ORIGINAL RESEARCH

Cost-Effectiveness of the Use of Autologous CellHarvesting Device Compared to Standard of Carefor Treatment of Severe Burns in the United States

Stacey Kowal . Eliza Kruger . Pinar Bilir . James H. Holmes IV .

William Hickerson . Kevin Foster . Scott Nystrom . Jeremiah Sparks .

Narayan Iyer . Katie Bush . Andrew Quick

Received: March 13, 2019 / Published online: May 7, 2019� The Author(s) 2019

ABSTRACT

Introduction: When introducing a new inter-vention into burn care, it is important to con-sider both clinical and economic impacts, as thefinancial burden of burns in the USA is signifi-cant. This study utilizes a health economicmodeling approach to estimate cost-effective-ness and burn center budget-impact for the useof the RECELL� Autologous Cell HarvestingDevice to prepare autologous skin cell suspen-sion (ASCS) compared to standard of care (SOC)

split-thickness skin graft (STSG) for the treat-ment of severe burn injuries requiring surgicalintervention for definitive closure.Methods: A hospital-perspective model usingsequential decision trees depicts the acute burncare pathway (wound assessment, debridement/excision, temporary coverage, definitive clo-sure) and predicts the relative differencesbetween use of ASCS compared to SOC. Clinicalinputs and ASCS impact on length of stay (LOS)were derived from clinical trials and real-worlduse data, American Burn Association NationalBurn Repository database analyses, and burnsurgeon interviews. Hospital resource use andunit costs were derived from three US burncenters. A budget impact calculation leveragesMonte Carlo simulation to estimate the overallimpact to a burn center.Results: ASCS treatment is cost-saving or cost-neutral (\2% difference) and results in lower

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.7993028.

Electronic supplementary material The onlineversion of this article (https://doi.org/10.1007/s12325-019-00961-2) contains supplementary material, which isavailable to authorized users.

S. Kowal (&) � E. Kruger � P. BilirIQVIA, 3110 Fairview Park Drive, Falls Church, VA,USAe-mail: skowal@us.imshealth.com

J. H. Holmes IVWake Forest University Baptist Medical Center,Winston-Salem, NC, USA

W. HickersonUniversity of Tennessee Health Science Center,Memphis, TN, USA

K. FosterArizona Burn Center, Phoenix, AZ, USA

S. NystromOffice of Assistant Secretary for Preparedness andResponse (ASPR), US Department of Health andHuman Services (HHS), Washington, USA

N. IyerBiomedical Advanced Research and DevelopmentAuthority (BARDA), Office of Assistant Secretary forPreparedness and Response (ASPR), US Departmentof Health and Human Services (HHS), Washington,USA

J. Sparks � K. Bush � A. QuickAVITA Medical, Valencia, CA, USA

Adv Ther (2019) 36:1715–1729

https://doi.org/10.1007/s12325-019-00961-2

LOS compared to SOC across expected patientprofiles and scenarios. In aggregate, ASCStreatment saves a burn center 14–17.3% annu-ally. Results are sensitive to, but remain robustacross, changing assumptions for relativeimpact of ASCS use on LOS, procedure time, andnumber of procedures.Conclusions: Use of ASCS compared to SOCreduces hospital costs and LOS of severe burnsin the USA.Funding: AVITA Medical.

Keywords: Autologous cell harvesting device;Budget impact; Burn care; Cost-effectiveness;Dermatology; Skin graft; Split-thickness

INTRODUCTION

Burn injuries represent approximately 1% ofnon-fatal injuries among US civilians [1], withnearly 500,000 burn victims seeking medicalcare and approximately 40,000 patients requir-ing hospitalization [2]. As a result of complexand individualized treatment, the managementof severe burns requires a high intensity ofhealthcare resource utilization and long inpa-tient stays that lead to high medical care costs.The economic burden of burns in the USA issignificant, estimated at over $7.9 billion peryear (2018, inflated from 2010) for hospitaliza-tions, emergency department visits, and deaths[3].

Burn management has evolved with theintegration of new technologies and treatmentparadigms into routine care, resulting in sig-nificant declines in the number of burn fatali-ties [4]. In past decades, mortality was commonfor burns greater than 20% total body surfacearea (TBSA) [4]. Today, new interventions haveallowed patients with burns covering 90% oftheir bodies to survive [5]. However, thereremain limited alternatives for effectivelymanaging patients, minimizing morbidity, andmitigating the substantial cost of burn injuryfor severe burns requiring surgical intervention[6].

RECELL� Autologous Cell Harvesting Device(ACHD) (AVITA Medical, Valencia, CA, USA) isan innovative technology recently FDA-

approved that allows the rapid preparation ofautologous skin cell suspension (ASCS) at thepoint-of-care for treatment of acute thermalburn wounds [7, 8]. ASCS may be applied eitheras a primary intervention for deep partial-thickness (DPT) burns with confluent dermis, oras an adjunct to widely meshed split-thicknessskin grafts (STSG) for mixed-depth and full-thickness (FT) burns (hereafter named FT/mixed-depth). Published clinical trials, com-passionate use data, and real-world evidencepoint to economic and clinical benefits of ASCSuse in burn care. Recent clinical trials illustratethat use of ASCS significantly minimizes donorskin harvesting requirements, enhances re-ep-ithelialization of widely meshed skin grafts, andmay decrease the need for follow-up recon-structive procedures [8–10]. Furthermore, whencompared to STSG, analysis of real-world burncenter records demonstrates that use of ACHD-generated ASCS, in isolation and in combina-tion with STSG, can reduce hospital length ofstay (LOS) for severe burn patients [7, 11].

In the current environment of healthcareresource scarcity, hospitals must increasinglyconsider both clinical efficacy as well as budget-impact when deciding whether to adopt newproducts. However, the complexity of burn carepresents a challenge when evaluating value formoney for new interventions. Numerousaspects of practice patterns vary, including thetiming of burn-depth diagnosis, excision tech-nique and timing, use of temporary dressings,dermal substitutes, autografting technique,intensity of inpatient rehabilitation, and criteriafor patient discharge and outpatient follow-up[12]. As a result, it is difficult to design andimplement randomized controlled trials (RCTs)or other direct studies of interventions that areapplicable across the spectrum of patient pro-files, burn types, and provider practice patterns.In this complex clinical scenario, therefore, itcan be useful to apply modeling methods toexplore the possible range of expected healthimpact and economic outcomes.

