# Presentation: 219922

## DHHS/FDA/CDRH

## Circulatory Support Devices Panel

**Boston Scientific Corporation**
**TAXUSTM**** Express****2****TM**** **** **
**Paclitaxel-Eluting **
**Coronary Stent System**
**P030025**
**November 20, 2003**

- DHHS/FDA/CDRH

## Overview of Presentation

**FDA Review Team**
**Product Description**
**Non-clinical Evaluation**
**Clinical & Statistical Evaluation**
**Panel Questions**

- DHHS/FDA/CDRH

## FDA Review Team

- DHHS/FDA/CDRH

**CDRH****	**Jennifer Goode, BS, Biomedical Engineer
- 	Stephen Hilbert, MD, PhD, Experimental Pathologist
- 	John Stuhlmuller, MD, Clinician
- 	Heng Li, PhD, Statistician
- 	Raju Kammula, DVM, PhD, Toxicologist
- 	Lee Schroeder, PhD, Lead Polymer Chemist
- 	Carolyn Vaughan, BS, Mechanical Engineer
- 	Lisa Kennell, BS, Microbiologist
- 	Steve Wood, PhD, Molecular Biologist
- 	Walter Scott, PhD, Patient Labeling
- 	Kent Berthold, Manufacturing
- 	Hesha Duggirala, PhD, Epidemiologist
- 	Sybil Wellstood, PhD, Bioresearch Monitoring

## FDA Review Team

- DHHS/FDA/CDRH

**CDER**	Nallaperumal Chidambaram, PhD, Chemist
- 	Angelica Dorantes, PhD, Pharmacokineticist** **
- 	Belay Tesfamariam, PhD, Toxicologist

## Regulatory History

**PMA (P030025) filed on June 19, 2003**
**Major Deficiency Letter sent to applicant on September 15, 2003**
**Applicant began submitting responses on September 30, 2003**
**Interactions continue to resolve outstanding non-clinical issues**

- DHHS/FDA/CDRH

## Product Description

**Combination Product**
**ExpressTM**** balloon-expandable 316L SS stent**
**Elective: 3.0 to 5.0mm Ø & up to 18 mm in length**
**Approved September 11, 2002**
**NOTE:****  Does not include an indication for “reducing restenosis”**
**Catheter delivery systems**
**Express****2****TM OTW**
**Express****2****TM Monorail**
**NOTE:****  Slightly different design from the ExpressTM delivery systems used in TAXUS IV trial**

- DHHS/FDA/CDRH

## Product Description

**Polymer coating**
**Translute******** Non-erodible polymer**
**Drug substance**
**Paclitaxel – FDA approved**
**Leveraged initial drug safety data from Drug Master File (Indena S.p.A.)**

- DHHS/FDA/CDRH

## Product Description

**TAXUS SR**
**Proposed product to be marketed**
**1 ********g/mm****2**** slow release formulation**
**Used in animal trials and TAXUS I, II, and IV**
**TAXUS MR**
**1 ********g/mm****2**** moderate release formulation**
**Used in animal trials and TAXUS II**

- DHHS/FDA/CDRH

## Proposed TAXUSTM Stent Matrix & Nominal Drug Dosage

- DHHS/FDA/CDRH

| Stent Diameter (mm) | Stent Length |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | 8 mm  | 12 mm | 16 mm | 20 mm | 24 mm | 28 mm | 32 mm |
| 2.5 | 50 g | 79 g | 108 g | 137 g | 151 g |  |  |
| 2.75 | 50 g | 79 g | 108 g | 137 g | 151 g | 180 g | 209 g |
| 3.0 | 50 g | 79 g | 108 g | 137 g | 151 g | 180 g | 209 g |
| 3.5 | 50 g
519 g | 79 g
819 g | 108 g
1119 g | 137 g
1419 g | 151 g
1570 g | 180 g
1870 g | 209 g
2170 g |

**Sizes used in TAXUS IV study**
**Nominal polymer dosages (same across all stent diameters)**

## Non-Clinical Evaluation

- DHHS/FDA/CDRH

**Pharmacology/Toxicity Testing **
***In vivo***** (Animal) Testing**
**ISO 10993 Biocompatibility of stent + polymer only**
**Stent/Delivery System Integrity Testing**
**Shelf Life/Stability**
**Coating Integrity**
**Sterility & Package Integrity Testing**

## Major OutstandingNon-Clinical Issues

- DHHS/FDA/CDRH

**Animal study results**
**Stability/Shelf life**
**Finalizing protocols and QC specifications with sponsor**
**Adequate product has been set aside for testing**

