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U.S. Department of Health and Human Services

Post-Approval Studies (PAS)

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The FDA has the authority to require sponsors to perform a post-approval study (or studies) at the time of approval of a premarket approval (PMA), humanitarian device exemption (HDE), or product development protocol (PDP) application. Post-approval studies can provide patients, health care professionals, the device industry, the FDA and other stakeholders information on the continued safety and effectiveness (or continued probable benefit, in the case of an HDE) of approved medical devices. This database allows you to search Post-Approval Study information by applicant or device information.

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Continued Follow-Up (HW-PAS-03)


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General
Study Status Progress Adequate
Application Number P100047 / PAS003
Date Current Protocol Accepted 02/14/2014
Study Name Continued Follow-Up (HW-PAS-03)
General Study Protocol Parameters
Study Design Prospective Cohort Study
Data Source New Data Collection
Comparison Group No Control
Analysis Type Descriptive
Study Population Transit. Adolescent B (as adults) : 18-21 yrs, Adult: >21
Detailed Study Protocol Parameters
Study Design Description Multicenter, prospective, a continued follow-up study consisting of patients from the HeartWare Trials under IDE G070199
Study Population Description patients at risk of death from refractory, advanced heart failure and implanted with a HVAS under IDE G070199
Sample Size at the time of PMA and Protocol approval a total of 152 patients (30 from the HW 003 BTT study and 122 from the CAP study) were potentially eligibile for participation
Data Collection Main: Transplant, explant, death

Observational: Overall survival on device, Final patient status, Re- hospitalizations, INTERMACS adverse events, Quality of Life (QOL) measures (KCCQ and EuroQol EQ-5D-5L), Functional Status (NYHA and 6- minute walk (6MW)).
Follow-up Visits and Length of Follow-up 5 years post implant of original device and every 6 months
Interim or Final Data Summary
Actual Number of Patients Enrolled This Post Approval Study is a continued follow-up of subjects from the IDE study (n=140) and the Continued Access Program (CAP) cohort (n=242). Of those subjects (n=382), only 152 (approximately 40%) were potentially eligible for continued follow-up at the time of the PAS enrollment. Additionally, after excluding subjects (a) who had been off the device (transplanted, or explanted for recovery) for greater than six months, (b) subjects who had their device exchanged to a non HeartWare device, (c) subjects at study sites where PAS participation was declined, and (d) subjects who declined participation only 101 subjects (approximately 26% of the original IDE and CAP subject population) were enrolled in the continued follow-up PAS.



Twenty-two subjects from the original IDE clinical study participated in this continued follow-up study, and 79 subjects from the CAP cohort participated in this continued follow-up study. Seventeen of the 101 enrolled subjects had the device explanted in order to receive a heart transplant at the time of PAS enrollment (1 from BTT, and 16 from CAP). Thus 84 subjects (approximately 22% of the original IDE and CAP cohorts) were utilizing the HeartWare device at time of PAS enrollment. All subjects from the IDE cohort had survived at least 36 months post-implant to be eligible for this study, and all subjects from the CAP cohort had survived at least six months post-implant to be eligible for this study.



Actual Number of Sites Enrolled The HeartWare Continued Follow-Up Post Approval Study 3 (HW-PAS-03) enrolled 25 study sites

Patient Follow-up Rate The overall follow up rate for this study is (n= 98/101) 97%. Three subjects withdrew and one relocated out of the vicinity of a study site.
Final Safety Findings The safety endpoints of interest are overall survival on device, final patient status, re-hospitalization and INTERMACs-defined adverse events.



Overall Survival on Device

Subjects in this PAS were followed for up to five years post original HVAD implant. As noted above, in the section detailing the number of subjects enrolled, subjects from the IDE had survived at least 36 months on device to be eligible for this PAS, and subjects from the CAP cohort had survived at least six months on device to be eligible for this PAS. Therefore the survival rates presented here are more representative of late (greater than six or 36 months on device) survival rather than overall survival on device. The Kaplan-Meier survival rate is 50.3% for the up to 20 month additional follow-up period that the BTT patients were followed in this PAS. For the CAP cohort, the Kaplan-Meier survival rate is 44.3% for the up to 54-month additional follow-up period in this PAS.



Final Patient Status

Sixty-seven subjects were alive at study completion from both on-device and off-device populations. Twenty-six were still utilizing an HVAD (21 were on their original device and five had at least one HVAD exchange) and 41 subjects were alive after being explanted for transplant. In the IDE cohort 8/22 (36.4%) died during continued follow-up, and in the CAP cohort 26/79 (32.9%) died during continued follow-up. Of the 34 total subjects who died, 64.7% died on the original device, 17.6% died post HVAD-explant for transplant and 17.6% died post HVAD-exchange.



Rehospitalization

Seventy-eight patients out of 84 subjects (approximately 93%) supported by HVAD at the beginning of this PAS had at least one re-hospitalization while on device, and 44 (approximately 52% ) had three or more re-hospitalizations while on-device during this PAS.



INTERMACS Adverse Events

Device Malfunction/Failure -- Of the 84 subjects supported by HVAD at the beginning of this PAS, there were 36subjects (approximately 43%) who had at least one device malfunction/failure events (number of events= 49) during this PAS. The three most common adverse events were infection, device malfunction/failure and bleeding. Of those 36 subjects with device malfunction/failure events, 34 had at least one serious device malfunction/failure events (number of events=44)..



