Gaining Consensus Around Patient Risk Groups and Prognostic Profiles to Guide CMV Management Among Patients With Allogeneic Hematopoietic Stem Cell Transplant: Insights From a Delphi Panel With Hematopoietic Stem Cell Transplant Experts.

INTRODUCTION: This study aimed to characterize patient risk groups and prognostic profiles to optimize clinical decision-making and guide appropriate medical cytomegalovirus (CMV) management among patients with allogeneic hematopoietic stem cell transplant (HSCT). METHODS: Between 8/2021 and 2/2022, a 3-round modified Delphi study was conducted to generate consensus among 10 international experts in HSCT and infectious diseases. Experts were asked about treatment and prognoses for patients in 7 distinct clinical scenarios. Furthermore, experts were asked to risk-stratify patients by pre-/post-transplant characteristics. Consensus around opting for/against a treatment was observed if ≥75% or <25% of experts reported ≥50% likelihood to recommend or if treatments were ranked inside/outside the top 2 options and ≥75% of experts were within 1 SD of mean ranks. RESULTS: Experts agreed on several unmet needs in CMV disease management post-HSCT, particularly avoidance of treatment-limiting toxicities with conventional CMV therapy and the emergence of both refractory and drug-resistant treatment failures. Experts considered CMV viral load, resistance profile, and route of administration as critical to treatment selection. For newer CMV therapeutic options, experts listed a lack of long-term use data, concerns over potential resistance, high cost, and limited availability as challenges restricting adoption and successful patient management. CONCLUSIONS: Experts achieved consensus around patient risk stratifications and factors influencing therapeutic options. Recommendations emerging from this Delphi study may support practicing physicians when confronted with challenging CMV scenarios in patients with HSCT.

Evaluation of clinical characteristics, health care resource utilization, and cost outcomes of hemophilia A carriers and noncarriers in the United States: A real-world comparative analysis.

BACKGROUND: Hemophilia A is often viewed as a male disease; females are usually considered asymptomatic hemophilia A carriers. However, hemophilia A carriers may experience mild-to-severe bleeding events. OBJECTIVE: To compare clinical characteristics, health care resource utilization, and costs incurred by hemophilia A carriers compared with a non-hemophilia A carrier female control population in the United States. METHODS: This retrospective observational cohort study used data from IBM MarketScan Commercial Claims and Encounters and Multi-State Medicaid Databases from January 1, 2016, to September 30, 2019. Patients with a hemophilia A carrier diagnosis were matched to a non-hemophilia A carrier female control group in a 1:2 ratio based on sociodemographic characteristics, pregnancy status, and insurance type. Billed annualized bleed rates, health care resource utilization, and annualized costs were evaluated. Generalized linear models compared annualized total costs in the hemophilia A carrier and control groups. RESULTS: After matching, the hemophilia A carrier group included 121 (Commercial) and 55 (Medicaid) patients, matched 1:2 in the control group. Patients in the hemophilia A carrier group (compared with the control group) had numerically higher joint-related health issues (Commercial: 11.6% vs 7.9%; Medicaid: 7.3% vs 4.5%) and lower soft-tissue disorders (Commercial: 13.2% vs 17.4%; Medicaid: 12.7% vs 14.5%). Musculoskeletal pain was higher (33.1% vs 31.0%) and lower (21.8% vs 25.5%) in the Commercial and Medicaid databases, respectively. Billed annualized bleed rates were higher in the hemophilia A carrier group (Commercial: 0.49 vs 0.33; Medicaid: 0.50 vs 0.29). Significantly more patients in the hemophilia A carrier group had minor bleeds (Commercial: 34.7% vs 22.3% [P = 0.001]; Medicaid: 43.6% vs 20.0% [P < 0.001]) and spontaneous bleeds (Commercial: 35.5% vs 21.5%; Medicaid: 47.3% vs 23.6% [P < 0.001 for both]). Outpatient visits represented the majority of health care resource utilization and were higher in the hemophilia A carrier group for all-cause and bleed-related claims; although less frequent, emergency department and inpatient visits followed a similar trend. In the Commercial and Medicaid databases, hemophilia A carriers incurred approximately 2 times higher mean (SD) all-cause health care total costs than patients in the control group (Commercial: $15,345 [21,871] vs $8,358 [11,939] per patient per year [PPPY]; Medicaid: $9,022 [19,461] vs $4,533 [9,532] PPPY). CONCLUSIONS: Hemophilia A carriers experienced more complications and incurred higher costs (resulting from more outpatient, emergency department, and inpatient visits) compared with patients in the control group. These data suggest that hemophilia A carriers have a high disease and economic burden and may benefit from early diagnosis and management to prevent long-term complications. DISCLOSURES: Dr Xing, Dr Bullano, Dr Caicedo, and Mr Farahbakhshian are employees of Takeda Pharmaceuticals U.S.A., Inc., hold Takeda stocks, and have been granted restricted stock shares; Drs Xing and Caicedo received support from Takeda Pharmaceuticals U.S.A., Inc., for travel to THSNA 2022, where the data included in this manuscript were presented. Dr Batt received consulting fees from Complete HEOR Solutions (CHEORS) LLC for the protocol development, data analysis, and interpretation of this study; she also holds stocks from Merck and Sanofi. Ms Kuharic is an employee of the University of Illinois at Chicago and has been supported by a Takeda fellowship during the execution of the study. Ms Chakladar and Ms Markan were employees of CHEORS LLC at the time of the study. CHEORS has received funding from Takeda Pharmaceuticals U.S.A., Inc., for conducting the analysis of this study. This study was funded by Takeda Pharmaceuticals U.S.A., Inc. The sponsor was involved in the study design; collection, analysis, and interpretation of data; development and review of the manuscript; and decision to submit manuscript to publication.