## Proposed Indications for Use

** **

- DHHS/FDA/CDRH

**The TAXUSTM Express****2****TM Paclitaxel-Eluting Coronary Stent Systems (Monorail and Over-the-Wire) are indicated for improving luminal diameter and reducing restenosis for the treatment of *****de *****novo lesions **_**<**_** 28 mm in length in native coronary arteries **_**>**_** 2.5 to **_**<**_** 3.75 mm in diameter.**

## Non-Clinical In Vivo Studies

**Stephen L Hilbert MD, PhD**
**Cardiac Support and Prosthetic Devices Branch**
**Center for Devices & Radiological Health**

- DHHS/FDA/CDRH

## Animal Model Justification

**Normal swine**
**Comparable vascular and cardiac anatomy**
**Vessel diameters suitable for the delivery and deployment of the clinical version of the device**
**Allows for comparison to historical data**

- DHHS/FDA/CDRH

## Non-Clinical In Vivo StudiesSpecific Aims

**Device handling characteristics**
**Safety**
**Device-tissue responses**
**General healing response**
**Device-related pathology**
**Device-specific findings**

- DHHS/FDA/CDRH

## Non-Clinical In Vivo StudiesExperimental Design

**Deployment to all three coronary arteries**
**Dual antiplatelet regimen (ASA + clopidogrel)**
**72 hours before implantation through implant duration**
**Targeted artery-to-balloon ratio**
**1:1 to 1:1.2**
**Implant duration**
**28 to 360 days**

- DHHS/FDA/CDRH

## Non-Clinical In Vivo StudiesExperimental Design

**Stent platforms evaluated**
**Bare metal stent**
**Polymer - coated metal stent**
**Polymer - drug coated metal stent**
**Drug dose density - 1 ****u****g/mm****2**
**MR formulation**
**SR formulation**
**	**
**	**

- DHHS/FDA/CDRH

## Non-Clinical In Vivo StudiesGraded Pathology Assessment 

**Mural thrombus**
**Endothelialization**
**Neointima**
**Luminal narrowing**
**Para-strut amorphous ****material (PAM)**

- DHHS/FDA/CDRH

**Medial remodeling**
**IEL disruption**
**EEL disruption**
**Inflammatory response**

## Non-Clinical In Vivo StudiesMorphometric Measurements

**Luminal area**
**IEL area**
**EEL area**
**Neointimal area**
**Lumen equivalent ****diameter**

- DHHS/FDA/CDRH

**Intimal thickness**
**Medial area**
**Stent profile**
**% stenosis**

## Non-Clinical In Vivo Studies Applicable to Safety for This PMA

**Bare metal stent**
**Polymer - coated metal stent**
**Polymer - drug coated metal stent**
**Safety Margin**
**MR - 1 ****u****g/mm****2**

- DHHS/FDA/CDRH

** **
**Overlapping Stents**
**MR - 1 ug/mm****2**
**SR  - 1 ug/mm****2**

## Non-Clinical In Vivo Studies Study Observations

**Similarities in findings across stent platforms**
**Neointimal formation**
**Endothelialization**
**No mural thrombosis**
**Inflammatory response**

- DHHS/FDA/CDRH

## Non-Clinical In Vivo Studies Study Observations

**Similarities in findings across stent platforms**
**Medial remodeling **
**In-growth of fibrous tissue**
**Loss of smooth muscle cells**
**Morphometric measurements **
**Stable EEL and luminal areas**
**Reflect medial remodeling**

- DHHS/FDA/CDRH

## Non-Clinical In Vivo Studies Study Observations

**Differences in findings across stent platforms**
**Qualitative differences **
**Medial remodeling**
**PAM**
**Dystrophic calcification**

- DHHS/FDA/CDRH

## Non-Clinical In Vivo Studies Study Observations

**Differences in findings across stent platforms**
**Magnitude of differences associated with:**
**Release formulation**
**MR > SR > polymer, bare metal**
**Segmental Analysis**
**Overlapping > Non-overlapping**

- DHHS/FDA/CDRH

## Non-Clinical In Vivo Studies Summary

**Device handling characteristics satisfactory**
**Device-tissue response is satisfactory**
**Neointimal formation**
**Endothelialization**
**No mural thrombus**

- DHHS/FDA/CDRH

## Non-Clinical In Vivo Studies Summary

**Device-related pathology **
**Medial remodeling**
**PAM appears to be resolving with time through 360 days **
**Microscopic dystrophic calcification is variably present**
**Vessel wall remains structurally intact**

