Principles for Good Practice in the Conduct of Non-interventional Studies: The View of Industry Researchers.

This reflection paper presents a consolidated view of EFPIA on the need for principles for good practice in the generation and use of non-interventional studies (NIS), including overarching principles such as the registration of hypothesis evaluating treatment effect (HETE) studies. We first define NIS and the important adjacencies to clinical trials and relationship with real-world evidence (RWE). We then outline the principles for good practice with respect to appropriate research design, study protocol, fit-for-purpose variables and data quality, analytical methods, bias reduction, transparency in conduct and use, privacy management and ethics review. We conclude with recommendations for action for the research community to promote trust and credibility in the use of NIS.

Economic Evaluation of Nivolumab Versus Docetaxel for the Treatment of Advanced Squamous and Non-squamous Non-small Cell Lung Cancer After Prior Chemotherapy in China.

OBJECTIVE: To evaluate the economic value of nivolumab versus docetaxel for advanced non-small cell lung cancer (aNSCLC) treatment after platinum-based chemotherapy in adults without epidermal growth factor receptor/anaplastic lymphoma kinase aberrations in China. METHODS: Partitioned survival models evaluated lifetime costs and benefits of nivolumab versus docetaxel by squamous and non-squamous histologies from a Chinese healthcare payer perspective. Progression-free disease, progressed disease, and death health states were considered over a 20-year time horizon. Clinical data were derived from the CheckMate pivotal Phase III trials (ClinicalTrials.gov identifiers: NCT01642004, NCT01673867, NCT02613507); patient-level survival data were extrapolated using parametric functions. China-specific health state utilities, healthcare resource utilisation, and unit costs were applied. Sensitivity analyses explored uncertainty. RESULTS: Nivolumab resulted in extended survival (1.489 and 1.228 life-years [1.226 and 0.995 discounted]) and quality-adjusted survival benefits (1.034 and 0.833 quality-adjusted life-years) at additional costs of ¥214,353 (US$31,829) and ¥158,993 (US$23,608) versus docetaxel in squamous and non-squamous aNSCLC, respectively. Nivolumab was associated with higher acquisition costs, lower subsequent treatment costs, and lower adverse event management costs than docetaxel in both histologies. Drug acquisition costs, discount rate for outcomes, and average body weight were key model drivers. Stochastic results aligned with the deterministic results. CONCLUSIONS: Nivolumab yielded survival and quality-adjusted survival benefits at incremental cost versus docetaxel in aNSCLC. As a traditional healthcare payer perspective was applied, the true economic benefit of nivolumab may be underestimated as not all treatment benefits and costs of relevance to society were considered.

Treatment patterns and outcomes among patients with small-cell lung cancer (SCLC) in Europe: a retrospective cohort study.

OBJECTIVE: Describe characteristics, treatment patterns and clinical outcomes of patients with small-cell lung cancer (SCLC). DESIGN: Retrospective chart review study defining several cohorts: (1) limited-stage disease (LD) SCLC initiating 1L therapy (1 L LD-SCLC), (2) extensive-stage disease (ED) SCLC initiating 1L therapy (1L ED-SCLC) and (3) patients initiating 2L therapy. SETTING: 39 physicians (medical oncologists, thoracic oncologists and/or pulmonologists) from France, Italy and the UK. PARTICIPANTS: Patients >18 years of age with a confirmed diagnosis of LD-SCLC or ED-SCLC and a full oncology medical history. Patients included initiated a 1L (2013-2015) or 2L (2013-2016) treatment (chemotherapy and/or radiotherapy-RT). PRIMARY AND SECONDARY OUTCOME MEASURES: Overall survival (OS) and progression-free survival (PFS). RESULTS: 231 patients in 1L LD-SCLC, 308 in 1L ED-SCLC and 225 with relapse/refractory SCLC initiating 2L treatment were included. The proportion of men was higher across all groups (56.8% to 68.5%) and mean age at time of diagnosis was 66.0 and 65.4 years in 1L LD-SCLC and 2L ED-SCLC cohorts. The majority of patients in LD-SCLC 1L group received chemotherapy with RT (76.2%). Patients initiating 2L therapy predominantly received chemotherapy alone (79.6%).Median OS in 1 L patients was 17.3 months in LD-SCLC and 8.8 months in ED-SCLC. Median PFS was 11.6 months in LD-SCLC and 6.1 months in ED-SCLC patients. Median OS in patients initiating 2L treatment was 6.6 months. OS from start of 2L treatment was lower in patients initially diagnosed with ED (5.1 months) than in patients initially diagnosed with LD (9.3 months) (p<0.0001). OS and PFS were assessed from the start of 1L or 2L therapy, depending on the cohort. CONCLUSIONS: Despite the availability of a high number of treatments and combinations, the prognosis of SCLC is still unsatisfactory, especially for those patients diagnosed with ED-SCLC, indicating high unmet need in this patient population.

