Fig. 26.1
GORE® HELEX® Septal Occluder (Image provided courtesy of W.L. Gore & Associates, Inc.)
This uniquely designed device was granted FDA approval in 2006 for the indication of percutaneous, transcatheter closure of ostium secundum ASDs. However, as with most PMA devices, the path to FDA approval for this indication was long and arduous requiring the contribution of many associates, years of dedicated work, and millions of dollars of investment. The product conception and evaluation were initiated in the mid-1990s. It was not until the summer of 1999 that the first implants of this device were conducted in Europe following CE Mark approval. Then, for US FDA approval, three clinical studies were conducted between 2000 and 2006, thus enabling FDA approval of the device in 2006. Even now, a Post Approval Study persists: 5-year follow-up will be completed in 2014.
Alongside this initial development effort, Gore further invested in improving the design and deliverability of its occluder constructs. The latest example of this continued investment is seen in the 2011 release of the new GORE® Septal Occluder in Europe (Fig. 26.2). This device differs from the GORE® HELEX® Septal Occluder in that it is constructed of five helical wires, rather than a single wire. The device was designed to maintain the desirable features of the GORE® HELEX® Septal Occluder, such as disc softness, conformability, retrievability, and safety, while being easier to use and allowing improved acute defect closure. Various distinct changes were implemented to assist with these design goals. First, the five-wire design enabled the discs to better appose the septal tissue upon deployment, thus leading to a higher acute closure rate of the defect while maintaining disc softness and conformability [5–7]. Second, the delivery system was enhanced with a handle, thus enabling the physician to more consistently and confidently implant the device. Constant throughout all Gore’s occluder designs was the requirement that the device must be fit for use, both in terms of safety and closure, for the application of septal defect occlusion.
Fig. 26.2
GORE® Septal Occluder (Image provided courtesy of W.L. Gore & Associates, Inc.)
With each product development effort, Gore follows an intense process to ready the device for clinical use, including functional performance testing, deployment reliability, biocompatibility, fatigue resistance, etc. The testing program required to assure device performance may take several years to design and complete, and itself may represent millions of dollars of investment. Nevertheless, this rigorous product development process provides Gore confidence that the product will perform as intended, and that additional investments in the conduct of clinical trials are worthwhile.
Clinical Trial Design
Beyond the supply of technology to support the targeted treatment option, companies in pursuit of a PFO-stroke FDA indication have also contributed through their design and sponsorship of clinical studies aimed to demonstrate the therapeutic benefit of PFO closure. This therapeutic benefit is not simply the ability of the device to occlude the defect, but also includes the requirement of demonstrating superiority of device closure against the standard therapy for the prevention of cryptogenic stroke, i.e. medical management.
Gore initiated its PFO-stroke study relatively late (2008) as compared to AGA Medical or NMT medical (2003). At that time, the GORE® HELEX® Septal Occluder had already received FDA approval for ostium secundum ASD occlusion, and was approved in Europe for both the repair of ostium secundum defects and PFO. In pursuit of the PFO-stroke indication for its device in the US, Gore, with the assistance of key consulting neurologists and cardiologists, developed a unique clinical study called the Gore REDUCE Clinical Study [8]. This study was designed as a prospective, randomized, controlled, multi-center trial intended to demonstrate safety and effectiveness of the GORE® HELEX® Septal Occluder and the GORE® Septal Occluder for PFO closure in patients with a PFO and history of cryptogenic stroke or imaging confirmed transient ischemic attack (TIA), i.e. infarction without persistent clinical symptoms. Patients are intended to be randomized to one of two treatment arms, either antiplatelet medical management alone or device closure of the PFO in conjunction with antiplatelet medical management. The primary endpoint of this study is a freedom from recurrent ischemic stroke, imaging confirmed TIA, or death due to stroke through 24 months post-randomization, while additionally considering any endpoint events that occur in patients up to 60 months post-randomization.
The trial is a multinational effort including the participation of sites from Denmark, Finland, Norway, Sweden, the United Kingdom, Canada, and the US. It is unique based on the use of imaging confirmed stroke/TIA for assessing its primary endpoint and a 2:1 device to medical management randomization strategy. Additionally, a second MR imaging exam is required for all implanted subjects, which will be performed at 2 years post randomization or after a suspected endpoint event, whichever occurs first. This second imaging exam provides an additional imaging endpoint, not offered by other PFO-stroke studies, to permit further comparisons across the treatment arms regarding subclinical infarcts.
As with the other randomized PFO-stroke studies, enrollment in the Gore REDUCE Clinical Study has been painfully slow. Here again, the company is placed in a position of weighing the investment associated with the continued commitment of monetary and human resources to this endeavor versus the potential reward of receiving the targeted indication. Additionally, the opportunity cost associated with not pursuing an alternative endeavor must be considered. The fact of the matter is that regulated clinical studies required for FDA approval are a costly venture. Sponsorship of a clinical trial typically involves payments for an assigned clinical study management staff, site initiations, data collection and management, payments associated with the randomized treatment and follow-up, a data capture system, core labs, data safety monitoring boards, clinical events committees, site monitoring, investigator meetings, etc. To put this into perspective, survey data of more than 200 medical technology companies reveal that the typical time and expense of a Pivotal Clinical Study required for FDA approval runs on the order of ~26 months and ~$40 M [3]. This translates to an average associated expense of roughly $1,500,000 per month, which is a staggering number when one notes that the CLOSURE I study took ~6 years to complete enrollment, the RESPECT study took ~9 years to complete, and the Gore REDUCE Clinical Study is on a similar enrollment trajectory.
Thus, given the level and duration of investment, companies must continually maintain a distinct awareness of the market dynamics and external influences that may increase or decrease the likelihood of receiving a positive return on their investment.
Market Opportunity
One of the key elements that pique a company’s interest in a new endeavor is a favorable assessment of market opportunity. Within the realm of PFO-stroke, the understanding of the potential market opportunity has significantly evolved over time. Peer reviewed publications, results from completed randomized clinical studies, and observations of device use in clinical practice have all served to significantly inform the field’s understanding of which patients may potentially benefit from device closure. Although this question has not been fully answered to date, there has been a significant refinement of the market opportunity assessment over the last decade.
To illustrate the dramatic shift in the understanding of the PFO-stroke market opportunity, it is useful to recollect the assumptions that were expressed early on within this field. For instance, in 2007 NMT Medical presented an overview of their company at the CIBC World Markets 18th Annual Healthcare conference. This meeting was attended by potential investors interested in nearly 160 various health care companies’ perspectives on corporate strategies, product development efforts, and future opportunities. Within NMT’s presentation, an assessment of the PFO-stroke (and TIA) opportunity was provided based on the company’s current understanding of the market [9]. Figure 26.3 details this simple appraisal of the US market opportunity. The assessment was very high level and summarily assumed that all patients with a PFO experiencing ischemic strokes/TIAs of cryptogenic origin would represent the total market opportunity for device closure. This market opportunity was described as nearly 250,000 potential patients per year, representing more than a billion dollars of annual revenue. These figures more than justified a company’s investment into the technology and clinical study infrastructure.