To the authors’ knowledge, there is no vali-dated economic model of the inpatient burncare pathway available for assessment of healtheconomic impact of new interventions versuscurrent standard of care (SOC). Recognizing the

1716 Adv Ther (2019) 36:1715–1729

importance of both the economic and clinicalimpacts of ASCS use in burn care, this studyutilizes a health economic modeling approachto represent current inpatient management ofburns and to capture the expected impact ofASCS compared to SOC. Specifically, we esti-mate the cost-effectiveness and burn centerbudget-impact for the use of ASCS compared toconventional STSG.

METHODS

Structure

A burn center perspective cost-effectivenessmodel (CEM) of the burn care pathway (Fig. 1),known as the Burn-MCM (medical countermeasure) Effectiveness Assessment Cost Out-comes Nexus (BEACON) model, evaluates asingle inpatient stay for the management of asevere burn.

The model takes patient characteristics asinput and then utilizes linked, sequential deci-sion trees across multiple modules to estimate

the clinical and economic outcomes associatedwith each phase of care, and overall, duringinpatient care. Each module represents asequential progression through key clinicalphases of burn care, including wound assess-ment, debridement/excision, temporary cover-age, and definitive closure. An overview of theburn care pathway and core assumptions isdetailed in supplementary materials. In brief, acohort of patients enters the model at the time ofwound assessment, and the depth of wound isdetermined. To simplify these analyses, it isassumed that all patients are diagnosed correctlyin the wound assessment phase. Followingwound assessment, a patient moves to debride-ment/excision where the wound is cleaned andmay also be excised for removal of necrotic tis-sue. For subsequent phases of burn care, man-agement options vary on the basis of burn depth.A patient diagnosed with DPT or FT/mixed-depth burn may receive temporary coverageduring the waiting period before the next treat-ment takes place or for dermal regeneration. Forthis ASCS-focused analysis, we do not explicitlymodel temporary coverage interventions.

Fig. 1 Burn model diagram. Wound assessment—thedepth of wound is assessed, and a patient’s wounds arediagnosed in terms of depth. Debridement or excision—perUS standard practice, DPT and FT/mixed-depth burns aresurgically excised in the operating room until viablebleeding tissue is reached to prepare the wound fordefinitive closure. SPT burns are assumed to be debrided toremove devitalized tissue and treated using conservativemanagement without surgery. Temporary closure—for thisASCS-focused analysis, we implicitly capture the impact oftemporary coverage on LOS and cost through predictiveequations derived from burn center data. However, we donot explicitly model the individual unit costs or

performance of potential temporary coverage (includingdermal regeneration) interventions. Note that interven-tions for temporary coverage are not explicitly modeled atthis time; however, their impact on total cost and length ofstay is implicitly considered with the NBR predictiveequations. Definitive closure—in this phase of burn care,wounds that are diagnosed as requiring surgery fordefinitive closure (DPT, FT/mixed-depth) and receiveSTSG or treatment with ASCS (with or without STSG).Rehabilitation—though not a discrete phase, the modelevaluates resources to capture key inpatient rehabilitationcost as well as the proportion of patients requiringcontracture operations

Adv Ther (2019) 36:1715–1729 1717

For phases of burn care not impacted byASCS treatment (namely, wound assessment,debridement/excision, temporary coverage),non-differential SOC was assumed to provide anevidence-based benchmark for patient out-comes under SOC in current clinical practice (asoutcomes such as LOS and total cost are affectedby all phases of care) and to isolate the incre-mental impact of ASCS use within the overallcontext of burn care management.

The budget impact model (BIM) builds onthe CEM to capture the impact of interventionson costs and patient outcomes for a burn centeroverall, accounting for key drivers specific tothe burn center, such as the expected patientmix by burn depth, TBSA burned, and otherindividual patient characteristics. The modelcompares costs for the two treatment pathways(with and without the use of ASCS) to isolatethe likely shift in costs related to ASCS.

The BIM samples from normal distributionsaround patient and burn characteristics fromthe American Burn Association National BurnRepository (NBR) to generate 200 proxy patientprofiles representing a real-world population ofpatients treated annually in the inpatient set-ting. For each unique patient profile, thedetailed CEM estimates patient-level outcomes(e.g., LOS, cost, number of surgical operations).A Monte Carlo simulation is then used to gen-erate the 200 profiles 100 times, enhancing thestability and precision of results. The combina-tion of a Monte Carlo approach and sampledpatient profiles enables the model to test theimpact of an intervention, given variation inpatient characteristics (e.g., input variability).The BIM aggregates results across the profiles tocalculate the total fiscal impact to a burn centerfor two treatment pathways, considering thelikely number of patients in each unique profile.

This article does not contain any new studieswith human or animal subjects performed byany of the authors.

Patient Profile

The target population for the model is adults(average 42 years of age), with severe burns ofTBSA C 10% receiving inpatient care, where

DPT and FT/mixed-depth burns are eligible forASCS.

Model inputs for additional factors thatinfluence patient outcomes, such as inhalationinjury, infection [hospital-acquired infection(HAI) and other infections], and sex, werederived from analysis of the NBR. The NBRincludes 10 years of cumulative data from burncenters, representing the largest data resourcefor burn injuries in the USA including demo-graphic, injury, and outcome information.Leveraging the NBR data (version 8.0,2002–2011), analyses were performed on asample of 21,175 surviving patients for whomkey data points were available. All analysesleveraging the NBR were based on patients withTBSA between 10% and 60% to reduce a taileffect where outlier patients with high TBSAmay skew predicted estimates. The NBRincludes only relative burn size information (as% TBSA). Therefore, the National Health andNutrition Survey (NHANES) [13] 2014–2016 wasanalyzed to determine the average absolutebody surface areas (BSA, cm2) for male andfemale subjects in the USA to convert percent-age TBSA from the NBR to an average size ofburns in terms of square centimeters, needed forcost calculations in the model.