- DHHS/FDA/CDRH

## Advisory Panel Question

**	****Does the combination of 9 month clinical data from the pivotal TAXUS IV (SR formulation) study and the adjunctive data from TAXUS I (SR formulation) and TAXUS II (SR and MR formulations) adequately address the potential concerns raised by the animal studies?**

- DHHS/FDA/CDRH

## Clinical Summary

**John Stuhlmuller, M.D.**
**Interventional Cardiology Devices Branch**
**Center for Devices & Radiological Health**

- DHHS/FDA/CDRH

## Clinical Studies

**Pivotal Study**
** ****TAXUS IV**
**Supporting Studies**
**TAXUS I**
**TAXUS II**
**TAXUS V**
**Peri-Approval Study**

- DHHS/FDA/CDRH

## Clinical Studies

**Pivotal Study**
**TAXUS IV**
**Supporting Studies**
**TAXUS I**
**TAXUS II**
**TAXUS V**
**Peri-Approval Study**

- DHHS/FDA/CDRH

## TAXUS IVStudy Design

**Prospective, multicenter and blinded**
**1:1 randomization to TAXUSTM stent    (SR formulation) or EXPRESSTM stent**
**Stratified Randomization**
**6 month post-procedure antiplatelet regimen**

- DHHS/FDA/CDRH

## TAXUS IVStudy Design

**TAXUS IV****Study Design**

**32**

**24**

**16**

**3.50**

**3.00**

**2.50**

**Stent diameter **
**(mm)**

**Stent Length**
**(mm)**

**Provisional overlapping for bail-out stenting**

**Multiple Stent Use**

**Not**
**available**

**Large diameters**

**Long lesions            (32 mm stent)**

**Small diameters**
**(< 3.0 mm)**

**Single Stent Use **

- DHHS/FDA/CDRH

## TAXUS IVPatient Outcome Assessment

**Effectiveness **
**Target Vessel Revascularization at 9 months**
**Safety**
**MACE**
**Stent Thrombosis**
**Vessel wall structure**

- DHHS/FDA/CDRH

## TAXUS IV Patient Outcome Assessment

**Primary Effectiveness Endpoint**

**0.0001**

**-7.3%****[-10.2%, -4.3%]**

**12.0%****(78/652)**

**4.7% (31/662)**

**TVR **
** **

**p-value**

**Difference**
**[95% C.I.]**

**Control**

**TAXUSTM**

## TAXUS IV Patient Outcome Assessment

**Safety Endpoints**

**0.7513 **

**0.8% ****(5/652) **

**0.6% (4/662) **

**Late thrombosis to 270 days**

**0.4487 **

**0.6% ****(4/652) **

**0.3% (2/662) **

**Stent thrombosis to 30 days**

**0.0002 **

**15.0% (98/652) **

**8.5% (56/662) **

**MACE to 270 days**

**p-value**

**Control**

**TAXUS******

**Safety Endpoint**

## TAXUS IV Patient Outcome Assessment

**Safety Endpoints**

**0.6210 **

**2.2% (2/93) **

**1.1% (1/94) **

**Late Acquired**

**0.6210 **

**1.1% (1/93) **

**3.2% (3/94) **

**Persistent**

**1.0000 **

**5.4% (5/93) **

**6.4% (6/94) **

**Resolved**

**Paired Data**

**0.7209 **

**3.0% (3/100) **

**4.0% (4/99) **

**To 270 Days**

**0.2415 **

**6.4% (7/109) **

**11.6% (13/112) **

**Post Procedure**

**p-value**

**Control**

**TAXUS****TM**

**Incomplete Apposition**

## Clinical Studies

**Pivotal Study**
** ****TAXUS IV**
**Supporting Studies**
**TAXUS I**
**TAXUS II**
**TAXUS V**
**Peri-Approval Study**

- DHHS/FDA/CDRH

## TAXUS IStudy Design

**Prospective, randomized, multicenter and                                    blinded clinical feasibility study**
**A total of 61 patients enrolled at 3 centers in Germany**
**NIRx Paclitaxel-Eluting Stent (SR formulation)**
**Primary study endpoints**
**MACE at 30 days**
**Angiographic restenosis at 6 months**
**Follow-up through 2 years completed**