Real-world analysis of patients with haemophilia A and haemophilia A carriers in the United States: Demographics, clinical characteristics and costs.

INTRODUCTION: Females with haemophilia A (HA [FHAs]) and HA carriers (HACs) have an increased risk of bleeding and complications compared to the general population. AIM: To examine the characteristics, billed annualised bleed rates (ABRb ), costs and healthcare resource utilisation for males with HA (MHAs), FHAs and HACs in the United States. METHODS: Data were extracted from the IBM® MarketScan® Research Databases (Commercial and Medicaid) for claims during the index period (July 2016 to September 2018) and analysed across MHAs, FHAs and HACs. RESULTS: Dual diagnosis females (DDFs; both HA and HAC claims) were grouped as a separate cohort. MHAs were generally younger than females (all cohorts) by up to 19 years (Commercial) and 23 years (Medicaid). ABRb  >0 was more frequent in females. Factor VIII claims were higher for MHAs versus female cohorts. Joint-related health issues were reported for 24.4 and 25.6% (Commercial) and 29.3 and 26.6% (Medicaid) of MHAs and FHAs, respectively; lower rates were reported in the other two cohorts. Heavy menstrual bleeding claims occurred for approximately a fifth (Commercial) to a quarter (Medicaid) of female cohorts. All-cause emergency department and inpatient visits in FHAs and DDFs were similar to, or more frequent than, those in MHAs; bleed-related inpatient visits were infrequent. In MHAs (Commercial), mean all-cause total costs ($214,083) were higher than in FHAs ($40,388), HACs ($15,647) and DDFs ($28,320) with similar trends for Medicaid patients. CONCLUSIONS: FHAs and HACs may be undermanaged and undertreated. Further research is needed to fully understand these cohorts' bleeding rates, long-term complications and costs.

Gaining consensus around patient risk groups and prognostic profiles to guide CMV management among patients with solid organ transplant: Insights from a Delphi panel with SOT experts.

INTRODUCTION: This study aimed to characterize patient risk groups and respective prognostic profiles to optimize clinical decision-making and guide appropriate medical cytomegalovirus (CMV) management among patients with solid organ transplant (SOT). METHODS: Between September 2021 and February 2022, a three-round modified Delphi study was conducted to generate consensus among 14 international experts in virology and organ transplantation. Experts were asked about treatment and prognoses for patients in seven distinct clinical scenarios. Furthermore, experts were asked to risk-stratify patients by pre-/post-transplant characteristics. Consensus around opting for/against a treatment was observed if ≥75% or <25% of experts reported ≥50% likelihood to recommend or if treatments were ranked inside/outside the top two options and ≥75% of experts were within 1 standard deviation of the mean rank. RESULTS: Experts agreed on several unmet needs in CMV disease management post-SOT, particularly avoidance of treatment-limiting toxicities with conventional CMV therapy and emergence of both primary refractory and drug resistant treatment failures. Experts considered CMV viral load, resistance profile, and route of administration as critical to treatment selection. For newer CMV therapeutic options, experts listed lack of long-term use data, concerns over potential resistance, high cost and limited availability as challenges restricting adoption, and successful patient management. CONCLUSION: Experts achieved consensus around patient risk stratifications and factors influencing therapeutic options. Recommendations emerging from this Delphi study may support practicing physicians when confronted with challenging CMV scenarios in SOT patients, but additional experiences with newer anti-CMV agents are needed to re-validate expert consensus and update post-transplant CMV guidelines.

Evaluating the financial impact of utilizing recombinant porcine factor VIII or recombinant FVIIa for patients with acquired hemophilia A.

OBJECTIVE: To evaluate the financial impact of utilizing rpFVIII or rFVIIa during a hospital admission for the diagnosis of acquired hemophilia A (AHA) by reviewing the margin between the cost to the hospital for providing care and the amount the hospital is reimbursed by the Centers for Medicare & Medicaid Services (CMS) in the US. METHODS: Data source was the Medicare Limited Data Set, which contains claims for hospitalizations, charges, and amounts reimbursed by CMS. Study patients were hospitalized with AHA and treated with rpFVIII and/or rFVIIa between 1/1/2015 and 12/31/2019. CMS Fiscal Year 2020 Impact Files, with hospital-level cost-to-charge ratios (CCRs), were used to estimate hospital costs. Sensitivity analyses were conducted to estimate margins at different CCRs. RESULTS: Hospital margins were, on average, positive with use of either rpFVIII or rFVIIa (rpFVIII: $51,548.89; rFVIIa: $35,943.80). Sensitivity analysis results suggest that the use of rpFVIII is similiar, compared with rFVIIa for a large majority of hospitals. CONCLUSIONS: While there may be higher reimbursement for rpFVIII hospitalizations, this analysis suggests that the use of rpFVIII, compared to rFVIIa, may have no impact on hospital finances for the majority of hospitals, despite rpFVIII's higher per unit cost.