Real-world effectiveness of immunotherapies in pre-treated, advanced non-small cell lung cancer Patients: A systematic literature review.

BACKGROUND: Clinical trials have shown immunotherapy (IO) to be more effective than chemotherapy in pre-treated, advanced non-small cell lung cancer (NSCLC). However, there is a lack of understanding of its effectiveness in clinical practice, and among patient groups that are often underrepresented in trials. We aimed to summarize the existing real-world evidence (RWE) on the survival outcomes of IO in second- or higher line in advanced NSCLC. METHODS: We conducted a systematic review of real-world observational studies that reported overall survival (OS) estimates with IO, primarily nivolumab, pembrolizumab or atezolizumab, in adult, previously treated advanced or recurrent NSCLC patients. Meta-analysis was conducted using random-effect models to pool 1- and 2-year OS rates across studies. Additional subgroups were examined among patients treated with IO, including the elderly, those with poor performance status (PS) and those exhibiting metastasis. RESULTS: In total, 66 studies were included, of which 46 (70%) included a nivolumab-specific study arm. Pooled 1-year and 2-year OS rates with nivolumab monotherapy were 45.6% (95% CI; 43.4-47.8) and 28.0% (95% CI; 24.8-31.4), respectively, compared to 43.9% (95% CI; 39.1-48.8) and 20.4% (95% CI; 14.7-27.6) in the mixed immune checkpoint inhibitors (ICI) group. OS rates with nivolumab were slightly lower in elderly compared to non-elderly populations. Poor PS was associated with worse survival rates, with a pooled one-year OS estimate of 27.1% in PS ≥ 2 vs 51.6% in PS < 2. The pooled 2-year OS rate with nivolumab in patients with and without brain metastases was 22.1% and 26.1% respectively, and this difference was significant in 36% of individual studies. CONCLUSIONS: While the OS benefits of IO seen in real-world studies among pre-treated, advanced NSCLC patients are consistent with pivotal clinical trials, these tend to vary for the more vulnerable patient groups, such as patients with poor PS, which are often excluded from trials. Further research is needed to investigate findings in patients with brain and liver metastases.

Three-year follow-up and patient-reported outcomes from CheckMate 078: Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer.

OBJECTIVES: In the phase 3 CheckMate 078 study, nivolumab prolonged overall survival (OS) and showed a favorable safety profile versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer (aNSCLC). However, long-term efficacy, safety, and health-related quality of life findings with second-line nivolumab are very limited in Asian patients with previously treated aNSCLC. Here, we report updated clinical data and patient-reported outcomes (PROs) from the phase 3 CheckMate 078 trial with a 3-year minimum follow-up. MATERIALS AND METHODS: Patients with aNSCLC and disease progression after platinum-doublet chemotherapy were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or unacceptable toxicity. The primary endpoint was OS; secondary endpoints included objective response rate, progression-free survival, safety, and disease-related symptom deterioration assessed using the Lung Cancer Symptom Scale (LCSS) by Week 12. Additional PRO assessments were exploratory endpoints. RESULTS: At ≥ 37.3 months follow-up, 3-year OS rates were 19% with nivolumab and 12% with docetaxel; 30% and 0% of responders remained in response for ≥ 3 years, respectively. Incidence of treatment-related adverse events occurring after 2 years was lower than during the first 2 years. No new treatment-related deaths were reported. By Week 12 of treatment, rates of disease-related symptom deterioration were 32% with nivolumab and 47% with docetaxel. Completion rates for PRO questionnaires were ≥ 80% in both arms. Clinically meaningful and sustained improvements in LCSS Average Symptom Burden Index scores and delayed time to first symptom deterioration were observed with nivolumab against docetaxel. CONCLUSIONS: At 3 years, nivolumab continued to demonstrate survival benefit versus docetaxel, exhibiting improvements in disease-related symptoms and overall health status in a predominantly Chinese patient population with previously treated aNSCLC. No new safety signals were observed. These findings are similar to the global population.