Clinical Inputs

Clinical inputs were derived from RCTs, a sur-vey of eight burn surgeons, NBR database anal-yses, and in-depth interviews with fourexperienced burn surgeons. Further, all modelassumptions were vetted by one or more burnsurgeons, and the output of the model wasbenchmarked against real-world data to validatethe modeling structure and ensure clinicalvalidity [14] (Table 1).

To ensure the model accurately accounts forpatient characteristics when predicting out-comes and costs, patient LOS associated withSTSG treatment was estimated using the NBR.LOS was predicted via a regression controllingfor TBSA, TBSA of partial-thickness burn, age(linear, squared and cubed to account for non-linearity), HAI, other infection, inhalationinjury, sex, whether or not they had one or

1718 Adv Ther (2019) 36:1715–1729

Table 1 Key clinical inputs

Variable Patient profile Input References

Wound assessment

Time until wound depth diagnosed/first

procedure

TBSA 10–20% 4.938 days Burn surgeon

survey (data

on file)TBSA 21%? 4.525 days

Debridement/excision

Average number of non-excisional

debridement procedures (FT/mixed-

depth)

TBSA 10% 0.48 NBR database

analyses (data

on file)TBSA 20% 0.32

TBSA 30% 0.30

TBSA 40% 0.32

Average number of non-excisional

debridement procedures (DPT)

TBSA 10% 0.56

TBSA 20% 0.47

TBSA 30% 0.52

TBSA 40% 0.62

Time per debridement procedure (mins) TBSA 10% 19 Burn centers

(data on file)TBSA 20% 38

TBSA 30% 47

TBSA 40% 62

Average number of excision procedures

(FT/mixed-depth)

TBSA 10% 2.49 NBR database

analyses (data

on file)TBSA 20% 2.98

TBSA 30% 3.57

TBSA 40% 4.27

Average number of excision procedures

(DPT)

TBSA 10% 2.18

TBSA 20% 2.37

TBSA 30% 2.64

TBSA 40% 3.03

Average time per excision procedure (mins) TBSA 10% 38 Burn centers

(data on file)TBSA 20% 75

TBSA 30% 90

TBSA 40% 120

Definitive closure

Conservative approximation: number of

autograft operations (STSG, FT/mixed-

depth & DPT)

TBSA 10–20% 1 Assumption

TBSA 21%? 2

Adv Ther (2019) 36:1715–1729 1719

more grafting procedures, and diabetes status[15]. Similarly, the numbers of non-excisionaldebridements (ICD-9: 86.28) and excisionaldebridements (ICD-9: 86.22) are predicted usingpredictive equations derived from the NBR,based on patient characteristics.

Definitive Closure

The impact of the use of ASCS is modeled in thedefinitive closure module. In this phase of care,wounds diagnosed as requiring surgery fortimely closure (DPT, FT/mixed-depth) canreceive ASCS or SOC. For burns treated with

Table 1 continued

Variable Patient profile Input References

NBR national average: number of autograft

operations (STSG, FT/mixed-depth)

TBSA 10% 2.46 NBR database

analyses (data

on file)TBSA 20% 3.14

TBSA 30% 3.83

TBSA 40% 4.54

NBR national average: number of

autograft operations (STSG, DPT)

TBSA 10% 2.23

TBSA 20% 2.69

TBSA 30% 3.15

TBSA 40% 3.63

Donor site size for STSG treatment (% of

burn)

TBSA 10–39% 61.1% Gravante [9]

TBSA 40%? 25% Holmes [8]

Donor site size for ASCS treatment (% of

burn)

All TBSA 1.3% Gravante [9]

Donor site size ASCS ? STSG (% of

burn)*

TBSA 10–39% 41.5% Holmes [8]

TBSA 40%? 17% Holmes [8]

Autograft operative time (mins) Burn wound site 1.6 per TBSA Burn surgeon

survey (data

on file)Donor site 2.1 per TBSA

Other

Odds ratio for LOS for ASCS relative to

SOC (up to 40% TBSA)

DPT 0.70 Park [11]

FT/Mixed 0.98 Park [11]

Odds ratio for LOS for ASCS relative to

SOC (over 40% TBSA)

DPT & FT/mixed 0.53 Holmes [19]

Proportion of patients requiring

contracture procedures (%)

STSG 37.5% Gravante [9]

ASCS 28.6%

Blood requirements per % TBSA (ml) Excision 20.51 Luo [22]

STSG 32.83

*Assumption based on meshing ratio of 4:1 for STSG and for ASCS ? STSG, relative reduction in donor site size forASCS ? STSG from Holmes 2018 [8]

1720 Adv Ther (2019) 36:1715–1729

ASCS, the model assumes ASCS alone for DPTburns and ASCS with meshed STSG for FT/mixed-depth burns, while all SOC patientsreceive conventional STSG.

Other key differences in patient manage-ment for ASCS versus SOC include number ofdefinitive closure procedures, procedure time,size of donor site, and LOS. In all scenariosconsidered in the model, definitive closure(healing) using ASCS is assumed to require onesurgical procedure (i.e., healing is achieved witha single ASCS treatment for a given patient)[7–10]. As outlined below, model assumptionsfor the number of procedures for SOC weredeveloped to capture the variability in practicepatterns.

As highlighted during burn surgeon inter-views and analysis of NBR data, surgical prac-tices for definitive closure vary on the basis ofsurgeon preference, as well as patient and burncenter characteristics. Therefore, estimated cost-effectiveness of ASCS is presented for two sce-narios to account for likely real-world variationin SOC STSG practices: (1) a conservativeapproximation, and (2) an NBR-based nationalaverage. The conservative approximation SOCscenario assumes a single conventional auto-grafting procedure with STSG for patients withTBSA B 20% and two conventional autograft-ing procedures with STSG for patients withTBSA[20%. For the NBR national averagescenario, the number of procedures to achievedefinitive closure via conventional autograftingwith STSG (by burn depth and TBSA) was pre-dicted using NBR data, with conventionalautografting procedures identified via ICD-9codes 86.61, 86.62, 86.63, and 86.69 [16]. It wasassumed that multiple codes were performed inthe same operation, and therefore the maxi-mum count of a single conventional autograft-ing ICD-9 procedure code represented wouldestimate the number of SOC definitive closureprocedures.

