Transcript slides

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
DHHS/FDA
DISCLOSURES
Ashley Boam
I have no real or apparent conflicts of
interest to report.
Components of a Drug-Eluting Balloon (DEB)
Combination Product
PTCA Balloon
Coating
Delivery System
Therapeutic Agent
DEB Regulatory Submission Pathway
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For a DEB identified as both a dilatation
catheter and drug-delivery device
– Otherwise primarily a drug delivery device
– Different regulatory path
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Investigational Device Exemption (IDE)
– Significant risk product (Class III)
– Required to conduct clinical trial in the US
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Premarket Approval Application (PMA)
– Comprehensive review of bench testing, animal
studies, & all clinical data
– Establish a reasonable assurance of safety and
effectiveness
DHHS/FDA
DEB Preclinical Testing Objectives
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Complete characterization of the finished
sterilized product
– Coating/drug loading characteristics – drug and
coating content, coating integrity & uniformity
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Particularly with varying balloon sizes
– In vitro/in vivo PK studies
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Serum and tissue levels
Adequate early time point sampling
– Methods and specifications to allow stability testing
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Adequate bench and animal studies to assess
safety prior to human studies
DHHS/FDA
Bench Testing
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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
DHHS/FDA
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
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Cytotoxicity
Sensitization
Hemocompatibility
Material-mediated pyrogenicity
DHHS/FDA
Preclinical Functional
Testing of PTCA Balloons
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Dimensional Verification
Balloon Rated Burst
Pressure
Balloon Compliance
(Diameter vs. Pressure)
Catheter Bond Strength
Tip Pull Test
Flexibility and Kink Test
Coating Integrity
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Balloon Preparation,
Deployment and Retraction
Balloon Fatigue (Repeat
Balloon Inflations)
Balloon Inflation and
Deflation Time
Torque Strength
Radiopacity
Particulate Evaluation
Other required information: Sterilization and
shelf life testing (both functional testing and
stability)
DHHS/FDA
Drug substance on DEB
See DES Draft Guidance:
http://www.fda.gov/downloads/Drugs/GuidanceCo
mplianceRegulatoryInformation/Guidances/UCM07
2193.pdf
DHHS/FDA
Animal Studies-Safety
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High dose density (greater than DES) and
drug delivery could lead to local toxicity
Safety/Healing
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Thrombus deposition
Inflammation
Re-endothelialization: SEM
Edge effects
Remodeling: Positive & negative
Safety margin overdose studies
Assessment of downstream myocardial
pathology
DHHS/FDA
Animal Studies-Effectiveness
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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
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Morphology similar to human ISR
Optional: Vasomotor function
DHHS/FDA
Clinical Trials
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Feasibility/FIM trial(s)
– Initial assessment of device performance and
safety and effectiveness
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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
DHHS/FDA
Indications for Use and
Control Groups
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De novo CAD control
– DES (or BMS in patients not able or unlikely to
comply with prolonged DAPT use)
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Coronary BMS restenosis control
– Approved DES for ISR (TAXUS Express or Liberté)
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If non-inferiority design, chose acceptable delta that also
maintains headroom vs. brachytherapy historical data
Peripheral artery control
– Approved stents or POBA
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Depends on standard of care and approval status tailored
to arterial target (e.g., SFA, tibial, etc.)
DHHS/FDA
Pivotal Study Duration
Science-Based Approach
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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
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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
DHHS/FDA
Other Clinical Trial Considerations
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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
DHHS/FDA
Clinical Imaging Cohort
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Measurements
– In-lesion and in-segment MLD, late lumen loss, &
%diameter stenosis
– Neointimal area and volume
– Edge effects & positive and negative remodeling
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Angio/IVUS assessment more challenging to
identify treatment site post-DEB treatment
– Blinding issues vs. a stent
– Approaches to minimize bias
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Other potential target – Vasomotion
DHHS/FDA
Antiplatelet Therapy
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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
DHHS/FDA
DEB Clinical Program Considerations
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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)
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Patient clinical follow-up through 4-5 years
– Assess rates of coronary thrombosis over time
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Track outcomes post-DEB restenosis treatment
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Plan for post-approval study
– Real world use beyond labeled indication
– Evaluate rates of ST, and CV death + MI
DHHS/FDA
Regulatory Paths for
Drug-Eluting Balloons
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Discussions with FDA early in DEB program
development recommended
– Utilize the pre-IDE process
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Satisfactory data for a coronary indication
does not automatically equal satisfactory
data for a peripheral indication
– Differences in drug content, vascular response,
downstream territories
DHHS/FDA
Contact Information
Interventional Cardiology Devices Branch
301-796-6343
[email protected]
[email protected]
DHHS/FDA