Initial treatment and survival in Danish patients diagnosed with non-small-cell lung cancer (2005-2015): SCAN-LEAF study.

Aim: To describe initial treatment patterns and survival of patients diagnosed with non-small-cell lung cancer (NSCLC) in Denmark, before immune checkpoint inhibitor and later-generation tyrosine kinase inhibitor use. Patients & methods: Adults diagnosed with incident NSCLC (2005-2015; follow-up: 2016). Initial treatments and overall survival (OS) are reported. Results: 31,939 NSCLC patients (51.6% stage IV) were included. Increasing use of curative radiotherapy/chemoradiation for stage I, II/IIIA and IIIB NSCLC coincided with improved 2-year OS. Systemic anticancer therapy use increased for patients with stage IV non-squamous NSCLC (53.0-60.6%) but not squamous NSCLC (44.9-47.3%). 1-year OS improved in patients with stage IV non-squamous NSCLC (23-31%) but not squamous NSCLC (22-25%). Conclusion: Trends indicated improved OS as treatments evolved between 2005 and 2015, but the effect was limited to 1-year OS in stage IV disease.

Epidemiology and Survival Outcomes for Patients With NSCLC in Scandinavia in the Preimmunotherapy Era: A SCAN-LEAF Retrospective Analysis From the I-O Optimise Initiative.

INTRODUCTION: SCAN-LEAF, part of the I-O Optimise initiative, is a retrospective, longitudinal study investigating the epidemiology, clinical care, and outcomes for patients with NSCLC in Scandinavia. We report overall survival (OS) trends for patients diagnosed with NSCLC in Sweden and Denmark between 2005 and 2015. METHODS: Swedish and Danish cohorts were established by linking national registries. Data on all adults diagnosed with incident NSCLC from January 1, 2005, to December 31, 2015, were included. For temporal analyses of OS trends, patients were stratified by TNM stage and histology. RESULTS: Between 2005 and 2015, a total of 30,067 and 31,939 patients from Sweden and Denmark, respectively, were diagnosed with NSCLC; the most common histological subtype was nonsquamous cell carcinoma (56.9% and 53.0%) and 48.4% and 51.6% were diagnosed at stage IV. Over the study period, significant improvements in short-term survival (1 y) were observed for patients with nonsquamous cell carcinoma in both countries, regardless of disease stage at diagnosis; however, improvements in longer-term survival (5 y) were limited to patients with stage I and II disease only. Conversely, among patients with squamous cell histology, improvements in short-term survival were only observed for stage I disease in Sweden and stage IIIA disease in Denmark, while significant improvements in longer-term survival were seen only for stage IIIA NSCLC in both countries. CONCLUSIONS: Despite some survival improvements between 2005 and 2015, an unmet need remains for patients with advanced NSCLC, particularly those with squamous cell histology. Future analyses will evaluate the impact of newer treatments on OS in NSCLC.

Cost-effectiveness of nivolumab monotherapy in the third-line treatment of small cell lung cancer.

