Use of quantitative bias analysis to evaluate single-arm trials with real-world data external controls.

PURPOSE: Use of real-world data (RWD) for external controls added to single-arm trials (SAT) is increasingly prevalent in regulatory submissions. Due to inherent differences in the data-generating mechanisms, biases can arise. This paper aims to illustrate how to use quantitative bias analysis (QBA). METHODS: Advanced non-small cell lung cancer (NSCLC) serves as an example, where many small subsets of patients with molecular tumor subtypes exist. First, some sources of bias that may occur in oncology when comparing RWD to SAT are described. Second, using a hypothetical immunotherapy agent, a dataset is simulated based on expert input for survival analysis of advanced NSCLC. Finally, we illustrate the impact of three biases: missing confounder, misclassification of exposure, and outcome evaluation. RESULTS: For each simulated scenario, bias was induced by removing or adding data; hazard ratios (HRs) were estimated applying conventional analyses. Estimating the bias-adjusted treatment effect and uncertainty required carefully selecting the bias model and bias factors. Although the magnitude of each biased and bias-adjusted HR appeared moderate in all three hypothetical scenarios, the direction of bias was variable. CONCLUSION: These findings suggest that QBA can provide an intuitive framework for bias analysis, providing a key means of challenging assumptions about the evidence. However, the accuracy of bias analysis is itself dependent on correct specification of the bias model and bias factors. Ultimately, study design should reduce bias, but QBA allows us to evaluate the impact of unavoidable bias to assess the quality of the evidence.

Real-world treatment patterns and survival outcomes for patients with stage III non-small cell lung cancer in Spain: a nationwide cohort study.

Background: The burden of non-small cell lung cancer (NSCLC) remains high in Spain, with lung cancer accounting for 20% of cancer-related deaths annually. Programs such as the Spanish Thoracic Tumour Registry (TTR) and the global I-O Optimise initiative have been developed to observe patients in clinical practice with the aim of improving outcomes. This analysis examined treatment patterns and survival in patients with stage III NSCLC from the TTR. These patients represent a heterogenous group with complex treatment pathways. Methods: The TTR is an ongoing, observational, prospective, and retrospective cohort multicentre study (NCT02941458) that follows patients with thoracic cancer in Spain. Adults aged ≥18 years with stage IIIA/IIIB NSCLC enrolled in the TTR between 01 Jan 2010 and 31 Oct 2019 were included in this analysis. Initial treatment received was described by cancer stage and histology (squamous and non-squamous NSCLC). Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) were calculated over a 5-year period. Results: A total of 1,838 patients were included in the cohort, including 1,082 with stage IIIA (58.9%) and 756 with stage IIIB (41.1%). Median follow-up was 18.3 months. The median age of patients was 66 years, and most had non-squamous NSCLC (54.0%), were male (81.2%), and were active or former smokers (93.4%). Overall, 26.3% of patients received surgical resection (37.0% for stage IIIA and 11.1% for stage IIIB). The most frequent initial treatment received was concurrent chemoradiotherapy for stage IIIA (30.2%) and stage IIIB (37.0%) patients. Median OS was lower in patients with stage IIIB than stage IIIA (28 vs. 37 months) disease and was lower for patients with squamous than non-squamous histology (19 vs. 26 months). Median PFS and OS varied when patients were stratified by initial treatment. Conclusions: This TTR analysis describes the clinical reality surrounding the initial management and survival outcomes for stage III NSCLC in Spain and presents survival outcomes comparable with other real-world evidence. It provides insights into the diverse approaches used before the availability of immunotherapies and targeted treatments in the non-metastatic NSCLC setting.

How Do People with Experience of Infertility Value Different Aspects of Assistive Reproductive Therapy? Results from a Multi-Country Discrete Choice Experiment.

