Closing in on the PumpKIN Trial of the Jarvik 2015 Ventricular Assist Device

The Infant Jarvik ventricular assist device (VAD; Jarvik Heart, Inc., New York, NY) has been developed to support the circulation of infants and children with advanced heart failure. The first version of the device was determined to have elevated hemolysis under certain conditions. The objective of this work was to determine appropriate modifications to the Infant Jarvik VAD that would result in acceptably low hemolysis levels. In vitro hemolysis testing revealed that hemolysis was related to the shape of the pump blade tips and a critical speed over which hemolysis would occur. Various design modifications were tested and a final design was selected that met the hemolysis performance goal. The new version was named the Jarvik 2015 VAD. Chronic in vivo tests, virtual fit studies, and a series of other performance tests were carried out to assess the device’s performance characteristics. In vivo test results revealed acceptable hemolysis levels in a series of animals and virtual fit studies showed that the device would fit into children 8 kg and above, but could fit in smaller children as well. Additional FDA-required testing has been completed and all of the data are being submitted to the FDA so that a clinical trial of the Jarvik 2015 VAD can begin. Development of a Jarvik VAD for use in young children has been challenging for various reasons. However, with the hemolysis issue addressed in the Jarvik 2015 VAD, the device is well-poised for the start of the PumpKIN clinical trial in the near future.

Introduction

The need for circulatory support devices for small children with advanced heart failure, most of whom will need a heart transplant, is substantial and has been growing over the past decade. According to the Organ Procurement and Transplantation Network,¹ 236 children below the age of 6 years received heart transplants in 2015. This is a 52% increase over the past decade. However, nearly a fifth of children awaiting a donor heart die each year.² A recent publication revealed that mortality of children on the cardiac transplant waiting list has decreased by more than 50% since 2005, the time when pediatric-specific ventricular assist devices (VADs) were introduced and which are now used to bridge 20% of pediatric patients to transplant.³ However, that publication also shows that an etiology of congenital heart disease and weights below 10 kg are the two greatest risk factors for mortality for children on the heart transplant waiting list. This was the case before pediatric-specific VADs were available and is still true.³ Consequently, the availability of effective circulatory support devices for small children, especially those with congenital heart disease, remains an unmet need.

In 2004, with the paucity of devices at that time and the documented public health need for a device to specifically support the circulation of small children with heart failure, the National Heart, Lung and Blood Institute (NHLBI) launched the Pediatric Circulatory Support Program. Through five separate contracts, this program supported the development of five novel circulatory support systems for infants and children from 2 to 25 kg with congenital or acquired cardiovascular disease.4, 5 The devices included an implantable mixed-flow VAD designed specifically for patients up to 2 years of age, another mixed-flow VAD designed to be implanted intravascularly or extravascularly depending on patient size, a compact integrated pediatric extracorporeal membrane oxygenator (ECMO) system, an apically implanted axial-flow VAD, and a paracorporeal or intracorporeal placed pulsatile-flow VAD. Good progress was made on these devices during the program, but significant work remained before any of them would be ready for clinical use.

To move pediatric circulatory support devices from the developmental stage to clinical application, the NHLBI launched the Pumps for Kids, Infants, and Neonates (PumpKIN) program in January 2010 when contracts were awarded to four different pre-clinical contractors: Ension, Inc. (PI: Mark Gartner, PhD), the University of Pittsburgh (PI: Harvey Borovetz, PhD), the University of Maryland, Baltimore (PI: Bartley Griffith, MD), and Jarvik Heart, Inc. (PI: Robert Jarvik, MD). The awards were made to support the work necessary to receive Investigational Device Exemptions (IDEs) from the US Food and Drug Administration (FDA) for these four different pediatric circulatory support devices with a target of October 2013. Three of the four contracts were awarded to contractors who had been part of the Pediatric Circulatory Support Program. The contract to the University of Pittsburgh was to develop the PediaFlow Ventricular Assist System with their consortium partners, the Children’s Hospital of Pittsburgh, Carnegie-Mellon University, LaunchPoint Technologies, and WorldHeart, Inc. The contract to the University of Maryland was to develop the Pediatric-Pump Lung (PediPL) with their corporate partner, Levitronix LLC. The contract to Ension, Inc. was for the pediatric Cardiopulmonary Assist System (pCAS), and the contract to Jarvik Heart was for the Infant Jarvik 2000 VAD, the predecessor to the Jarvik 2015 VAD. It should be noted that when the PumpKIN Program began, the Berlin Heart EXCOR Pediatric VAD, a pediatric-specific VAD used to bridge children with weights as low as 3 kg to cardiac transplantation, was only being used in the United States under compassionate use granted by the FDA. Berlin Heart eventually received approval of its Humanitarian Device Exemption application in 2011 to commercially distribute the EXCOR Pediatric VAD as a bridge to transplant in pediatric patients in the US.

NHLBI awarded a contract to the New England Research Institutes, Inc (NERI) in April 2012 to be the Data and Clinical Coordinating Center (DCCC) for the PumpKIN clinical trials of the circulatory support devices for which IDEs were granted. In this capacity, NERI has overall responsibility for the operation of the trials and provides the necessary administrative guidance, oversight, and support to achieve the objectives of the trials. Their initial tasks involved coordination and writing of the protocols and the manuals of operations and procedures for the trials and providing these and other needed clinical information to the four device contractors for their IDE applications. Because two devices were ventricular assist systems (the PediaFlow and the Infant Jarvik 2000) and two were compact ECMO systems (the PediPL and the pCAS), two very different protocols were developed for the two types of devices. While many parts were similar for the protocols of similar devices, each was distinct based on the characteristics of the specific device.