Information on donor site size harvested forASCS and SOC STSG, as well as the proportionof patients requiring a contracture release pro-cedure associated with ASCS treatment, is basedon RCTs [8–10]. The number of ACHD devicesused to prepare ASCS is determined by the per-centage TBSA burned. On the basis of product

information [17] one device can be used toprepare up to 24 ml of ASCS, which treats up to1920 cm2 of burn wound. For patients withTBSA up to 40%, Gravante et al. demonstratedthat average donor site per percent TBSA ofburn was 61.1% for SOC STSG and 1.25% forASCS [9]. For patients with TBSA over 40%, sizeof donor site per percent TBSA was estimated at25% based on a survey of eight practicing sur-geons for SOC STSG, with a 32% reduction(relative to SOC STSG) due to use of ASCS basedon randomized clinical data [10]. Impact ofreduced donor site in the model is captured viareduced time to harvest donor skin and reducedtime and resources to dress the donor site. Inaddition to reducing size of the donor site perpercent TBSA, use of ASCS is associated withreduced patient pain related to donor site har-vesting and reduced number of additional pro-cedures arising from limited availability ofdonor sites to support SOC STSG [10].

The impact of ASCS on LOS was derived frompublished, real-world evidence from Australia[11] as the device for preparation of ASCS hasonly recently become available outside of clin-ical trials in the USA [18]. Specifically, to esti-mate the effect of ASCS on LOS, odds ratios (OR)for DPT (0.7) and FT/mixed-depth (0.98) burndepths were applied to SOC-based LOS, as esti-mated by the NBR equation for burns up to 40%TBSA [11]. For burns with TBSA C 40%, com-passionate use data from the USA was used toinform the impact of ASCS treatment on LOS(OR 0.53) [19]. Routine daily patient care out-side of the operating room was assumed thesame for ASCS and STSG. As such, changes inLOS costs are representative of reduced LOSonly and conservatively do not assume anychange in costs per day outside of key proce-dures. Daily care included daily dressing chan-ges for both the burn wounds and donor sites,performed by one nurse and one technicianwith an estimated 1 min of staff time per squarecentimeter of burn, as estimated by a survey ofeight burn surgeons. For operating room costs,key differences related to ASCS use includereduced number of procedures as well asreduced time for donor skin harvesting anddonor skin wound dressings.

Adv Ther (2019) 36:1715–1729 1721

After definitive closure, the model accountsfor inpatient rehabilitation costs. On the basisof burn surgeon input, for all patients, onephysical therapy and one occupational therapyappointment was assumed for each day ofinpatient stay. The model also accounts for theproportion of patients requiring surgery forcontracture release, with rates for ASCS andSOC based on published clinical data [8, 9]. Forpatients requiring contracture release, weassumed a 3-day hospital stay for the procedurebut do not assume rehabilitation costs, therebypresenting a conservatively low estimate of thecost of contracture.

Costs and Resource Use

Key cost elements include staffing (nurses, scrubtechnicians), costs per day (or bed costs), oper-ating room time and related resources, wound-related resources (e.g., wound dressings), andthe price of the device(s) used to prepare ASCS.The model results presented herein conserva-tively assumed that burn surgeon and anesthe-siologist time is billed separately and does notrepresent a cost to the burn center. As a result oflimitations in obtaining nuanced data onanesthesia cost by each inpatient procedure, anon-differential lump sum anesthesia cost wasconservatively applied to all patients undergo-ing surgery regardless of receiving SOC or ASCS.The cost of ASCS use (per 1920 cm2 of burnwound) is based on the $7500 list price of theACHD used to prepare ASCS. Hospital resourceuse (e.g., materials, procedure time) and unitcosts were derived from survey data obtainedfrom three US burn centers. All unit costs rep-resent 2017 USD and are reflective of averagecosts reported by surgery centers (Table 2).

Analyses

Cost-Effectiveness AnalysisThe BEACON model is fully customizable tosupport use of individual burn center data. Theresults presented are based on national aggre-gate trends. The model predicts outcomes forpatients with any TBSA; however, results pre-sented herein focus on TBSA ranges that are

common in real-world care [20]. Specifically,results are reported for adult patients (averageage 42 years) with TBSA 10%, 20%, 30%, and40% for DPT and FT/mixed-depth, controllingfor comorbidities as derived from NBR data. Theselected patient profiles for TBSA and burndepths were chosen to illustrate a range of cost-effectiveness outcomes with ASCS use.

While overall patient characteristics wereheld consistent across model runs for DPT andFT/mixed-depth burn depths, underlying modelinputs were varied (per Table 1) to account for

Table 2 Key cost and resource use inputs

Provider resourceuse element

Unit Cost (USD 2017)

Cost per day for burn

patients

Per day $6795.00

Burn surgery

operating room

time

Per hour $3720.00

Nurse time Per hour $56.10

Scrub tech time Per hour $39.00

Blood transfusion

(packed cells, whole

blood)

Per liter $117.00

Escharotomy Per excision $500.00

Wound dressings

inpatient

Per cm2 $0.09

Physical therapy Per session $21.75

Occupational therapy Per session $15.75

Contracture surgery

first

100 cm2 $100.00

Contracture surgery

subsequent

100 cm2 $50.00

Anesthesiology Per patient $2694.00

List price for

Autologous Cell

Harvesting Device

for preparation of

ASCS

Per device $7500.00

1722 Adv Ther (2019) 36:1715–1729

the impact of wound depth on LOS and amountof donor skin harvested (and associated impacton surgery time). Two scenarios were ana-lyzed—assuming a conservative approximationand using NBR-based national averages to pre-dict number of SOC STSG procedures. One-waysensitivity analysis (OWSA) was conducted foreach patient profile (Table 3).