AIMS: Present cost-effectiveness analysis of nivolumab monotherapy vs. commonly prescribed third-line (3 L+) treatment in small cell lung cancer (SCLC). MATERIALS AND METHODS: A three health states partitioned survival model (progression-free, progressed disease, and death; US payer perspective) was developed. The systematic literature review identified no randomized controlled or single-arm trials with separate outcomes for 3 L + SCLC patients. Topotecan was chosen as a comparator because it is frequently prescribed in real-world practice for 3 L SCLC. Clinical inputs for topotecan were derived from the Flatiron database with inclusion/exclusion criteria matched to patients treated with 3 L + nivolumab in CheckMate 032. Intravenous (IV) and oral topotecan clinical efficacy were assumed equivalent. Base-case analysis used a 20-year lifetime horizon. An annual discount rate of 3.0% for costs and outcomes was applied. Uncertainty was assessed using sensitivity analyses adjusted for key parameters. RESULTS: Incremental cost per quality-adjusted life-year (QALY) gained with nivolumab was US$153,312 vs. IV topotecan and US$123,003 vs. oral topotecan, respectively. When results were disaggregated, nivolumab-related costs were mainly driven by drug acquisition costs, and topotecan-related costs were primarily due to adverse event treatment. Mean overall survival (OS) was 21.69 months with nivolumab and 5.80 months with IV or oral topotecan. More favorable outcomes were found by the landmark response analyses. Deterministic sensitivity analyses showed that changes to the discount rate for costs and outcomes and body weight had the greatest impacts on results. LIMITATIONS: Included use of real-world data for OS outcomes associated with 3 L topotecan, use of second-line topotecan data for progression-free survival, and no indirect costs. CONCLUSIONS: Based on the literature on willingness-to-pay for a QALY in metastatic cancer, nivolumab monotherapy might represent a cost-effective option for 3 L + treatment of SCLC compared with IV and oral topotecan. Sensitivity analysis using response-based methods yielded further favorable cost-effectiveness estimates.

Small cell lung cancer treatment and survival in Portugal: A retrospective analysis from the I-O Optimise initiative.

OBJECTIVE: We aim to describe treatment patterns and overall survival (OS) among a Portuguese cohort of patients with small cell lung cancer (SCLC). METHODS: This study utilised a database held by IPO-Porto, Portugal's largest oncology hospital. Adult patients diagnosed with SCLC at IPO-Porto between January 2012 and June 2017, with follow-up to December 2017, were included. Patients were stratified into subgroups with limited disease (LD) or extensive disease (ED). Treatment analyses were performed from 2015 onwards. RESULTS: Overall, 227 patients diagnosed with SCLC (37 LD; 190 ED) were analysed. Median OS (interquartile range [IQR]) was 15.0 months (3.8-39.3) for LD-SCLC and 5.0 months (1.7-10.3) for ED-SCLC. Among 19 patients diagnosed with LD-SCLC from 2015 onwards, 12 (63.2%) received initial treatment with systemic anticancer therapy (SACT) ± radiotherapy; 6 (31.6%) received best supportive care (BSC). Among 89 patients with ED-SCLC, 57 (68.5%) received SACT ± palliative radiotherapy; 28 (31.5%) received BSC. For patients receiving platinum doublet chemotherapy (±radiotherapy), median OS (IQR) was not reached for LD-SCLC and 5.4 months (2.3-10.9) for ED-SCLC. CONCLUSION: This real-world data analysis from a large Portuguese oncology hospital demonstrates a high disease burden for patients diagnosed with SCLC, particularly those with ED, and highlights a need for more effective therapies.

Two-year survival with nivolumab in previously treated advanced non-small-cell lung cancer: A real-world pooled analysis of patients from France, Germany, and Canada.

OBJECTIVES: Immune checkpoint inhibitors have become the standard of care for metastatic non-small-cell lung cancer (NSCLC) progressing during or after platinum-based chemotherapy. Real-world clinical practice tends to represent more diverse patient characteristics than randomized clinical trials. We sought to evaluate overall survival (OS) outcomes in the total study population and in key subsets of patients who received nivolumab for previously treated advanced NSCLC in real-world settings in France, Germany, or Canada. MATERIALS AND METHODS: Data were pooled from two prospective observational cohort studies, EVIDENS and ENLARGE, and a retrospective registry in Canada. Patients included in this analysis were aged ≥18 years, had stage IIIB/IV NSCLC, and received nivolumab after at least one prior line of systemic therapy. OS was estimated in the pooled population and in various subgroups using the Kaplan-Meier method. Timing of data collection varied across cohorts (2015-2019). RESULTS: Of the 2585 patients included in this analyses, 1235 (47.8 %) were treated in France, 881 (34.1 %) in Germany, and 469 (18.1 %) in Canada. Median OS for the total study population was 11.3 months (95 % CI: 10.5-12.2); this was similar across France, Germany, and Canada. The OS rate was 49 % at 1 year and 28 % at 2 years for the total study population. In univariable Cox analyses, the presence of epidermal growth factor receptor mutations in nonsquamous disease, liver, or bone metastases were associated with significantly shorter OS, whereas tumor programmed death ligand 1 expression and Eastern Cooperative Oncology Group performance status 0-1 were associated with significantly prolonged OS. Similar OS was noted across subgroups of age and prior lines of therapy. CONCLUSION: OS rates in patients receiving nivolumab for previously treated advanced NSCLC in real-world clinical practice closely mirrored those in phase 3 studies, suggesting similar effectiveness of nivolumab in clinical trials and clinical practice.