Estimating Productivity Loss from Breast and Non-Small-Cell Lung Cancer among Working-Age Patients and Unpaid Caregivers: A Survey Study Using the Multiplier Method.

Background. Traditional approaches to capturing health-related productivity loss (e.g., the human capital method) focus only on the foregone wages of affected patients, overlooking the losses caregivers can incur. This study estimated the burden of productivity loss among breast cancer (BC) and non-small-cell lung cancer (NSCLC) patients and individuals caring for such patients using an augmented multiplier method. Design. A cross-sectional survey of BC and NSCLC patients and caregivers measured loss associated with time absent from work (absenteeism) and reduced effectiveness (presenteeism). Respondents reported pre- and postcancer diagnosis income, hours worked, and time to complete tasks. Exploratory multivariable analyses examined correlations between respondents' clinical/demographic characteristics-including industry of employment-and postdiagnosis productivity. Results. Of 204 patients (104 BC, 100 NSCLC) and 200 caregivers (100 BC, 100 NSCLC) who completed the survey, 319 participants (162 BC, 157 NSCLC) working ≥40 wk/y prediagnosis were included in the analysis. More than one-third of the NSCLC (33%) and BC (43%) patients left the workforce postdiagnosis, whereas only 15% of caregivers did. The traditional estimate for the burden of productivity loss was 66% lower on average than the augmented estimate (NSCLC patients: 60%, BC patients: 69%, NSCLC caregivers: 59%, and BC caregivers: 73%). Conclusions. Although patients typically experience greater absenteeism, productivity loss incurred by caregivers is also substantial. Failure to account for such impacts can result in substantial underestimation of productivity gains novel cancer treatments may confer by enabling patients and caregivers to remain in the workforce longer. Our results underscore the importance of holistic approaches to understanding this impact on both patients and their caregivers and accounting for such considerations when making decisions about treatment and treatment value. Highlights: Cancer can have a profound impact on productivity. This study demonstrates how the disease affects not only patients but also the informal or unpaid individuals who care for patients.An augmented approach to calculating health-related productivity loss suggests that productivity impacts are much larger than previously understood.A more comprehensive understanding of the economic burden of cancer for both patients and their caregivers suggests the need for more support in the workplace for these individuals and a holistic approach to accounting for these impacts in treatment decision making.

A real-world study comparing pre-post billed annualized bleed rates and total cost of care among non-inhibitor patients with hemophilia A switching from FVIII prophylaxis to emicizumab.

OBJECTIVE: Factor VIII (FVIII) replacement and emicizumab have demonstrated efficacy for prevention of bleeds among patients with hemophilia A (PwHA) compared to on-demand (OD) use. Evidence investigating clinical outcomes and healthcare costs of non-inhibitor PwHA switching from prophylaxis with FVIII concentrates to emicizumab has not been well-established within large real-world datasets. This study aimed to investigate billed annualized bleed rates (ABRb) and total cost of care (TCC) among non-inhibitor PwHA switching from FVIII-prophylaxis to emicizumab-prophylaxis. METHODS: This retrospective, observational study was conducted using IQVIA PharMetrics Plus, a US administrative claims database. The date of first claim for emicizumab was defined as the index date. OD patients and inhibitor patients were excluded. Bleeds were identified using a list of 535 diagnosis codes. Bayesian models were developed to estimate the probability ABRb worsens and TCC increases after switching to emicizumab. Wilcoxon rank-sum tests were used to test statistical significance of changes in ABRb and TCC after switch. RESULTS: Among the 121 identified patients, the difference in mean ABRb between FVIII-prophylaxis (0.68 [SD = 1.28]) and emicizumab (0.55 [SD = 1.48]) was insignificant (p = .142). The mean annual TCC significantly increased for patients switching from FVIII-prophylaxis ($518,151 [SD = $289,934]) to emicizumab ($652,679 [SD = $340,126]; p < .0001). The Bayesian models estimated a 21.0% probability of the ABRb worsening and a 99.9% probability of increasing TCC after switch. CONCLUSIONS: This study found that in male non-inhibitor PwHA, switching from FVIII prophylaxis to emicizumab incurs substantial cost increase with no significant benefit in ABRb. This evidence may help guide providers, payers, and patients in shared decision-making conversations around best treatment options.

Bleeding in patients with hemophilia who have inhibitors: Modeling US medical system utilization and cost avoidance between recombinant factor VIIa products with different clinical dosing requirements.