Budget Impact AnalysisTo estimate budget impact, a burn centertreating 200 patients annually was simulated.Consistent with the CEM, individual patientcharacteristics were extracted from the NBR,including average age, sex, and comorbidities.This information represents national aggregate

data on the mix of patient types, burn depth,and TBSA for a burn center. As highlighted inTable 3, the BIM includes the full range ofpatient and burn characteristics expected topresent in the USA. Therefore, while the targetCEM profiles described above highlight therange in outcomes across potential patient andburn types, the BIM considers the relative mixof TBSA ranges.

The BIM requires categorization of patientsinto discrete burn depths of superficial partial-thickness (SPT), DPT, and FT/mixed-depth.Burn depth is not a discrete variable in the NBR;however, continuous variables of TBSA of FTand PT are reported. These variables were usedto categorize a patient as FT/mixed-depth if

Table 3 Cost-effectiveness and budget impact patient profiles Source: Inputs based on analysis of NBR data

Details of patient profiles for the cost-effectiveness model

TBSA

Patient characteristics 10% 20% 30% 40%

Female (%) 26% 23% 27% 27%

BSA (cm2) 19,808 19,856 19,788 19,783

Size of burn (cm2) 1981 3971 5936 7913

Comorbidities

Inhalation injury (%) 4% 9% 13% 25%

Hospital-acquired infection (HAI) (%) 1% 3% 4% 9%

Other infection (%) 2% 5% 4% 5%

Diabetes (%) 6% 6% 3% 4%

Details of default settings for a burn center with 200 adult patient annually

Full-thickness/mixed-depthNo. Patients (%)

Deep partial-thicknessNo. Patients (%)

Superficial partial-thicknessa

No. Patients (%)

Wound depth distribution 40 (20%) 58 (29%) 102 (51%)

Proportion of burns

TBSA 40% ? (average 48%) 5 (13%) 5 (8%) 7 (7%)

TBSA 21–40% (average 28%) 15 (38%) 20 (35%) 26 (25%)

TBSA 10–20% (average 15%) 19 (49%) 33 (57%) 69 (68%)

a Superficial partial-thickness patients receive no STSG or ASCS, as they are assumed to heal within 21 days. Note: May notsum to 100% because of rounding of number of patients in simulation

Adv Ther (2019) 36:1715–1729 1723

50%? of their burn was FT depth and as SPT ifthey had zero surgical procedures in the NBR,with remaining burns classified as DPT.

RESULTS

Cost-Effectiveness Analysis

In the conservative approximation scenario ofASCS use, spend was cost-neutral (\2%) or cost-saving in all profiles. Using the NBR nationalaverages to predict number of STSG operationsin an alternate scenario, all patient profilesshowed cost savings with use of ASCS. In bothscenarios, reduced number of definitive closureprocedures enabled through use of ASCS usewas driven by reduced need for donor skin.Accordingly, mitigating availability of donorskin as a limiting factor, fewer surgical opera-tions were required to achieve definitive clo-sure. A key finding was that cost savingsincrease as burn size increases owing to overallreduction in the number of operations, dressingtime, and associated costs (Table 4).

LOS was reduced for all patient profilesmodeled, but the relative shift in LOS was mostfavorable for large burns. The OR for LOS withASCS, relative to NBR-derived SOC estimates,was most favorable for DPT burns as well as forburns with TBSA of 40% or more, which led togreater reductions in LOS and associated inpa-tient costs for these patients. Notably, for FT/mixed-depth burns of 40% TBSA, the projectedreduction in LOS was almost 28 days (SOC,59 days; ASCS, 31 days). Further, large relativeLOS reductions were seen across all TBSA rangesfor DPT, with ASCS-reductions in LOS increas-ing along with increases in TBSA percentages.Across all patient profiles, the use of ASCStranslates to roughly a 20% reduction in reha-bilitation costs (* $2000 savings per acute carestay), due to a reduced proportion of patientsrequiring surgical procedures for contracturerelease and reduced number of days as inpa-tients with physical therapy and occupationaltherapy visits.

In OWSA, the OR for ASCS impact on LOS foreach strategy is the primary driver of results forall depths and burn sizes. Additional influential

variables include the size of the donor site andthe number of operations for SOC. Neverthe-less, for all patient profiles, the use of ASCSconsistently led to cost savings or cost-neutralresults when varying model inputs acrossexpected high and low ranges, which suggeststhat model results remain robust across expec-ted uncertainties or variations in individualmodel parameters. OWSA diagrams can befound in supplementary materials.

Budget Impact Analysis

Aggregating patient profiles to view results for aburn center, use of ASCS is expected to reduceoverall costs by an estimated 14–17.3% annu-ally. Under the conservative scenario for esti-mating SOC STSG procedures, use of ASCSreduced costs by an estimated 14% ($5.3 mil-lion for the burn center, average $26.6 thou-sand per patient). When estimating SOC STSGprocedures per NBR averages, overall relativesavings increased to 17.3% ($6.8 million for theburn center, $34.1 thousand per patient).Reductions in costs are driven by reducednumber and duration of procedures performedfor definitive closure, change in LOS, andreduced rehabilitation needs (Table 5). Notably,use of ASCS led to an estimated 32% and 37%reduction in definitive closure procedures rela-tive to SOC for the conservative and NBR sce-narios, respectively.

