The Challenge of Early Crossover in Oncology Trials

This paper provides preparatory reading, to facilitate discussion during the meeting on “The Challenge of Early Crossover in Oncology Trials” to be held in Adelaide, Australia, in October 2014. The paper is not exhaustive, and does not cover every issue associated with treatment crossover (also called treatment switching) in detail. However it aims to provide an overview of the key issues associated with treatment crossover in the context of oncology randomised controlled trials (RCTs). In Section 2 of this paper we will define what we mean by treatment switching. In Section 3 we will describe why treatment switching causes a problem for the analysis of trials, from the perspective of a range of stakeholders. This will take into account clinical development programmes and the challenges of designing these in the face of international variations in clinical, regulatory and coverage practice with respect to evidence requirements and expectations. In Section 4 we will introduce approaches that may be taken to adjust for treatment switching and in Section 5 we will summarise the performance of these methods in simulation studies. This paper is supplemented by five additional papers: Background Paper 2 provides details on case studies submitted by Workshop participants; Background Papers 3-5 provide relevant guidance and recommendations on the use of switching adjustment methods made by regulatory and reimbursement agencies from around the world. Brief background and introduction to these papers are provided in Sections 6 and 7 of this paper. Background Paper 6 presents the proposed confidentiality rules for the Workshop. In the final section of the current paper, we highlight areas that have not been addressed by currently available guidance documents

Pre-read document 1 : challenges in valuing and paying for combination regimens in oncology

This document was prepared as a pre-read paper for people attending an international workshop convened by Bellberry, Ltd. The workshop was held to discuss the challenges in valuing and paying for combination regimens in oncology. Cancers often arise through multiple biological mechanisms, meaning that treatments that target only one of these mechanisms may not provide long lasting benefit to patients. Therefore, it is common to treat cancers with multiple treatments, called combination therapies. Combination therapies are often expensive, especially when multiple on-patent treatments are combined, which makes paying for them challenging for health systems around the world. This is particularly the case when different companies own the on-patent treatments that are combined, because this may inhibit flexibility in pricing. Hence, this report primarily considers the case where combination therapies consist of two or more on-patent treatments, owned by two or more companies. This pre-read document introduces and illustrates the challenges associated with combination therapies, considers how different approaches used by health systems to determine whether new treatments should be paid for may affect these challenges, and presents a review of options for addressing these challenges, with the aim of facilitating debate on how best to ensure patient access to clinically effective combination therapies

Vacuum-UV negative photoion spectroscopy of CH3F, CH3Cl and CH3Br

Using tunable vacuum-UV radiation from a synchrotron, negative ions are detected by quadrupolar mass spectrometry following photoexcitation of three gaseous halogenated methanes CH$_3$X (X = F,Cl,Br). The anions X$^-$, H$^-$, CX$^-$, CHX$^-$ and CH$_2$X$^-$ are observed, and their ion yields recorded in the range 8-35 eV. The anions show a linear dependence of signal with pressure, showing that they arise from unimolecular ion-pair dissociation, generically described as AB + h$v$ $\rightarrow$ A$^-$ + B$^+$ (+ neutrals). Absolute cross sections for ion-pair formation are obtained by calibrating the signal intensities with those of F$^-$ from both SF$_6$ and CF$_4$. The cross sections for formation of X$^-$ + CH$_3$$^+$ are much greater than for formation of CH$_2$X$^-$ + H$^+$. In common with many quadrupoles, the spectra of $m$/$z$ 1 (H$^-$) anions show contributions from all anions, and only for CH$_3$Br is it possible to perform the necessary subtraction to obtain the true H$^-$ spectrum. The anion cross sections are normalised to vacuum-UV absorption cross sections to obtain quantum yields for their production. The appearance energies of X$^-$ and CH$_2$X$^-$ are used to calculate upper limits to 298 K bond dissociation energies for D$^o$ (H$_3$C-X) and D$^o$ (XH$_2$C-H) which are consistent with literature values. The spectra suggest that most of the anions are formed indirectly by crossing of Rydberg states of the parent molecule onto an ion-pair continuum. The one exception is the lowest-energy peak of F$^-$ from CH$_3$F at 13.4 eV, where its width and lack of structure suggest it may correspond to a direct ion-pair transition

Measuring the mass of a sterile neutrino with a very short baseline reactor experiment