BACKGROUND: A mainstay of treatment in patients with hemophilia with inhibitors (PWIs) is the use of a recombinant factor VIIa (rFVIIa) bypassing agent. A new rFVIIa product may allow reduced rFVIIa utilization for on-demand treatment of bleeding episodes (BEs). OBJECTIVE: A decision analytic health economic model was developed to compare the utilization and consequent need for bleed-related clinical encounters of 2 rFVIIa products, with the International Nomenclature Name of eptacog alfa (EA) and eptacog beta (EB). METHODS: This study uses recent, peer-reviewed, and published data from clinical trials with similar endpoints for 1 million insured male lives in the United States. rFVIIa product utilization was modeled in hemophilia (A and B) PWI for on-demand treatment of BEs with rFVIIa treatment. Estimated annual BE rates were modeled to include prophylaxis and on-demand management. The clinical encounter avoidance estimates are based on refractory bleeding through 24 hours. RESULTS: In a cohort of 1 million insured, 5-6 patients with hemophilia A or B with inhibitors annually receive on-demand treatment for a total of 59 mild/moderate BEs. The model suggests that EB requires less unit utilization per BE (13,125 µg and 17,850 µg for the 75µg/kg and 225µg/kg dose regimens, respectively) than EA 90 µg/kg dosing (20,178µg), with wholesale acquisition costs expanding the difference. Further, both EB initial dose regimens would permit decreased total nonmedication health plan spending for the acute treatment of BEs by reducing the need for clinical encounters arising from BEs that fail to respond within 24 hours. CONCLUSIONS: With reduced infusion requirements, the model consistently shows that EB could generate lower insured-cohort drug utilization, as well as reduce costly clinical encounters by keeping mild and moderate BEs amenable to home bypassing agent management. DISCLOSURES: The article was funded by HEMA Biologic, LLC. The authors approved all content and results in this article without being subject to sponsor censorship. Mr Jensen, Mr Cyr, and Ms Hathway are employees of PRECISIONheor, which provides consulting services to the pharmaceutical industry, including HEMA Biologics, LLC. Dr Batt is an advisor to PRECISIONheor. Dr Alexander is a former employee of HEMA Biologics, LLC, and provides consulting services to the pharmaceutical industry.

Indirect Treatment Comparison of Damoctocog Alfa Pegol versus Turoctocog Alfa Pegol as Prophylactic Treatment in Patients with Hemophilia A.

PURPOSE: To assess the efficacy and FVIII consumption of BAY 94-9027 versus N8-GP in prophylaxis in adolescent and adult patients with severe hemophilia A (HA). PATIENTS AND METHODS: A systematic literature review was conducted to identify studies on the efficacy of BAY-94-9027 and N8-GP for prophylaxis in patients with HA aged ≥12 years without a history of inhibitors. Eight studies met systematic literature review inclusion criteria, but only data from PROTECT VIII on BAY 94-9027 and PATHFINDER 2 on N8-GP could be used for an indirect comparison. Matching-adjusted indirect comparison (MAIC) and simulated treatment comparison were performed. RESULTS: No significant differences (unadjusted and adjusted) were observed in the mean annualized bleeding rate (ABR) for any bleed and proportion of patients with zero bleeds when comparing BAY 94-9027 to N8-GP. The adjusted treatment difference [incidence rate ratio (IRR)] in terms of ABR was 1.11 (95% CI, 0.85-1.44). The odds ratio (OR) of any bleed, measuring the relative effect of BAY 94-9027 versus N8-GP on the proportion of patients with zero bleeds, was 1.03 (95% CI, 0.60-1.77). FVIII consumption was significantly lower in BAY 94-9027 [mean adjusted difference=-1292.57 IU/kg/year (95% CI, ‒2152.44 to ‒432.70)]; a 26.7% reduction in consumption of BAY-94-9027. The results of the sensitivity analyses were similar to the main analysis for mean ABRs, percentages of patients with zero bleeds, and significant reduction in rFVIII consumption. For patients on BAY 94-9027 every-5-days and every-7-days, no differences versus every-4-days N8-GP were observed for the mean ABR for any bleed [IRR=0.90 (95% CI, 0.68‒1.20)] and proportion of patients with zero bleeds [OR=1.06 (95% CI, 0.56‒2.02)]. CONCLUSION: BAY 94-9027 prophylaxis demonstrated 26.7% lower annual consumption when compared to N8-GP with similar efficacy in terms of ABR and percentage of patients with zero bleeds.

A Delphi Consensus Approach for Difficult-to-Treat Patients with Severe Hemophilia A without Inhibitors.

INTRODUCTION: Over the past decade, there has been an increase in novel therapeutic options to treat hemophilia A. It is still unclear how these novel treatments are used in the management of patients with hemophilia A, particularly those with challenging clinical scenarios who are typically excluded in clinical trials. PURPOSE: This study aimed to understand the areas of consensus and disagreement among hematologists regarding the preferences toward therapeutic approaches for difficult-to-treat patients with severe hemophilia A without inhibitors. PATIENTS AND METHODS: During February-June 2020, a three-round modified Delphi study was conducted to generate consensus among 13 US experts in the field of hemophilia. Experts were asked about their preferences toward therapeutic options for patients with challenging clinical situations, including age-related morbidities (eg, myocardial infarction, joint arthropathy), increasing demand for high-impact physical activities, early onset osteoporosis, and newborns with hemophilia A. Consensus was defined as ≥75% agreement between the panelists. RESULTS: Consensus was reached on many, but not all cases, leaving uncertainty about appropriateness of therapeutic approaches for some patients where clinical evidence is not available or driven by physicians' or patients' preferences toward therapeutic options. A majority of panelists preferred FVIII replacement therapy rather than emicizumab prophylaxis for the challenging cases presented due to established evidence on safety, efficacy, and level of bleed protection for FVIII treatment. CONCLUSION: Recommendations emerging from this study may help guide practicing hematologists in the management of challenging hemophilia A cases. Future studies are needed to address treatment options in the clinical cases where no consensus was reached.