DISCUSSION

This study evaluated the impact of ASCS onpatient LOS, number and duration of definitiveclosure procedures, inpatient resource use, andthe estimated cost impact to a burn center fortreatment of severe burns in the USA. At apatient level, use of ASCS for burn treatment(regardless of burn depth) was predicted to becost saving or cost neutral vs SOC when apply-ing the conservative approximation (for SOCprocedures) and consistently cost saving for allpatient profiles when applying the NBR predic-tive equations (for SOC procedures). All sensi-tivity analyses continued to show cost-saving orat least cost-neutral results, demonstrating that

1724 Adv Ther (2019) 36:1715–1729

Table4

Costandeffect

results

bydepthandTBSA

Burndepth

TBSA

Results

measure

Con

servativeapproxim

ationscenario

NBR-based

nation

alaveragescenario

SOC

ASC

SDifference$/days

(%)

SOC

ASC

SDifference$/days

(%)

FT/m

ixed-depth

10%

Totalcosts

$174,857

$176,031

$1174(0.7%)

$181,560

$176,031

–$5529(–

3.0%

)

TotalLOS

21.2

20.8

–0.4(–

2.0%

)21.2

20.8

–0.4(–

2.0%

)

No.

procedures

1.0

1.0

0(0.0%)

2.5

1.0

–1.5(–

59.3%)

20%

Totalcosts

$281,679

$286,001

$4322(1.5%)

$301,386

$286,001

–$15,385(–

5.1%

)

TotalLOS

32.4

31.8

–0.6(–

2.0%

)32.4

31.8

–0.6(–

2.0%

)

No.

procedures

1.0

1.0

0(0.0%)

3.1

1.0

–2.1(–

68.2%)

30%

Totalcosts

$416,268

$410,249

–$6019(–

1.4%

)$438,191

$410,249

–$27,942(–

6.4%

)

TotalLOS

45.0

44.1

–0.9(–

2.0%

)45.0

44.1

–0.9(–

2.0%

)

No.

procedures

2.0

1.0

–1(–

50.0%)

3.8

1.0

–2.8(–

73.9%)

40%

Totalcosts

$549,200

$335,830

–$213,370

(–38.9%)

$579,292

$335,830

–$243,462

(–42.0%)

TotalLOS

59.4

31.3

–28.2

(–47.4%)

59.4

31.3

–28.2

(–47.4%)

No.

procedures

2.0

1.0

–1(–

50.0%)

4.5

1.0

–3.5(–

78.0%)

DPT

10%

Totalcosts

$133,693

$102,714

–$30,979(–

23.2%)

$139,348

$102,714

–$36,634(–

26.3%)

TotalLOS

15.6

10.9

–4.7(–

30.0%)

15.6

10.9

–4.7(–

30.0%)

No.

procedures

1.0

1.0

0(0.0%)

2.2

1.0

–1.2(–

55.1%)

20%

Totalcosts

$193,573

$151,560

–$42,013(–

21.7%)

$209,089

$151,560

–$57,529(–

27.5%)

TotalLOS

21.2

14.9

–6.4(–

30.0%)

21.2

14.9

–6.4(–

30.0%)

No.

procedures

1.0

1.0

0(0.0%)

2.7

1.0

–1.7(–

62.8%)

30%

Totalcosts

$276,670

$205,882

–$70,788(–

25.6%)

$290,407

$205,882

–$84,525(–

29.1%)

TotalLOS

28.1

19.7

–8.4(–

30.0%)

28.1

19.7

–8.4(–

30.0%)

No.

procedures

2.0

1.0

–1(–

50.0%)

3.1

1.0

–2.1(–

68.2%)

40%

Totalcosts

$359,875

$228,723

–$131,152

(–36.4%)

$379,182

$228,723

–$150,459

(–39.7%)

TotalLOS

37.0

19.5

–17.5

(–47.4%)

37.0

19.5

–17.5

(–47.4%)

No.

procedures

2.0

1.0

–1(–

50.0%)

3.6

1.0

–2.6(–

72.5%)

Notethatonlydifferentialdefin

itiveclosureproceduresareshow

nin

themainresults

table,asSO

Cbeforedefin

itiveclosurewasassumed

non-differential(see

Table1forinform

ation

onnu

mberof

debridem

entandexcision

procedures)

Adv Ther (2019) 36:1715–1729 1725

the core model results remain robust acrossexpected uncertainties in individual modelparameters.

Results of the CEM illustrate consistent cost-saving results across a range of individualpatient profiles, as highlighted by the burndepth and TBSA ranges presented. Leveragingthe individual patient results from the CEM, theBIM considered the mix of patients and burncharacteristics expected to present in the USAannually, concluding projected net savings to aburn center overall.

The underlying clinical driver associatedwith ASCS use is the reduced requirement forharvesting of donor skin, which leads to areduced number of procedures and faster heal-ing time [8–10]. While favorable results wereobserved across a range of patient profiles, themodeled impact of ASCS on LOS is likely con-servative. Using the Australian real-world data,use of ASCS alone for DPT burns allowed for agreater reduction in LOS (OR 0.7) compared toASCS with meshed-STSG for FT/mixed depthburns (OR 0.98) [11]. However, the higher rela-tive OR for FT/mixed depth burns (0.98) may beconservatively biased given the majority ofpatients (92%) had TBSA less than 20%. Thenumber of procedures needed for definitiveclosure for SOC increases with TBSA and,therefore, the benefits of a single procedure forASCS also increased at the same time as expec-ted LOS reductions. This trend of increasedASCS benefits with higher TBSA for FT/mixeddepth wounds was also supported by US-basedcompassionate use data. Specifically, forpatients with an average TBSA of 62% (range40–91%) use of ASCS with meshed-STSGshowed an OR of 0.53 compared to SOC [19].Therefore, it is expected that the impact of ASCSon LOS for FT/mixed depth burns may begreater than estimated in this analysis.

As with any modeling exercise, this study issubject to limitations relevant to interpretationof results. The primary limitation is that datacomparing LOS for ASCS treatment versus SOC,outside of compassionate use and within-inpatient controls, was not available in the USA.Therefore, we estimated the LOS for SOCpatients in the US setting, and then applied theOR derived from a real-world study fromT

able5

Budgetim

pact

modelresults

Costs

bycategory

(200

patients)

Con

servativeapproxim

ationscenario

NBR-based

nation

alaveragescenario

SOC

ASC

SDifference$(%

)SO

CASC

SDifference$(%

)

Wound

assessment

$481,550

$481,550

$0(0.0%)

$482,821

$482,821

$0(0.0%)

Debridement/excision

$2141,040

$2141,040

$0(0.0%)

$2,142,983

$2,142,983

$0(0.0%)

Definitive

closure

$4496,118

$3895,555

–$600,562

(–13.4%)

