Issues and Current Situations in the Development of Endovascular Treatment Devices for Pediatric Cardiology in the US – US Industry Dan Gutfinger, MD, PhD

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Full time employment Abbott/St. Jude Medical . ©2016 Abbott. All rights reserved. SE2943009 Rev A

Trends in Pediatric Cardiology Multiple endovascular treatment options for congenital heart disease have emerged in recent years Transcatheter heart valve Transcatheter structural heart defect closure Transcatheter vascular stenting More procedures are being performed in smaller and younger pediatric patients and more patients with congenital heart disease are entering adulthood* Limited number of devices are approved for pediatric use Clinicians are using adult devices off-label for pediatrics Clinicians are requesting devices for emergency/compassionate use in pediatrics *Canadian Journal of Cardiology 30, no. 1 (2014): 75-86.

Challenges in Development & Clinical Evaluation of Devices for Pediatrics Small size – miniaturization of the device and delivery system; the need for multiple device sizes Somatic growth – ability easily to replace or enlarge the device Biocompatibility in pediatric sized subject - nickel serum level; drug safety Post-implant management – anticoagulation therapy to prevent device thrombosis Long-term Durability – implant duration may be long; bioprosthetic tissue may encounter accelerated deterioration Clinical Trial Execution – slow enrollment; high risk subjects; loss of follow-up Cost – long timeline; limited financial incentive for product development; small population

New Medical Devices for Pediatrics Mitral valve PDA occluder Bioresorbable scafolds Devices having impact on the greatest number of pediatric patients Pediatric Cardiology (2016) 37:925–931

Pediatric Mitral Valve Line extension to adult mechanical valve line Small size – 15mm valve with a 7mm profile Surgically implanted – following attempted repair; cannot be enlarged; Anticoagulation – based on adult guidelines; challenging in infants <6 months. Clinical Trial Execution -slower than expected with on-going emergency use requests; high risk subjects; most <1 year old SJMTM Masters HPTM 15mm Rotatable Mechanical Heart Valve* HALO IDE Study (N=20) *Caution: Investigational device. Limited by Federal (or U.S.) law to investigational use. Not available for sale in the U.S

PDA Occluder for Premature Infants Line extension to PDA occluder device families Multiple small sizes – 9 sizes; smallest 3mmx2mm; 4Fr delivery catheter; flexible delivery cable. Transcatheter implant – intra-ductal placement; excluded from circulation; enlargement not needed Anticoagulation therapy not needed. Nickel serum testing – not practical in small infants (<2 kg) AMPLATZERTM Ductal Occluder II Additional Sizes* TorqVue™ LP Catheter (4Fr) ADO II AS IDE Study (N=40) *Caution: Investigational device. Limited by Federal (or U.S.) law to investigational use. Not available for sale in the U.S

Absorb GT1TM Bioresorbable Vascular Scaffold (BVS) System Bioresorbable Scafolds for Pulmonary Artery Stenosis & Aortic Coarctation Pediatric BVS Requirements – low profile (<6Fr access sheath) with size expandable to 8 mm diameter; length 15-20mm Modify design – modify dimensions of adult BVS for pediatric applications; existing design has limited applicability Extensive testing – to monitor next generation stent thickness, weight, and radial strength overtime to demonstrate drug safety in pediatric subjects Absorb GT1TM Bioresorbable Vascular Scaffold (BVS) System A Polylactide Bioresorbable Scaffold Eluting Everolimus for Treatment of Coronary Stenosis

Summary There is a growing need for developing and demonstrating the clinical safety and probably benefit of medical devices for pediatric cardiology. Key challenges include the ability to miniaturize devices and allow for device enlargement or resorption. Cost and timeline make the development opportunities limited. The ability to extend the line of an adult product to pediatrics provides an acceptable pathway from an industry perspective.