Aaron V. Kaplan

Medical Device Development From Prototype to Regulatory Approval

The treatment of cardiovascular disease has changed dramatically over the past 2 decades, allowing patients to live longer and better-quality lives. The introduction of new therapies (both drugs and devices) has contributed much to this success. Nowhere has this been more evident than in interventional cardiology, where percutaneous coronary intervention has evolved in the past 2 decades from a quirky experimental procedure to a therapeutic cornerstone for patients with coronary artery disease. In 2002, approximately 800 000 percutaneous coronary intervention procedures were performed in the United States alone, compared with some 350 000 coronary bypass surgeries. This explosive growth has been fueled by the availability of new devices (guidewires, angioplasty balloons, stents, etc) coupled with validation by clinical data, primarily in the form of randomized clinical trials. However, important differences have evolved in the clinical-regulatory environment between the United States and Europe that have impacted the location of clinical testing and the relative timing of commercial availability. This has led to substantial differences in the speed of introduction and the extent of testing of these devices in the United States and Europe. A prime example of this difference can be seen in the introduction of the drug-coated stent that became available in European countries 1 year before its arrival in the United States. The Dartmouth Device & Drug Development Symposium was held in October 2003 with joint inventor, entrepreneur, industry, clinical, and regulatory participation, in an effort to characterize the process by which new interventional devices are currently developed and approved. There was also an effort made to identify a series of “sticking-points” in the process, and to suggest some ways in which the efficiency of the process might be improved. This article will review these findings.nnAlthough large medical device companies typically develop successive iterations of existing devices, most …

Outcomes Following Coronary Stenting in the Era of Bare-Metal vs the Era of Drug-Eluting Stents

CONTEXTnAlthough drug-eluting stents reduce restenosis rates relative to bare-metal stents, concerns have been raised that drug-eluting stents may also be associated with an increased risk of stent thrombosis. Our study focused on the effect of stent type on population-based interventional outcomes.nnnOBJECTIVEnTo compare outcomes of Medicare beneficiaries who underwent nonemergent coronary stenting before and after the availability of drug-eluting stents.nnnDESIGN, SETTING, AND PATIENTSnObservational study of 38,917 Medicare patients who underwent nonemergent coronary stenting from October 2002 through March 2003 when only bare-metal stents were available (bare-metal stent era cohort) and 28,086 similar patients who underwent coronary stenting from September through December 2003, when 61.5% of patients received a drug-eluting stent and 38.5% received a bare-metal stent (drug-eluting stent era cohort). Follow-up data were available through December 31, 2005.nnnMAIN OUTCOME MEASURESnCoronary revascularization (percutaneous coronary intervention, coronary artery bypass surgery), ST-elevation myocardial infarction, survival through 2 years of follow-up.nnnRESULTSnRelative to the bare-metal stent era, patients treated in the drug-eluting stent era had lower 2-year risks for repeat percutaneous coronary interventions (17.1% vs 20.0%, P < .001) and coronary artery bypass surgery (2.7% vs 4.2%, P < .01). The difference in need for repeat revascularization procedures between these 2 eras remained significant after risk adjustment (hazard ratio, 0.82; 95% confidence interval, 0.79-0.85). There was no difference in unadjusted mortality risks at 2 years (8.4% vs 8.4%, P =.98 ), but a small decrease in ST-elevation myocardial infarction existed (2.4% vs 2.0%, P < .001). The adjusted hazard of death or ST-elevation myocardial infarction at 2 years was similar (hazard ratio, 0.96; 95% confidence interval, 0.92-1.01).nnnCONCLUSIONnThe widespread adoption of drug-eluting stents into routine practice was associated with a decline in the need for repeat revascularization procedures and had similar 2-year risks for death or ST-elevation myocardial infarction to bare-metal stents.

Does Safe Dosing of Iodinated Contrast Prevent Contrast-Induced Acute Kidney Injury?