Understanding the evolution of coverage policies for prophylaxis treatments of hemophilia A without inhibitors: a payer Delphi panel.

BACKGROUND: The landscape for hemophilia A prophylaxis is rapidly expanding from factor VIII replacement therapy to include novel treatments such as nonfactor replacement therapies that may enhance coagulation (e.g., emicizumab) or inhibit anticoagulant pathways (e.g., fitusiran and concizumab). For payers, this expansion presents challenges in balancing well-established treatments with new options that cost more and have lesser known real-world safety and efficacy. OBJECTIVE: To evaluate likely coverage practices for hemophilia A prophylaxis therapies among U.S. payers given evolving real-world data on safety and efficacy. METHODS: A 3-round modified Delphi process was conducted with representatives of U.S. commercial health plans who had considerable expertise in managing populations of patients with hemophilia. Round 1 consisted of an online questionnaire; round 2 involved an online discussion about the aggregated results from round 1; and round 3 allowed participants to revise their responses from round 1 based on insights gained during round 2. Questions elicited ratings, rankings, and estimates on access restrictions based on given safety and efficacy information for hemophilia A prophylaxis therapies. Consensus was reached if ≥ 74% of panelists (14 of 19) were within 1 SD of the median group estimate during round 3. RESULTS: 19 Payers participated in the research. Among them, 94% dealt with commercial insurance, 94% with Medicare, and 81% with Medicaid; 79% had spent ≥ 5 years in their current role. Panelists reported limited access restrictions on hemophilia A prophylaxis therapies; the most common restrictions were prior authorization (n = 16, 84%) and quantity level limits (n = 13, 67%). Tiering and step therapy were reported by 7 respondents (39%). Respondents agreed that there was an 80% median likelihood that ≥ 9 additional patients with any safety event (e.g., thrombotic event, death) per year would trigger access restrictions, with the median likelihood of restrictions increasing to 95% for another ≥ 10 patients with safety events per year. Respondents also agreed that > 5 thrombotic events requiring treatment per patient per year would have a 98% median likelihood of leading to access restrictions and that ≥ 5 years of real-world safety and efficacy data would be highly likely (95% median likelihood) to affect coverage decisions. Noncoverage was highly unlikely (ranked fifth or sixth of 6 by 14 respondents), as was no restriction-coverage parity (ranked sixth of 6 by 10 respondents). All else being equal, cost continues to affect access policies, with respondents agreeing that a 13%-30% difference in net cost may lead to preferred formulary treatment for a drug with superior efficacy and noninferior safety, inferior efficacy and noninferior safety, or noninferior efficacy and inferior safety. CONCLUSIONS: Payers prefer treatments with well-understood efficacy, safety, and cost over newer treatments with uncertain long-term effects. Relatively unrestricted access to legacy and new hemophilia A prophylaxis will likely continue unless additional real-world safety concerns or major cost differences emerge. DISCLOSURES: Financial support for this study was provided by Takeda Pharmaceutical Company, which was involved in study concept and design. Graf, Tuly, Harley, and Pednekar are employees of PRECISIONheor, a research consultancy to the health and life sciences industries that was contracted by Takeda to conduct this study and write the manuscript. Batt served as a consultant on this project through PRECISIONheor.

Physical activity and bleeding outcomes among people with severe hemophilia on extended half-life or conventional recombinant factors.

BACKGROUND: Few have assessed physical activity (PA) and annual bleed rates (ABRs) among people with hemophilia on extended half-life (EHL) factors (recombinant factor VIII Fc [rFVIIIFc]/recombinant factor IX Fc [rFIXFc]) and conventional factors (recombinant factor VIII [rFVIII]/recombinant factor IX [rFIX]). OBJECTIVE: To assess changes in PA and ABR at consecutive annual visits in individuals with severe hemophilia A and B (HA/HB) on prophylactic treatment with rFVIIIFc/rFIXFc versus rFVIII/rFIX. PATIENTS/METHODS: We conducted a retrospective chart review of 344 people with severe HA/HB (ages 6-35) receiving prophylaxis with rFVIIIFc/rFIXFc (EHL factors) or rFVIII/rFIX (conventional factors) for ≥6 months in 2014-2015. Differences in changes in outcomes from 2014 to 2015 were compared across the treatment groups. RESULTS: Baseline characteristics and adherence to the prophylactic regimen were similar across the treatment groups. Greater increase in weekly PA frequency and duration were observed among all EHL groups, except for children treated with rFIXFc. The increase in PA frequency was greater among the children on rFVIIIFc group, adults on rFVIIIFc group, and adults on rFIXFc group by 1.2, 1.2, and 1.4 events/week, respectively, compared to their rFVIII/rFIX counterparts. The increases in PA duration were 44, 60, and 80 min/wk greater among the children on rFVIIIFc, adults on rFVIIIFc, and adults on rFIXFc groups, respectively. Larger reductions in total ABR were observed in children and adults treated with rFVIIIFc compared to rFVIII (0.4 and 0.7 fewer bleeds). Larger reductions were also observed in spontaneous ABR in adult rFVIIIFc and rFIXFc groups (0.8 and 0.3 fewer bleeds, respectively). CONCLUSIONS: This study suggests that rFVIIIFc/FIXFc agents can positively impact PA while maintaining low ABRs.