$6,047,354

$3,936,108

–$2111,246(–

34.9%)

Rehabilitation

$995,604

$772,729

–$222,875

(–22.4%)

$996,079

$773,201

–$222,877

(–22.4%)

LOS

$29,153,546

$24,665,265

–$4488,281(–

15.4%)

$29,220,479

$24,736,277

–$4484,202(–

15.3%)

Othera

$547,355

$547,355

$0(0.0%)

$547,213

$547,213

$0(0.0%)

Totalcosts

$37,815,213

$32,503,495

–$5311,718(–

14.0%)

$39,436,928

$32,618,602

–$6818,326(–

17.3%)

Average

costperpatient

$189,076

$162,517

–$26,559(–

14.0%)

$197,185

$163,093

–$34,092(–

17.3%)

aOtherincludescostsforanesthesiaandescharotom

y.Note:Resultsmay

differin

phasesoutsideof

defin

itiveclosurebecauseof

rand

omizationin

theMonteCarlo

simulation

1726 Adv Ther (2019) 36:1715–1729

Australia to estimate the impact of ASCS versusSOC for burns less than 40% TBSA. While theuse of a relative effect in the form of an oddsratio follows best practices for modeling, itshould be noted that we do not explicitlyaddress any underlying differences between theUS and Australian health systems that mayimpact the ASCS-related shift in LOS. Forpatients with 40%? TBSA, data from a singleburn center were used that found a 47%reduction in LOS for patients receiving ASCStreatment compared to age and burn severitymatched controls in a limited compassionateuse sample (* 10 adult patients) [19]. Never-theless, results and assumptions have been ver-ified by US burn surgeons. Furthermore,substantial and consistent clinical and financialbenefits from use of ASCS in compassionate useexperience in the USA has been reported [19].

Secondly, information about the costs andtiming of procedures were obtained from asmall sample of burn centers or from a survey ofburn surgeons. These represent average costs asreported by the centers and, therefore, do notexplicitly address the likely range in true paidcosts when considering the mix of insurancetypes across patients. As mentioned earlier,surgical management of burns varies acrossburn centers and surgeons. Accordingly, staffand healthcare costs, as well as definitive clo-sure procedure times, may also vary. Conclu-sions from the OWSA suggest that resultsremain robust across expected, known varia-tions as well as potential shifts in costs due toinsurance status of patients. Furthermore, theuse of random sampling from distributions inthe BIM highlights that conclusions also remainrobust across variations in key inputs. Theauthors also conducted an external benchmarkagainst predicted costs across patient profiles inthe NBR to check validity of final results, con-cluding that predicted costs for SOC were con-sistent with NBR data [15].

Finally, several simplifying assumptions weremade to develop a transparent, flexible model.First, individual unit costs and temporary cov-erage interventions (e.g., allograft, xenograft,skin substitute, or dermal analogs) were notexplicitly considered. Temporary closure costsand patient impacts are only implicitly captured

via the NBR-based predictive equations. Next, asis the case with clinical practice, the modelassumes correct diagnosis when determiningpathways for a diagnosed burn. Accuracy ofburn depth diagnosis varies on the basis of burncenter practices as well as timing of diagnosis,and published literature suggests that inaccu-rate diagnosis can occur, especially for SPT andDPT burns [21]. The most important impact ofthis assumption on model results is that thenumber of DPT burns eligible for ASCS (eithermisdiagnosed SPT or true DPT burns) may beuncertain. However, given that the use of ASCSis expected to result in savings for DPT burns,some amount of inherent misdiagnosis likelyleads to an underestimate of cost savings for anyincorrectly diagnosed SPT burns. Further, theNBR does not code diagnosis changes (i.e., burndepth conversion) over time and, therefore,does not highlight whether diagnoses werecorrect or incorrect. However, the predictiveequations derived from the NBR implicitlycapture the effects of how incorrectly diagnosedpatients impact average outcomes for proce-dures and LOS. Also, the model assumes onlyone procedure for a patient with ASCS. Whilethis is consistent with trends seen in real-worlduse in Australia as well as early clinical trial data[7], there may be instances when patientsundergo more than one procedure given veryhigh TBSA or provider preferences. Finally, themodel does explicitly consider the cost ofretreatment for ASCS or SOC, but the impact ofretreatment on LOS may be implicitly capturedin the NBR predictive equations for LOS.

Although the aforementioned limitationsexist, best-practice modeling methods wereused, and key assumptions were validated byburn surgeons, thereby ensuring that the ana-lytic conclusions are clinically valid and usefulto the burn community.

CONCLUSIONS

The BEACON model was developed to facilitateevaluation of cost-effectiveness of new inter-ventions within burn care, as measured by theclinical outcomes and relative costs for man-agement of burns in the USA. As a first step, the

Adv Ther (2019) 36:1715–1729 1727

model was used to estimate the potentialimpact of treatment with ASCS for inpatientburn management for individual patient pro-files and for burn centers, given current SOCpractice patterns and the distribution of patientcharacteristics seen nationally. Overall, ASCSuse reduces costs associated with the currenttreatment of severe burns, with greater savingsseen in larger FT/mixed-depth burns and acrossall DPT burns. The cost savings are due toreductions in LOS, the number of operationsrequired to close the burn wound, the donorsite size, and associated donor site wound care.

Future analyses should seek to replace LOSparameters with real-world data for the USAacross a broader range of patient profiles, and toobtain more data on costs and the timing ofprocedures from more hospitals to improvegeneralizability. Furthermore, information fromindividual burn centers could be integrated toidentify how ASCS treatment is likely to impactcosts and resource use given their current SOCpractices. Finally, given that the model capturesthe full spectrum of burn care, future analysescould leverage the modeling framework toevaluate additional new interventions, alone orin combination with ASCS treatment, andthereby estimating the synergistic impacts ofdifferent interventions on the cost of burn care.

