Market Entry Agreements for Innovative Pharmaceuticals Subject to Indication Broadening: A Case Study for Pembrolizumab in The Netherlands.

OBJECTIVES: Managed entry agreements and especially financial-based agreements are commonly used in European countries for innovative cancer pharmaceuticals. These agreements facilitate access to innovative treatments while mitigating financial risks for payers. This study focuses on the confidential price agreement made by the Dutch government for the reimbursement of pembrolizumab, the implications of broadening indications on cost-effectiveness, and the viability or desirability of said agreement. METHODS: We selected 5 indications in which pembrolizumab was deemed effective and developed portioned survival models for each indication. Survival and progression-free survival data from the published trials were utilized to recreate individual patient data, and we extrapolated-using parametric models-to a time horizon of 30 years. Inputs for both quality of life and costs were derived from the available literature and were indexed. RESULTS: The incremental cost-effectiveness ratios ranged between €35 313 and €322 349 per quality-adjusted life-year, depending on the indication. Only 1 indication fell under the €80 000 (or €100 000) cost-effectiveness threshold. When applying the average reported discount on intramural pharmaceuticals in The Netherlands, incremental cost-effectiveness ratios ranged between €20 881 and €252 934 per quality-adjusted life-year gained, and the €80 000 (or €100 000) threshold was met in 3 indications out of 5. CONCLUSIONS: Our results show that pembrolizumab could be cost-effective in some indications, depending on the confidential price agreement established. However, the possibility of reimbursing not cost-effective care when the price is anchored in 1 indication remains possible. Indication-based pricing could help align value and price for innovative pharmaceuticals that are subject to indication broadening.

Evaluation of patient registries supporting reimbursement decisions: the case of oxaliplatin for treatment of stage III colon cancer.

BACKGROUND: Access with evidence development has been established for expensive intramural drugs in The Netherlands. The procedure involves a 4-year period of conditional reimbursement. During this period, additional evidence has to be gathered usually through a patient registry. Given the costs and time involved in gathering the data, it is important to carefully evaluate the registry. OBJECTIVES: This study aimed to develop a model for the regular evaluation of patient registries during an access with evidence development process and find the optimal length of the registry period. METHODS: We used data from a recent registry in The Netherlands on oxaliplatin as a treatment option for stage III colon cancer. We added simulated follow-up data to the empirical data available and applied value of information analysis to balance the gains of extending the period and amount of data gathering against the costs of registering patients. RESULTS: We show that given the assumptions on cohort size, follow-up time, and purpose of the registry, the current (partly simulated) registry was not very efficient. Notably, the observation period could have been stopped to make a definite reimbursement decision after a maximum of 2 years rather than the fixed 4-year period. CONCLUSIONS: Patient registries may be an efficient way to gather data on new medical treatments, but they need to be carefully designed and evaluated, in particular regarding their follow-up time. For each purpose, data gathering can be tailored to make sure decisions are taken at the moment that sufficient data are available.

Comparison of treatment outcome in metastatic colorectal cancer patients included in a clinical trial versus daily practice in The Netherlands.

The external validity of trial results is a matter of debate, and no strong evidence is available to support whether a trial may have a positive or a negative effect on the outcome of patients. Methods. We compared the results of stage IV colorectal cancer patients treated within a large Dutch phase III trial (CAIRO), in which standard chemotherapy and standard safety eligibility criteria were used, to patients treated outside the trial during the trial accrual period in a representative selection of 29 Dutch hospitals. Non-trial patients were identified by the Netherlands Cancer Registry (NCR), and were checked for the trial eligibility criteria. Results. The NCR registered 1946 stage IV colorectal cancer patients who received chemotherapy, of whom 394 patients were included in the CAIRO trial and 30 patients in other trials. Thus, the CAIRO trial participation rate was 20%. In the 29 hospitals, 162 patients received chemotherapy in the trial and 396 patients received chemotherapy outside the trial. Of the non-trial patients, 224 patients fulfilled the trial eligibility criteria. The overall survival of eligible non-trial patients was comparable to trial patients (HR 1.03, p = 0.70). However, non-eligible non-trial patients had a significantly worse outcome (HR 1.70, p < 0.01). Conclusion. These data provide evidence in a common tumor type that trial results have external validity, provided that standard eligibility criteria are being observed. Our finding of a worse outcome for patients not fulfilling these criteria strongly argues against the use of cancer treatments in other patient categories than included in the original trials in which these treatments were investigated.

