A review and validation of overall survival extrapolation in health technology assessments of cancer immunotherapy by the National Institute for Health and Care Excellence: how did the initial best estimate compare to trial data subsequently made available?

Background: Validation of overall survival (OS) extrapolations of immune-checkpoint inhibitors (ICIs) during the National Institute for Health and Care Excellence (NICE) Single Technology Assessment (STA) process is limited due to data still maturing at the time of submission. Inaccurate extrapolation may lead to inappropriate decision-making. The availability of more mature trial data facilitates a retrospective analysis of the plausibility and validity of initial extrapolations. This study compares these extrapolations to subsequently available longer-term data.

Methods: A systematic search of completed NICE appraisals of ICIs from March 2000 to December 2017 was performed. A targeted search was also undertaken to procure published OS data from the pivotal clinical trials for each identified STA made available post-submission to NICE. Initial Kaplan-Meier curves and associated extrapolations from NICE documentation were extracted to compare the accuracy of OS projections versus the most mature data.

Results: The review identified 11 STAs, of which 10 provided OS data upon submission to NICE. The extrapolations undertaken considered parametric or piecewise survival models. Additional data cut-offs provided a mean of 18 months of OS beyond the end of the original data. Initial extrapolations typically under-estimated OS from the most mature data cut-off by 0.4–2.7%, depending on the choice of assessment method and use of the manufacturer- or ERG-preferred extrapolation.

Conclusion: Long-term extrapolation of OS is required for NICE STAs based on initial immature OS data. The results of this study demonstrate that the initial OS extrapolations employed by manufacturers and ERGs generally predicted OS reasonably well when compared to more mature data (when available), although on average they appeared to underestimate OS. This review and validation shows that, while the choice of OS extrapolation is uncertain, the methods adopted are generally aligned with later-published follow-up data and appear appropriate for informing HTA decisions.     

Psychometric validation of anti-clot treatment scale and treatment satisfaction questionnaire for medication version II in Japanese patients with atrial fibrillation

Aims: The Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM-II) are validated treatment satisfaction patient-reported outcome (PRO) instruments. The ACTS includes two domains: Burdens and Benefits; the TSQM-II includes four: Effectiveness, Side Effects, Convenience, and Global Satisfaction. Japanese-language versions of the ACTS and TSQM-II have been developed and linguistically validated. This study aimed to assess their psychometric properties in Japanese patients with atrial fibrillation (AF).

Materials and methods: ACTS and TSQM-II data from 534 patients with AF were collected in a Japanese post-marketing surveillance study of a direct oral-anticoagulant, rivaroxaban. Four key psychometric properties, in line with best practice guidelines from the US Food and Drug Administration, were examined using traditional psychometric methods: acceptability, scaling assumptions, reliability (i.e. internal consistency reliability, test-retest reliability), and construct validity (i.e. convergent validity and known groups).

Results: ACTS Burdens and Benefits and TSQM-II Effectiveness, Convenience, and Global Satisfaction scales were found to be acceptable (e.g. item-level missing data at baseline <4%), with all scales having good internal consistency (Cronbach’s alpha > 0.80). test-retest reproducibility intraclass correlation coefficients for the ACTS Burdens and Benefits were 0.59 and 0.65, respectively, and between 0.54–0.61 for the TSQM-II scales. Known-groups validity for the ACTS and TSQM-II was supported by differences in scale scores by positive and negative impact (p?<?0.05). Correlations between the ACTS and TSQM-II (convergent validity) were lower than expected (range r?=?0.09–0.48), but in line with the original ACTS development study.

Limitations: Evaluation of test-retest reproducibility was limited by assessment period, which was longer (3 months) than recommended guidelines (usually up to 2 weeks).

Conclusions: Overall, Japanese versions of ACTS and TSQM-II scales satisfied internal consistency reliability and traditional validity criteria. Our study supports the ACTS and TSQM-II as appropriate PRO instruments to measure satisfaction with anticoagulant treatment in Japanese patients with AF.

Trial registration: NCT01598051, clinicaltrials.gov; registered April 20, 2012.     