Economic Evaluation of Single versus Combination Immuno-Oncology Therapies: Application of a Novel Modelling Approach in Metastatic Melanoma.

BACKGROUND: Existing economic model frameworks may not adequately capture the atypical treatment response patterns in immuno-oncology (I-O) compared with conventional therapies and thus may fail to represent the full clinical value associated with disease dynamics and improved survival. OBJECTIVE: A cost-effectiveness analysis (CEA) of the I-O Regimen (nivolumab/ipilimumab) versus ipilimumab alone in advanced melanoma was carried out by applying a 5-state partitioned survival model (PSM) as a case study, to explore the I-O treatment response and clinical outcomes. The findings were compared with those of a conventional 3-state PSM. MATERIALS AND METHODS: The case study extends the conventional 3-state PSM, by separating the pre-progression state into non-responders and responders, and the post-progression state into normal and I-O progression to account for delayed treatment effects preceding clinical response. Model states were populated using patient-level data (where possible), mapping from the best overall response (BOR), and survival analysis with flexible and traditional parametric methods. Survival functions were applied to progression-free survival (PFS) and overall survival (OS) endpoints across treatment arms using the 4-year follow-up data (data available at the time of the research; since then 5-year follow-up data have been published) from the CheckMate 067 trial. Information on BOR was used as a means of differentiating the I-O treatment response in addition to the outcomes of progression-free and progressed disease. A UK National Health Service and personal social services (NHS/PSS) perspective over a lifetime horizon was used with outcomes discounted at 3.5% annually. RESULTS: The 5-state PSM generated an increase in quality adjusted life years (QALYs) in both treatment arms and gave a more granular description of patients' health profiles compared with the traditional 3-state PSM. The incremental QALY increased by 13% (from 2.62 to 2.95 QALYs) and the incremental cost decreased by 12% (£29,125 to £25,678) with the 5-state model. In both models, the Regimen had an incremental cost-effectiveness ratio (ICER) relative to ipilimumab alone within the lower bound of the National Institute for Health and Care Excellence (NICE) reference range (£20,000 per QALY gained). CONCLUSION: A 5-state economic model, incorporating relevant I-O health states, can be more informative to gain insight into treatment response and progression differences that are not commonly captured in existing economic models. Clinical trial endpoints, including those relating to treatment response, which are not directly reported in ongoing I-O trials, can be mapped on to the proposed modelled health states (although assumptions are required to do so). Improvements in reporting treatment response in future I-O clinical trials could help to further validate and improve the proposed model framework.

Indirect comparison of nivolumab ± ipilimumab (CheckMate 032) versus other treatments for recurrent small-cell lung cancer.

Aim: To estimate the comparative efficacy of nivolumab ± ipilimumab versus alternative treatments for small-cell lung cancer after at least one prior line of chemotherapy. Materials & methods: A systematic literature review identified six randomized controlled trials (RCTs) that could be connected in a network. The Kaplan-Meier survival curves from these RCTs were synthesized using network meta-analysis models. Aggregate-level matching was used to connect CheckMate 032 to the RCTs. Results: CheckMate 032 was connected to the network by Amrubicin Clinical Trial-1. Nivolumab ± ipilimumab had a more durable tumor response and more favorable long-term survival versus topotecan via intravenous and versus amrubicin. Conclusion: Compared with chemotherapies for recurrent small-cell lung cancer, nivolumab ± ipilimumab improves response duration, which may translate to long-term survival benefits.

