1. Bioresorbable Stent Clinical Study: FDA
Andrew Farb, MD
P F Adrian Magee MD
Division of Cardiovascular Devices
Center for Devices and Radiological Health (CDRH)
Food and Drug Administration
10 min
Sunday, February 21, 2016
4:20 PM – 4:30 PM, Room: Congressional AB
Japan-US Synergies: BRS
CRT 2016
Washington, DC
February 22, 2016

2. No Conflicts of Interest

3. Attributes of an ‘Ideal’ Bioresorbable Stent (BRS)
At least comparable to current DES in deliverability
Provides adequate mechanical support for a sufficient period of time to ensure luminal patency
Elute a safe and effective antiproliferative drug to inhibit neointimal growth
Bioresorb safely and completely

4. BRS: US Regulatory Classification and Pathway for Approval
Significant risk Class III devices
Combination Product (comprises a regulated device and a drug)
- CDER consultants participate in CDRH interactions and review
Pathway
Investigational Device Exemption (IDE)
Required to conduct a 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 for FDA approval
Manufacturing facility and site inspections prior to approval

5. Targeting IDE Approval
Identify and justify bench & animal studies to provide adequate safety information to support the IDE
Leverage clinical information (if available)
Consider Early Feasibility Study
Utilize the Pre-Submission process to discuss test methods with FDA to avoid wasted steps and misspent resources

6. Early Feasibility Study (EFS) Program
CDRH priority program intended to facilitate the clinical evaluation of medical devices in the US under the IDE regulations
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
Device that may be early in development, typically before the design has been finalized
Small number of subjects
Contact for EFS program:

7. Initial Clinical Assessments Early Feasibility and Traditional Feasibility Studies
Preliminary insights: BRS performance, safety & effectiveness
In-Cath Lab
Appropriate lesion selection and preparation prior to device deployment ( e.g. pre-dilatation requirements)
Device, deliverability, visibility and early integrity (? fracture)
Appropriate device sizing (? need/value for enhanced imaging modalities (e.g., QCA, IVUS, OCT)
Need/Value/Limitations of post dilatation
Performance in bailout and overlap situations
Rates of device and procedure success
Follow-up
Mechanistic insights via follow-up imaging (e.g., late lumen loss, vessel remodeling, device absorption)
Clinical event rate estimates to guide pivotal trial development

8. Pivotal Trial Considerations
RCT recommended for initial marketing approval
Demonstrate superiority or non-inferiority to an approved current generation DES
For non-inferiority statistical hypothesis testing, choose and justify a clinically acceptable non-inferiority margin
Adequate total sample size to detect clinically important events with adequate precision

9. Clinical Endpoints Primary endpoint
Target lesion failure (TLF) at 12 months
Composite of cardiac death, target vessel MI and ID-TLR
Secondary endpoints
Device and procedure success rates
Individual components of composite endpoints
Scaffold/stent thrombosis

10. Supplementary Evaluations
Angiographic imaging assessments
Late lumen loss, neointimal growth, binary restenosis rates, & negative remodeling
BRS absorption
Optional value-added investigations
Vasomotion studies
Restoration of normal vasomotion - marker of functional endothelium
MSCT evaluation
Other imaging assessments
Late adaptive positive remodeling and lumen enlargement
Plaque features and beneficial plaque modification
Opportunities for additional labeling claims

11. 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

12. 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 evaluation of degradation products (oligomers) evolved from both coating and stent substrate
Methods and specifications to allow stability testing
Discuss test methods with FDA for efficient use of resources

13. Targeting PMA Approval - Clinical
Utilize all appropriate clinical data to demonstrate
“A reasonable assurance of safety & effectiveness”
Pivotal Trial Results
US and non-US pivotal trial data acceptable
Need to address poolability
Other Non-US studies may be used to support PMA
High quality studies
Prespecified event definitions
Methods to minimize bias
Adequate subject follow-up
Independent adjudication

14. Post-Approval Study
Longer-term follow-up of pivotal trial subjects to assess rates of late events (as BRS degradation proceeds to completion)
TLF composite endpoint events and individual components of the composite
BRS thrombosis
Newly enrolled post-market cohort
Address training program and pre-market lessons learned
Evaluate real world use
Provide insights into BRS performance when used beyond the labeled indication
Can use nested IDE studies for additional indications

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

16. Back Up Slides

17. 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

18. 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 18

19. 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

20. Animal Studies Characterize in-vivo PK profile
Histopath studies to describe important safety and potential effectiveness parameters
Early (when BRS still intact and providing radial support)
During degradation, at a time of significant mass loss
Post-complete degradation
Does adverse negative remodeling occur after loss of radial support?
Sponsors can justify why the duration of their animal studies is adequate to support initiation of a clinical study
Longer-term studies may be ongoing during clinical studies
Full necropsies recommended to exclude adverse off-target effects and supplement biocompatibility bench tests

21. Non-Traditional Assessments
Quality of life and patient reported endpoints
Need to be clinically important to be of value to patients, physicians, and payers (e.g. Angina)
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.