Changes in mortality associated with cancer drug approvals in the United States from 2000 to 2016.

AIMS: To estimate the extent to which the approvals of new pharmacological therapies were associated with cancer mortality in the USA between 2000 and 2016. MATERIALS AND METHODS: The analysis quantified cancer drug approvals across the 15 tumor types with the highest incidence. Number of approvals in a given time period for each tumor was translated into a treatment stock measure, defined as a weighted sum of new indication approvals since 1976. The primary outcome was the annual tumor-specific cancer mortality, defined as the number of deaths per 100,000 U.S. population. The analysis used a multivariable ordinary least squares and a fixed effects model, controlling for incidence (new cases per 100,000 U.S. population) and the primary exposure, the treatment stock measure by year. RESULTS: Between 2000 and 2016, deaths per 100,000 population across the 15 most common tumor types declined by 24%. Additionally, 10.2 new indications were approved per year across the 15 most common tumor types. Cancer drug approvals were associated with statistically significant deaths averted in 2016 for colorectal cancer (4,991, p = 0.004), lung cancer (33,825, p < 0.001), breast cancer (11,502, p < 0.001), non-Hodgkin's lymphoma (6,636, p < 0.001), leukemia (4,011, p < 0.001), melanoma (1,714, p < 0.001), gastric cancer (758, p = 0.019), and renal cancer (739, p < 0.001). Between 2000 and 2016, new cancer treatments were correlated with 1,291,769 (p < 0.001) total deaths prevented across the 15 most common tumor types. LIMITATIONS AND CONCLUSIONS: Cancer drug approvals between 2000 and 2016 were associated with significant reduction in deaths from the most common cancers in the USA. Mortality changes were largest in prevalent tumor types with relatively more approvals, i.e. lung cancer, breast cancer, melanoma, lymphoma and leukemia. Future research evaluating the relationship between drug approvals and cancer mortality post 2016 is needed.

Characterizing female patients with haemophilia A: Administrative claims analysis and medical chart review.

AIM: Haemophilia A (HA) is a male-predominant disorder, yet women and girls can have factor VIII (FVIII) deficiency with bleeding events requiring treatment. This study aimed to identify and characterize female patients with HA. METHODS: Administrative claims dated 01 January 2012-31 July 2016 were accessed for patients with 18 months' coverage by commercial or Medicare Advantage with Part D insurance. Patients were included by HA diagnoses or treatments and/or bleeding-related diagnoses or procedures, and excluded by haemophilia B or qualitative platelet disorder diagnoses. A sample of charts was examined for bleeding history, HA therapies and bleeding treatments. All-cause healthcare utilization and costs were also described. RESULTS: Among 353 patients meeting initial inclusion criteria, 86 charts were procured, with 8 patients identified as having HA. Their mean age was 60 ± 17 years and most were Medicare-insured. The mean Charlson Comorbidity Index score was 2.50 ± 2.56; the most prevalent comorbid conditions involved coagulation/haemorrhage, fluid/electrolyte balance and non-traumatic joint disorders. Over 18 months, a mean of 54 ambulatory visits and 120 pharmacy fills were observed; mean medical costs were $86 694 and pharmacy costs were $25 396. CONCLUSIONS: Identifying females with HA is challenging using healthcare claims, because diagnostic nomenclature is unclear for female patients treated for bleeding events. Although chart abstraction enhanced claims data, very few female patients were identified with HA. Nevertheless, even in a small sample, sizeable burden in comorbidity and healthcare use was observed. Improved nomenclature and coding for HA diagnoses for women and girls is key to improving research and treatment.

Integrating expert opinion with clinical trial data to extrapolate long-term survival: a case study of CAR-T therapy for children and young adults with relapsed or refractory acute lymphoblastic leukemia.