Relative value assessment: characterizing the benefit of oncology therapies through diverse survival metrics from a US perspective.

OBJECTIVES: The introduction of innovative, high-cost oncology treatments, coupled with mounting budgetary pressures, necessitates value trade-offs across cancer types. Defining value is critical to informing decision-making. A cost-value analysis tool was used to assess relative clinical value from a US perspective using multiple outcome metrics for a variety of metastatic cancers. METHODS: Literature published (January 1, 2000-August 31, 2016) was reviewed to identify outcome metrics for approved treatments for metastatic cancers. Data were extracted or derived for median and mean overall survival (OS), landmark survival rates, and other survival metrics, and compared across treatments vs their respective trial comparators, with and without considering costs. RESULTS: Reported survival metrics varied by agent within cancer type. For treatment of prostate cancer, abiraterone yielded the highest improvement in 1-year survival rate (13.7%, previously treated), whereas enzalutamide yielded the highest median OS improvement (4.8 months, previously treated) and sipuleucel-T, the highest mean OS improvement (3.6 months, previously untreated) vs their respective trial comparators. For treatment of non-small cell lung cancer vs their respective trial comparators, nivolumab yielded the highest improvement in mean OS (11.9 months) and 3-year survival rate (12.6%), each in previously treated squamous disease, whereas afatinib yielded the highest median OS improvement (4.1 months, previously untreated EGFR del19 and L858R mutants). Cost-value analysis results varied with the applied survival metric. CONCLUSIONS: Although median OS is the traditional gold standard oncology efficacy metric, it fails to capture long-term survival benefits-the ultimate goal of cancer treatment-offered by new treatment modalities. Diverse metrics are needed for comprehensive value assessments of cancer therapies.

Cohort versus patient level simulation for the economic evaluation of single versus combination immuno-oncology therapies in metastatic melanoma.

Background: Model structure, despite being a key source of uncertainty in economic evaluations, is often not treated as a priority for model development. In oncology, partitioned survival models (PSMs) and Markov models, both types of cohort model, are commonly used, but patient responses to newer immuno-oncology (I-O) agents suggest that more innovative model frameworks should be explored. Objective: A discussion of the theoretical pros and cons of cohort level vs patient level simulation (PLS) models provides the background for an illustrative comparison of I-O therapies, namely nivolumab/ipilimumab combination and ipilimumab alone using patient level data from the CheckMate 067 trial in metastatic melanoma. PSM, Markov, and PLS models were compared on the basis of coherence with short-term clinical trial endpoints and long-term cost per QALY outcomes reported. Methods: The PSM was based on Kaplan-Meier curves from CheckMate 067 with 3-year data on progression free survival (PFS) and overall survival (OS). The Markov model used time independent transition probabilities based on the average trajectory of PFS and OS over the trial period. The PLS model was developed based on baseline characteristics hypothesized to be associated with disease as well as significant mortality and disease progression risk factors identified through a proportional hazards model. Results: The short-term Markov model outputs matched the 1-3 year clinical trial results approximately as well as the PSMs for OS but not PFS. The fixed (average) cohort PLS results corresponded as well as the PSMs for OS in the combination therapy arm and PFS in the monotherapy arm. Over the lifetime horizon, the PLS produced an additional 5.95 quality adjusted life years (QALYs) associated with combination therapy relative to ipilimumab alone, resulting in an incremental cost-effectiveness ratio (ICER) of £6,474 per QALY, compared with £14,194 for the PSMs which gave an incremental benefit of between 2.2 and 2.4 QALYs. The Markov model was an outlier (∼ £49,000 per QALY in the base case). Conclusions: The 4- and 5-state versions of the PSM cohort model estimated in this study deviate from the standard 3-state approach to better capture I-O response patterns. Markov and PLS approaches, by modeling state transitions explicitly, could be more informative in understanding I-O immune response, the PLS particularly so by reflecting heterogeneity in treatment response. However, both require a number of assumptions to capture the immune response effectively. Better I-O representation with surrogate endpoints in future clinical trials could yield greater model validity across all models.

