Market drivers that vary geographically account for some big differences in the distribution of the coronary stent market across the currently available stent types, and these differences will continue when bioabsorbable stents (and others) are introduced to the market over the next few years.
The local market forces dictating these differences include:
Regulatory timelines in one market that can delay new product introductions by a year or more compared to another market
Regulatory control that either limits or facilitates introduction of local market ("me too") stent developers.
Differences in clinical adoption of advanced technologies driven by local practice patterns
Price sensitivities that can vary considerably from one geography to the next, with the potential to severely restrict the adoption of advanced technologies and/or force price reductions
The coronary stent market illustrated distinct differences in market segmentation on the basis of geography, challenging assumptions of the expected market shares of current and potential stent manufacturers competing in each local market. One of the most distinct differences is the relative adoption of drug-eluting stents in China (captured in Asia/Pacific, below) versus either the U.S. or Europe.
My posts on advanced medical technology, drawing frequently from our market reports, are worth emphasizing for their global perspective. Some two decades ago, it became apparent to me that that the global market perspective is not reserved for big, multi-national companies and their global presence. My understanding of this came about from the experience of seeing clients of all sizes showing their interest — their compelling need — to examine markets outside the U.S. Whether trends like the formation of the European Union and the easing of trade across its member states’ borders, the odd appearance of market economies under Communist China, the economic development of democratic states in South America or even the emergence of newly accessible markets in Eastern Europe — too many changes were making it such that medium or even small sized companies could not overlook opportunities beyond their domestic borders.
Now, I would find it rather striking to see a company focusing its efforts on only one country. As a corollary, I find it equally striking that some market analyses are still peddled that focus only on specific countries. Certainly, I understand the somewhat misguided incentive to do so — it’s easier to focus on one country, one set of patient demographics, one set of regulatory challenges.
Yet, for the cost of product development, the consistent demand by patients for therapeutic outcome regardless of where they live, the available channels to get products into new countries, the ease with which competitors’ innovations will make it cross-border — it simply makes no sense to focus on one particular market.
So I rarely find the need among savvy clients to pressure them into broadening their perspective. They have already long since reinforced the premise, to me, that the information they seek on medical markets is not complete unless it considers the global perspective.
Because if they don’t get a good handle on global markets, they will promptly lose advantage to their competitors.
The coronary stent market has represented a marvelous opportunity for many medical technology companies, but even though it is a huge market now, and has generated enormous cash flow for early entrants, it runs significant risk for current manufacturers as well as those seeking to gain share of this multi-billion dollar global market. The reason is that preconceived notions tend to be strong in this market. There are several such notions that either aren’t well represented by recent trends or may be flat out wrong:
·Bare metal stents will continue to hold a significant share of the coronary stent market due to lingering concerns over drug eluting stents
·Drug-eluting stents have established themselves as unquestionably competitive with coronary artery bypass
·The majority of coronary artery disease caseload will indefinitely be represented by angioplasty/stenting or coronary artery bypass grafting
·Given clinical results, the opportunities for coronary stents are uniform across different geographies
·Robotic, totally endoscopic coronary artery bypass (TECAB) and other advanced technologies to make bypass less traumatic and therefore more competitive with angioplasty/stenting may generate positive clinical results, but economics make them non-competitive
·The nature of healthcare demand for coronary artery disease treatment will make this largely area price insensitive to the pressures of healthcare reform
·Post-surgical restenosis has been adequately addressed by drug-eluting stents, creating a substantial hurdle for competitive anti-restenosis alternatives
Now, admittedly, some of you readers already know where some of the assumptions above have simply gone awry. However, it is striking that medtech markets are often characterized by slow recognition by the industry of the changing drivers and dynamics underpinning market success.
See report #C245, “Worldwide Drug-Eluting, Bare and Other Coronary Stents Market, 2009”.
In the $7 billion+ worldwide market for drug-eluting coronary stents, a consistent theme is now the myriad challenge to existing players from the host of emerging competitors, particularly since the advent of drug-eluting stents (DES). Although not so long ago the DES market was monopolized by J&J/Cordis, then split and controlled by J&J and Boston Scientific, those were the old days. The market is now being progressively divvied up by a crowd of DES manufacturers, and some, like Abbott, with its successful Xience stent, are giving J&J and Boston Scientific a real run for their money.
