1. 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

2. Ashley Boam DISCLOSURES
I have no real or apparent conflicts of interest to report.

3. Novel DES in Development or Trials
New drugs
Degradable polymers
DES with biologics
Programmable stent lengths
Dedicated bifurcation DES
Bioabsorbable stents (BAS)
There are multiple new devices on the DES horizon of which BAS are just one important example

4. Characterization of Biodegradable Stents (BAS)
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?
In characterizing BAS, the Answers to these questions will help guide the testing paradigm
Potential Adv: short duration DAPT, retreatment of TV options, drug delivery, CT/MR imaging, plaque modification (VP)

5. 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
The preclinical testing of the finished product includes

6. BAS Preclinical Evaluation Bench Testing
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?
For BAS bench testing, there are differences from standard test for non-BAS systems. For example, Standard tests such as stent durability and coating durability no longer as relevant

7. BAS Preclinical Evaluation Biocompatibility Testing
Standard tests may need to be altered
Extraction conditions
Time exposure
Separate testing of degradation products may be appropriate
Discuss test methods with FDA
For Biocompatibility,

8. 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
For animal studies,

9. 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
And Additional parameters may need to be considered

10. Clinical Trials Feasibility/FIM trial(s) Pivotal trial
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
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
For trial designs,

11. Other Important Clinical Assessments
Procedural results
Device handling: Tracking, deliverability, crossing, deployment, balloon deflation, catheter withdrawal, post-dilatation
Device success: Achievement of an acceptable post-deployment 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
Other Important Clinical outcomes to be assessed include

12. Clinical Imaging 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
Clinical outcomes paramount but imagining remains particularly important in evaluating BAS systems

13. BAS Imaging Considerations
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

14. BAS Clinical Program Considerations
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)
Patient clinical follow-up through 5 years
Assess rates of stent thrombosis over time
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
For the BAS program as a whole, comprising all patients studied in feasibility, pivotal, and continued access studies,

15. Conclusions BAS add multiple levels of complexity to FDA review
Discussions with FDA early in new BAS program development highly recommended
DES Draft Guidance document

16. Contact Information
Interventional Cardiology Devices Branch