Treatment patterns and costs of care for patients with relapsed and refractory Hodgkin lymphoma treated with brentuximab vedotin in the United States: A retrospective cohort study.

OBJECTIVES: Although brentuximab vedotin (BV) has changed the management of patients with relapsed or refractory Hodgkin lymphoma (RRHL), little information is available on routine clinical practice. We identified treatment patterns and costs of care among RRHL patients in the United States (US) treated with BV. METHODS: A retrospective observational study of adults initiating BV for RRHL from 2011-2015, with ≥6 months of data prior to and following BV initiation, was conducted. Treatments were classified based on dispensations and chemotherapy administration. Median total and monthly costs were estimated based on all-cause healthcare resource use in 2015 US dollars (USD). RESULTS: The cohort comprised 289 patients (59% male; mean age at diagnosis, 42 years) with a mean follow-up of 250 weeks. Eleven percent had BV salvage therapy prior to ASCT, and 32% had BV for a relapse post-ASCT. 43% received treatment post-BV, most commonly allogeneic stem cell transplant (SCT) and bendamustine (both 10.2%). Median (IQR) total costs from BV initiation to censoring were 294,790 (142,110-483,360) USD; and were highest among those treated with BV prior to ASCT (up to 421,900 [300,940-778,970] USD). Median monthly costs were almost 20,000 USD per month, and up to 25,000 USD per month among those with BV and ASCT. Medications were the greatest driver of median monthly costs. CONCLUSIONS: Median total all-cause costs were almost 300,000 USD, and median monthly costs approximately 20,000 USD, per patient treated. Patients requiring treatment following BV continue to incur high costs, highlighting the economic burden associated with managing patients in the RRHL setting.

Modelling the Survival Outcomes of Immuno-Oncology Drugs in Economic Evaluations: A Systematic Approach to Data Analysis and Extrapolation.

BACKGROUND: New immuno-oncology (I-O) therapies that harness the immune system to fight cancer call for a re-examination of the traditional parametric techniques used to model survival from clinical trial data. More flexible approaches are needed to capture the characteristic I-O pattern of delayed treatment effects and, for a subset of patients, the plateau of long-term survival. OBJECTIVES: Using a systematic approach to data management and analysis, the study assessed the applicability of traditional and flexible approaches and, as a test case of flexible methods, investigated the suitability of restricted cubic splines (RCS) to model progression-free survival (PFS) in I-O therapy. METHODS: The goodness of fit of each survival function was tested on data from the CheckMate 067 trial of monotherapy versus combination therapy (nivolumab/ipilimumab) in metastatic melanoma using visual inspection and statistical tests. Extrapolations were validated using long-term data for ipilimumab. RESULTS: Modelled PFS estimates using traditional methods did not provide a good fit to the Kaplan-Meier (K-M) curve. RCS estimates fit the K-M curves well, particularly for the plateau phase. RCS with six knots provided the best overall fit, but RCS with one knot performed best at the plateau phase and was preferred on the grounds of parsimony. CONCLUSIONS: RCS models represent a valuable addition to the range of flexible approaches available to model survival when assessing the effectiveness and cost-effectiveness of I-O therapy. A systematic approach to data analysis is recommended to compare the suitability of different approaches for different diseases and treatment regimens.

Screening for sickle cell and thalassaemia in primary care: a cost-effectiveness study.

