The Process of Bringing New Drug-Eluting Stents to MarketWill They See the Light of Day?*
David R. Holmes, Jr, MD, FACC ,*,
Manesh Patel, MD
Mayo Clinic, Rochester, Minnesota
Duke University, Durham, North Carolina
Key Words: DES • randomized clinical trial
The ZoMaxx stent (Abbott Laboratories, Abbott Park, Illinois) is a product that will likely never see the light of day despite the performance of pilot human registry experiences and a randomized trial that enrolled 401 patients presented in this issue of JACC: Cardiovascular Interventions (1). The lessons from an experience such as this have important implications that extend beyond the scope of this individual trial. These lessons are derived from issues relating to economic and business considerations and trial design.
 |
Economic and Business Issues
|
|---|
As is true with any proposed commercial product, the goal of business is to provide shareholder value, service to the intended consumer, and a return on investment. In the medical field, in this particular situation with drug-eluting stents (DES), the considerations are complex—in part because of regulatory issues. These regulatory issues have important implications for business decisions. Bringing a complex product such as a DES—in this case a trilayer composite with two outer layers of 316L stainless steel and an inner layer of tantalum (which would have been very valuable because it improves radio opacity); zotarolimus, a drug specifically developed for use in DES without any other application; and a polymer drug carrier of phosphorylcholine—involves many hurdles. With the heightened awareness of safety, specifically late and very late stent thrombosis, and the need for longer term surveillance follow-up even after device approval, the costs of bringing a new stent to market have significantly increased. Some new stents may never be marketed in the U.S. because of these financial and regulatory hurdles, even though these new stents may have specific advantages such as improved side-branch access or better deliverability in tortuous arterial segments. The ZoMaxx stent had potential advantages, as it was designed to "address the need for thin stent width and low profile, while maintaining radial strength and adequate visibility on fluoroscopy" (1).
At the same time, increasing numbers of stent technologies have amplified the relative competition in the field. Competitive products deemed to have an advantage may leapfrog other existing or developing technology. Given the long regulatory process, the field may change significantly from the point of product conception to device application, such that a "new" technology may be obsolete before it is ever approved or fully adopted.
In the particular case of the ZoMaxx stent, after acquiring another company with a competitive DES, the manufacturer (Abbott Laboratories) apparently decided to shelve this specific DES. That may be a real loss to the field because of the potential advantages that this unique stent may have had in terms of deliverability and enhanced radio opacity (related to the tantalum).
|
Trial Design Issues
|
|---|
Randomized trials demonstrating clinical benefit are the foundation required for device approval and use. The ZoMaxx trial was based upon the surrogate end point of late lumen loss. Surrogate end points are used with increasing frequency because they typically require smaller trial patient population sizes and thus can be carried out more quickly with less cost. By definition, surrogates such as late loss represent only a part of the physiology and clinical effect of a device, and thus they have the potential disadvantage of not reflecting what the patient and clinicians are really concerned about, namely, clinical outcome such as death, myocardial infarction, or repeat revascularizations.
Selection of late lumen loss in this trial as the primary end point was probably made in part based upon the results of the intravascular ultrasound trial (2), which enrolled 40 patients in Brazil and which documented in-stent and in-segment late lumen loss of 0.20 ± 0.35 mm and 0.17 ± 0.35 mm, respectively, at 4 months. The expectation of the study investigators would have been that, compared with the well-described late loss with Taxus stents (3,4), this end point would be positive for the ZoMaxx stent. However, not only was the late lumen loss not favorable for the ZoMaxx stent, it was even worse and statistically inferior. Of interest, despite failing to meet preset noninferiority criteria, the investigators spend considerable time and space discussing in the manuscript why this is not relevant because a "retrospective analysis revealed that the inherent disturbances of normality, homogeneity, and similar shape were not met by either cohort" (1). Such post hoc retrospective analyses are not convincing for regulatory agencies or nonvested parties.
The reasons for the discrepancy between the pilot IVUS trial results may relate to differences in patient population and differences in lesions treated. However, they also may relate to late lumen loss being measured at 4 months in the pilot study but not until 9 months in this current study. That raises the possibility of late catch-up, which has now been documented with another DES (Xience, Abbott Laboratories) (5).
