Vijayveer Bonthapally

Costs, length of stay, and mortality of super‐refractory status epilepticus: A population‐based study from Germany

Super‐refractory status epilepticus (SRSE) is a severe condition in which a patient in status epilepticus (SE) for ≥24 h does not respond to first‐, second‐, or third‐line therapy. The economic impact of SRSE treatment remains unclear. A health insurance research database was used for a population‐based estimation of SRSE‐associated inpatient costs, length of stay, and mortality in Germany.

Patient-Reported Outcomes Labeling for Products Approved by the Office of Hematology and Oncology Products of the US Food and Drug Administration (2010-2014)

PURPOSE To review the use of patient-reported outcome (PRO) data in medical product labeling granted by the US Food and Drug Administration (FDA) for new molecular entities and biologic license applications by the FDA Office of Hematology and Oncology Products (OHOP) between January 2010 and December 2014, to elucidate challenges faced by OHOP for approving PRO labeling, and to understand challenges faced by drug manufacturers to include PRO end points in oncology clinical trials. METHODS FDA Drug Approval Reports by Month were reviewed to obtain the number of new molecular entities and biologic license applications approved from 2010 to 2014. Drugs approved by the FDA OHOP during this period were selected for further review, focusing on brand and generic name; approval date; applicant; indication; PRO labeling describing treatment benefit, measures, end point status, and significant results; FDA reviewer feedback on PRO end points; and study design of registration trials. First in class, priority review, fast track, orphan drug, or accelerated approval status was retrieved for selected oncology drugs from 2011 to 2014. Descriptive analyses were performed by using Microsoft Excel 2010. RESULTS Of 160 drugs approved by the FDA (2010-2014), 40 were approved by OHOP. Three (7.5%) of the 40 received PRO-related labeling (abiraterone acetate, ruxolitinib phosphate, and crizotinib). Compared with nononcology drugs (2011-2014), oncology drugs were more likely to be orphan and first in class. The majority of oncology drug reviews by FDA were fast track, priority, or accelerated. CONCLUSION Although symptoms and functional decrements are common among patients with cancer, PRO labeling is rare in the United States, likely because of logistical hurdles and oncology study design. Recent developments within the FDA OHOP to capture PROs in oncology studies for the purpose of product labeling are encouraging.

Assessing the impact of restricted follow-up and small sample sizes on survival estimations in prostate cancer using registry data.

294 Background: Economic evaluations in oncology aim to assess the value of new therapies in the long term based on clinical trial data that often have restricted follow-up times (< 5 years) and small sample sizes (< 500 patients). This requires the use of extrapolation assumptions on long-term survival that go beyond the observed data. In this analysis, differences in survival extrapolation methods are tested in samples of sizes and follow-up reflecting typical clinical trials against a background of known survival in prostate cancer from a US based cancer registry. METHODS Data from the National Cancer Institutes Surveillance Epidemiology and End Results (SEER) registry on long-term survival in patients with stage IV prostate cancer were employed. The data set comprised those patients diagnosed between 1988 and 2003, with follow-up data available until 2012. Additional survival for those who received surgery (compared to those who did not), was estimated based on extrapolations using standard parametric statistical models (exponential, Weibull, log-logistic, log-normal, Gamma) fitted to the observed data. Survival analyses were run for 5 sample size scenarios (n = 27,670, 1000, 500, 200, 50) and 6 follow-up scenarios (follow-up years = 25, 20, 10, 5, 2, 1) yielding 30 combination scenarios. Performance of the methods was tested relative to the maximum follow-up, maximum sample size scenario (i.e. reference case) from the SEER registry. RESULTS Log-logistic and log-normal models were associated with flat tails which led to inflated survival estimations. For scenarios with smaller sizes, gamma models often did not converge. Exponential models were the most frequently reported as best model fit (in approximately 50% of scenarios). Also, gains in OS were consistent when exponential models were selected, and closely matched gain in OS from the reference case. CONCLUSIONS Since clinical trials in oncology are often associated with small patient sample sizes and restricted follow-up, selecting an exponential model may lead to the most consistent and stable results based on the experiment constructed here. Further research should confirm these results for other types of cancer.

Brentuximab vedotin in relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant: A cost-effectiveness analysis updated with 5-year follow-up data from the pivotal trial.

19 Background: In 2015, the Scottish Medicines Consortium (SMC) made a positive recommandation for brentuximab vedotin (BV) in patients with relapsed or refractory (R/R) Hodgkin lymphoma (HL) who have received autologous stem cell transplantation (ASCT) based on 3-year follow-up data from the pivotal phase 2 single-arm trial (SG035-0003; NCT00848926). At 3-years, the incremental cost-effectiveness ratio (ICER) for brentuximab vedotin compared with chemotherapy +/- radiotherapy (C/R) was £43,731 per quality-adjusted life year (QALY). This study re-evaluated the cost-effectiveness analysis with 5-year follow-up data from the pivotal trial. METHODS A partitioned survival model was developed using a Scottish health system perspective over a lifetime time-horizon. Three health states were evaluated: progression-free survival (PFS), post-progression survival, and death. The relevant comparators were C/R, or C/R with intent to allogeneic stem cell transplantation. Clinical outcomes (PFS and overall survival [OS]) for BV were estimated based on data from the pivotal trial in 102 patients. A naïve comparison with the specified comparators was conducted using published survival data. ICERs were calculated with measures of the clinical outcomes, direct costs and QALYs. Deterministic and probabilistic sensitivity analyses were conducted to evaluate the robustness of the model. RESULTS The 5-year follow-up data reduced the base case ICER for BV from £43,731 to £38,769 per QALY versus C/R and increased the probability of cost-effectiveness. The variation in ICER for BV generated by the deterministic sensitivity analyses was also reduced resulting from reduced uncertainty in the estimation of long term clinical outcomes. CONCLUSIONS This update has strengthened the cost-effectiveness evidence for BV in patients with R/R HL post-ASCT. The 5-year follow-up has reduced the uncertainty in the long term outcomes and reduced the ICER, which is low in comparison to other treatments for orphan diseases approved by UK agencies. BV may therefore represent a cost-effective treatment option for this patient group.