BACKGROUND: Haemoglobinopathies, including sickle cell disease and thalassaemia (SCT), are inherited disorders of haemoglobin. Antenatal screening for SCT rarely occurs before 10 weeks of pregnancy. AIM: To explore the cost-effectiveness of offering SCT screening in a primary care setting, during the pregnancy confirmation visit. DESIGN AND SETTING: A model-based cost-effectiveness analysis of inner-city areas with a high proportion of residents from ethnic minority groups. METHOD: Comparison was made of three SCT screening approaches: 'primary care parallel' (primary care screening with test offered to mother and father together); 'primary care sequential (primary care screening with test offered to the mother and then the father only if the mother is a carrier); and 'midwife care' (sequential screening at the first midwife consultation). The model was populated with data from the SHIFT (Screening for Haemoglobinopathies In First Trimester) trial and other sources. RESULTS: Compared to midwife care, primary care sequential had a higher NHS cost of £34,000 per 10,000 pregnancies (95% confidence interval [CI] = £15,000 to £51,000) and an increase of 2623 women screened (95% CI: 1359 to 4495), giving a cost per additional woman screened by 10 weeks of £13. Primary care parallel was dominated by primary care sequential, with both higher costs and fewer women screened. CONCLUSION: The policy judgement is whether an earlier opportunity for informed reproductive choice has a value of at least £13. Further work is required to understand the value attached to earlier informed reproductive choices.

[Treatment patterns in advanced breast cancer with anthracycline and taxanes and their costs in three public hospitals of Mexico]. / Patrones de tratamiento y costo de atención del cáncer de mama avanzado con falla a antraciclinas y taxanos en 3 hospitales públicos de México.

OBJECTIVES: In Mexico, breast cancer is the second leading cause of cancer mortality among females. For patients with advanced breast cancer (ABC) resistant to anthracyclines and taxanes (AT), there are limited treatment options. There is a scarcity of data regarding clinical management of this population and treatment costs at this stage of the disease. The objective of this study was to describe the treatment patterns of care for metastatic breast cancer after AT and the associated cost from the point-of-view of the Mexican Public Health Care Sector. METHODS: Between January 1, 2004 and December 31, 2007, a retrospective cohort of adult female ABC patients resistant to AT was developed by reviewing and extracting key data from medical charts. We conducted a retrospective, transversal and descriptive analysis of the patient data. Target population data files were obtained from 414 patients from 3 public hospitals in México. RESULTS: Capecitabine, vinorelbine and cyclophosphamide were the most commonly prescribed agents, however clinical drug therapy management of the disease was different within and among the three hospitals included in the study. This difference translated into a disparity of prescription costs, ranging from an average of $122.22 pesos/patient/month (cyclophosphamide, IC 95% $94.43-$150.01) to $37,835.53 pesos/patient/month (capecitabine+trastuzumab IC 95% $34,953.18-$40,717.88) for the first treatment after AT. CONCLUSIONS: The results highlight a lack of standardized care for patients and suggest that differences in treatment patterns are not only a reflection of scarcity of scientific data and diversity of prescription preferences among physicians but also of economic restrictions. Ultimately, there is a clear unmet medical need to be addressed through evidence-based medicine alternatives that support efficacy and cost effectiveness treatments.

The costs of epilepsy misdiagnosis in England and Wales.

BACKGROUND: The management of epilepsy incurs significant costs to the United Kingdom (UK) National Health Service (NHS). Making a diagnosis of epilepsy can, however, be difficult and misdiagnosis frequently occurs when patients are seen by non-specialists. This study estimates the financial costs of epilepsy misdiagnosis in the NHS in England and Wales. METHODS: Standard costing methods were applied to estimate the costs attributable to epilepsy misdiagnosis. The primary data were published in UK studies on the prevalence of epilepsy, epilepsy misdiagnosis and costs identified from Medline, Cinahl and Embase (1996-May 2006). RESULTS: An estimated total of 92,000 people were misdiagnosed with epilepsy in England and Wales in 2002. The average medical cost per patient per year of misdiagnosis was 316 pounds sterling, with the chief economic burdens being inpatient admissions (45%), inappropriate prescribing of antiepileptic drugs (AEDs) (26%), outpatient attendances (16%) and general practitioner (GP) care (8%). The estimated annual medical costs in England and Wales were 29,000,000 pounds sterling, while total costs could reach up to 138,000,000 pounds sterling a year. CONCLUSIONS: Allowing for uncertainty, and considering the analysis exclusively from the NHS/CBS (community based services) perspective the opportunity costs of misdiagnosis are substantial. There is a need for health care commissioners to ensure that misdiagnosis is kept to a minimum by ensuring that individuals with a recent onset suspected seizure are seen as soon as possible by a specialist medical practitioner with training and expertise in epilepsy.