Adjuvant chemotherapy in stage III colon cancer: guideline implementation, patterns of use and outcomes in daily practice in The Netherlands.

BACKGROUND: Little is known about how well guidelines about adjuvant chemotherapy in colon cancer are followed in daily practice. We evaluated the current guideline, which is based on the MOSAIC trial, by examining implementation, treatment patterns and disease-free survival. MATERIAL AND METHODS: We analysed a population-based cohort of 391 patients treated with adjuvant chemotherapy for stage III colon cancer in 2005-2006. Data were gathered from the Dutch Cancer Registry and medical records of 19 hospitals. Patients were classified according to whether or not they fulfilled MOSAIC trial eligibility criteria. RESULTS: The administered regimens were: fluorouracil-leucovorin (17 patients), capecitabine (93), fluorouracil-leucovorin plus oxaliplatin (145), and capecitabine plus oxaliplatin (136). After its inclusion in national guidelines, oxaliplatin was prescribed in 16 hospitals within six months. Patients receiving oxaliplatin were younger and had less comorbidity than other patients. Dose schedules corresponded well with guidelines. Two-year disease-free survival probability of oxaliplatin patients meeting MOSAIC eligibility criteria was 78.4% (95% CI 72.5-84.3), which was comparable to MOSAIC trial results. CONCLUSION: Guidelines for adjuvant chemotherapy in stage III colon cancer are generally well followed in daily practice. However, uncertainty remains regarding the optimal treatment of elderly patients and patients with comorbidities, which underscores the need for practical clinical trials including these patients.

The unit costs of inpatient hospital days, outpatient visits, and daycare treatments in the fields of oncology and hematology.

OBJECTIVES: Many economic evaluations are conducted in the fields of oncology and hematology, partially owing to the introduction of new expensive drugs in this field. Even though inpatient days, outpatient visits, and daycare treatments are frequently the main drivers of total treatment costs, their unit costs often lack generalizability. Therefore, we aimed to determine the unit costs of inpatient hospital days, outpatient visits, and daycare treatments specifically for oncological and hematological diseases in The Netherlands from the hospital's perspective. METHODS: Unit costs were collected from 30 oncological and hematological departments of 6 university and 24 general hospitals. Costs included direct labor and indirect labor, hotel and nutrition, overheads and capital. Ordinary least squares regression models were constructed to examine the degree of association between unit costs and hospital and hospital department characteristics. All costs were based on Euro 2007 cost data. RESULTS: At university hospitals, the unit costs per inpatient day were determined at €633 in oncological and €680 in hematological departments. At general hospitals, the mean costs per inpatient day were €400. Unit costs for inpatient hospital days, outpatient visits. and daycare treatments equalled the relative ratio 100:21:44. Direct labor costs were the major cost driver and the type of hospital (university, yes/no) was a strong predictor of unit costs. CONCLUSIONS: The present study provided unit costs for inpatient hospital days, outpatient visits, and daycare treatments in the fields of oncology and hematology. The results may be used as Dutch reference unit prices in economic evaluations assessing oncological and hematological diseases.

Real-world cost-effectiveness of oxaliplatin in stage III colon cancer: a synthesis of clinical trial and daily practice evidence.