But the challenges for the DES market, which are significant enough in the emergence of many DES designs seeking clinical, cost and other competitive advantages, are not limited to DES competition. Angioplasty and stenting face a range of competitive challenges in the clinical management of coronary heart disease that force manufacturers to consider the advantages and limitations of DES and all of the alternatives.
Minimally invasive coronary artery bypass grafting (MIDCAB, TECAB, etc.). The primary threat that DES posed to coronary artery bypass was that, with the dramatic reduction in restenosis offered by drug-eluting stents, a percutaneous procedure had outcomes that rivaled CABG (to varying degrees, depending upon whether you talked to a cardiac surgeon or an interventional cardiologist). Given a choice between sternotomy and femoral puncture (and associated recovery and cost), the cath lab procedure won out. However, the onus on surgical instrumentation manufacturers has been fully understood, such that various minimally invasive alternatives to traditional CABG are now dramatically narrowing the gap in trauma between angioplasty/stenting and CABG.
Irreversible electroporation for anti-restenosis. This technique, using very short electric field pulses to destroy cells in the intima, is yet unproven and still needs to be fit into an overall intervention, but nonetheless offers a potential alternative to drug-elution to prevent restenosis. Whether this technology (currently under development at Hebrew University of Jerusalem) succeeds in product approval and clinical development is less the issue than the fact that multiple technologies and approaches are being developed to target restenosis.
Atherosclerosis-reducing drugs (HDL therapy). There was great fanfare when Esperion Therapeutics’ drug, ETC-1002, demonstrated preclinical results indicating an ability to reduce atherosclerosis. The ability to sidestep the entire issue of needing to be less- or minimally-invasive by drug therapy represents a real challenge to not only stents but also bypass procedures.
Drug-eluting balloons. A handful of companies are developing drug-coated balloon catheters as an alternative to balloon angioplasty and stenting and for those who would not benefit from percutaneous procedures, such as those in whom antiplatelet therapy is neither recommended nor desired.
Late-stage thrombosis. The sudden threat, in 2006, that DES products might have a major drawback as a result of the formation of life-threatening clots was ultimately tempered by data indicating the threat was not as significant as feared. However, we remain in a period during which the clinical history of drug-eluting stents has yet to fully illustrate the risks of each of the approved drug-eluting stents on the market. Indeed, some competitors whose products show great promise may ultimately prove to have unforeseen flaws.
Competition in stent alternatives, for the time being, still represents the greatest challenge to competitors. The $7 billion worldwide coronary stent market creates big incentive for players to simply displace market share from other stent manufacturers. But if competitors do not keep in view the full breadth and depth of competition — from any source — they will face obsolescence sooner or later.
See the MedMarket Diligence report #C245, "Worldwide Coronary Stent Market, 2008-2017."
The evolution of the coronary stent market, like most medical device markets, has been driven by manufacturers focused on expanding the use of coronary stents into new caseload as well as penetrating the market shares of competitors.
Clinicians, for their turn as gatekeepers in this effort, are guided in the adoption of stent technologies by the availability of clinical evidence supporting expansion of stent use to patients whose coronary heart disease might otherwise be addressed by coronary artery bypass graft (CABG) surgery, with their selection of the specific stent used determined (to the extent that price is not an overriding attribute) by how well each stent’s clinical data stands up under scrutiny of possible clinical complications.
Manufacturers then take a hard view of both cost and complication rates. Below are shown the potential complications ensuing from stent implantation and which have therefore become a focus of stent technology development:
Potential Complications Related to Implantation of Cardiovascular Stents
Source: MedMarket Diligence report #C245, "Worldwide Market for Drug-Eluting, Bare Metal and Other Coronary Stents, 2008-2017."
