Presentation to the Pediatric Advisory Committee September 16, 2015 Contegra Pulmonary Valved Conduit Humanitarian Device Exemption (HDE) H020003 George Aggrey, MD, MPH Epidemiologist Division of Epidemiology Office of Surveillance and Biometrics Center for Devices & Radiological Health 1
Presentation Outline Device description & distribution numbers Actions taken based on the 2014 PAC meeting Medical device report review Literature review Conclusions and recommendation Question to the PAC 2
Device Description Contegra is a glutaraldehyde-crosslinked, heterologous bovine jugular vein with a competent tri-leaflet venous valve. Available in 6 sizes, and 2 models. 3
Indications for Use Correction or reconstruction of the right ventricular outflow tract (RVOT) in patients aged less than 18 years with any of the following congenital heart malformations: Pulmonary Stenosis Tetralogy of Fallot Truncus Arteriosus Pulmonary Atresia Transposition with Ventricular Septal Defect (VSD) Replacement of previously implanted, but dysfunctional, pulmonary homografts or valved conduits. 4
Distribution Numbers The HDE Annual Distribution Number (ADN) is defined as the number of devices reasonably needed to treat, diagnose, or cure a population of 4,000 individuals in the United States - The ADN for Contegra is 4,000 633 Contegra devices were sold in the U.S. in 2014-398 were implanted - At least 367 were implanted in pediatric (<22 year old) patients 5
Actions Taken Based on the 2014 PAC Discussion Labeling revisions made - to address the device size issues, coronary artery compression, conduit neointimal dehiscence and conduit dissection Follow-up investigation on discolored glutaraldehyde solution event: - No discoloration observed during manufacturing - A translucent amber color over time under normal storage conditions is expected - Factors of temperature, PH and buffering (labeling includes storage conditions) - Shelf life study: no effect on product performance - No other MDRs received since Aug 2006 6
Medical Device Report Review 7
MDR Review: Method MAUDE (Manufacturer and User Facility Device Experience) Database MDR Search Criteria - Brand Name: containing Contegra Valve - Date Report Received: 06/01/14 05/31/15 Search Result: 79 MDRs - 49 MDRs excluded 1 MDR same event from a different reporting source 48 MDRs submitted by manufacturer in this period based on its literature review; these MDRs are covered by our 2014 and 2015 literature reviews - 30 MDRs (Data set for this MDR Review) 8
MDR: Patient Demographic Demographic Format Value (Excluding values not reported) Number of MDRs containing the demographic Reporting Country US : OUS 72% : 28% Patient Gender Male : Female 46% : 54% Patient Age Pediatric : Adult 83% : 17% Pediatric & Adult Age Range 17 days 51 years Average Age 7.0 ± 10.6 years Pediatric Only Age Range 17 days 13 years Average Age 4.4 ± 3.6 years 21 : 8 (29 Total) 12 : 14 (26 Total) 22 : 2 (24 Total) 9
MDR: Primary Reported Problem by Patient Age and TTEO* Primary Reported Problem Total MDR Count Pediatric ( 21) Patient Age (years) Adult (>21) Age not reported TTEO* (months) Range Stenosis 12 8 2 2 1-110 42 Device size issue 4 2 0 2 0-45 11 Increased pressure gradients Pulmonary insufficiency/ Coaptation issue Mean 2 2 0 0 5-79 42 2 2 0 0 0.4-45 23 Structural deterioration 1 1 0 0 6 - Thrombus 1 1 0 0 2 - Bleeding 1 1 0 0 1 - Infection 1 0 0 1 No info - Death 1 0 0 1** 2.7 -- Explant (reason not reported) 5 5 0 0 2-134 49 Total 30 22 2 6 -- -- * TTEO: Time to Event Occurrence ** One death in this period was reported to be unrelated to the Contegra device. 10
Conclusions Based on the MDR Review The adverse events reported in this review period were known events. No new safety issues were identified. As with our last review, FDA continued to receive reports on the issue of device size in this reporting period. Device labeling revisions have been made on the issue. 11
Literature Review 12
Methods Database: PubMed Period: 07/01/14 (end of literature search presented to PAC last year) through 05/31/15 Search terms: Contegra or Bovine Jugular Vein or Pulmonary Valved Conduit Limited to: English, Human study 13
Article Selection Articles identified (n=13) Articles excluded (n = 4) Non study device (Melody valve, n=3) Off label use (Fontan procedure, n=1) Full-text articles assessed for eligibility (n=9) Articles included in qualitative synthesis (n=7) Full articles excluded (n = 2) Combined data (non-study, n=1) CT/MRI evaluation in Contegra; Unknown number of patients with the device (n=1) 14