Neurological Dysfunction Adverse Events – Of the 84 subjects supported by HVAD at the beginning of this PAS, 16 (19.0%) had at least one neurological dysfunction events (number of events=23) during this continued follow-up. Six of the 84 subjects (7.1%) had at least one CT confirmed ischemic cerebrovascular accidents (ICVAs) (number of events=7), nine(10.7%) subjects had at least one who had 12 CT confirmed hemorrhagic cerebrovascular accidents (HCVAs) (number of events=12), and 4 had a transient ischemic attacks (TIAs) (number of events=4).

Final Effect Findings The effectiveness endpoints of interest are quality of life measures, functional testing scores (KCCQ, 6 Minute Walk Test and NYHA Class), NIH Stroke Scale, and the modified Rankin Score.



Quality of Life

Across all study visits, 68% or more of study subjects completed the EQ-5D-DL assessment. The CAP cohort had a EQ-5D-DL score ranging from 70 at 18 months post-implant to 82 at 12 months post-implant. BTT cohort scores range from 58 at 60 months-post-implant to a high of 70 at 48 months post-implant.



Functional Status Testing

Across all study visits, approximately 75% of subjects or more had a KCCQ completed. The average KCCQ score increased from 36.8 at baseline to 60.6 at 60-months post-implant. In the CAP cohort, the average KCCQ score increased from 36.9 at baseline to 57.6 at 60 months post-implant. The BTT cohort average KCCQ score increased from 36.6 at baseline to 66.4 at 60 months post-implant.



All subjects completed the 6 Minute Walk Test at follow-up visits except for the Baseline where 97% completed the Test, and at six months where 94% completed the Test. The overall average distance walked for the 6 Minute Walk Test increased from baseline at 55 meters to 200 meters at 60 months post-implant. In the CAP cohort, the average distance walked increased from 37 meters to 195 meters from baseline to 60 months post-implant. In the BTT cohort, it increased from 115 meters to 209 meters from baseline to 60 months post-implant.



Across all study visits, approximately 75% of subjects or more had a NYHA class assessment completed. The overall NYHA class changed from 95% NYHA Class IV at baseline to 5.6% NYHA Class IV at 60 months post-implant. In the BTT cohort, NYHA class change from 90.5% NYHA Class IV at baseline to 12.5% NYHA Class IV at 60 months post-implant. In the CAP cohort, NYHA Class changed from 96.8% NYHA Class IV at baseline to 0% NYHA Class IV at 60 months post-implant.



NIH Stroke Scale

Over 70% of the subjects completed the NIH Stroke Scale, with more than half of the visits having greater than 80% completion. The average NIH Stroke Scale score was between 0-0.5 at all timepoints where results were available, and no subjects reported a score greater than 6 at any timepoint.



Modified Rankin Scale Score

Over 85% of subjects completed the mRS assessment at all timepoints, with most of the visits having over 95% completion. Over 75% of subjects who completed the mRS assessment had an mRS of 0 at all timepoints and over 90% of all subjects who completed the mRS assessment had an mRS less than or equal to 3 at follow-up timepoints. During this PAS, seven subjects had an mRS score greater than 3. Of these seven subjects, six had scores of higher than 3 after a neurologic adverse event and one subject was enrolled in the PAS with an mRS of 4. Fifteen of 16 subjects who had a neurological adverse event during this PAS, had an mRS score assessed in association with the event. Of those, six subjects had a score of greater than 3 after the event.

Study Strengths & Weaknesses Strengths: The HeartWare Continued Follow up study (HW-PAS-03) is the first long-term follow-up study of HVAD as a Bridge to Transplant device. For patients similar to those enrolled in the IDE study and who survive an intermediate duration (six months or longer), or a long duration (36 months or longer) on HVAD support, this study provides a good estimate of longer-term patient outcomes and incidence of adverse events.



Additionally, this study’s utilization of a standardized set of Adverse Event definitions (INTERMACs’ Adverse Event definitions) allows for comparison to other studies.



The completion of Quality of Life Measures (e.g. KCCQ) and Functional Status assessments (e.g. Six Minute Walk Test, mRS scores, and NIH Stroke Scale) was high.



Weaknesses:

Only a small proportion of the IDE and CAP subjects (approximately one quarter or 101/382) were followed in this PAS due to competing risks (e.g. transplant or death) and low enrollment for this continued follow-up study. Survival estimates and longer-term safety and effectiveness results can only be interpreted from the time of enrollment into this PAS study (all subjects enrolled in this study had already survived at least for 6-months on HVAD support). Additionally, results should be interpreted with caution because of the opportunity for selection bias. Approximately 33% (51/152) of subjects potentially eligible for continued follow-up were not enrolled in the study. We do not know all the longer-term results for those subjects or if they differed from the subjects who did agree to be followed longer-term.

Recommendations for Labeling Changes Yes


Continued Follow-Up (HW-PAS-03) Schedule

Report Schedule
Report
Date Due
FDA Receipt
Date
Applicant's Reporting Status
six month report 05/21/2013 05/20/2013 On Time
one year report 11/20/2013 11/13/2013 On Time
18 month report 05/21/2014 05/14/2014 On Time
two year report 12/19/2014 12/18/2014 On Time
three year report 12/20/2015 11/19/2015 On Time
four year report 11/19/2016 11/17/2016 On Time
five year report 11/19/2017 11/16/2017 On Time
final report 03/30/2018 03/29/2018 On Time


Contact Us

Mandated Studies Program
Food and Drug Administration
10903 New Hampshire Ave.
Silver Spring, MD 20993-0002
Email: MandatedStudiesPrograms@fda.hhs.gov

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