1. Regulatory Requirements for Drug Eluting Balloons
Ashley Boam, MSBE for:
Andrew Farb, M.D.
Interventional Cardiology Devices Branch
Division of Cardiovascular Devices
U.S. FDA/CDRH
THE DRUG ELUTING BALLOON SYMPOSIUM
CRT 2010
Washington, DC
February 22, 2010

2. Ashley Boam DISCLOSURES
I have no real or apparent conflicts of interest to report.

3. Components of a Drug-Eluting Balloon (DEB) Combination Product
PTCA Balloon
Delivery System
Coating
Therapeutic Agent
Recall that DEB are combination products whose assessment includes both the component parts as well as the device as whole

4. DEB Regulatory Submission Pathway
For a DEB identified as both a dilatation catheter and drug-delivery device
Otherwise primarily a drug delivery device
Different regulatory path
Investigational Device Exemption (IDE)
Significant risk product (Class III)
Required to conduct clinical trial in the US
Premarket Approval Application (PMA)
Comprehensive review of bench testing, animal studies, & all clinical data
Establish a reasonable assurance of safety and effectiveness
All DES are Class III Significant risk products so that testing in a clinical trial in the US requires submission and approval of a Investigational Device Exemption (IDE)
This is followed by submission of a Premarket Approval Application (PMA) which includes

5. DEB Preclinical Testing Objectives
Complete characterization of the finished sterilized product
Coating/drug loading characteristics – drug and coating content, coating integrity & uniformity
Particularly with varying balloon sizes
In vitro/in vivo PK studies
Serum and tissue levels
Adequate early time point sampling
Methods and specifications to allow stability testing
Adequate bench and animal studies to assess safety prior to human studies
The preclinical testing of the finished product includes

6. Bench Testing See FDA Guidance documents
For PTCA component: Draft Class II Special Controls Guidance for PTCA Catheters
For Drug component: Draft Coronary DES Guidance
Additional specific bench tests to support indication (e.g., ISR, coronary vs. peripheral arterial beds, small vessels)
Testing to evaluate expected worst case clinical use and encompass product matrix
Coating integrity and particulate testing are necessary

7. Preclinical testing of PTCA Balloons (Including DEBs)
– Biocompatibility
Entire device without drug coating
Balloon + drug coating material separately
If drug retained in tissue>30 days, implant biocompatibility testing needed
Cytotoxicity
Sensitization
Hemocompatibility
Material-mediated pyrogenicity

8. Preclinical Functional Testing of PTCA Balloons
Dimensional Verification
Balloon Rated Burst Pressure
Balloon Compliance (Diameter vs. Pressure)
Catheter Bond Strength
Tip Pull Test
Flexibility and Kink Test
Coating Integrity
Balloon Preparation, Deployment and Retraction
Balloon Fatigue (Repeat Balloon Inflations)
Balloon Inflation and Deflation Time
Torque Strength
Radiopacity
Particulate Evaluation
All DES are Class III Significant risk products so that testing in a clinical trial in the US requires submission and approval of a Investigational Device Exemption (IDE)
This is followed by submission of a Premarket Approval Application (PMA) which includes
Other required information: Sterilization and shelf life testing (both functional testing and stability)

9. Drug substance on DEB See DES Draft Guidance:
In consideration of the components of DEB, let’s first consider the drug to be eluted itself

10. Animal Studies-Safety
High dose density (greater than DES) and drug delivery could lead to local toxicity
Safety/Healing
Thrombus deposition
Inflammation
Re-endothelialization: SEM
Edge effects
Remodeling: Positive & negative
Safety margin overdose studies
Assessment of downstream myocardial pathology
Add – device handling deliverability, tracking, balloon inflation, withdrawal etc

11. Animal Studies-Effectiveness
Inhibition of neointimal proliferation
Proof of principle vs. a stent (or POBA if appropriate) control group
Normal coronary arteries
In-stent restenosis disease model may be particularly useful for safety & effectiveness considerations, drug delivery, & PK
Morphology similar to human ISR
Optional: Vasomotor function

12. Clinical Trials Feasibility/FIM trial(s)
Initial assessment of device performance and safety and effectiveness
Pivotal trial for coronary indication
RCT recommended for initial FDA approval
Target lesion failure (TLF) rate primary endpoint
Superiority or non-inferiority to approved stent
For trial designs,

13. Indications for Use and Control Groups
De novo CAD control
DES (or BMS in patients not able or unlikely to comply with prolonged DAPT use)
Coronary BMS restenosis control
Approved DES for ISR (TAXUS Express or Liberté)
If non-inferiority design, chose acceptable delta that also maintains headroom vs. brachytherapy historical data
Peripheral artery control
Approved stents or POBA
Depends on standard of care and approval status tailored to arterial target (e.g., SFA, tibial, etc.)
FDA open to discussions of for niche coronary indications – small vessels, side branches of bifurcation lesions requiring treatment

14. Pivotal Study Duration Science-Based Approach
Study duration depends on clinical indication and vascular biology
For ISR, restenosis a function of neointimal thickening
For de novo CAD treatment, restenosis post-POBA a function of neointimal proliferation + adventitial constrictive remodeling
Preclinical animal & PK studies help define when healing complete and drug eliminated from periarterial tissues
Candidate antiproliferative drugs on DEB delay healing
For coronary ISR indication, 9 months study may be acceptable
For de novo CAD treatment, 12 months probably indicated

15. Other Clinical Trial Considerations
Describe pre-dilatation procedure (e.g., undersized balloon)
Clarify single use or multiple use of individual DEB
Procedural results
Acute device success rate important
Achievement of acceptable post-deployment stenosis with the test device alone
Frequent use of adjunctive stents may confound results
Procedure success: Includes DEB plus adjunctive procedures/ devices
Clinical success: Device success without in-hospital MACE
Other Important Clinical outcomes to be assessed include

16. Clinical Imaging Cohort
Measurements
In-lesion and in-segment MLD, late lumen loss, & %diameter stenosis
Neointimal area and volume
Edge effects & positive and negative remodeling
Angio/IVUS assessment more challenging to identify treatment site post-DEB treatment
Blinding issues vs. a stent
Approaches to minimize bias
Other potential target – Vasomotion
Clinical outcomes paramount but imaging remains particularly important in evaluating DEB systems

17. Antiplatelet Therapy
Propose and justify duration of thienopyridine use post-DEB use
Attempt to limit confounders
Patients already on extended thienopyridines
Patients treated with DES on second coronary lesion at time of index procedure

18. DEB Clinical Program Considerations
Need adequate number of patients treated to detect uncommon but important safety events
Not all patients need to be part of a randomized trial
Can use multiple trials (both US and OUS)
Patient clinical follow-up through 4-5 years
Assess rates of coronary thrombosis over time
Track outcomes post-DEB restenosis treatment
Plan for post-approval study
Real world use beyond labeled indication
Evaluate rates of ST, and CV death + MI
For the DEB program as a whole, comprising all patients studied in feasibility, pivotal, and continued access studies,

19. Regulatory Paths for Drug-Eluting Balloons
Discussions with FDA early in DEB program development recommended
Utilize the pre-IDE process
Satisfactory data for a coronary indication does not automatically equal satisfactory data for a peripheral indication
Differences in drug content, vascular response, downstream territories

20. Contact Information
Interventional Cardiology Devices Branch