An analysis of the world's neutrino oscillation data, including sterile neutrinos, (M. Sorel, C. M. Conrad, and M. H. Shaevitz, Phys. Rev. D 70, 073004) found a peak in the allowed region at a mass-squared difference $\Delta m^2 \cong 0.9$ eV$^2$. We trace its origin to harmonic oscillations in the electron survival probability $P_{ee}$ as a function of L/E, the ratio of baseline to neutrino energy, as measured in the near detector of the Bugey experiment. We find a second occurrence for $\Delta m^2 \cong 1.9$ eV$^2$. We point out that the phenomenon of harmonic oscillations of $P_{ee}$ as a function of L/E, as seen in the Bugey experiment, can be used to measure the mass-squared difference associated with a sterile neutrino in the range from a fraction of an eV$^2$ to several eV$^2$ (compatible with that indicated by the LSND experiment), as well as measure the amount of electron-sterile neutrino mixing. We observe that the experiment is independent, to lowest order, of the size of the reactor and suggest the possibility of a small reactor with a detector sitting at a very short baseline.Comment: 4 pages, 2 figure

Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy

Trametinib, a selective inhibitor of mitogen-activated protein kinase kinase 1 (MEK1) and MEK2, significantly improves progression-free survival compared with chemotherapy in patients with BRAF V600E/K mutation–positive advanced or metastatic melanoma (MM). However, the pivotal clinical trial permitted randomized chemotherapy control group patients to switch to trametinib after disease progression, which confounded estimates of the overall survival (OS) advantage of trametinib. Our purpose was to estimate the switching-adjusted treatment effect of trametinib for OS and assess the suitability of each adjustment method in the primary efficacy population. Of the patients randomized to chemotherapy, 67.4% switched to trametinib. We applied the rank-preserving structural failure time model, inverse probability of censoring weights, and a two-stage accelerated failure time model to obtain estimates of the relative treatment effect adjusted for switching. The intent-to-treat (ITT) analysis estimated a 28% reduction in the hazard of death with trametinib treatment (hazard ratio [HR], 0.72; 95% CI, 0.52–0.98) for patients in the primary efficacy population (data cut May 20, 2013). Adjustment analyses deemed plausible provided OS HR point estimates ranging from 0.48 to 0.53. Similar reductions in the HR were estimated for the first-line metastatic subgroup. Treatment with trametinib, compared with chemotherapy, significantly reduced the risk of death and risk of disease progression in patients with BRAF V600E/K mutation–positive advanced melanoma or MM. Adjusting for switching resulted in lower HRs than those obtained from standard ITT analyses. However, CI are wide and results are sensitive to the assumptions associated with each adjustment method

Developing a health state classification system from NEWQOL for epilepsy using classical psychometric techniques and Rasch analysis: a technical report

Aims: Resource allocation amongst competing health care interventions is informed by evidence of both clinical- and cost-effectiveness. Cost-utility analysis is increasingly used to assess cost effectiveness through the use of Quality Adjusted Life Years (QALYs). This requires health state values. Generic measures of health related quality of life (HRQL) are usually used to produce these values, but there are concerns about their relevance and sensitivity in epilepsy. This study develops a health state classification system for epilepsy from the NEWQOL battery, a validated questionnaire measuring QoL in epilepsy. The classification system will be amenable to valuation for calculating QALYs. Methods: Factor and other psychometric analyses were undertaken to investigate the factor structure of the battery, and assess the validity and responsiveness of the items. These analyses were used alongside Rasch analysis to select the dimensions included in the classification system, and the items used to represent each domain. Analysis was carried out on a trial dataset of patients with epilepsy (n=1611). Rasch and factor analysis were performed on one half of the sample and validated on the remaining half. Dimensions and items were selected that performed well across all analyses. Results: The battery was found to demonstrate reliability and validity but responsiveness across time periods for many of the items was low. A six dimension classification system was developed: worry about seizures, depression, memory, cognition, stigmatism and control, each with four response levels. Conclusions: It is feasible to develop a health state classification system from a battery of instruments using a combination of classical psychometric, factor and Rasch analysis. This is the first condition-specific health state classification developed for epilepsy and the next stage will produce preference weights to enable the measure to be used in cost-utility analysis.quality adjusted life years; health related quality of life; Rasch analysis; preference-based measures of health; health states; epilepsy