- DHHS/FDA/CDRH

## TAXUS IPatient Outcome Assessment

**Effectiveness **
**Persistent drug effect is maintained through 2 years by angiography and IVUS assessments**
**Safety**
**Vessel wall remains structurally intact at 2 years**
**No safety issues noted**

- DHHS/FDA/CDRH

## Clinical Studies

**Pivotal Study**
** ****TAXUS IV**
**Supporting Studies**
**TAXUS I**
**TAXUS II**
**TAXUS V**
**Peri-Approval Study**

- DHHS/FDA/CDRH

## TAXUS II Study Design

**Prospective, randomized, OUS multicenter, and blinded**
**NIRx Paclitaxel-Eluting Stent**
**TAXUS II SR Cohort**
** ****267 patients at 28 centers in 12 countries **
**TAXUS II MR Cohort**
** ****270 patients at 28 centers in 12 countries **
**Primary study endpoints**
**MACE at 6 months**
**Angiographic restenosis at 6 months**
**Follow-up through 1 year completed**

- DHHS/FDA/CDRH

## TAXUS II SR CohortPatient Outcome Assessment

**Effectiveness **
**Clinical benefit maintained at 1 year **
**Safety**
**Vessel wall remains structurally intact in the TAXUS arm compared to control arm at 6 months**
**No safety issues noted**

- DHHS/FDA/CDRH

## TAXUS II MR CohortPatient Outcome Assessment

**Effectiveness **
**Clinical benefit maintained at 1 year **
**Safety**
**Vessel wall remains structurally intact in the TAXUS arm compared to control arm at 6 months**
**No safety issues noted**

- DHHS/FDA/CDRH

## TAXUS II SR vs. TAXUS II MRPatient Outcome Assessment

**Effectiveness **
**Similar clinical benefit at 1 year **
**Safety**
**Similar vessel wall measurements by angiography and IVUS at 6 months**
**TAXUS II MR provides preliminary clinical evidence of safety margin for SR formulation**
**No safety issues noted**

- DHHS/FDA/CDRH

## Clinical Studies

**Pivotal Study**
** ****TAXUS IV**
**Supporting Studies**
**TAXUS I**
**TAXUS II**
**TAXUS V**
**Peri-Approval Study**

- DHHS/FDA/CDRH

## TAXUS V Study Design

**Prospective, multicenter and blinded**
**1:1 randomization to TAXUSTM (SR formulation) stent or EXPRESSTM stent**
**Smaller diameters and longer lesions**
**Single or overlapping stents**

- DHHS/FDA/CDRH

## TAXUS VPatient Outcome Assessment

**Study remains blinded**
**30-day follow-up on 1080 of 1103 patients enrolled to date**
**Safety**
**Total of 122 MACE events**
**10 episodes of stent thrombosis in 8 patients**
**Acute-3, subacute-6 and late-1**
**No safety issues noted with broader range of stent use**

- DHHS/FDA/CDRH

## Clinical Studies

**Pivotal Study**
** ****TAXUS IV**
**Supporting Studies**
**TAXUS I**
**TAXUS II**
**TAXUS V**
**Peri-Approval Study**

- DHHS/FDA/CDRH

## TAXUSPeri-Approval Study

**Proposed enrollment of 2000 patients**
**Phase I – 500 patients**
- Continued Access Protocol under IDE
- Assess format and function of web-based registry
**Phase II – 1500 patients**
- Post-approval web-based registry

- DHHS/FDA/CDRH

## TAXUSPeri-Approval Study

**Total sample size appropriate for detecting low rates of adverse events**
**With sample size of 2000 patients, an adverse event that occurs at a rate of 1.0% can be detected with an upper 95% confidence limit of 1.4%**

- DHHS/FDA/CDRH

## Clinical Summary

**Similar clinical benefit maintained through 1 year for both groups**
**Similar vessel measurements in both groups at 6 months**
**No safety issues noted**

**TAXUS II SR**
**TAXUS II MR**

**Supporting**

**Clinical benefit maintained through 2 years**
**Vessel wall structurally intact at 2 years**
**No safety issues noted**

**TAXUS I**

**Supporting**

**Clinical benefit at 9 months**
**Vessel wall structurally intact at 9 months**
**No safety issues noted**

**TAXUS IV**

**Pivotal**

**Conclusions**

**Study **
**Name**

**Study**
**Type **

## Clinical Summary

**Proposed enrollment of 2,000 patients**
**Phase I – 500 patients pre-approval**
**Phase II – 1500 patients post-approval**
**Satisfactory proposal**

