1. Regulatory Challenges for Biodegradable Scaffold Approval
Andrew Farb, M.D.
Interventional Cardiology Devices Branch
Division of Cardiovascular Devices
U.S. FDA/CDRH
BIOABSORBABLE SCAFFOLDING SYMPOSIUM
CRT 2012
Washington, DC
February 6, 2012

2. Andrew Farb, MD
I have no real or apparent conflicts of interest to report.

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 Biodegradable (Bioabsorbable) Scaffolds (Stents)
Regulatory submissions
Investigational Device Exemption (IDE)
Significant risk Class III products
Required to conduct clinical studies 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. Drug Component of a Drug-Eluting Biodegradable Scaffolds (BDS)
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 Component of a Drug-Eluting Biodegradable Scaffolds (BDS)
Drug 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 are required prior to human exposure via a DES
Same data required as in “Phase I IND” for drug development
See DES Draft Guidance

8. Characterization of BDS
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 BDS balance the need for mechanical integrity with the potential advantages of degradation over time?
As a functional mechanical scaffold, how long is long enough?

9. Nonclinical 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

10. BDS Bench Testing
Characterize the degradation profile including weight loss and mass loss
Standard tests should be conducted with special caveats:
Test mechanical properties in a physiologically relevant environment at multiple time points to fully characterize the impact of degradation on mechanical integrity
Time points for long-term testing are determined by expected BDS performance
Structural fatigue through time point of complete tissue coverage
Chronic particulates through time point of significant mass loss
Acceleration of mechanical loading should be synchronized with accelerated degradation

11. Animal Studies
Duration of studies and tissue evaluation methods adequate to capture critical safety and potential effectiveness parameters
Early, when the BDS 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

12. Feasibility/FIH Clinical Studies
Provide initial insights into BDS performance and safety and effectiveness
BDS visibility, deliverability & early fracture
Need for quantitative imaging (QCA, IVUS, OCT) for optimal sizing
Performance in bailout situations
Device and procedural success rates
Follow-up imaging
Acceptable clinical and imaging data in feasibility study used to justify a larger pivotal trial

13. Pivotal Trial “More-comers” inclusion/exclusion criteria
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
Alpha set at for non-inferiority study
Longer-term follow-up of pivotal trial subjects to capture events post-complete BDS degradation

14. Separate Imaging Study
Particularly important if BDS or investigational plan modified after FIH/feasibility studies
Mechanistic imaging information
Assess neointimal growth & negative remodeling
Relevant imaging time points to assess scaffold absorption
Optional value-added investigations
Restoration of normal vasomotion
Marker of functional endothelium
Markers of plaque stabilization (beneficial plaque modification)
Late adaptive positive remodeling

15. BDS Clinical Program Considerations for Regulatory Review
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 non-US)
Discuss non-US trials with FDA – design, events definitions & adjudication, long-term follow-up
Assess rates of stent thrombosis over time
Assess DAPT use and duration following BDS implantation

16. Post-Approval Study Real world use beyond labeled indication
Nested registries for additional indications
Potential opportunity to evaluate shorter duration of post-PCI P2Y12 receptor inhibitor use if supported by available scientific evidence

17. The Future of BDS What is their optimal role in PCI?
Workhorse device vs. niche patient/lesion device?
Will innovative promise translate into clinical benefit?
Can we safely shorten P2Y12 receptor inhibitor treatment duration?
Are vasomotion and plaque modification clinically relevant surrogates?
Challenging to conduct a successful pivotal randomized trial
Currently, TLF rates at 1 year are in the single digits for non-complex lesions/patients with approved DES

18. Conclusion
Bioabsorbable drug-eluting scaffolds add multiple levels of complexity to FDA review
Discussions with FDA early in new BDS program development highly recommended
DES Draft Guidance document