EXPAND Study Design and Conduct


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Discussion/Questions to Panel EXPAND Study Design and Conduct
The following important trial design and study conduct issues may affect the interpretability and validity of the study dataset and analyses:
Study Design
a. Design: EXPAND was carried out as a single-arm investigation and there were limited data for subjects not included in a Per Protocol (PP) population (equivalent to Transplant Recipient [TR] population).
b. Safety: There was no pre-specified primary safety endpoint hypothesis test.
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EXPAND Study Design and Conduct – cont’d
c. Effectiveness: The primary effectiveness endpoint was defined as allograft survival at POD 30 following transplantation in the absence of severe Primary Graft Dysfunction (PGD) involving the left or right ventricle in the first 24 hours post-transplantation. This endpoint was tested against a performance goal of 65%, and moderate PGD was not included.
d. Donor heart inclusion criteria: EXPAND’s donor heart eligibility criteria do not identify organs that are uniformly deemed unacceptable for transplantation if preserved using cold static preservation techniques, raising the possibility that there was overlap between hearts accepted for OCS Heart perfusion in the EXPAND (including EXPAND CAP) and PROCEED II studies.
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EXPAND Study Design and Conduct – cont’d
Study Conduct
e. Revisions to Donor Heart Inclusion Criteria: The sponsor’s dataset reflects EXPAND donor heart inclusion criteria that were revised after data lock and after the PMA had undergone FDA review. The donor heart inclusion criteria modifications affected 20 donor hearts. Additional criteria were assigned in all instances where donor heart inclusion criteria were revised, of which 17 modifications changed the assignment of single-criterion hearts to multiplecriteria hearts. There were no donor hearts for which criteria were removed.
f. PGD Classification Changes: Despite objective definitions of PGD intended to standardize classifications using data collected within 24 hours after completion of transplant surgery, multiple site-identified PGD classifications in EXPAND were changed during the adjudication process, which took place months or years after the transplant. These changes raise the possibility that individual endpoint determinations in EXPAND were subjective to some degree.
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EXPAND Study Design and Conduct – cont’d
1. Please discuss the impact of these study design and study conduct issues on assessing the safety and effectiveness and benefit-risk profile of the OCS Heart System.
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EXPAND Inclusion Criteria
The EXPAND Study intended to utilize hearts that otherwise would not have been accepted for transplant. However, EXPAND’s donor heart eligibility criteria do not identify organs that are uniformly deemed unacceptable for transplantation if preserved using cold static preservation techniques.
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EXPAND and CAP Donor Heart Single Inclusion Criterion

Donor inclusion criteria

ECCT ≥ 4

% of Single Criterion Hearts

EF ≥ 40% ≤ 50%

Downtime ≥ 20 min

LVH (> 12 ≤ 16 mm)

Luminal irregularities, no CAD

≥ 55 y/o

EtOH

TOTAL

TR EXPAND Hearts (n=75)
18
45%
10 4 3 2 2 1 40 (53%)

TR = Transplanted

TR CAP Hearts (n=41)
15
1 4 1 3 24

TR Pooled Hearts (n=116)
33
52%
11 8 4 2 2 4 64 (55%)
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EXPAND Inclusion Criteria – cont’d
2. Please discuss whether there was overlap between the standard hearts studied in the PROCEED II randomized trial and hearts studied in EXPAND and EXPAND CAP. If you believe there was overlap between “extended” and standard donor hearts, please discuss the effect that commercial availability of the OCS Heart device may have on the availability of acceptable donor hearts for transplantation, and overall long-term survival.
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Transplantability
OCS Heart arterial lactate level was the principle criterion given for not continuing to transplantation after preservation of the donor organ on the OCS Heart System for 5 PROCEED II donor hearts, 18 EXPAND donor hearts, and 4 EXPAND CAP donor hearts. FDA is unclear as to the utility of this metric as the principle criterion for determining transplantability, noting that 2 EXPAND CAP hearts were transplanted with arterial lactate levels of 6.3 and 7.8mmol/L at the end of OCS perfusion (one of which had an initial arterial lactate > 5mmol/L), as well as the many (>50%) turned down hearts that had final arterial lactate levels < 5mmol/L.
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Transplantability cont’d
3. Please discuss the accuracy and reliability of lactate levels as the principle determinant for not transplanting accepted donor hearts. In your discussion, please consider the impact on patients who undergo sternotomy in preparation for transplant in whom the transplant was not performed due to lactate levels greater than the target range.
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PROCEED II and EXPAND Study Analysis
Long term survival: In PROCEED II, the observed all-cause mortality rate following
transplantation was higher after donor heart preservation using the OCS Heart device than after cold static preservation (SOC); the magnitude of the survival benefit for patients transplanted with standard of care hearts was clinically meaningful and persisted over the long term.
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EXPAND Study Design and Conduct