Perhaps in no other market is it more imperative for current competitors to keep their eyes on the horizon than in the market for treatments of coronary artery disease. As I have ranted previously (search "coronary artery disease" on this blog), alternative treatments stretch from device to surgery to biotech and options too difficult to categorize. And the options continue to grow. In the biotech area, cell therapy has moved to human studies:
Researchers at UCSF Medical Center started enrolling patients in an early-stage adult stem cell therapy, developed by Osiris Therapeutics Inc., for first-time heart attack patients. (Continued at link.)
Currently, the majority of coronary artery disease treatments are captured by coronary artery bypass grafting ot angioplasty/stenting. These options are likely to remain the most used for some time, with technology development on both sides (bioabsorbable and other stents versus minimally invasive bypass, etc.), but manufacturers must keep their eyes open as clinical research extends on the horizon into non-surgical or even non-interventional options.
See the MedMarket Diligence report #C245 on "Coronary Stents Worldwide".
A wide range of regulatory approval conditions are applied to wound management products. The decision about regulatory classification for a given wound management product lies with the regulatory authority of the country in which the product is to be marketed and the manufacturing site making the product comes within their jurisdiction by virtue of the intent to market the product.
In the USA, medical devices fall within one of three categories depending on the complexity of the product and the invasiveness of its application. Fabric dressings are simple and minimally invasive, and to are designated as Class I devices, whereas products containing biomaterials of human or animal origin are in Class III. Some products that may be considered as examples of “Advanced Wound Care” (AWC, an abbreviation that is used widely in report #S247, and is synonymous with “advanced wound management”) are classified as Class II.
Medical devices require an investigational device exemption for clinical evaluation in humans; they are regulated through and receive 510(k) approval through a pre-market approval scheme regulated by the FDA in the USA, and are approved through the CE Marking process which was introduced in the early 1990s in Europe.
Class I devices in Europe require development and manufacture to be performed under international standard quality control systems, and device dossiers to be managed by the manufacturing company. Class II devices require the dossiers to be submitted for review, and Class III devices require a more substantial device dossier to be compiled and submitted for review with more rigorous toxicological and clinical evaluation. In Europe, devices which incorporate biological materials derived from animals are classed automatically as Class III devices.
In the USA, pharmacological developments (with a pharmacologically active therapeutic benefit) automatically require an investigational new drug (IND) application. Biologic materials are reviewed for a biologics license application (BLA) through an IND by the CBER division of the FDA (CBER stands for Center for Biologic Evaluation and Research).
General wound care products generally fall within the Class I or Class II device categories around the world; any products containing mammalian proteins are Class III devices. The route for approval of more sophisticated products, like those designed to deliver an active therapeutic endpoint, such as pharmaceuticals and tissue engineering products, is more complex and less consistent in different regions around the world.
A wide range of regulatory approval conditions are applied to cell-based therapy products. Many of the technical challenges associated with creating a new tissue-engineered product are focused on the clinical proof phase, the regulatory requirements associated with making, proving effectiveness and safety of the product, and a number of controls on product claims and usage. Often the approach to achieving regulatory approval seems to be arduous, inconsistent and arbitrary. This is best illustrated by the complexity of approval for new tissue engineered products that exist today.
Autologous products for skin are currently available in the USA and new approaches to offering these cells wrapped up in customized services are becoming prevalent around the world. Allogeneic cell-based products for treatment of burn victims, skin conditions, and chronic wound care are now approved from a small number of suppliers in the USA, and several more on their way around the world.
Autologous tissue and cells transplanted during surgery do not have any regulatory requirements placed upon them by the US FDA. However, the devices used to carry out the surgical procedure are regulated as Class I medical devices. These products are required to be manufactured under Good Manufacturing Practices; they are regulated as Devices, and require 510(k)s in the USA. In Europe they are Class I medical devices.
Donated cadaveric tissue products produced to aid surgical construction must be manufactured under Good Manufacturing Practices (GMP) with ATSB or FDA approved manufacturing in the USA, and require Pre-Market Application (PMA) in the USA if extensively processed between removal from donor and transplantation to recipient. These products are classified as Medical Devices. They require extensive infectious disease screening and testing, with procedures which closely control good handling practices. They require pre-market approval as they represent a substantial risk due to risk of spreading infectious agents. These products fall under the Center for Biologic Evaluation and Research (CBER) in the USA, and are classified in Europe as Class III devices requiring a substantial and reviewed device dossier, as they contain biologically derived materials. Minimally manipulated products do not require a PMA. A number of companies such as LifeCell sell products in this category, and a number of other companies are developing products in this area.