A New Approach for Sampling Ordered Parameters in Probabilistic Sensitivity Analysis

Background Probabilistic sensitivity analysis (PSA) in cost-effectiveness analysis involves sampling a large number of realisations of an economic model. For some parameters, we may be uncertain around the true mean values of the variables, but the ordering of the values is known. Typical sampling approaches lack either statistical or clinical validity. For example, sampling using a common number generator results in extreme dependence and independent sampling can lead to realisations with incorrect ordering. Methods We propose a new sampling approach for ordered parameters, the Difference Method approach, which samples the parameters of interest via a difference parameter. If the parameters of interest are bounded, it involves transforming the variables so that they are unbounded and then sampling via the difference parameter. We have provided an Excel workbook to implement the method. The proposed approach is illustrated with an example sampling ordered parameters for utility and cost. Results The DM approach has a number of advantages when comparing with the typical approaches used in practice. The DM approach generates PSA samples which have similar summary statistics as the given values in our examples whilst maintaining the constraint that one value was greater than another. The method also implies plausible positive correlation between the two ordered variables. Conclusions Both clinical and statistical validity should be checked when producing PSA samples. The DM approach should be considered as a solution to potential problems in generating PSA samples for ordered parameters

The Cost of Costing Treatments Incorrectly: Errors in the Application of Drug Prices in Economic Evaluation Due to Failing to Account for the Distribution of Patient Weight

AbstractBackgroundThe cost of pharmaceuticals dosed by weight or body surface area (BSA) can be estimated in several ways for economic evaluations. A review of 20 recent National Institute for Health and Care Excellence appraisals showed that 17 of them took the mean weight or BSA of patients, 2 costed the individual patient data from trials, and 2 fitted a distribution to patient-level data.ObjectivesTo investigate the estimated drug costs using different methodologies to account for patient characteristics for pharmaceuticals with a weight- or BSA-based posology. The secondary objective was to explore the suitability of general population data as a proxy for patient-level data.MethodsPatient-level data were pooled from three clinical trials and used to calculate a hypothetical cost per administration of eight licensed pharmaceuticals, applying the three methods used in recent National Institute for Health and Care Excellence appraisals. The same analysis was performed using data from the Health Survey for England (in place of patient-level data) to investigate the validity of using general population data as a substitute for patient-level data.ResultsCompared with using patient-level data from clinical trials, the mean patient characteristics (weight or BSA) led to an underestimation of drug cost by 6.1% (range +1.5% to −25.5%). Fitting a distribution to patient-level data led to a mean difference of +0.04%. All estimates were consistent using general population data.ConclusionsEstimation of drug costs in health economic evaluation should account for the distribution in weight or BSA to produce accurate results. When patient data are not available, general population data may be used as an alternative

Developing a health state classification system from NEWQOL for epilepsy using classical psychometric techniques and Rasch analysis: A technical report

Aims: Resource allocation amongst competing health care interventions is informed by evidence of both clinical- and cost-effectiveness. Cost-utility analysis is increasingly used to assess cost effectiveness through the use of Quality Adjusted Life Years (QALYs). This requires health state values. Generic measures of health related quality of life (HRQL) are usually used to produce these values, but there are concerns about their relevance and sensitivity in epilepsy. This study develops a health state classification system for epilepsy from the NEWQOL battery, a validated questionnaire measuring QoL in epilepsy. The classification system will be amenable to valuation for calculating QALYs. Methods: Factor and other psychometric analyses were undertaken to investigate the factor structure of the battery, and assess the validity and responsiveness of the items. These analyses were used alongside Rasch analysis to select the dimensions included in the classification system, and the items used to represent each domain. Analysis was carried out on a trial dataset of patients with epilepsy (n=1611). Rasch and factor analysis were performed on one half of the sample and validated on the remaining half. Dimensions and items were selected that performed well across all analyses. Results: The battery was found to demonstrate reliability and validity but responsiveness across time periods for many of the items was low. A six dimension classification system was developed: worry about seizures, depression, memory, cognition, stigmatism and control, each with four response levels. Conclusions: It is feasible to develop a health state classification system from a battery of instruments using a combination of classical psychometric, factor and Rasch analysis. This is the first condition-specific health state classification developed for epilepsy and the next stage will produce preference weights to enable the measure to be used in cost-utility analysis