**Peri-Approval**

**Pre- and Post-approval**

**Extends lesion range treated in TAXUS IV**
**Preliminary evidence of safety for broader range of use in > 1,000 patients at 30 days**

**TAXUS V**

**Supporting**

**Conclusions**

**Study **
**Name**

**Study**
**Type **

## Statistical Summary

**Heng Li, Ph.D.**
**Division of Biostatistics**
**Center for Devices & Radiological Health**

- DHHS/FDA/CDRH

## TAXUS IV Study Design

**Prospective, multi-center, randomized, double-blind clinical trial for safety and effectiveness.  **
**Randomization effective in controlling bias.**

- DHHS/FDA/CDRH

## Handling protocol deviation

**Deregistered patients (12) are excluded from analysis**
**Protocol deviations not extensive**
**Different approaches to address  protocol deviations do not seem to affect the statistical significance of the results of the statistical test planned for the primary endpoint**

- DHHS/FDA/CDRH

## Subgroup Analyses

**No safety issues identified**
**Due to the issues of multiplicity and/or insufficient power, results of the subgroup (e.g., gender, diabetics) analyses are to be viewed as mostly hypothesis-generating rather than definitive**

- DHHS/FDA/CDRH

## Panel Questions

**TAXUSTM**** Express****2****TM**** **** Paclitaxel-Eluting **
**Coronary Stent System**
**P030025**

- DHHS/FDA/CDRH

## Evaluation of Safety

**Does the combination of 9 month clinical data from the pivotal TAXUS IV (SR formulation) study and the adjunctive data from TAXUS I (SR formulation) and TAXUS II (SR and MR formulations) adequately address the potential concerns raised by the animal studies?**

- DHHS/FDA/CDRH

## Evaluation of Safety

**2a.****	****Are the clinical studies presented adequate to address concerns about possible adverse effects from interactions with drugs typically administered to the target patient population? **

- DHHS/FDA/CDRH

## Evaluation of Safety

**2b.****	****Please comment on whether the clinical studies adequately address other drug interactions that are likely to be important or of interest.  If not, what other information or studies should be provided?  Specifically, please consider the potential for the following types of interactions:**
**with anti-neoplastic agents ****	**
**with chemotherapeutic agents, where a hypersensitivity reaction could be induced**

- DHHS/FDA/CDRH

## Evaluation of Safety

**Do the clinical data submitted from the pivotal TAXUS IV (SR formulation) study plus the data from the adjunctive TAXUS I (SR formulation), and TAXUS II (SR and MR formulations) studies, provide reasonable assurance of safety?**

- DHHS/FDA/CDRH

## Evaluation of Effectiveness

**Does the clinical data at 270 days presented on the TAXUSTM stent from the pivotal TAXUS IV study provide reasonable assurance of effectiveness?**

- DHHS/FDA/CDRH

## Product Labeling

**5a.****	****Does the evidence presented on the TAXUS******** product support the proposed labeling indication?**

- DHHS/FDA/CDRH

## Product Labeling

**5****b.****	****Please comment on whether the labeling should specify that multiple stents should only be used for bailout purposes (e.g., dissection, insufficient lesion coverage) and whether in these cases the shortest stent available (i.e., 8mm) should be used.**

- DHHS/FDA/CDRH

## Product Labeling

**5c.****	****Please comment on whether the labeling should address the potential combination of the TAXUS******** stent with an additional drug-eluting stent in the same vessel.**

- DHHS/FDA/CDRH

## Product Labeling

**5d.****	****Please comment on whether the labeled recommendation for post-procedural antiplatelet regimen is appropriate, and whether additional recommendations on procedural anticoagulation regimens are warranted.**

- DHHS/FDA/CDRH

## Product Labeling

**5e.****	****Please comment on any other aspects of the labeling, such as:**
**Contraindications**
**Warnings/Precautions (such as use with brachytherapy, conjunction with other procedures, etc.)**
**Drug pharmacology, pharmacokinetics or specific drug safety information (e.g., use in special populations, warnings, precautions)**

- DHHS/FDA/CDRH

## Post-Market Evaluation

**6.****	****Please discuss long-term adverse effects that may be associated with TAXUSTM stents and whether the proposed 5–year follow-up on the clinical trial cohorts and the proposed pre/post-marketing study are appropriate to evaluate the chronic effects of the implantation of the TAXUSTM stent.  If not, what additional information should be collected?  Specifically, discuss how long patients should be followed, and what endpoints and adverse events should be measured.****	**

- DHHS/FDA/CDRH

## DHHS/FDA/CDRH