Overview of the Qualitative Articles Study design 4 retrospective 3 case reports Study location Europe (2) United States (1) Australia (1) Spain (1) Canada (1) Pakistan (1) Sample size 24-244 Mixed population* (2 studies) 4 d -30 yrs (median 4.7 yrs) 8 d- 47 yrs (median 9.9 yrs) Exclusively Pediatric Population 4 mon 10 yrs (median) 2 5 yrs (range) Follow-up time 3 9 yrs (mean) *Ugaki 2015 and Van Dick 2015 had mixed adult-pediatric patients. 15
Survival Rate >85% at 10 years Mortality Early (>30 days): 0.8-2.7 % 1-3 Late (>30 days): 0% - 6.1% 1-2 1 Contegra-related death (late mortality) 4 Survival at years 1 yr: 94.7% 1 5 yrs: 90-92.8% 1-3 7 yrs: 90% 1 10 yrs: 88.6-90.8% 1-2 Contegra vs. Homograft (Yong et al 2015): Survival (%) 5 yrs: 90 vs. 89, p= 0.58 Contegra vs. Homograft vs. Hancock (Vitanova et al, 2014): Survival (%) 10 yrs: 89 vs. 85 vs. 89, p = 0.9 1. Ugaki et al 2015 2. Vitanova et al 2014 3. Yong et al 2015 4. Weldin et al 2015 16
Endocarditis-Free Rate (%) Van Dijck 2015 5 years* 10 years* Contegra (n=53) 87.8 77.3 Homograft (n=517) 98.7 97.3 Melody (n=107 ) 84.9 Not available * p < 0.001 (Contegra vs. Homograft, log-rank test) 17
Endocarditis Rate: 9.4% at 3 yrs Ugaki 2015 Follow up (yrs) Endocarditis rate (%) Contegra (n = 244) 3.2 9.4 Homograft (n = 135) 4.3 0.7 p < 0.001 18
Stenosis / Insufficiency Rate (%) Moderate stenosis-free Moderate insufficiencyfree Vitanova 2014, 5 yr 10 yr 5 yr 10 yr < 1yr old Contegra (n= 31) 75 36 75 44 Homograft (n=55) 85 59 92 65 Hancock conduit 69 50 87 52 (n=44) Contegra vs. Homograft p= 0.01 for both stenosis and insufficiency 19
Graft Failure Rate (%) Stenosis + Ugaki 2015 Stenosis Regurgitation Regurgitation Contegra (n=244) 11.9 8.6 1.2 Homograft (n=135) 8.9 10.4 4.4 p-value 0.3944 0.5820 0.0740 20
Reoperation-Free Rate (%) 1 yr 5 yrs 7 yrs 10 yrs Contegra 96 59-79 64 38 Yong et al 2015 Contegra 75 Homograft 85 Ugaki 2015 Contegra 96 79 64 Homograft 95 76 69 Vitanova 2014 Contegra 59 38 Homograft 69 38 Hancock 54 20 21
Case Reports: Safety Information 1. Hidalgo-Garcia 2015: 4 yrs old, Contegra at 2 yrs of age for D-TGA, VSD and pulmonary stenosis, recurrent endocarditis due to rare pathogens (A. aphrophilus and Staph. Lugdunensis). Pulmonary embolism necessitating conduit replacement. Severe LV dysfunction due to compression of RCA 9 months post discharge. 2. Weldin 2015: 2 yrs old, Contegra at 19 months to correct TGA, VSD and RVOT stenosis. Echo at 9 months revealed increased velocity across distal conduit. F/U echo scheduled for 3 months. Child died 2 weeks after last visit due to acute neointimal dissection of the Contegra conduit. 22
Conclusions Based on the Literature Review Compared to Homograft and/or Hancock, Contegra showed: Similar long term survival through 5 and 10 years Higher endocarditis rates Comparable graft failure rates due to stenosis and or regurgitation Comparable rates of reoperation 23
Literature Review Limitations Retrospective or case report study. Thus, the covariates were not balanced in comparing Contegra, Homograft, or Hancock, and results may not be as robust as for RCTs. Follow-up times varied in comparing Contegra to other conduits, which could influence observed rates. Outcomes of device use in mixed pediatric and adult population not stratified by pediatric and adult groups. Contegra conduits were implanted over a long time frame (1994-2012) and the standard of care could have changed during this period of time. 24
CDRH Conclusions No new concerns regarding safety of the device were identified. - Endocarditis rates are consistent with data previously reported in the literature (Albanesi 2014, endocarditis rate 11.3%) The HDE for this device remains appropriate for the pediatric population for which it was granted. Albanesi et al. Incidence and risk factors for Contegra graft infection following right ventricular outflow tract reconstruction: long-term results. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. Jun 2014;45(6):1070-1074. 25
CDRH Recommendation FDA will continue surveillance and report the following to the PAC in 2016: Distribution numbers MDR review results Literature review results 26
Question to the PAC Does the Committee agree with CDRH s conclusions and recommendations? 27