1. Regulatory Challenges for Biodegradable Scaffolds Approval
Andrew Farb, M.D.
Interventional Cardiology Devices Branch
Division of Cardiovascular Devices
U.S. FDA/CDRH
DES Bioabsorbable and DCB Technologies
CRT 2013
Washington, DC
February 25, 2013

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

3. The Potential Advantages of Biodegradable Scaffolds (BDS)
Effective revascularization without an implanted permanent intra-arterial metallic prosthesis
Low thrombosis rates
Shorter duration of DAPT vs. permanent platform stents
Restoration of normal vasomotion
Beneficial plaque modification
Opportunity for non-invasive imaging assessment of patency

4. Fundamental Scientific Questions That Guide Nonclinical and Clinical Evaluation
How does the 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 for optimal performance by a BDS?

5. Regulatory Approaches to the Evaluation of BDS

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

7. 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 at US sites
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

8. 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

9. 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)

10. 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See DES Draft Guidance

11. Targeting IDE and PMA Approval
To initiate an IDE study:
Identify and justify bench & animal studies to provide adequate safety information to support the IDE
Leverage available clinical information
Include risk mitigation strategies in the clinical study protocol
For PMA approval: 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
Consider benefit-risk principles
Discuss test methods early with FDA to avoid wasted steps and mis-spent resources

12. Bench Testing All standard bench tests still apply
BMS Guidance:
DES Draft Guidance:
But with some additional considerations
Test mechanical properties (e.g., radial stiffness and radial strength) in a physiologically relevant environment at multiple time points to fully characterize the impact of degradation on mechanical integrity 12

13. BDS Bench Testing
Characterize the degradation profile including molecular weight loss and mass loss
Standard tests should be conducted with caveats:
Test mechanical properties in a physiologically relevant environment at time points to fully characterize the effect of degradation on mechanical integrity
Time points for long-term testing are determined by expected BDS performance
Structural fatigue testing through time of complete tissue coverage
Particulates testing through time of significant mass loss
Acceleration of mechanical loading synchronized with accelerated degradation
Putting results in context
Understand that stent and coating integrity should look different over time
Characterize degradation products & clinical relevance of “particulates”
Particulates assessment is by definition different (since 1 or more components intended to degrade)
Understanding of pattern and amount of degradation (number and size distribution) is important
Bolus of particles shed (e.g., at point of critical mass loss) can still represent safety concern
Consider the entire story told by bench and animal observations

14. Animal Studies In-vivo PK profile
Duration of histopath studies adequate to capture critical safety and potential effectiveness parameters
Early (BDS still intact)
During degradation
Post-complete degradation: Does absence of rigid scaffold lead to adverse arterial remodeling & edge effects
Evaluate potential toxicity of degradation products
Based on acceptable results from short & medium-term studies (and outcomes consistent with degradation profile), long-term animal studies may be completed after initiation of the clinical study

15. Early Feasibility and Traditional Feasibility Clinical Studies
Provide initial insights into BDS performance and basic safety & effectiveness, e.g.:
BDS handling, visibility, deliverability & early fracture
Optimal device sizing and the need for quantitative imaging (QCA, IVUS, OCT)
Performance in bailout and overlap
Device and procedural success rates
Follow-up imaging information: late loss, remodeling
Acceptable feasibility data support a larger pivotal trial

16. 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

17. Other Clinical Investigations
Imaging cohort provides mechanistic imaging information
Assess scaffold absorption
Assess neointimal growth & negative remodeling
Optional value-added investigations
Vasomotion studies
Restoration of normal vasomotion - marker of functional endothelium
Plaque assessment: Plaque size stabilization & beneficial plaque modification
Late adaptive positive remodeling

18. Targeting PMA Approval
Need adequate number of subjects to detect uncommon but clinically important safety events
Utilize data from all appropriate studies
Not all patients need to be part of the pivotal trial
Can use global approach (US and non-US subjects/studies)
Discuss non-US studies with FDA as early as possible – design, event definitions & adjudication, long-term follow-up, & poolability
Assess stent thrombosis rates
Assess DAPT use and duration following BDS implantation

19. 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

20. 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