Tissue engineered implants represent a broad category of materials from those that are substantially donated allogeneic tissue with cells removed, to those products that are completely biologically based such as follicle and placental cell infusions.
Synthetic products are Class II devices, requiring PMA approval and good manufacturing practices in the USA, and the equivalent CE Mark and Class II approval in Europe.
Biologically derived products are approved through the mutual recognition process in Europe as biological pharmaceuticals and require PMA approval in the USA, and manufacture to good manufacturing practice standards. These products are regulated by the CBER in the USA as biologics requiring a Biologics License Application.
With medtech investments in July and August each at over $400 million, I had hopes (expectations?) that September would continue the trend, but through Sept. 30, medtech financings for the month totaled "only" $328 million. Of course, this is still a healthy amount, especially considering that September investment tends to be lower on a relative basis anyway.
September 2009 Medtech Financings:
Endosense, Inc., has raised $36 million in a Series B financing (catheter ablation of cardiac arrhythmias)
Athena Feminine Technologies has raised $2 million in a Series A financing (pelvic floor electrical stimulation for treatment of urinary incontinence)
ValenTx, Inc., has raised $22 million in Series B financing (minimally invasive treatment of obesity)
LifeWave Hi-Tech Medical Devices Ltd has raised $1.5 million in a secondary offering (electrical stimulation device for chronic wound treatment)
Uptake Medical, Inc., has raised $3.4 million of a planned $13.4 million financing according to a regulatory filing (broncoscopic catheters for treatment of emphysema and chronic obstructive pulmonary disease)
Nuveta, Inc., has raised $800K in a Series A financing (in vitro fertilization technologies)
Virtual Ports, Ltd., has raised $2.6 million in early stage financing (developing surgical endoscopy technology)
Pervasis Therapeutics, Inc., has raised $17 million in a Series C financing (Vascugel, a product derived from tissue-engineered allogeneic endothelium for enhancing blood vessel repair)
Calypso Medical Technologies, Inc., has raised $50 million in venture capital financing (tumor localization technology for use during external beam radiation therapy)
Update Medical, Inc., has raised $3.4 million of a planned $13.3 million financing (bronchoscopic lung volume reduction treatment for COPD)
NewCardio, Inc., has raised $2.9 million in a private placement (platform technology for improvement in 12-lead EKG)
Spinal Kinetics, Inc., has raised $5.3 million in a financing round (artifical discs for treatment of spinal injuries and degenerative disc disease)
Gamma Medica-Ideas, Inc., has raised $24 million in its institutional investor financing round (digital molecular imaging system for detection of cancer)
Micell Technologies, Inc., has received a $15 million investment from St. Jude Medical (drug-coated stents designed to be less thrombogenic)
Monteris Medical, Inc., has raised $2 million of a planned $3.5 million round of financing (tumor ablation applicable to brain)
Ionix Medical, Inc. (formerly OncoStim), has raised $18.3 million in financing according to a regulatory filing (minimally invasive device for treatment of BPH and prostate cancer)
Sleep Solutions, Inc., has raised $20 million according to a regulatory filing (sound analysis technology for in-home monitoring of sleep-disordered breathing)
MedShape Solutions, Inc., announced that it had closed $10 million in equity funding (memory shape device technologies in orthopedics)
Zogenix, Inc., closes $51 million Series B funding (needlefree subcutaneous drug delivery system)
Urodynamix Technologies Ltd raises $1.5 million in private placement (near infrared spectroscopy in diagnosis and treatment of urinary incontinence)
Spartek Medical, Inc., has raised $3.2 million in financing according to a regulatory filing (minimally invasive treatment of degenerative disc disease)
ActiViews Ltd has raised $5 million in a financing round (optical guidance in CT, fluoroscopy and MRI for oncology diagnosis)
ThermalTherapeutic Systems, Inc., has raised $2.75 million in a new round of funding (portable device to heat and circulate sterile fluids)
Blue Belt Technologies, Inc., has raised $2.4 million in a Series A round of funding (surgical instruments in orthopedics and neurosurgery)
Inspired Surgical Technologies, Inc., has raised $1 million in financing according to a regulatory filing (photonic based surgical technologies platform)
Satiety, Inc., has raised $25.3 million of a planned $33 million round of financing (obesity device)
The identification of those atherosclerotic plaques most likely to result in heart attack when they embolize is a goal with multiple benefits. These "vulnerable plaques", if effectively picked up via technques like intravascular ultrasound (see below), can become the focus of prevention and a more precise target of intervention. The alternative is, at least in principle, a less cost-effective — or clinically effective — practice of cardiology. In an era of critical attention on high health care costs, such a prospect is of paramount importance.
