Incorporating technology diffusion estimates in health economic methods - Application in a preterm birth screening case study

Low implementation of cost-effective health technologies results in inefficient use of resources in a health system. Despite this, estimates of implementation or diffusion are not routine components of analyses performed within health technology assessments (HTA), potentially due to a lack of a) methods to obtain diffusion estimates and b) understanding of the impact of diffusion estimates on health economic outcomes. This thesis contributes a) a method to estimate health technology diffusion prior to HTA and b) a modelling framework that assesses the potential impact of diffusion estimates on cost-effectiveness and expected value of information and implementation (EVII) analysis using modelling, qualitative and elicitation methods. These were illustrated in a preterm birth (PTB) screening case study. The modelling framework included extensions to an existing EVII model to make it dynamic and allow research to affect implementation; and the development of a dynamic cost-effectiveness analysis (DCEA) model that reflects price changes precipitated by diffusion and hence, the reimbursement decision. Drivers of diffusion were identified for the case study technology, aiding the design of implementation strategies. The developed method for predicting diffusion requires transformation of elicited expert beliefs to inform an existing diffusion model. Application in the PTB screening model showed that the dynamic EVII method can 1.) help more accurately assess the losses the health care payer incurs when there is decision uncertainty and low implementation and 2.) provide more realistic assessments of implementation strategies and evidence generation schemes. The applied DCEA model showed that changes in price triggered by technology diffusion significantly affect cost-effectiveness results. The method for predicting health technology diffusion and the EVII and DCEA frameworks are foreseen to be relevant in the context of HTAs of medical devices, diagnostics and drugs; particularly when there is low implementation or there is potential for future price changes conditional on diffusion

Filgotinib for Treating Moderately to Severely Active Ulcerative Colitis:An Evidence Review Group Perspective of a NICE Single Technology Appraisal

The National Institute for Health and Care Excellence invited the manufacturer (Galapagos) of filgotinib (Jyseleca®), as part of the Single Technology Appraisal process, to submit evidence for the clinical effectiveness and cost effectiveness of filgotinib for treating moderately to severely active ulcerative colitis in adults who have had an inadequate response, loss of response or were intolerant to a previous biologic agent or conventional therapy. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group. This paper summarises the company submission, presents the Evidence Review Group’s critical review on the clinical and cost-effectiveness evidence in the company submission, highlights the key methodological considerations and describes the development of the National Institute for Health and Care Excellence guidance by the Appraisal Committee. The company submission included one relevant study for the comparison of filgotinib versus placebo: the SELECTION trial. As there was no head-to-head evidence with any of the comparators, the company performed two separate network meta-analyses, one for the biologic-naïve population and one for the biologic-experienced population, and for both the induction and maintenance phases. The Evidence Review Group questioned the validity of the maintenance network meta-analysis because it assumed all active treatments to be comparators in this phase, which is not in line with clinical practice. The economic analysis used a number of assumptions that introduced substantial uncertainty, which could not be fully explored, for instance, the assumption that a risk of loss of response would be independent of health state and constant over time. Company and Evidence Review Group results indicate that at its current price, and disregarding confidential discounts for comparators and subsequent treatments, filgotinib dominates some comparators (golimumab and adalimumab in the company base case, all but intravenous and subcutaneous vedolizumab in the Evidence Review Group’s base case) in the biologic-naïve population. In the biologic-experienced population, filgotinib dominates all comparators in both the company and the Evidence Review Group’s base case. Results should be interpreted with caution as some important uncertainties were not included in the modelling. These uncertainties were mostly centred around the maintenance network meta-analysis, loss of response, health-related quality-of-life estimates and modelling of dose escalation. The National Institute for Health and Care Excellence recommended filgotinib within its marketing authorisation, as an option for treating moderately to severely active ulcerative colitis in adults when conventional or biological treatment cannot be tolerated, or if the disease has not responded well enough or has stopped responding to these treatments, and if the company provides filgotinib according to the commercial arrangement.</p

Durvalumab for the Treatment of Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer:An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of the Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (AstraZeneca) of durvalumab (IMFINZI(TM)) to submit evidence for the clinical and cost effectiveness of durvalumab for the treatment of patients with locally advanced, unresectable, stage III non-small cell lung cancer whose tumours express programmed death-ligand 1 (PD-L1) on >= 1% of tumour cells and whose disease has not progressed after platinum-based chemoradiation therapy. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical- and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The CS included a systematic review that identified one randomised controlled trial, comparing durvalumab with SoC. Participants with tumours expressing PD-L1 on >= 1% of tumour cells accounted for approximately 40% of the total participants. In this subgroup, a benefit in progression-free survival (PFS) [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.31-0.63] and overall survival (HR 0.54, 95% CI 0.35-0.81) was reported. Adverse events were comparable between both treatments, but more serious adverse events were reported for durvalumab (64/213 [30%] vs. 18/90 [20%]). The ERG's concerns regarding the economic analysis included a likely overestimation of PFS for the durvalumab arm, the choice of timepoint for treatment waning, as well as the way treatment waning was incorporated in the model, and potential overestimation of utility values without applying an age- or treatment-related decrement. The revised ERG base-case resulted in a deterministic incremental cost-effectiveness ratio of 50,238 pound per quality-adjusted life-year gained, with substantial remaining uncertainty. NICE recommended durvalumab as an option for use within the Cancer Drugs Fund only in a subpopulation (concurrent platinum-based chemoradiation therapy) with a commercially managed access agreement in place

The development of sentence-interpretation strategies in monolingual German-learning children with and without specific language impairment

Previous research on sentence comprehension conducted with German-learning children has concentrated on the role of case marking and word order in typically developing children. This paper compares, the performance of German-learning children with language impairment (age 4-6 years) and without language impairment (aged 2-6, 8-9 years) in two experiments that systematically vary the cues animacy, case marking; word-order, and subject-verb agreement. The two experiments differ with regard to the choice of case marking: in the first it is distinct but in the second it is neutralized. The theoretical framework is the competition model developed by Bates and Mac Whinney and their collaborators, a variant of the parallel distributed processing models. It is hypothesized that children of either population first appreciate the cue animacy that can be processed locally, that is, "on the spot," before they turn to more distributed cues leading ultimately up to subject-verb agreement, which presupposes the comparison of various constituents before an interpretation can be established. Thus agreement is more "costly" in processing than animacy or the (more) local cue initial NP. In experiment I with unambiguous case markers it is shown that the typically developing children proceed from animacy to the nominative (predominantly in coalition with the initial NP) to agreement, while in the second experiment with ambiguous case markers these children turn from animacy to the initial NP and then to agreement. The impaired children also progress from local to distributed cues. Yet, in contrast to the control group, they do not acknowledge the nominative in coalition with the initial NP in the first experiment but only in support of agreement. However, although they do not seem to appreciate distinct case markers to any large extent in the first experiment, they are irritated if such distinctions are lacking: in experiment II all impaired children turn to. animacy (some in coalition with the initial NP and/or particular word orders). In the discussion, the relationship between short-term memory and processing as well as the relationship between production and comprehension of case markers and agreement are addressed. Further research is needed to explore in more detail "cue costs" in sentence comprehension

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting