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

Abstract

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.     

Interfirm learning in environmental safety: evidence from the bakken

This paper examines whether firm learning economies lead to reduced environmental incidents in Bakken unconventional oil drilling. We model the relationship between environmental safety and learning in preventing environmental incidents. We do not find evidence that firm or interfirm learning leads to increased environmental safety. We do find evidence that idiosyncratic quality of matches between firms and subcontractors is associated with improved environmental safety.     

Private and state-led contract farming in Zimbabwe: Accumulation,social differentiation and rural politics

Contract farming schemes often amplify existing patterns of socio-economic differentiation. In Zimbabwe, processes of differentiation were underway before the current expansion of contract farming and they have deepened through the Fast Track Land Reform process. This article examines how pre-existing dynamics of differentiation shape the forms of contract farming adopted, as well as which groups of farmers gain access and on what terms. Social differentiation partly explains the outcomes of contract farming, even if contract farming in turn results in further differentiation. This article contrasts private sector-led contract farming of tobacco and state-led financing of maize production (the ‘command agriculture’ programme) in two high-potential sites and across different forms of land use. Unlike in many other settings, contract farming in Zimbabwe is highly influenced by the state, through the regulation of private sector arrangements and the establishment of a state-led contracting programme. The state-led programme boosted maize production amongst medium-scale farmers and resulted in an embedding of patronage relations. Meanwhile, the private-led contract farming has supported a widespread boom of tobacco production, mainly amongst smallholders. We find therefore that contract farming is highly dependent on the contingent, politically mediated processes of social differentiation.     

Teachers learning about technology and technology education: Insights from a professional development experience

The introduction of technology education in primary and secondary schools during the past 10–15 years around the world has presented a number of difficulties for teachers, primarily related to their coming to understand the phenomenon of technology and to conceptualise the technology learning area in line with national frameworks. This paper reports on a professional development experience that aimed to assist a small group of primary school teachers to develop their understandings of technology and technology education. A theoretical model framed a series of professional development interactions between the researchers and the experienced teachers who were new to teaching technology. Data sources included teacher interviews, video recordings of the activities, teacher made models, and extracts from their reflective journals. The study presented some insights into how professional development experiences for teachers new to technology could be organised and implemented to best support their developing technology practices and understandings.     

Teacher Perceptions of Design and Technology: A Study of Disjunction between Policy and Practice

This study examines the curriculum directions being charted by a sample of county secondary school design and technology teachers in England and Wales. The purposes of design and technology are analysed, and the syllabuses and examinations used reviewed, together with how design folios are incorporated into teaching. In addition, teacher reports on student-teacher classroom performance, and student-teacher evaluations of their teaching practice experiences are analysed. It was found that teacher perceptions are highly pragmatic and technical, with the pupils‘ intended learning outcomes largely being defined instrumentally in terms of product output rather than in design process terms. A disjunction is found between the statutory Order on Design and Technology and its implementation, with many teachers ’constructing‘ their design and technology education programmes within a ’craft paradigm‘. The discussion offers possible explanations for this and concludes that it has as much to do with the perceived status of Design and Technology as a school subject as with a ’product – process‘ debate. This revised version was published online in August 2006 with corrections to the Cover Date.     

The principle of the conservation of business relationship energy: or many kinds of new beginnings

The relationship termination phase has received rather less attention in the literature than other aspects of relationship development. In this article we focus on the stage when the firms involved stop doing business with each other. We argue that relationship ending is problematic in that, even when trading stops, there still seems to exist a kind of “relationship energy” which continues on, especially in the social bonds that have been created. We propose a new principle of the “conservation of relationship energy” which states that it cannot be destroyed and that it can only be transformed and transferred to other relationships, manifesting itself in a variety of ways. “Relationship energy” provides opportunities for the same relationship to be reactivated at a later time, and helps or hinders the formation and continuation of other relationships as this energy travels with people to other organizations and contexts. The principle is illustrated using three case studies of relationships that have ended, drawn from the IMP2 database. The analysis provides new ways of analyzing the relationship termination phase as a more dynamic ongoing process and suggests new ways of evaluating relationship outcomes.     

AUSTRALASIAN ECONOMIC HISTORY: RESEARCH CHALLENGES AND BIG QUESTIONS

This paper reports a debate on the 'big questions' and 'research challenges' facing economic history in Australia and New Zealand. Noting the changes in research direction that occurred in the discipline over the past 50 years, and the resource challenges it currently faces, it identifies many areas of potentially fruitful research. These include the environment, market regulation and industry development, the interaction of peoples and culture, and the examination of units other than the national economy. While there is potential for exciting and diverse research, an immediate challenge is the training of the next generation of economic historians.     

Multivariate Mixed Models for Open-Ended Contingent Valuation Data: Willingness To Pay For Conservation of Monk Seals

Although dichotomous choice (DC) contingent valuation (CV) has been recommended by the US NOAA 'blue-ribbon' panel for large-scale contingent valuation studies, useful information can still be obtained from smaller, open-ended (OE) studies, often undertaken as a precursor to a DC survey. The CV study considered here was carried out in Greece and looked at willingness-to-pay (WTP) for protecting the Mediterranean monk seal (Monachus-monachus) in the Aegean area. This is the most endangered seal in the world, and the application of the CV methodology was the first such application in Greece. The OE data consist of two responses: first, a binary response detailing whether or not respondents were in principle prepared to pay for the protection of this seal; secondly, those respondents who answered 'yes' to the first question were then asked to state their maximum WTP for such protection. A multivariate binomial – log-normal mixture model is used to develop a bid function including explanatory variables such as income, sex, age and education. Such a modelling approach provides an alternative to more commonplace tobit estimation. However, the model is extended to include further information which was collected on:(a) an increased WTP amount given in response to information that the initial WTP amount may not be enough to prevent the extinction of the seal;(b) respondents were asked to divide their final WTP amount between use, option and existence values, the latter requiring a multivariate model with four binary and four continuous responses per individual in the same model.The discussion focuses on the methodological issues raised with some comment on the substantive interpretation of results.     

Scientific management and the pursuit of control in Britain to c.1960

The intellectual content and intentions of scientific management theories, aimed at industrial performance and harmony, were largely absent from British management practice for a great part of the last century. The limited interpretation of scientific management in Britain was characterised by a focus on control, at the heart of which was the use of piecework. Criticisms of piecework surfaced notably in the 1960s, linked to criticisms of scientific management as a whole. This article argues that any failure of piecework was not necessarily a failure of scientific management, given the latter's diluted role in twentieth century British management practice.