Background—Previous work on contrast-induced acute kidney injury (CI-AKI) has identified contrast volume as a risk factor and suggested that there is a maximum allowable contrast dose (MACD) above which the risk of CI-AKI is markedly increased. We hypothesized that there is a relationship between contrast volume and CI-AKI and that there might be reason to track incremental contrast volumes above and below the MACD limit. Methods and Results—Consecutive patients undergoing percutaneous coronary intervention (PCI) were prospectively enrolled from 2000 to 2008 (n=10 065). Patients on dialysis before PCI were excluded (n=155). MACD was defined as (5 mL×body weight [kg])/baseline serum creatinine [mg/dL]) and divided into categories in which 1.0 reflects the MACD limit: ⩽MACD ratios (<0.5, 0.5 to 0.75, and 0.75 to 1.0) and >MACD (1.0 to 1.5, 1.5 to 2.0, and >2.0). CI-AKI was defined as a ≥0.3 (mg/dL) or ≥50% increase in serum creatinine from baseline or new dialysis. Multivariable regression was conducted to evaluate the effect of exceeding the MACD on CI-AKI. Twenty percent of patients exceeded the MACD. Risk-adjusted CI-AKI increased by an average of 45% for each category exceeding the MACD (odds ratio, 1.45; 95% confidence interval, 1.29 to 1.62) Adjusted odds ratios for each category exceeding the MACD were 1.60 (95% confidence interval, 1.29 to 1.97), 2.02 (95% confidence interval, 1.45 to 2.81), and 2.94 (95% confidence interval, 1.93 to 4.48). CI-AKI for contrast dose <MACD showed no statistical difference (P=0.5). Conclusions—Contrast volume is a key risk factor for CI-AKI and matters the most in the highest-risk patient. The incremental use of contrast beyond the MACD is associated with an increased risk of CI-AKI.

Intramural Delivery of Agent via a Novel Drug-Delivery Sleeve Histological and Functional Evaluation

BACKGROUNDnThe infusion sleeve is a novel drug-delivery catheter system designed to deliver an agent under controlled conditions into the arterial wall at the site of angioplasty. The purpose of the present study was to characterize the delivery agent via the infusion sleeve in ex vivo and in vivo models.nnnMETHODS AND RESULTSnThe delivery of horseradish peroxidase via the infusion sleeve was studied in a porcine explanted heart model. Under physiological conditions, arteries underwent balloon injury (approximately 10% overstretch), after which horseradish peroxidase (2.5 mL) was delivered at specific pressures. Cross-sectional analysis demonstrated greater staining when the agent was delivered at increasing pressures. The infusion sleeve was evaluated in an in vivo canine coronary model. With an infusion sleeve loaded over a standard dilatation catheter through a 9F guide, overstretch balloon injury was performed, after which fluoresceinated heparin was delivered. Animals were killed 2 hours after delivery. Fluoresceinated heparin-treated segments demonstrated high fluorescence signals, localizing with smooth muscle cell nuclei with less activity in the interstitium. The functional significance of intramural heparin delivery was studied in a porcine carotid model. In the presence of 111In-labeled platelets, arteries underwent overstretch injury followed by delivery of heparin (50 or 100 units/kg) or vehicle. Platelet deposition was reduced at 30 minutes (57%, P < .01) and 12 hours (39%, P = .06) compared with saline controls.nnnCONCLUSIONSnAgent delivery via the infusion sleeve is pressure dependent; transmural delivery is possible with minimal disruption of arterial wall architecture; the infusion sleeve is compatible with standard angioplasty equipment; and heparin delivery at the site of balloon injury significantly reduces platelet deposition in a porcine model for a minimum of 12 hours.

Post-market approval surveillance: A call for a more integrated and comprehensive approach

The availability of new therapies over the past 2 decades has dramatically changed the practice of medicine. The introduction of medical devices has ushered in the era of minimally invasive procedures, thus fundamentally changing many surgical disciplines and creating new sub-specialties. Nowhere has the impact of new device technology been more dramatic than in the discipline of interventional cardiology. In addition to driving the growth of the medical device industry, device development has spawned entire new industries devoted to the coordination and administration of clinical trials. For a company to market a new high-risk device in the United States it must obtain approval from the Food and Drug Administration (FDA) based on the ability to demonstrate safety and effectiveness.1 For a new interventional device like a drug-eluting stent, this is typically accomplished by performing large, multicentered, randomized controlled studies. These studies are performed by clinical investigators at research institutions on highly selected patients that may represent a small sector of the population for which the device is being developed. FDA approval is typically limited to the patient population studied, which is specifically outlined in the package labeling and instructions for use. Nevertheless, it is generally understood that after market release, devices are commonly used outside the narrow confines of the pivotal study’s selection criteria by operators with a wide spectrum of training and experience at institutions lacking the infrastructure or competency of the research institutions where the pivotal trials were performed. It is assumed that the benefits of device use demonstrated in the pivotal trials can be generalized to a wider patient population in the general clinical community. Whereas large resources have been devoted to the early development and clinical evaluation of new medical devices, few resources have been focused on post-market surveillance, which is the systematic evaluation of …