BACKGROUND: Long-term clinical outcomes are necessary to assess the cost-effectiveness of new treatments over a lifetime horizon. Without long-term clinical trial data, current practice to extrapolate survival beyond the trial period involves fitting alternative parametric models to the observed survival. Choosing the most appropriate model is based on how well each model fits to the observed data. Supplementing trial data with feedback from experts may improve the plausibility of survival extrapolations. We demonstrate the feasibility of formally integrating long-term survival estimates from experts with empirical clinical trial data to provide more credible extrapolated survival curves. METHODS: The case study involved relapsed or refractory B-cell pediatric and young adult acute lymphoblastic leukemia (r/r pALL) regarding long-term survival for tisagenlecleucel (chimeric antigen receptor T-cell [CAR-T]) with evidence from the phase II ELIANA trial. Seven pediatric oncologists and hematologists experienced with CAR-T therapies were recruited. Relevant evidence regarding r/r pALL and tisagenlecleucel provided a common basis for expert judgments. Survival rates and related uncertainty at 2, 3, 4, and 5 years were elicited from experts using a web-based application adapted from Sheffield Elicitation Framework. Estimates from each expert were combined with observed data using time-to-event parametric models that accounted for experts' uncertainty, producing an overall distribution of survival over time. These results were validated based on longer term follow-up (median duration 24.2 months) from ELIANA following the elicitation. RESULTS: Extrapolated survival curves based on ELIANA trial without expert information were highly uncertain, differing substantially depending on the model choice. Survival estimates between 2 to 5 years from individual experts varied with a fair amount of uncertainty. However, incorporating expert estimates improved the precision in the extrapolated survival curves. Predictions from a Gompertz model, which experts believed was most appropriate, suggested that more than half of the ELIANA patients treated with tisagenlecleucel will survive up to 5 years. Expert estimates at 24 months were validated by longer follow-up. CONCLUSIONS: This study provides an example of how expert opinion can be elicited and synthesized with observed survival data using a transparent and formal procedure, capturing expert uncertainty, and ensuring projected long-term survival is clinically plausible.

Matching-adjusted indirect comparisons of annualized bleeding rate and utilization of BAY 94-9027 versus three recombinant factor VIII agents for prophylaxis in patients with severe hemophilia A.

Background: BAY 94-9027 is an extended half-life recombinant factor VIII (rFVIII) that prevents bleeding in persons with hemophilia A at twice-weekly, 5-day, and 7-day dosing intervals. In rare diseases such as hemophilia, where small populations preclude head-to-head comparisons in randomized controlled trials, outcomes from different studies can be compared by matching-adjusted indirect treatment comparisons (MAICs) via matched summary statistics of individual patient data. This study compared MAIC-adjusted outcomes of BAY 94-9027 with other FVIII agents for prophylaxis of hemophilia. Methods: Weighted patient data from the BAY 94-9027 PROTECT VIII trial were used to compare annualized bleeding rates (ABRs), percentage of patients with zero bleeds, and factor utilization against published data on rFVIII-Fc fusion protein (rFVIIIFc), BAX 855, and recombinant antihemophilic factor/plasma/albumin-free method (rAHF-PFM). Results: After matching BAY 94-9027 and comparators, the mean BAY 94-9027 utilization was significantly lower than rFVIIIFc pre- and post-matching (66.2 vs 82.2 IU/kg/week; 66.5 vs 82.2 IU/kg/week; both P<0.001). Median BAY 94-9027 utilization (IU/kg/week) trended lower than BAX 855 (64.3 vs 87.4) and rAHF-PFM (2004 study: 64.0 vs 107.5; 2012 study: 63.6 vs 109.9). Mean ABRs and percentages of patients with zero bleeds were similar post-matching between BAY 94-9027 and comparators. Conclusion: BAY 94-9027 demonstrated similar MAIC-adjusted ABR with lower utilization than rFVIIIFc, BAX 855, and rAHF-PFM.

The potential impact of CAR T-cell treatment delays on society.

OBJECTIVES: To date, breakthrough chimeric antigen receptor (CAR) T-cell therapies, such as tisagenlecleucel, indicated for pediatric acute lymphoblastic leukemia (pALL) and diffuse large B-cell lymphoma (DLBCL), and axicabtagene ciloleucel, indicated for DLBCL, although clinically effective, have been limited by treatment delays. Our study measured the social value of CAR T-cell therapy (CAR T) for relapsed or refractory pALL and DLBCL in the United States and quantified social value lost due to treatment delays. STUDY DESIGN: We used an economic framework for therapy valuation, measuring social value as the sum of consumer surplus and manufacturer profit. Consumer surplus is the difference between the value of health gains from a therapy and its incremental cost, while accounting for indirect costs and benefits to patients. METHODS: For 20 incident cohorts of pALL (n = 20 × 400 = 8000) and DLBCL (n = 20 × 5902 = 118,040), we quantified patient value, calculated as the value of additional quality-adjusted life-years gained with CAR T, minus the incremental cost of CAR T compared with standard of care (SOC). We calculated manufacturer profits using a range of production costs given uncertainties in the production process. Patient value and manufacturer profits were summed to obtain total social value. We measured social value lost from treatment delays, assuming that patients received the SOC while awaiting CAR T-cell treatment. RESULTS: Depending on production costs, as much as $6.5 billion and $34.8 billion in social value was generated for patients with pALL and DLBCL, respectively. However, with 1, 2, or 6 months of treatment delay (assuming $200,000 production costs), the pALL population lost 9.8%, 36.2%, and 67.3% of social value, respectively, whereas the DLBCL population lost 4.2%, 11.5%, and 46.0%, relative to no delay. CONCLUSIONS: The social value of CAR T is significantly limited by treatment delays. Efficient payment mechanisms, adequate capital, and payment policy reform are urgently needed to increase patient access and maximize the value of CAR T.