Yet another issue is the power calculation in these studies. Of interest in this study are 8 patients who reportedly had an impact on outcome. These 8 patients had treatment of ostial lesions and by random chance were all in the ZoMaxx stent group. In the final analyses, the presence of an ostial lesion in only 8 patients was the most significant multivariate predictor of target vessel revascularization (p = 0.002). To have the development of a promising DES be decided in part on the random occurrence of 8 patients is disturbing. Had these patients been evenly distributed, the target lesion revascularization rates might have been very different. In a highly competitive market, such small differences have great importance. The researchers conclude "that the efficacy of a given DES continues to be difficult to predict empirically, and that long-term comparative clinical testing of each new formulation is required prior to its widespread application." This is certainly true with the proviso that trial design and power calculations must be optimized.
The final issue of a comparator is also important. Should all "new" DES be required to be compared with currently available DES? If so, which drug-eluting stent should be the control? Now with potentially 4 available DES, how are investigators, clinicians, and patients to decide and evaluate these different comparisons? Possibilities include the newest approved DES, the DES with the longest track record (that is to say, the oldest one), or the newest bare-metal stent. Other related issues will be duration of follow-up and role of post-market surveillance to name but a few.
The ZoMaxx stent will presumably never see the light of day. In a time when the menu of DES in the pipeline remains relatively limited, the loss of a product that might have substantial advantages is very real.
|
Footnotes
|
|---|
* Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology. 
* Reprint requests and correspondence: Dr. David R. Holmes, Jr., Mayo Clinic, Cardiovascular Diseases and Internal Medicine, 200 First Street, SW, Rochester, Minnesota 55905 (Email: holmes.david{at}mayo.edu).
|
REFERENCES
|
|---|
- Chevalier B, DiMario C, Neumann F-J, et al. ZoMaxx I Investigators A randomized, controlled, multi-center trial to evaluate the safety and efficacy of zotarolimus- versus paclitaxel-eluting stents in de novo occlusive lesions in coronary arteries: the ZoMaxx I trial J Am Coll Cardiol Intv 2008;1:524-532.[Abstract/Free Full Text]
- Abizaid A, Lansky AL, Fitzgerald PJ, et al. Percutaneous coronary revascularization using a trilayer phosphorylcholine-coated zotarolimus-eluting stent Am J Cardiol 2007;99:1403-1408.[CrossRef][Web of Science][Medline]
- Ellis SG, Popma JJ, Lasal JM, et al. Relationship between angiographic late loss and target lesion revascularization after coronary stent implantation: analysis from the Taxus-IV trial J Am Coll Cardiol 2005;45:1193-2000.[Abstract/Free Full Text]
- Escolar E, Mintz GS, Popma J, et al. Meta-analysis of angiographic versus intravascular ultrasound parameters of drug-eluting stent efficacy (from Taxus IV, V, and VI) Am J Cardiol 2007;100:621-626.[CrossRef][Web of Science][Medline]
- Serruys P. SPIRIT II study: a clinical evaluation of the Xience V everolimus eluting coronary stent system in the treatment of patients with de novo native coronary artery lesionsPresented at: Annual Scientific Session of the SCAI-ACC i2 Summit/American College of Cardiology, March/April 2008Chicago, IL.
Related Article
-
A Randomized, Controlled, Multicenter Trial to Evaluate the Safety and Efficacy of Zotarolimus- Versus Paclitaxel-Eluting Stents in De Novo Occlusive Lesions in Coronary Arteries: The ZoMaxx I Trial
- Bernard Chevalier, Carlo Di Mario, Franz-Josef Neumann, Flavio Ribichini, Philip Urban, Jeffrey J. Popma, Peter J. Fitzgerald, Donald E. Cutlip, David O. Williams, John Ormiston, Eberhard Grube, Robert Whitbourn, Lewis B. Schwartz for the ZoMaxx I Investigators
J. Am. Coll. Cardiol. Intv. 2008 1: 524-532.
[Abstract]
[Full Text]
[PDF]
|
Top
Economic and Business Issues
Trial Design Issues