Late-breaking results from the PROSPECT clinical trial shed new light on the types of vulnerable plaque that are most likely to cause sudden, unexpected adverse cardiac events, and on the ability to identify them through imaging techniques before they occur. See link.
Other results coming out of this year’s TCT meeting have also shown revealing data and conclusions about coronary stents.
Results from the SPIRIT IV trial, comparing safety and efficacy of everolimus-eluting and Paclitaxel-eluting stents in treatment of coronary lesions, were described today (see link), below:
SAN FRANCISCO, CA SEPTEMBER 23, 2009 Late-breaking data from SPIRIT IV, a large-scale multi-center study of nearly 4,000 patients in the U.S., shows that an everolimus-eluting stent demonstrated enhanced safety and efficacy in the treatment of de novo native coronary artery lesions when compared to a paclitaxel-eluting stent, and showed that "low late loss" may be achieved with drug-eluting stents without sacrificing safety.
As intense as the original competition was between Boston Scientific (TAXUS, Paclitaxel) and J&J/Cordis (CYPHER, Sirolimus), the competition in the stent wars is heating up with the apparent efficacy of Everolimus (Abbott and others, including Boston Scientific) and a litany of other drugs in various stages of development for drug-eluting stents.
Below is a sampling of the different drugs in development by manufacturers of drug-eluting stents (from report #C245).
Companies and Drugs for Use in Drug-Eluting Stents
Aachen Resonance GmbH
Dual drug: zotarolimus and dexamethasone
amg International GmbH
amg Vascular Products
Atrium Medical Corp.
B. Braun Melsungen
Pimecrolimus bioabsorbable, CoCr
Blue Medical Devices
Paclitaxel, second generation
Paclitaxel, third generation, platinum chromium alloy
Boston Scientific (developed by Labcoat)
Sirolimus; biodegradable to bare metal
CID SRL (formerly Sorin)
EuroCor (Opto Circuits)
Global Therapeutics (Cook Medical)
ITGI Medical Ltd.
(Undisclosed) Pericardium covered stent
J&J: Conor Medsystems
Pimecrolimus; biodegradable, absorbable
JW Medical Systems
Rapamycin with biodegradable polymer coating
JW Medical Systems (Parent company Shandong Weigao) / Biosensors International
Sirolimus with biodegradable polymer coating
Tacrolimus with biodegradable polymer coating
Lepu Medical (AKA Beijing Lepu Medical Device)
Medlogics Device Corporation (MDC)
Sirolimus with biodegradable coating
MicroPort Scientific Corporation
Undisclosed drug, biodegradable, absorbable
(Undisclosed; polymer drug delivery system)
Sirolimus; bioabsorbable polymer
Relisys Medical Devices
Sahajanand Medical Technologies
Paclitaxel, rapamycin (cobalt base)
Source: MedMarket Diligence Report #C245, “Worldwide Drug-Eluting, Bare Metal and Other Coronary Stents, 2008-2017.”
The market for drug-eluting stents is on a track to be increasingly fragmented and competitive as a result of the aggressive development. The market is also a moving target as the alternatives multiply and shift with continued demonstration of results (drug-eluting balloons, bioabsorbable stents and the resilience of cardiac surgeons performing CABG).