The Value of Progression-Free Survival in Metastatic Breast Cancer: Results From a Survey of Patients and Providers.

Background. Value assessments and treatment decision making typically focus on clinical endpoints, especially overall survival (OS). However, OS data are not always available, and surrogate markers may also have some value to patients. This study sought to estimate preferences for progression-free survival (PFS) relative to OS in metastatic breast cancer (mBC) among a diverse set of stakeholders-patients, oncologists, and oncology nurses-and estimate the value patients and providers place on other attributes of treatment. Methods. Utilizing a combined conjoint analysis and discrete choice experiment approach, we conducted an online prospective survey of mBC patients and oncology care providers who treat mBC patients across the United States. Results. A total of 299 mBC patients, 100 oncologists, and 99 oncology nurses completed the survey. Virtually all patients preferred health state sequences with contiguous periods of PFS, compared with approximately 85% and 75% of nurses and oncologists, respectively. On average, longer OS was significantly (P < 0.01) preferred by the majority (75%) patients, but only 15% of nurses preferred longer OS, and OS did not significantly affect oncologists' preferred health state. However, in the context of a treatment decision, whether a treatment offered continuous periods of stable disease holding OS constant significantly affected nurses' treatment choices. Patients and providers alike valued reductions in adverse event risk and evidence from high-quality randomized controlled clinical trials. Conclusions. The strong preference for observed PFS suggests more research is warranted to better understand the reasons for PFS having positive value to patients. The results also suggest a range of endpoints in clinical trials may have importance to patients.

The value of novel immuno-oncology treatments.

OBJECTIVES: To assess the value to society of improved survival from novel immuno-oncology (I-O) treatments. STUDY DESIGN: Case studies of ipilimumab for the treatment of advanced unresectable melanoma and nivolumab for advanced previously treated squamous non-small cell lung cancer (NSCLC). METHODS: Published data and survival analysis were used to estimate survival gains. We valued the gains using an economic model developed for application to discrete changes in life expectancy. We estimated aggregate utilization and value to society using cancer registry data and literature. We assessed the share of social value that flowed to the pharmaceutical manufacturer as sales revenue based on publicly available prices. RESULTS: For advanced melanoma, our analysis estimated an average real-world life expectancy (discounted at a 3% rate) of 32.4 months with ipilimumab versus 14.2 months with an existing standard of care. Treatment of advanced NSCLC with nivolumab generated a life expectancy of 28.1 months versus 14.3 months with an existing standard of care. Depending on model assumptions, the value of these survival gains ranged from $232,000 to $697,000 for a patient with melanoma and from $180,000 to $586,000 for one with NSCLC. Using a midpoint value to aggregate across treated patients over a 5-year window, the total value to society was estimated at $1.9 billion for ipilimumab in advanced melanoma and $1.7 billion for nivolumab in NSCLC. Less than 30% of the total value flowed to the pharmaceutical manufacturer in the form of profit. CONCLUSIONS: The novel I-O treatments studied here generate substantial survival gains and, thus, social value. Less than half of this value accrued to the pharmaceutical manufacturer as sales revenue.

The Option Value of Innovative Treatments for Metastatic Melanoma.

Background Treatment options in oncology have increased in recent years due to the quick pace of innovation. In the cancer care landscape, therapies that enable patients to live to the next innovation have additional value, "option value," from the benefit of surviving to the next innovation. In such disease areas, providers and payers should consider this value when gauging the value of new therapies. The purpose of this study is to develop a model to estimate the additional survival patients attain from a therapy that allows them to live to benefit from further advances in care, and to apply the model to immunotherapy for metastatic melanoma. Methods The benefit of a therapy extends beyond immediate tumor control; it can also allow patients to live to benefit from further advances in care. This is a therapy's option value. Using data from the SEER cancer registry and clinical trial publications, we developed a model to estimate option value and applied it to ipilimumab, the first immune checkpoint modulator used to treat metastatic melanoma. Because ipilimumab extends survival, select patients benefited from survival extension to live to benefit from the introduction of PD-1 inhibitors (i.e. pembrolizumab and nivolumab). We calculated the option value of ipilimumab in terms of additional life-months patients gained by living to become potential candidates for PD-1 inhibitors, discounting at 3% per year. Results Patients taking ipilimumab as a second-line therapy for metastatic melanoma gained 10.5 months compared to patients taking the prior standard of care. Patients diagnosed in 2011, 2012, and 2013 gained an additional 1.6, 2.8, and 5.1 months of life expectancy, respectively, by living to see the introduction of PD-1 inhibitors. This equates to an option value of 15%, 27%, and 49%, respectively, of the conventionally calculated survival gain from ipilimumab. Ipilimumab had greater option value for patients diagnosed in later years who were more likely to live to the introduction of PD-1 inhibitors. Conclusions Therapies that enable patients to see further advances in care have option value. Option value is particularly important to patients with disease areas undergoing rapid innovation.