1. Regulatory Challenges for Bioasorbable Stent Approval
Andrew Farb, M.D.
Interventional Cardiology Devices Branch
Division of Cardiovascular Devices
U.S. FDA/CDRH
BIOABSORBABLE STENT SYMPOSIUM
CRT 2011
Washington, DC
February 28, 2011

2. Andrew Farb, 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 Including Bioabsorbable (Bioresorbable) Stents
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. Current Expectation: Drug-Eluting Bioabsorbable Stents (BAS)
Drug may be studied
Evaluated on another approved DES
E.g., sirolimus, paclitaxel, zotarolimus, everolimus
Studied for a different indication
Currently being studied under an investigational new drug (IND) application

6. Drug on a DES Drug substances may be unstudied
Never tested in humans in the US
Defined as “NME” – New Molecular Entity
Drugs that are analogs of studied drugs are considered to be NME’s
-Limus analogs (e.g., biolimus A9)

7. Requirements for a New Drug Substance on a DES
Safety data required prior to human exposure to DES
Same data required as in “Phase I IND” for drug development
See DES Draft Guidance

8. 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
Bioabsorbable DES

9. Characterization of 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?

10. 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

11. 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

12. Animal Studies
Implant duration evaluation to capture critical safety and potential effectiveness parameters
Early, when the 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

13. Animal Studies Safety and effectiveness characterization
Neointimal growth & inflammatory responses
Thrombus deposition & re-endothelialization
Remodeling: Stent and proximal & distal edges
Safety margin overlap/overdose studies
Assessment of downstream myocardial pathology
Evaluate embolization due to bulk degradation
Optional: Vasomotor function & use of disease models

14. 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
Longer-term follow-up to capture events after stent degradation

15. 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 labeled indication
Pooling of post-market data with pre-market data to increase precision around point estimates of CV death, MI, & ST

16. Other Important Clinical Assessments
Procedural results
Device handling: Tracking, deliverability, crossing, deployment, acute recoil, balloon deflation, catheter withdrawal, post-dilatation
Device success: Achievement of an acceptable post-deployment angio result with the test device alone
Is radial force adequate?
Clinical success: Device success without in-hospital MACE
Evaluate BAS visibility during imaging
Assess frequency of geographic miss
Ability to accurately deploy overlapping stents in bailout situations

17. 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
Mal-apposition & stent fracture
Vasomotion
Plaque modification

18. BAS Are Truly Innovative Devices, But …
What is their optimal role in PCI?
Workhorse device vs. niche patient/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

19. Challenges in Characterization of Biodegradable Stents
BAS add multiple levels of complexity to FDA review
Discussions with FDA early in new BAS program development highly recommended
DES Draft Guidance document