1. Bioabsorbable DES and Biodegradable Polymers – FDA View
Andrew Farb, M.D.
Interventional Cardiology Devices Branch
Division of Cardiovascular Devices
U.S. FDA/CDRH
WORKSHOP WITH THE FDA
CRT 2011
Washington, DC
March 1, 2011

2. Andrew Fab, MD
No disclosures

3. Components of a DES System Combination Product
Stent
Delivery System
Drug Eluting Stent
Therapeutic Agent
Coating Technology

4. FDA’s Approach to All DES
Regulatory submissions
Investigational Device Exemption (IDE)
Significant risk Class III products
Required to conduct clinical trial in the US
Premarket Approval Application (PMA)
Comprehensive review of bench testing, animal studies, and all clinical data
Establish a reasonable assurance of safety and effectiveness
Manufacturing inspection prior to approval

5. Additional Considerations for Degradable Polymer Coatings on Permanent Stents
Testing paradigm for bench, animal, biocompatibility, and clinical evaluations guided by
The degradation profile (mechanism and time course)
The degradation products and what are their biologic activities

6. Characterization of Bioabsorbable Stents (BAS)
Fundamental questions that guide testing
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 potential advantages of degradation over time?
As a functional mechanical scaffold, how long is long enough?

7. 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
Discuss test methods with FDA

8. BAS Bench Testing
Standard tests such as stent and coating durability less relevant vs. non-BAS
Test mechanical properties in a physiologically relevant environment
Conduct mechanical tests at multiple time points to fully characterize the impact of degradation on mechanical integrity
Characterize degradation products and amount/type of particulates, which can still pose a risk even though degradation is intentional
Testing of degradation products for biocompatibility may be appropriate

9. Animal Studies
Implant duration evaluation to capture critical safety and potential effectiveness 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

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
Primary endpoint: Target lesion failure at 12 months
Composite of cardiac death, target vessel MI and TLR
Frequency & duration of patient follow-up reflects degradation profile
To adequately capture outcomes before, during, and after stent degradation

11. 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)
Discuss OUS trials with FDA – design, events definitions & adjudication, long-term follow-up
Assess rates of stent thrombosis over time
Assess DAPT use and duration following BAS implantation
Post-approval study - Real world use beyond label
Pooling of post-market data with pre-market data to increase precision around point estimates of CV death, MI, & ST

12. Clinical Imaging and Functional Assessment
Follow-up imaging to confirm absorption
QCA & IVUS/OCT to address effects of loss of rigid scaffold on restenosis
In-stent & in-segment MLD, vessel area, lumen area, late lumen loss & %diameter stenosis
Neointimal area and volume in-stent & in-segment
Stent area (late recoil) & remodeling
Vasomotion
Plaque modification

13. Are BAS the Next Stage in the PCI Innovation Continuum?
POBA
Bare metal stents
Permanent polymer DES
Thinner strut Permanent polymer DES
Biodegradable polymer DES/Non-polymer DES
Bioabsorbable DES

14. The Potential Advantages Of BAS
Coronary targets
Improved healing profile
Reduced inflammatory response to permanent foreign body and polymer
Shorter duration DAPT
Lower stent thrombosis rates
Improved arterial “health”
Restoration of normal vasomotion – Functional endothelium
Adaptive chronic positive remodeling & lumen enlargement
Beneficial plaque modification

15. The Potential Advantages Of BAS
Coronary targets (continued)
Opportunities for assessment with non-invasive imaging
Side branch access after stent absorption
Opportunities for repeat coronary treatment without rigid scaffold
Non-coronary targets
Pediatric interventions that can allow for vessel growth
Aortic coarctation
Branch pulmonary arterial stenosis

16. BAS Are Truly Innovative Devices, But …
What is their optimal role in PCI?
Workhorse device
Niche lesion device
Will innovative promise translate into clinical benefit?
Are vasomotion and plaque modification clinically relevant surrogates?
Can we safely shorten thienopyridine treatment duration?
Clinical trials challenge
Current era of single digit TLF rates at 1 year for non-complex lesions/patients with approved DES

17. Challenges in Characterization of Biodegradable Stents
Biodegradable polymers and bioabsorbable stents add multiple levels of complexity to FDA review
FDA welcomes discussions with sponsors regarding novel DES programs