Funding on the PediaFlow device was halted before the contract ended after WorldHeart was acquired by HeartWare International, Inc. in August, 2012. Following the acquisition, HeartWare decided not to assume the responsibilities that WorldHeart had agreed to under their subcontract to the University of Pittsburgh. Without a way to remedy the contract with the University of Pittsburgh, it was terminated in early 2013.

In the second quarter of 2013, the remaining three contractors requested supplemental funds and time to complete the work and obtain IDEs by the contract end date (January 2014). Additional funding and time to obtain the IDEs were provided to Jarvik Heart and the University of Maryland. Ension was not provided any supplemental funding due to the costs and timing to complete a substantial amount of additional work on the pCAS and the reality of budget constraints resulting from federal budget sequestration in 2013.

It should also be noted that in August 2011 Thoratec Corp. acquired the medical division of Levitronix LLC and became the University of Maryland’s new corporate partner in the work on the PediPL device. However, in November 2013, Thoratec terminated its sub-award agreement with the University of Maryland. These setbacks made it impossible to submit the IDE application by the contract’s end in January 2014. However, Thoratec agreed to transfer the IP back to the University of Maryland and to be an original equipment manufacturer supplier as needed in the event that the University of Maryland wished to pursue the completion of the work on the PediPL.

Because of various technical challenges, Jarvik Heart also did not achieve the goal of obtaining an IDE by the end of their contract in January 2014. At this point, NHLBI opted to allow NERI, under their DCCC contract, to serve as an administrative center where they would subcontract with one or more of the PumpKIN device contractors to complete the remaining work on their devices until IDEs were approved. At that time, a decision was made to limit the PumpKIN clinical studies to the first VAD and ECMO system to receive approval. Proposals were invited from each of the four original PumpKIN device contractors and proposals were submitted by Jarvik Heart, the University of Maryland, and Ension, Inc. Upon review of the proposals, Jarvik Heart and the University of Maryland were selected by NERI based on proposed remaining work, timeline to complete the work, coordination plans, qualifications of personnel and vendors, and budget. The selection and continued funding of these two contractors was approved by NHLBI. Unfortunately, before the award to the University of Maryland was made, the University of Maryland could not obtain a guarantee from Thoratec that a company that was being set up to continue the work and produce the device would be able to commercialize the product after the trial was completed. Without such an agreement, the University of Maryland could and would not continue the work. As a result, only Jarvik Heart received funding and continued working towards an IDE for the Infant Jarvik 2000 VAD after January 2014.

The Infant Jarvik 2000 VAD was designed for intracorporeal placement and was about the size of a AAA battery. The device had no inflow cannula because it was designed to be implanted through the apex of the heart. The outflow cannula was an 8 mm expanded polytetrafluoroethylene (ePTFE) Vascutek reinforced Maxiflo graft (Vascutek Ltd., Inchinnan, Scotland, UK) that was anastomosed to the ascending aorta. The Jarvik Heart analog controller used to control the speed of the device was connected to the pump via six multi-stranded wires. The speed and flow of the device ranged from 18,000 to 28,000 rpm and 0.5 to 1.5 LPM (with an afterload of 45 mmHg), respectively.

After the requirements for the IDE submission for the Infant Jarvik 2000 VAD were completed, the IDE application was submitted by Jarvik Heart, Inc. in April 2014. A disapproval letter from the FDA received in May 2014 included questions about some of the tests that were performed. To address some of the questions, additional tests were performed. The new test results, along with additional information, clarifications, and justifications, were provided in response to the FDA questions in an amendment to the IDE application in September 2014. The IDE was disapproved again, specifically for the results from the in vitro hemolysis tests. These tests were run per the “Standard Practice for Assessment of Hemolysis in Continuous Flow Blood Pumps,” ASTM F1841-97, with deviations for testing a continuous flow VAD intended for pediatric subjects instead of adult subjects, such as a differential pressure of 45 mmHg rather than 100 mmHg. The testing was performed at the Texas Heart Institute on six test devices while running at the maximum intended speed of 28,000 rpm. The in vitro hemolysis results of the Infant Jarvik 2000 are shown in Figure 1. The mean Normalized Index of Hemolysis (NIH) over the 5-hour test for each ranged from 0.20 to 1.04 grams of plasma-free hemoglobin/100 liters of blood (bovine) and the overall mean for all six pumps over the test was 0.70 g/100 L. A Medtronic BP-50 (Medtronic, Dublin, Ireland), a centrifugal blood pump approved for pediatric use for up to 6 hours, was used as a control for the tests; the mean NIH value for the BP-50 tested on three separate days ranged from 0.003 to 0.059 g/100 L.

The PumpKIN team, consisting of NHLBI, the DCCC, and Jarvik Heart staff, had considered the hemolysis test results as too elevated before submitting the amended IDE application. Although the team anticipated the IDE application would not be approved based on the hemolysis results, the team decided to submit the application (1) to determine if the FDA identified any other engineering issues to address, (2) to obtain the FDA’s advice on the hemolysis issue as the PumpKIN team began deliberating options to address the hemolysis issue at that time, and (3) to determine if the proposed clinical trial design was satisfactory to evaluate the safety and probable benefit of the device.

The objectives of the studies conducted and described below were to determine appropriate modifications to the Infant Jarvik VAD that would result in low, acceptable hemolysis levels and still meet the program goal to be for infants and children from 2 to 25 kg with congenital or acquired cardiovascular disease. Demonstration of achieving acceptable hemolysis levels would be assessed by in vitro hemolysis testing and appropriate chronic in vivo testing.