Brentuximab vedotin (BV) consolidation post-autologous stem cell transplant (ASCT) in patients (pts) with Hodgkin lymphoma (HL) at risk of residual disease: Number needed to treat (NNT) analysis.

20 Background: AETHERA (NCT01100502) is a randomized Phase 3 study of BV and best supportive care (BSC) vs placebo (PBO) and BSC in the treatment of pts at risk of residual HL post-ASCT. BV consolidation therapy post-ASCT significantly improved progression-free survival (PFS) by independent review vs PBO (HR = 0.57, P = 0.001) and was FDA approved. Most common grade ≥ 3 adverse events were neutropenia (29% BV vs 10% PBO) and peripheral sensory neuropathy (10% vs 1%). The aim of this study was to determine the NNT with BV to avoid 1 additional event, disease progression/death. METHODS The NNT with BV was calculated as the inverse of the absolute risk reduction (ARR); ARR was the PFS event rate per investigator (INV) assessment in the PBO arm minus the event rate in the BV arm of the AETHERA trial. The AETHERA trial recruited pts ≥ 18 yrs at risk of residual HL post-ASCT defined by ≥ 1 of: history of refractory HL; relapse/progression < 12 months after frontline therapy; extranodal involvement at time of pre-ASCT relapse. Pts were randomized to receive BV 1.8 mg/kg or PBO on day 1 of each 21-day cycle, for up to 16 cycles/disease progression. RESULTS 329 pts (median age 32 yrs [range 18-76]; 53% male) received BV (n = 165) or PBO (n = 164). Fewer PFS events per INV analysis were experienced by pts in the BV arm vs PBO arm. The NNT with BV to prevent a disease progression/death ranged from 4.08 (95% CI 2.94, 6.96) to 7.79 pts (95% CI 5.05, 16.4) over 48 months (Table). At 24 months (time majority of pts have progressed post-ASCT), the NNT to prevent a disease progression/death was 4.92 pts (95% CI 3.29, 10.39). CONCLUSIONS AETHERA data suggest that, at various time points, 1 in every 5-8 pts treated with BV consolidation therapy will benefit by avoiding disease progression/death. This further demonstrates BVs clinical benefit in the post-ASCT consolidation setting. CLINICAL TRIAL INFORMATION NCT01100502. [Table: see text].

Cost-effectiveness of brentuximab vedotin in relapsed or refractory systemic anaplastic large cell lymphoma.

18 Background: Systemic anaplastic large cell lymphoma (sALCL) is a rare T-cell lymphoma. For patients who fail front-line therapy, outcomes are poor and there is no current defined standard of care. Brentuximab vedotin has demonstrated high objective response rates and is approved for patients with relapsed or refractory (R/R) sALCL. However, the cost-effectiveness of brentuximab vedotin compared with conventional chemotherapy has not been explored. METHODS A lifetime Excel-based partitioned survival model was used to compare survival outcomes from the pivotal phase-2 single-arm brentuximab vedotin trial of 58 R/R sALCL patients with good Eastern Corporative Oncology Group (ECOG) performance status after one or more prior therapies (SG035-0004); with 40 sALCL patients from a Canadian cancer registry receiving first-line conventional salvage chemotherapy (65% with ECOG 0 or 1) between 1980 and 2012 and followed for up to 20 years. Extrapolation of brentuximab vedotin survival after the trial period assumed the same rate of change as for conventional chemotherapy. A United Kingdom National Health Service perspective was adopted. Costs included drug acquisition and administration, and medical care for adverse events and pre- and post-progression. Utility values elicited by response and by progression, and disutilities associated with adverse events were applied to estimate quality-adjusted life years (QALYs). RESULTS The incremental cost-effectiveness ratio (ICER) for brentuximab vedotin was £35,390 per QALY gained versus conventional chemotherapy. ICERs were between £28,112 and £61,921 across a range of alternative model assumptions. Comparing only first-line salvage patients in both groups reduced the ICER to £26,766. Conversely, considering only patients with good ECOG performance status increased the ICER to £38,186. Using probabilistic sensitivity analysis, at willingness-to-pay of £38,000, the probability that brentuximab vedotin is cost-effective was > 50%. CONCLUSIONS Brentuximab vedotin may represent a cost-effective intervention compared to conventional chemotherapy for this patient population with limited therapeutic options.