Medical Product Development: Commercial Success Extends Beyond Regulatory Approval James P. Oberhauser, Ph.D.

Transcription

1 Medical Product Development: Commercial Success Extends Beyond Regulatory Approval James P. Oberhauser, Ph.D. Associate Director, Device Development and Clinical Packaging Engineering Gilead Sciences, Inc. Foster City, CA USA

2 Medical Device Commercialization: Lessons Learned This presentation is a treatise on what not to do, an example of failing to heed fundamental market signals and instead allowing hope to become a strategy. We will touch upon four main areas: Parallel Competitive Innovation Development of Clinical Data Evolution of Market Dynamics Product Life Cycle Management Considerations

3 Medical Device Commercialization: Outline Background Interventional Cardiology Innovation in Percutaneous Coronary Intervention Bioresorbable Vascular Scaffold (BVS) Technology Parallel Shifts: Competitive Innovation Clinical Results Market Dynamics Development of Clinical Data Product Life Cycle Management Take-Home Messages

4 History of Interventional Cardiology: Coronary Blood Supply Coronary arteries are supplied by the ascending aorta The coronaries receive about 5% of the blood flow The coronary arteries are on the outside of the heart (epicardial surface) If they become narrowed or blocked by atherosclerosis or thrombus, angina or a heart attack can occur Graphic source:

5 History of Interventional Cardiology: Atherosclerosis What is Atherosclerosis? Athero means gruel or paste Sclerosis means hardening Characterized by: Buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall Results in: Plaque formation Abnormal blood flow Diminished oxygen supply to target organs Graphic source:

6 History of Medical Device Solutions in PCI: Treatment Pre-Procedure Post-Procedure Indication for Percutaneous Coronary Intervention (PCI)* improving coronary luminal diameter in patients, including those with diabetes mellitus, with symptomatic heart disease due to de novo native coronary artery lesions.

7 Evolution of PCI Therapy: Device Innovations 1977 Andreas Gruentzig performs the first PTCA in Zurich, Switzerland 1988 Julio Palmaz and Richard Schatz develop a stainless steel stent for coronary applications Duke Bioresorbable Scaffold Researchers develop Balloon early concepts of bioresorbable Angioplasty devices aimed (PTCA) at functioning as a temporary scaffold in the coronary vessel 1983 Further research results in a bioresorbable PLLA scaffold in a balloonexpandable design Bare Metal Stents (BMS) 1988 The idea for developing a temporary coronary scaffold began in the 1980s

8 BVS Technology: Early Resistance van der Giessen WJ, et al. Circ. 1996;94:

9 BVS Technology: Early Resistance Fischell TA. Circ. 1996;94: Polymer Coatings for Stents: Can We Judge a Stent by Its Cover? Tim A. Fischell, M.D. The Heart Institute at Borgess Medical Center, Kalamazoo, Mich. The article by van der Giessen et al 1 in this issue of Circulation provides an important perspective on the challenges associated with the development of a truly biocompatible polymeric stent coating. A number of investigators have worked diligently over the past several years to explore the feasibility of a completely bioabsorbable stent. 2 The impetus for this approach was the perception that the long-term implantation of metallic stents might provide a chronic inflammatory stimulus and/or lead to medial atrophy with aneurysm formation that could negate the immediate- and intermediate-term (6 months) advantages of stenting compared with the use of balloon angioplasty in the coronary circulation. 3 4 However, recent studies have suggested that concerns about late restenosis and aneurysm formation with metallic stents in atherosclerotic human coronary arteries are likely unfounded. 5 The excellent longterm biocompatibility of stainless steel stents, combined with the substantive difficulties in developing a polymeric stent with a high-performance delivery system, radiopacity, and competitive structural characteristics (eg, radial hoop strength) have led previously enthusiastic polymer stent proponents to focus their efforts on developing biocompatible polymeric coatings for metal stents. Such a hybrid device (metal backbone plus polymer coating) would provide the mechanical advantages of stenting, including reduction in early elastic recoil and the elimination of unfavorable late remodeling, and at the same time provide a platform for local drug delivery to decrease stent thrombogenicity and/or neointimal hyperplasia. Although appealing in concept, the potential difficulties in the successful development of a biocompatible hybrid (polymer/metal) stent are highlighted by the present study. In this study using an animal model performed at three leading interventional cardiology centers, the investigators examined the histological responses to five biodegradable (polyglycolic acid/polylactic acid, polycaprolactone, polyhydroxybutarate valerate, polyorthoester, and polyethylenoxide/polybutylene terepthalate) and three nonbiodegradable (polyurethane, silicone, The and excellent polyethylene terephthalate) long-term polymers applied biocompatibility to a 90 arc of the balloon-expandable of stainless Wiktor tantalum stent. steel These particular stents, polymers combined were selected due to their potential for excellent biocompatibility based on previous in vitro and in vivo testing. 1 The vessel wall responses at the (noncoated) tantalum wire implantation sites were used as the with control and the compared substantive with the histopathological difficulties responses seen surrounding in developing the polymer. The authors a polymeric found that all of the implanted stent polymer coatings have were led associated with a significant inflammatory and exaggerated neointimal proliferative response. In addition, their data suggest that at least some of the polymer coatings may have provoked an enhanced thrombotic response. previously enthusiastic polymer stent proponents to focus their efforts on developing biocompatible polymeric coatings for metal stents. As pointed out by the authors, the inflammatory response evoked by these polymers demonstrates the limitations of screening compounds with the use of in vitro or subcutaneous implant assays for biocompatibility. The intravascular environment is indeed unforgiving and does not readily tolerate foreign bodies. In addition to the usual tissue biocompatability issues, the exposure to flowing blood with the potential for activation of platelets, the extrinsic clotting cascade, or both provide a challenge to identify a compound that could be used in a hybrid stent design without aggravating the thrombotic risks. These challenges are exaggerated in the coronary circulation due to the potential for enhanced platelet activation at high shear rates in smaller vessels. 6 In the present study, the potentially prothrombotic behavior of the polymer-coated stents may be only partially attributable to the polymer per se. One of the limitations of the present study was that the polymer was applied in a nonuniform manner with a comparatively thick layer (75 to 125 μm).