Information in stock prices: the case of the 2016 U.S. presidential election

On the day before the 2016 U.S. presidential election, the odds of Hillary Clinton winning the presidency, according to political prediction markets, were above 90%. Surprisingly, Donald Trump won the Electoral College handily. In this study, we examine how movements in specific stock prices foreshadowed the eventual outcome. Specifically, we conduct a series of standard event-study tests focused on pharmaceutical companies, which became a focal point during the presidential campaign. Results show that while stocks of pharmaceutical companies significantly underperformed the market prior to the election, prices substantially increased beginning three days before the election outcome. This increase is both statistically significant and economically meaningful and robust to various event-study methodologies. These results suggest that some sectors of the stock market seemed to anticipate the election outcome.     

Stuck in the middle: Impacts of grade configuration in public schools

We examine the implications of separating students of different grade levels across schools for the purposes of educational production. Specifically, we find that moving students from elementary to middle school in 6th or 7th grade causes significant drops in academic achievement. These effects are large (about 0.15 standard deviations), present for both math and English, and persist through grade 8, the last year for which we have achievement data. The effects are similar for boys and girls, but stronger for students with low levels of initial achievement. We instrument for middle school attendance using the grade range of the school students attended in grade 3, and employ specifications that control for student fixed effects. This leaves only one potential source of bias–correlation between grade range of a student's grade 3 school and unobservable characteristics that cause decreases in achievement precisely when students are due to switch schools–which we view as highly unlikely. We find little evidence that placing public school students into middle schools during adolescence is cost-effective.     

Solving the Misesian migration conundrum

This paper reviews Ludwig Von Mises’ concerns surrounding unrestricted immigration and relates them to the current debate surrounding immigrants’ impact on destination countries’ institutions. It then outlines a policy of generally unrestricted immigration with selective restrictions that addresses Mises’ concerns and concerns about destination country institutions, while still achieving the majority of the economic gains that unrestricted immigration is forecast to achieve.

     

Quantitative growth effects of subsidies in a search theoretic R&D model

Should government subsidize R&D and does it matter how these subsidies are allocated? We examine these questions in a dynamic model where R&D is described as sequential sampling from a distribution of new ideas. Successful discoveries affect future available resources and incentives for further R&D. Consequently, there may be under-investment in R&D. We study the effect of government interventions aimed at fostering growth through R&D. Calibrating the model with aggregate data from the Israeli business sector allows us to quantitatively compare two forms of support resembling those actually used to encourage R&D in the Israeli business sector: (i) an unrestricted subsidy that may be used at the recipients' discretion to finance R&D or other investments, (ii) a subsidy earmarked by the government for R&D activities only. While there is no theoretical way to determine which of the two subsidies will have a greater impact on search for new ideas and growth, we find that in the calibrated economy both subsidies have a significant but similar impact on the economy's output and TFP growth rates. Accordingly, in the case of the Israeli business sector, the incentives to conduct R&D were sufficiently strong, and no R&D-specific encouragement was needed. However, a sensitivity analysis reveals that for economies characterized by other parameter values this result may not be true. Correspondence to: B. Bental     

Regulation and taxation: A complementarity

I show how quantity regulation can lower elasticities and thereby increase optimal tax rates. Such regulation imposes regulatory incentives for particular choice quantities. Their strength varies between zero (laissez faire) and infinite (command economy). In the latter case, regulation effectively eliminates any intensive behavioral responses to taxes; a previously distortionary tax becomes a lump sum. For intermediate regulation (where some deviation is feasible), intensive behavioral responses are still weaker than under zero regulation, and so quantity regulation reduces elasticities, thereby facilitating subsequent taxation. I apply this mechanism to labor supply and present correlational evidence for this complementarity: hours worked in high-regulation countries are compressed, and these countries tax labor at higher rates.     

The rhetorical fantasy of energy transitions: implications for energy policy and analysis

This article explores the rhetoric of four energy transitions. It begins by summarising research on the intersection of fantasy, technology and the sociology of expectation. It then looks at how ideas of progress, modernity, cheapness, abundance and hope influence the way society perceives new energy technologies, causing them to overestimate benefits and underestimate challenges. Our rhetorical analysis finds in case studies of steam engines, gasoline automobiles, hydroelectric dams and nuclear reactors that newly ‘discovered’ sources of energy or newly invented technologies are always assumed to provide infinitely abundant energy and to have the potential to create positive utopian changes in society. We conclude by noting the salient implications of these rhetorical themes for energy planners, analysts and scholars.