OBJECTIVES: Previous cost-effectiveness analyses of oxaliplatin have been based on randomised trials whereas current Dutch policy requires evidence from daily practice. The objective of this study was to examine the real-world cost-effectiveness of oxaliplatin plus fluoropyrimidines (FL) versus FL-only as adjuvant treatment of stage III colon cancer. METHODS: A Markov model was developed to estimate lifetime cost and quality-adjusted life-years from a hospital perspective. The effectiveness of the oxaliplatin arm was modelled by combining published efficacy data from the pivotal clinical registration trial (MOSAIC trial) with real-world (RW) data from a Dutch population-based observational study. RW patients were categorised into "eligible" or "ineligible", depending on whether the patients fulfilled the MOSAIC trial eligibility criteria. Ineligible RW patients (18 %) had a poorer prognosis than eligible RW patients (82 %) and MOSAIC trial patients. The effectiveness of the comparator was modelled using MOSAIC trial results. All cost inputs were based on RW patients and reported in Euro 2012. Cost-effectiveness analyses were performed for four different scenarios: (1) cost-effectiveness analyses based on MOSAIC trial patients; (2) cost-effectiveness analyses using MOSAIC and eligible RW patients; (3) cost-effectiveness analyses using MOSAIC and both eligible and ineligible RW patients, assuming oxaliplatin had an equal effect in ineligible and eligible patients; (4) cost-effectiveness analyses using MOSAIC and both eligible and ineligible RW patients, assuming oxaliplatin had no effect amongst ineligibles. For each scenario, univariate and probabilistic sensitivity analyses were undertaken. RESULTS: MOSAIC trial patients and eligible RW patients treated with oxaliplatin had comparable 2-year disease-free survivals (79.5 vs. 78.4 %). Oxaliplatin showed an incremental QALY gain of 1.02, 1.13, 1.17 and 0.93 and incremental cost of 9,961, 11,055, 9,814 and 11,854 in scenarios 1-4, respectively. The corresponding incremental cost-effectiveness ratios (ICERs) were 9,766, 9,783, 8,388 and 12,746 in scenarios 1-4, respectively. In all scenarios, univariate and probabilistic sensitivity analyses indicated that the ICERs are acceptable and robust under a wide range of model assumptions. CONCLUSIONS: The ICERs of the different scenarios that resulted from combining MOSAIC trial data with data from Dutch daily practice all suggest that FL + oxaliplatin is cost-effective versus FL alone in the adjuvant treatment of colon cancer. This article illustrates how one could design and implement a real-world cost-effectiveness study to yield internally valid results that could also be generalisable.

Practical feasibility of outcomes research in oncology: lessons learned in assessing drug use and cost-effectiveness in The Netherlands.

OBJECTIVE: To investigate the practical feasibility to develop evidence on drug use and cost-effectiveness in oncology practice. PATIENTS AND METHODS: Feasibility was examined using three Dutch case studies. Each case study investigated the degree of appropriate drug use and its incremental cost-effectiveness. Detailed data were retrospectively collected from hospital records. In total, 391, 316 and 139 patients with stage III colon cancer, metastatic colorectal cancer and multiple myeloma were included in 19, 29 and 42 hospitals, respectively. RESULTS: The methods used in the case studies were feasible to develop evidence on some aspects of drug use including types of treatments used, dosages, dose modifications and healthcare costs. Aspects such as baseline patient characteristics, reasons to start or stop a treatment and treatment effects were less feasible because of missing values. Despite difficulties to correct for confounding by indication, it was possible to estimate incremental cost-effectiveness by synthesising evidence in two of the three case studies. CONCLUSION: It is possible to generate evidence about drug use and cost-effectiveness in oncology practice to facilitate informed decision-making by both payers and physicians. This can improve quality of care and enhance the efficient allocation of resources. However, the optimal approach differs between drugs and their indications. Generating high-quality evidence requires active interdisciplinary collaboration. Patient registries can facilitate data collection but cannot resolve all issues. In most circumstances it is inevitable to use data-synthesis to obtain valid incremental cost-effectiveness estimates, but for some indications it will not be feasible to derive a valid and precise estimate.