10 Evolution of PCI Therapy: Device Innovations Andreas Gruentzig performs the first PTCA in Zurich, Switzerland Julio Palmaz and Richard Schatz develop a stainless steel stent for coronary applications Drug eluting stents are introduced to the European and U.S. markets Absorb launches in the European and U.S. markets Researchers develop early concepts of bioresorbable devices aimed at functioning as a temporary scaffold in the coronary vessel 1983 Bare Metal Stents (BMS) Coronary Drug Eluting Stents (DES) XIENCE V Durable Polymer DES Absorb Fully Bioresorbable Vascular XIENCE V CE Launch 2006 Scaffold (BVS) The idea for developing a temporary coronary scaffold began in the 1980s However, polymer technology was still in infancy so metallic implants advanced

11 Drug-Eluting Stents vs. Plain Old Balloon Angioplasty : Short-Term vs. Long-Term Results Stent or Lesion Thrombosis Target Vessel Reinfarction Brodie BR, et al. J. Interven. Cardiol. 2014:27: 21-28

12 Promise of BVS Technology: Target Lesion Failure Increasing Steadily Post-Procedure Stone, G. SPIRIT IV 3 year data, TCT 2011 TLF = cardiac death, target vessel MI, or ischemic-driven TLR

13 Absorb BVS: Phases of Functionality ¹,2 Serruys PW, et al. EuroInterv. 2014;9: Sources: Rita 2: Lancet. 1997;350: ; Courage: N. Engl. J. Med. 2007;365: ; SPIRIT IV: Stone GW, TCT 2013; FAME I: N. Engl. J. Med. 2009;360: Cohort B OCT images - courtesy of RJ van Geuns, Erasmus Medical Center, Netherlands

14 Absorb BVS: Physical Description

15 Absorb BVS: Risks In 2007, Absorb had collected positive safety signals from a 30-patient, single-arm study in EU and New Zealand and held a large lead in BVS development. Abbott began ramping up headcount and financial investment. What risks might one have seen? Improvements in ease-of-use for future generations of metallic drugeluting stents Improvements in clinical outcomes for future generations of metallic drug-eluting stents Lag time in showing BVS clinical benefits (2+ years post-procedure) delaying an efficacy signal Lower pricing for metallic DES

16 PCI Innovation: U.S. DES Launches APR 2003 FEB 2008 OCT 2008 NOV 2011 SEP 2014 JUL 2016 J&J Cordis CYPHER Medtronic Endeavor TAXUS Liberte Abbott XIENCE Prime Abbott XIENCE Alpine Abbott Absorb BVS ION APR 2010 FEB 2012 Medtronic Resolute Integrity TAXUS Express 2 Abbott XIENCE V PROMUS PROMUS Element Plus Promus PREMIER Abbott XIENCE Xpedition SYNERGY MAR 2004 JUL 2008 NOV 2011 SEP 2012 OCT 2015

