1. Regulatory Requirements for Bioresorbable Scaffold Technology in the US
Andrew Farb, MD
Division of Cardiovascular Devices
Center for Devices and Radiological Health (CDRH)
Food and Drug Administration
10 min
4:15 Empire Room
BRS Technologies
CRT 2015
Washington, DC
February 23, 2015

2. Conflict of Interest
No conflicts of interest to report.

3. Guiding Concepts for the Nonclinical and Clinical Assessment of Bioresorbable Scaffolds or Stents (BRS)
The ideal BRS should:
Provide adequate mechanical support for a sufficient period of time to ensure luminal patency
Elute an a safe and effective antiproliferative drug to inhibit neointimal growth
Bioresorb safely and completely

4. FDA’s Approach to All DES Including BRS
Significant risk Class III devices
Regulatory submissions
Investigational Device Exemption (IDE)
Required to a conduct clinical study 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

5. Drug Component of a Drug-Eluting BRS A Combination Product
One of 3 choices:
Studied drug
Evaluated on another approved DES
Studied for a different indication
Currently being studied under an investigational new drug (IND) application
Unstudied drug – New molecular entity
Never tested in humans in the US (e.g., new -limus analogs)
Mention combination product
CDER consultants participate in CDRH interactions and review

6. Targeting IDE Approval
To initiate an IDE study:
Identify and justify bench & animal studies to provide adequate safety information to support the IDE
Leverage clinical information (if available)
Utilize the Pre-Submission process to discuss test methods with FDA to avoid wasted steps and misspent resources

7. Early Feasibility Study (EFS) Program
Intent - CDRH priority program intended to facilitate the clinical evaluation of medical devices in the US under the IDE regulations
Definition of an EFS - Small number of subjects for a device that may be early in development, typically before the design has been finalized
Key Guidance Principle - Approval of an EFS IDE may be based on less nonclinical data than would be needed to support the initiation of a larger clinical study
Guidance Provisions - A regulatory toolkit that enables sponsors and regulators to think in new ways about:
Device development
Appling benefit-risk principles and risk mitigation strategies
Justifying the appropriate data needed to move from bench to clinical study
The implementation of timely device and clinical protocol modifications
Contact: and

8. Bench Testing for BRS Standard bench tests
BMS Guidance:
DES Draft Guidance:
But with some additional considerations vs. a permanent platform DES
may want to mention importance of fully characterizing degradation/mass loss profiles for selection of appropriate time points for testing
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 8

9. BRS Bench Testing Goals and Principles
Characterize device degradation and mass loss profiles
Test mechanical properties in a physiologically relevant environment to characterize the time-dependent effect of degradation on mechanical integrity
Time points for long-term testing are determined by expected BRS performance
Structural fatigue testing through the time of needed radial strength
Particulate testing to the time of device tissue coverage
In fatigue testing, synchronize accelerated degradation with acceleration of mechanical loading
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

10. Animal Studies Characterize in-vivo PK profile
Adequate histopathology studies to capture important safety and potential effectiveness parameters
Early (when BRS still intact and providing radial support)
During degradation, at the time of significant mass loss
Post-complete degradation: Assess whether the absence of radial support is associated with significant negative remodeling
Longer-term studies may be completed after initiation of the clinical study based on acceptable results from short & medium-term studies
Evaluate potential local and off-target toxicity of degradation products
Supplement to biocompatibility bench tests

11. Initial Clinical Assessments Early Feasibility and Traditional Feasibility Studies
Provide initial insights into BRS performance and basic safety and effectiveness information
Device handling, visibility, deliverability, and early fracture
Optimal device sizing and the need for enhanced imaging (QCA, IVUS, OCT)
Performance in bailout and overlap situations
In-lab device and procedural success rates
Mechanistic insights via follow-up imaging: late loss, remodeling
Estimates of clinical event rates to guide design of pivotal trials
Generate clinical data to support a pivotal trial

12. Pivotal Trial “More-comers” inclusion/exclusion criteria
RCT recommended for initial marketing approval
Superiority or non-inferiority to an approved DES
Primary endpoint - 12 month target lesion failure (TLF) rate
Composite of cardiac death, target vessel MI and TLR
Type I error for non-inferiority trials
Secondary endpoint : Scaffold/stent thrombosis rate

13. Other Clinical Evaluations
Follow-up imaging assessment for mechanistic insights
Scaffold absorption
Neointimal growth and negative remodeling
Optional value-added investigations
Vasomotion studies
Restoration of normal vasomotion - marker of functional endothelium
Plaque assessment for plaque size stability & beneficial plaque modification
Late adaptive positive remodeling
Opportunities for powered secondary endpoints for claims in labeling

14. Non-Traditional Assessments
Quality of life endpoints
Need to be clinically important to be of value to patients, physicians, and payers
Key requirements of patient reported outcome instruments:
Reliability: Ability to yield consistent, reproducible estimates of true treatment effect
Validity: Extent to which the instrument measures the concept of interest
Ability to detect change and meaningful differences
reliability or ability to yield consistent, reproducible estimates of true treatment effect.
Content validity is the extent to which the instrument measures the concept of interest. Content validity is supported by evidence from qualitative studies that the items and domains of an instrument are appropriate and comprehensive relative to its intended measurement concept, population, and use.

15. Patient Reported Outcomes (PROs)
Assessment instruments must be useable and understood by study subjects
Usually included as secondary endpoints
Pre-specified in clinical study protocol
Requires statistical planning to control type I error
Utilize an appropriate recall period
Blinding critically important for PROs to avoid bias
Should be supported by the other objective studies and consistent with the totality of the data

16. Targeting PMA Approval – Non-Clinical
Complete characterization of the finished sterilized product
Coating/drug loading characteristics – drug and carrier content, coating integrity and uniformity
In vitro and in vivo elution of both coating and stent substrate
Methods and specifications to allow stability testing
Discuss test methods with FDA to avoid wasted steps and misspent resources

17. Targeting PMA Approval - Clinical
A reasonable assurance of safety & effectiveness
Adequate total sample size to detect clinically important events with adequate precision
Can utilize all appropriate studies
Not all subjects need to be part of the pivotal trial
Global approaches acceptable (US and non-US data)
Discuss use of non-US studies to support PMA
High quality studies with prespecified event definitions, independent adjudication, methods to minimize bias, and adequate subject follow-up
Address poolability

18. Post-Approval Study
Longer-term follow-up of pivotal trial subjects to assess rates of late events (e.g., post-complete BRS degradation, if applicable)
Primary endpoint events and individual components
Scaffold/stent thrombosis
Real world use beyond labeled indication
Can consider nested IDE studies for additional indications

19. Conclusion
Bioresorbable drug-eluting scaffolds/stents add multiple levels of complexity to FDA review
Early and ongoing interaction with FDA recommended for efficient device non-clinical and clinical evaluation and regulatory review