ACKNOWLEDGEMENTS

Funding/Support. Sponsorship for this studyand article processing charges were funded byBiomedical Advanced Research DevelopmentAuthority (Contract HHSO100201500028C)and AVITA Medical, Valencia, CA, USA. Allauthors had full access to all of the data in thisstudy and take complete responsibility for theintegrity of the data and accuracy of the dataanalysis.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Stacey Kowal is an employee ofIQVIA and received funding to conduct theresearch. Eliza Kruger was an employee of IQVIAand received funding to conduct the research.Pinar Bilir is an employee of IQVIA and receivedfunding to conduct the research. JeremiahSparks is an employee of Avita Medical. AndrewQuick is an employee of Avita Medical. KatieBush is an employee of Avita Medical. JamesHolmes received consultation fees for contri-butions to input collection and model valida-tion. William Hickerson received consultationfees for contributions to input collection andmodel validation. Kevin Foster received con-sultation fees for contributions to input collec-tion and model validation. Narayan Iyer is anemployee of BARDA, the Office of AssistantSecretary for Preparedness and Response andthe United States Department of Health andHuman Services throughout the duration of thestudy. Scott Nystrom was an employee of Officeof Assistant Secretary for Preparedness andResponse, US Dept. of Health and Human Ser-vices. The publication of study results was notcontingent on the sponsor’s approval or cen-sorship of the manuscript.

Compliance with Ethics Guidelines. Thisarticle does not contain any new studies withhuman or animal subjects performed by any ofthe authors.

Disclaimer for HHS. The findings and con-clusions in this report are those of theauthor(s) and do not necessarily represent theviews of the Department of Health and HumanServices or its components.

Data availability. The datasets generatedduring and/or analyzed during the currentstudy are available from the correspondingauthor on reasonable request.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercialuse, distribution, and reproduction in anymedium, provided you give appropriate credit

1728 Adv Ther (2019) 36:1715–1729

to the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

REFERENCES

1. Pruitt B, Mason A. Epidemiological, demographic,and outcome characteristics of burn injury. In:Herndon D, editor. Total burn care. London:Saunders; 1996. p. 13.

2. American Burn Association. Burn incidence andtreatment in the United States: 2016. 2016. http://www.ameriburn.org/resources_factsheet.php. Acces-sed 3 Dec 2018.

3. CDC. 20 Leading causes of nonfatal injury, UnitedStates. 2015, All races, both sexes, disposition: allcases. 2015. https://webappa.cdc.gov/sasweb/ncipc/nfilead.html. Accessed 5 Mar 2018.

4. Klein MB, Goverman J, Hayden DL, et al. Bench-marking outcomes in the critically injured burnpatient. Ann Surg. 2014;259:833.

5. National Institutes of Health. Research portfolioonline reporting tools. Burns and traumatic injury2010. 2010. https://report.nih.gov/nihfactsheets/Pdfs/BurnsandTraumaticInjury(NIGMS).pdf. Acces-sed 6 Apr 2017.

6. Hranjec T, Turrentine FE, Stukenborg G, et al. Burn-center quality improvement: are burn outcomesdependent on admitting facilities and is there avolume-outcome ‘‘sweet-spot’’? Am Surg.2012;78:559–66.

7. Lim J, Liew S, Chan H, et al. Is the length of time inacute burn surgery associated with poorer out-comes? Burns. 2014;40:235–40.

8. Holmes J, Molnar J, Carter J, et al. A comparativestudy of the ReCell� device and autologous spit-thickness meshed skin graft in the treatment of acuteburn injuries. J Burn Care Res. 2018;39:694–702.

9. Gravante G, Di Fede M, Araco A, et al. A random-ized trial comparing ReCell� system of epidermalcells delivery versus classic skin grafts for thetreatment of deep partial thickness burns. Burns.2007;33:966–72.

10. Holmes J, Molnar J, Shupp J, et al. Demonstrationof the safety and effectiveness of the RECELL� sys-tem combined with split-thickness meshed auto-grafts for the reduction of donor skin required totreat mixed-depth burn injuries. Burns. 2018.https://doi.org/10.1016/j.burns.2018.11.002.

11. Park JH, Heggie KM, Edgar DW, et al. Does the typeof skin replacement surgery influence the rate ofinfection in acute burn injured patients? Burns.2013;39:1386–90.

12. Israel JS, Greenhalgh DG, Gibson AL. Variations inburn excision and grafting: a survey of the Ameri-can Burn Association. J Burn Care Res.2017;38:e125–32.

13. CDC. National Health and Nutrition Survey(NHANES) 2013-14. 2014. https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx?BeginYear=2013. Accessed 17 June 2017.

14. Bilir P, Kruger E, Kowal S, et al. Abstract: Inpatientcost of acute care for severe burn patients: valida-tion of economic model for adults and children. In:ISPOR 2018. Baltimore, 2018.

15. Kruger E, Bilir P, Kowal S, et al. Abstract: Relation-ship between patient characteristics and length ofstay for severe burn patients: analysis of the Amer-ican Burn Association National Burn Repository. In:ISPOR 2018. Baltimore, 2018.

16. American Burn Association. National Burn Reposi-tory Database Version 8.0. 2012.

17. Avita Medical. INSTRUCTIONS FOR USE: RECELL�

Autologous cell harvesting device. 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/PremarketApprovalsPMAs/UCM621327.pdf. Accessed 7 Feb2019.

18. FDA. September 20, 2018 Approval Order—RECELLAutologous cell harvesting device. 2018. https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/PremarketApprovalsPMAs/ucm621291.htm. Accessed 2 Feb 2018.

19. Holmes JH, Molnar JA, Williams JW, et al. Com-passionate use of ReCell in large burns: a single-center U.S. experience. Auckland: ANZBA; 2016.

20. American Burn Association. National Burn Reposi-tory 2017 update: report of the data from2008-2017. 2018. http://www.ameriburn.org/resources_factsheet.php. Accessed 8 Jan 2019.

21. Hoeksema H, Van de Sijpe K, Tondu T, et al.Accuracy of early burn depth assessment by laserDoppler imaging on different days post burn.Burns. 2009;35:36–45.

22. Luo G, Fan H, Sun W, et al. Blood loss duringextensive escharectomy and auto-microskin graft-ing in adult male major burn patients. Burns.2011;37:790–3.

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