17 Strut Thickness PCI Innovation: Decreasing Strut Thickness Thicker struts perturb flow more and may increase chances of platelet activation and thrombosis. Thicker struts also increase profile and negatively impact deliverability. 153 mm CYPHER Absorb 74 mm SYNERGY Time

18 PCI Innovation: Reducing Compliance of Delivery Balloon Next generation DES were mounted on low compliance delivery balloons, which facilitated more direct stenting and less lesion preparation (i.e., less pre-dilatation). Absorb inherited the semi-compliant delivery balloon used with Abbott s XIENCE V stent system, and no change in the balloon was contemplated until Physician habits evolved when the low compliance delivery balloons were introduced.

19 ID-TLR at 1-Year PCI Innovation: Improving Clinical Data Clinical data improved with each generation of DES, making the margin for improvement more difficult to achieve. Non-inferiority trials became the norm. 4.9% CYPHER Comparator bare metal stent had a 1-year TLR of 20% Absorb achieved non-inferiority relative to XIENCE at 1-year in its pivotal U.S. trial XIENCE V Resolute Integrity Absorb 1.1% SYNERGY Time

20 DES U.S. Price PCI Innovation: DES Pricing Pressure As drug-eluting stents deliver increasingly strong clinical results for all offerings, they have become a commodity product with little to differentiate one offering from another aside from perceived preference on the part of physicians. $3, Price has become the tool to compete in garnering contracts $ Time

21 DES U.S. Price PCI Innovation: DES Pricing Pressure As drug-eluting stents deliver increasingly strong clinical results for all offerings, they have become a commodity product with little to differentiate one offering from another aside from perceived preference on the part of physicians. $3, Price has become the tool to compete in garnering contracts $ Time

22 PCI Innovation: ABSORB II Clinical Data: 3-Year Results Absorb took a hit in OCT 2016, however, when 3-year data from the ABSORB II study in the European Union delivered disappointing results. Result Absorb XIENCE p-value TLR 6.2% 1.9% MACE 10.5% 5.0% 0.04 Target Vessel MI 7.1% 1.2% Definite Thrombosis 2.5% 0.0% 0.06 Vasomotion mm mm 0.49 In 2012, physicians were given completely different instructions regarding pre- and postdilatation than those provided in 2014 for the ABSORB III U.S. pivotal trial. Those instructions and the semi-compliant delivery balloon likely contributed significantly to the unfortunate results.

23 BVS Innovation: Mitigation of Various Risks? Is it surprising that a first-generation device struggled to compete successfully against third- and fourth-generation devices? Likely not. What should one do? APR 2003 FEB 2008 OCT 2008 NOV 2011 SEP 2014 J&J Cordis CYPHER Medtronic Iterate and Abbott XIENCE Abbott XIENCE Endeavor TAXUS Liberte Prime Alpine FEB 2012 ION Medtronic Resolute Improve APR 2010 Absorb Integrity JUL 2016 Abbott Absorb BVS TAXUS Express 2 Abbott XIENCE V PROMUS PROMUS Element Plus Promus PREMIER Abbott XIENCE Xpedition SYNERGY MAR 2004 JUL 2008 NOV 2011 SEP 2012 OCT 2015

24 BVS Innovation: Mitigation of Various Risks? The trouble is that development of the next-generation Absorb did not begin until JAN 2014, delaying launch until multiple years after the initial Absorb launch. APR 2003 FEB 2008 OCT 2008 NOV 2011 SEP 2014 JUL 2016 J&J Cordis CYPHER Medtronic Endeavor TAXUS Liberte Abbott XIENCE Prime Abbott XIENCE Alpine Abbott Absorb BVS ION APR 2010 FEB 2012 Medtronic Resolute Integrity TAXUS Express 2 Abbott XIENCE V PROMUS PROMUS Element Plus Promus PREMIER Abbott XIENCE Xpedition SYNERGY MAR 2004 JUL 2008 NOV 2011 SEP 2012 OCT 2015

25 Conclusions: What Did We Learn? Markets can change quickly. What was once opportunity can quickly become commodity, eroding the value proposition of a new offering. Time is risk. Products that take a long-time to show value are increasingly risky ventures. Beware commoditization. Disruptive technology is only disruptive if there is room for clinical improvement. Product life cycle management is critical. Anticipating market evolutions and initiating next-generation development early is essential for new technology to overtake a market.

26 Conclusions: What Did We Learn? Be wary of repeating one s mistakes.