates” when the stent
is meant to degrade?
DHHS/FDA
BAS Preclinical Evaluation
Biocompatibility Testing

Standard tests may need to be
altered
– Extraction conditions
– Time exposure

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Separate testing of degradation
products may be appropriate
Discuss test methods with FDA
DHHS/FDA
BAS Preclinical Evaluation
Animal Studies

Measurement time points may need to
be modified to better capture critical
safety parameters
– Early – when BAS is still intact
– During degradation
– Post-complete degradation
Assess whether absence of rigid scaffold leads
to adverse arterial remodeling & edge effects
 Evaluate potential toxicity of degradation
products

DHHS/FDA
Animal Studies

Safety and effectiveness parameters
– Neointimal growth
– Inflammation
– Thrombus deposition
– Re-endothelialization
– Remodeling & edge effects

Safety margin overdose studies

Assessment of downstream myocardial pathology
– Evaluate embolization due to bulk degradation

Optional: Vasomotor function & use of disease models
DHHS/FDA
Clinical Trials

Feasibility/FIM trial(s)
– Initial assessment of device performance and safety and
effectiveness

Pivotal trial
– RCT recommended for initial marketing approval
– Superiority or non-inferiority to approved DES
– Target lesion failure primary endpoint

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Composite of cardiac death, target vessel MI and TLR
Duration of patient follow-up reflects degradation
profile
– To adequately capture outcomes before, during,
and after stent degradation
DHHS/FDA
Other Important Clinical Assessments

Procedural results
– Device handling: Tracking, deliverability, crossing,
deployment, balloon deflation, catheter withdrawal,
post-dilatation
– Device success: Achievement of an acceptable postdeployment angio result with the test device alone
– Clinical success: Device success without in-hospital
MACE

If BAS visibility on fluoroscopy is an issue:
– Assess frequency of geographic miss
– Ability to accurately deploy overlapping stents in
bailout situations
DHHS/FDA
Clinical Imaging
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Follow-up imaging to confirm absorption
QCA & IVUS to address effects of loss of rigid
scaffold on restenosis
– In-stent & in-segment MLD, late lumen loss &
%diameter stenosis
– Stent area
– Neointimal area and volume
– Positive and negative (constrictive) remodeling
– Edge effects

Consider exploratory use of OCT
DHHS/FDA
BAS Imaging Considerations

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Is stent mal-apposition relevant for a
biodegradable stent?
Angio/IVUS assessment more challenging to
identify treatment site with fully
bioabsorbed stent
– Blinding issues vs. a non-degradable stent
– Utilize measurements that minimize bias

Other targets – potential value added
– Vasomotion
– Plaque modification
DHHS/FDA
BAS Clinical Program Considerations
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Need adequate number of patients to detect uncommon
but clinically important safety events
– Not all patients need to be part of a randomized trial
– Can use multiple trials (both US and OUS)
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Patient clinical follow-up through 5 years
– Assess rates of stent thrombosis over time
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Assess dual antiplatelet therapy use and duration of
thienopyridines following BAS implantation
Plan for post-approval study
– Real world use beyond labeled indication
– Evaluate rates of ST, and CV death + MI
DHHS/FDA
Conclusions
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BAS add multiple levels of complexity to
FDA review
Discussions with FDA early in new BAS
program development highly
recommended
DES Draft Guidance document
http://www.fda.gov/downloads/Drugs/Guidance
ComplianceRegulatoryInformation/Guidances/UC
M072193.pdf
DHHS/FDA
Contact Information
Interventional Cardiology Devices Branch
301-796-6343
[email protected]
[email protected]
DHHS/FDA