DrugEluting Stents In Depth What are the FDA

Drug-Eluting Stents In Depth: What are the FDA Requirements for Label Expansion? by Ashley B. Boam, MSBE Interventional Cardiology Devices Branch FDA/CDRH/ODE/DCD February 22, 2010 DHHS/FDA

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

Typical “On-Label” Population n de novo lesions n single or dual vessel disease n length < 30 mm n diameters 2. 25/2. 5 – 3. 5/4. 0 mm n no major side branches (≥ 2. 0 mm) n not ostial, CTO, SVG, no thrombus n etc. DHHS/FDA

Possible Label Expansions n Treatment of vessels that are: – Diameters – 2. 25 mm or 4. 0 mm – Lengths - >30 mm – Bifurcations – Left main n Treatment of patients that are: – STEMI – non. STEMI ACS DHHS/FDA

Smaller, wider, longer n To date, most randomized studies limited to 2. 53. 5 mm diameter and <30 mm length – Approach for 2. 25 mm and 4. 0 mm diameters was single-arm study compared to performance goal based on historical data – Now that several approved DES available, include these diameters in randomized trial n For lesion lengths >30 mm to ~36 mm, singlearm study compared to performance goal; once longer stent lengths available, include in randomized cohort DHHS/FDA

Dedicated Bifurcation Stents Great variability of bifurcation disease and PCI strategies n PCI associated with increased MACE rates vs. non-bifurcation lesions n Most clinical studies support a simple PCI approach n – Parent vessel DES and provisional SB treatment n No FDA-approved PCI devices for bifurcation disease – PCI for bifurcation is off-label – Bifurcation disease has been a specific exclusion criterion in DES RCTs DHHS/FDA

Dedicated Bifurcation Stents n RCT needed – No established OPC or performance goal – Multiple anatomic, procedural, and patient covariates requiring adjustment precludes a non-randomized trial n Proposed Control group: Approved DES in parent vessel with provisional SB treatment – Justify alternative approaches for specific Medina lesion subsets – Clearly define strategy for SB treatment in protocol § SB imaging only or functional assessment by FFR? – Specify & justify other techniques: e. g. , kissing balloon DHHS/FDA

Dedicated Bifurcation Stents Endpoints selected to demonstrate both clinical benefit to patients and benefit of customized stent/deployment procedure vs. conventional PCI n Co-primary clinical endpoint: TLF (CV death, TV MI, & TLR) at 12 months n – Either superiority or non-inferiority acceptable – Inclusive of events related to parent vessel or SB n Co-primary procedural endpoint – Superiority vs. Control – Consider variables (e. g. , side branch access, procedure time, biomarker elevation, or other assessments) demonstrate value added for the test bifurcation device vs. conventional PCI n Imaging cohort – angio and IVUS – Assess for strut malapposition and strut fracture DHHS/FDA

DES for Left Main Important high-risk population for which a standard of care exists – CABG n Challenges in LM studies include: n – Identification of the patient population § all LM § with or without MVD § non-bifurcations – Selection of primary endpoint § MACCE composite (as in SYNTAX)? § split MACCE? – – n primary - death, MI, stroke secondary – revascularization More discussion tomorrow at FDA Town Hall DHHS/FDA

DES in STEMI Several previous small studies in STEMI n HORIZONS – large global RCT of DES vs. BMS in STEMI population (presented TCT 2008) n 12 month outcomes n – Efficacy – significant reduction in ischemic TLR (7. 5% BMS vs. 4. 5% Taxus) – Safety - no differences in MACE, all-cause mortality, death + reinfarct Outcomes fit with known pathology in STEMI n Relatively small differences predicted between DES and BMS n – – – larger diameter vessels shorter, more focal lesions non-stenotic lesions DHHS/FDA

Next Trials in STEMI n Currently not approved indication for DES n If Taxus gains indication for STEMI: – RCT vs. Taxus would be acceptable n If no DES with indication for STEMI – Equipoise still exists? – Consider RCT vs. BMS n In general, longer term outcomes (>1 year) and role of DAPT still of interest DHHS/FDA

DES for NSTEMI ACS n UA/NSTEMI – subset of ACS associated with an increased risk of cardiac death and subsequent MI n Defined by ECG ST-segment depression or prominent Twave inversion and/or positive biomarkers of necrosis (e. g. , troponin) in the absence of ST-segment elevation and with clinical evidence of ischemia n Move to troponin as “preferred biomarker” provides opportunity for new look at the population for trials of PCI with DES n Consider troponin+ patients with non-thrombotic lesions as target patient population DHHS/FDA

Trials for DES in NSTEMI n FDA is open to proposals; suggestions below n For DES already approved for stable patients – Single arm study of T+ patients (non-thrombotic lesions) – Comparison to PG based on results in stable patients + clinically acceptable margin – Alternative: Use of data from all-comers postmarket studies using above approach (if hypotheses prespecified under IDE) DHHS/FDA

Trials for DES in NSTEMI n For new DES – RCT – enroll stable and T+ patients (non-thrombotic lesions) – Control for stable patients is approved DES – Compare T+ patients to approved DES and PG – PG based on published studies of DES PCI in ACS (ACUITY, TRITON, others? ) 12 month primary endpoint still relevant in both cases n Also plan to assess: n – Follow-up >1 year – Impact of DAPT > 1 year DHHS/FDA

Contact Information Ashley Boam ashley. boam@fda. hhs. gov 301 -796 -6341 DHHS/FDA