Postmarket Surveillance for Drug-Eluting Coronary Stents: A Comprehensive Approach

The development and introduction of new medical devices have radically changed the practice of medicine. No area of medicine has been affected more than cardiology, with new devices facilitating the effective treatment of coronary artery disease (percutaneous coronary interventions [PCIs]/stents), valvular heart disease (mechanical and bioprosthetic valves), and electrophysiological disorders (pacemakers and automatic implantable cardiodefibrillators). In addition to fueling the growth of the medical device industry, this explosion of technology has driven the development of new medical subspecialties, eg, interventional cardiology and electrophysiology. Other areas of medicine, including orthopedics and general surgery, have witnessed similar transformations. The current regulatory pathway for a significant-risk first-in-class medical device is typically a long, expensive, and risky process, culminating in a pivotal trial designed to demonstrate safety and efficacy. The pivotal trial phase is typically the most time-consuming and costly phase of the process. In the United States, medical devices are regulated by the Center for Devices and Radiological Health at the Food and Drug Administration (FDA), which has been charged by Congress to seek the “least burdensome means” when determining the scope of data required to evaluate the safety and efficacy necessary for device approval.1 Thus, pivotal trials by intention are designed to select patient cohorts most likely to demonstrate procedural benefit while limiting patient/study subject risk within the shortest time frame that can provide meaningful data. The realities of logistics, time, and resources limit the size and duration of most new device trials to 800 to 1500 patients, limiting the power of these trials to detect events with an occurrence rate of <1%. Furthermore, pivotal trials are conducted by the most experienced physician operators at medical centers with sufficient patient volume and research infrastructure to recruit and conduct clinical studies. Some have questioned whether results obtained under these settings from such …

Quantitative evaluation of local drug delivery using the InfusaSleeve catheter

BACKGROUNDnRestenosis is the most common long-term complication after angioplasty. Local delivery of pharmacologic agents at the site of angioplasty holds promise as a means of achieving higher concentrations of drug in the arterial wall than can be obtained by systemic infusion. In this study, a novel local drug delivery catheter system, the InfusaSleeve catheter, was evaluated in a porcine coronary balloon injury model. The purpose of the study was to evaluate the efficacy of solute transfer to the arterial wall and the influence of varying supporting angioplasty balloon pressure.nnnMETHODS AND RESULTSnTen pigs (total of 22 arterial segments) underwent overstretch balloon injury (artery/balloon ratio 1:1.29) with a standard angioplasty balloon. In 7 animals (16 arterial segments) horseradish peroxidase (HRP; 10 mg/ml) was administered locally after injury, by tracking the local infusion catheter as a sheath over the angioplasty balloon to the intended site of arterial drug delivery. Supporting angioplasty balloons were inflated to one of the three different pressures. In 3 pigs HRP (10 mg/ml) was administered intravenously. No significant arterial injury caused by the local delivery device was evident on histological examination (disruption of the internal lamina elastica, arterial media, or thrombosis). Radial concentrations of the HRP reaction product in the first 150 microns of the arterial wall were quantified against known standards by measurement of light transmission through tissue sections. Mean HRP concentrations were not significantly different from those obtained by intravenous infusion using a supporting pressure of 1 atm or a supporting pressure of 3 atm of the underlying angioplasty balloon. However, a supporting pressure of 6 atm resulted in a 6-fold greater mean HRP concentration in the arterial wall than that which could be achieved by systemic administration of an equal volume of tracer (P < 0.001).nnnCONCLUSIONnThus solute can be delivered throughout the coronary media by the InfusaSleeve, with the magnitude of wall uptake related to support pressure. Local delivery at 6 atm support pressure produced substantially greater uptake than did systemic delivery.

Medical Device Regulatory Landscape The Imperative of Finding Balance

The past 60 years have witnessed fundamental advances in our understanding and treatment of cardiovascular disease, prolonging and improving patients lives. Central to these improvements has been the introduction of medical devices, including mechanical and biological heart valves, heart rhythm devices, and balloon angioplasty and stents. The introduction of these technologies has been dependent on an entrepreneurial medical device sector, coupled with an equally robust infrastructure to clinically develop and evaluate these new technologies. After approval and commercialization, continued study of device performance under “real world” conditions is crucial to ensure that the clinical potential is being realized.nnCentral to a healthy medial device “ecosystem” is a robust regulatory system. Regulators must ensure that a device performs reliably and is adequately characterized, allowing physicians and patients to use it appropriately. Determining if/when a device is appropriate for approval is difficult and challenging and requires balancing its safety-efficacy profile. The technical sophistication required to make these determinations has grown as device complexity has grown. The stakes are very high, as illustrated by the recent Fidelis AICD lead recall, affecting 268 000 patients worldwide.1nnThese safety concerns must be balanced by the harm inflicted by withholding beneficial technology from patients. There is wide variation in how devices are regulated among countries with well-developed health care delivery systems, for example, the United States and Europe as well as Japan and Canada. The recent Food and Drug Administration (FDA) approval of the Sapien Transcatheter Heart Valve has brought these differences into sharp focus. In this commentary, we review the differences between the US and European Regulatory systems and how they have affected the investigational and approval process.nn### Sapien Transcatheter Heart Valve: A Case StudynnOn November 2, 2011, the Sapien Transcatheter Heart Valve (TAVR), manufactured by Edwards Lifesciences, was approved by the US FDA.2 The approval of the Sapien …

Humanitarian Use Devices/Humanitarian Device Exemptions in Cardiovascular Medicine

The Second Dartmouth Device Development Symposium held in October 2004 brought together leaders from the medical device community, including clinical investigators, senior representatives from the US Food and Drug Administration, large and small device manufacturers, and representatives from the financial community to examine difficult issues confronting device development. The role of the Humanitarian Use Device/Humanitarian Device Exemption (HUD/HDE) pathway in the development of new cardiovascular devices was discussed in this forum. The HUD/HDE pathway was created by Congress to facilitate the availability of medical devices for orphan indications, ie, those affecting <4000 individuals within the United States each year. The HUD/HDE pathway streamlines the approval process and permits less well-characterized devices to enter the market. HDE approval focuses primarily on issues of safety and scientific soundness and does not require demonstration of efficacy. In the 7 years since the first device was approved in 1997, a total of 35 HDEs have been granted (23 devices, 6 diagnostic tests). As the costs to gain regulatory approval for commonly used devices increase, companies often seek alternative ways to gain market access, including the HUD/HDE pathway. For a given device, there may be multiple legitimate and distinct indications, including indications that meet the HUD criteria. Companies must choose how and when to pursue each of these indications. The consensus of symposium participants was for the HUD/HDE pathway to be reserved for true orphan indications and not be viewed strategically as part of the clinical development plan to access a large market.

772-3 Heparin Delivery at the Site of Angioplasty with a Novel Drug Delivery Sleeve: Initial Clinical Series

The LocalMed InfusaSleeve (IS) is a multi-lumen array with distal micro perforations designed to deliver agent at the site of angioplasty. Prior to the procedure, the IS is loaded onto a standard dilatation catheter (DC). Using standard technique, angioplasty is performed with the IS retracted. After lesion dilatation, the IS is tracked over the DC, aligning the micro perforation region of the IS with the balloon. The balloon is reinflated bringing the array into close proximity to the arterial wall. Agent(s) is delivered at specific pressures independent of balloon inflation. We have previously shown that agent delivery into the wall is dependent upon balloon inflation and drug delivery pressures. A pilot series was performed to evaluate the safety of heparin delivery via the IS. A total of 21 patients [emergent/urgent (2), elective cases (19)] with lesions at a variety of anatomic sites [LAD(10), LCx(3), ramus intermedius(1), RCA(6) and vein graft (1)] and complexity [ACC/AHA Lesion Type: A(8), B1(l0), B2(3)] were attempted. Following PTCA, heparin (1,000 U/ml) was delivered via the IS into the arterial lumen (balloon inflation pressurexa0=xa00.5 atm, drug delivery pressurexa0=xa040 psi). Failure to track the IS was noted in 2 cases. In 2 cases (RCA) a dissection was noted following agent infusion [NHLBI Type: A(1), B(1)]. The IS was used in conjunction with standard guide catheters [8 fr (15), 9 fr (6)], DC and guide wires. At discharge, no complications were noted. We Conclude 1) The IS can be used safely at a variety of anatomic sites, 2) The IS is compatible with standard PTCA equipment. 3) Local delivery of agent via LocalMed InfusaSleeve is a promising approach to reduce abrupt closure and restenosis.