OBJECTIVES: Assistive reproductive therapies can help those who have difficulty conceiving but different forms of assistive reproductive therapies are associated with different treatment characteristics. We undertook a large, multinational discrete choice experiment to understand patient preferences for assistive reproductive therapies. METHODS: We administered an online discrete choice experiment with persons who had experience with subfertility or assistive reproductive therapies in the USA, UK, the Nordic region (Denmark, Norway, Sweden, Finland), Spain, and China. Attributes encouraged trade-offs between effectiveness, risk of adverse effects, treatment (dis)comfort, (in)convenience, cost per cycle and shared decision making. We used multinomial logit and mixed-logit models to estimate preferences and attribute importance by country/region, and estimated willingness to pay for changes in attribute levels. RESULTS: A total of 7565 respondents participated. Mixed logit had a better fit than multinomial logit across all samples. Preferences moved in expected directions across all samples, but the relative importance of attributes differed between countries. Willingness to pay was greatest for improvements in effectiveness and a greater degree of shared decision making, and we observe a substantial 'option value' independent of treatment characteristics. Unexpectedly, preferences over cost were insignificant in the Chinese sample, limiting the use of willingness to pay in this sample. CONCLUSIONS: Respondents balanced concerns for effectiveness with other considerations, including the cost and (dis)comfort of treatment, and the degree of shared decision making, but there is also substantial option value independent of treatment characteristics, demonstrating value of assistive reproductive therapies to individuals with experience of subfertility. We hypothesise that price insensitivity in the Chinese sample may reflect a degree of social desirability bias.

Association between mode of delivery and body mass index at 4-5 years in White British and Pakistani children: the Born in Bradford birth cohort.

BACKGROUND: Globally, it is becoming more common for pregnant women to deliver by caesarean section (CS). In 2020, 31% of births in England were CS, surpassing the recommended prevalence of CS. Concerns have been raised regarding potential unknown consequences of this mode of delivery. Childhood adiposity is also an increasing concern. Previous research provides inconsistent conclusions on the association between CS and childhood adiposity. More studies are needed to investigate the consequences of CS in different populations and ethnicities. Therefore, this study investigates the association between mode of delivery and BMI, in children of 4-5 years and if this differs between White British (WB) and Pakistani ethnicities, in Bradford UK. METHODS: Data were obtained from the Born in Bradford (BiB) cohort, which recruited pregnant women at the Bradford Royal Infirmary, between 2007 and 2010. For these analyses, a sub-sample (n = 6410) of the BiB cohort (n = 13,858) was used. Linear regression models determined the association between mode of delivery (vaginal or CS) and BMI z-scores at 4-5 years. Children were categorised as underweight/healthy weight, overweight and obese, and logistic regression models determined the odds of adiposity. Effect modification by ethnicity was also explored. RESULTS: Multivariable analysis found no evidence for a difference in BMI z-score between children of CS and vaginal delivery (0.005 kg/m2, 95% CI = - 0.062-0.072, p = 0.88). Neither was there evidence of CS affecting the odds of being overweight (OR = 1.05, 95% CI = 0.86-1.28, p = 0.65), or obese (OR = 0.98, 95% CI = 0.74-1.29, p = 0.87). There was no evidence that ethnicity was an effect modifier of these associations (p = 0.97). CONCLUSION: Having CS, compared to a vaginal delivery, was not associated with greater adiposity in children of 4-5 years in this population. Concerns over CS increasing adiposity in children are not supported by the findings reported here using the BiB study population, of both WB and Pakistani families.

Is the public supportive and willing to pay for a national assistive reproductive therapies programme? Results from a multicountry survey.

OBJECTIVES: To understand attitudes towards infertility and willingness to pay (WTP) towards a publicly funded national assistive reproductive therapies (ART) programme. DESIGN: Attitudes survey with dichotomous and open-ended WTP questions. SETTING: Online survey administered in the USA, UK, Norway, Sweden, Finland, Denmark and China. PARTICIPANTS: 7945 respondents, analysed by country. Nordic respondents were pooled into a regionally representative sample. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measures were proportion of sample agreeing with different infertility-related and ART-related value statements and supporting a monthly contribution to fund a national ART programme, expressed in local currency. Secondary outcome measure was maximum WTP. RESULTS: Across the nationally representative samples, 75.5% of all respondents agreed with infertility as a medical condition and 82.3% and 83.7% with ART eligibility for anyone who has difficulty having a baby or a medical problem preventing them from having a baby, respectively. 56.4% of respondents supported a defined monthly contribution and 73.9% supported at least some additional contribution to fund a national ART programme. Overall, converting to euros, median maximum WTP was €3.00 and mean was €15.47 (95% CI 14.23 to 16.72) per month. Maximum WTP was highest in China and the USA and lowest in the European samples. CONCLUSIONS: This large, multicountry survey extends our understanding of public attitudes towards infertility and fertility treatment beyond Europe. It finds evidence that a majority of the public in all sampled countries/regions views infertility as a treatable medical condition and supports the idea that all infertile individuals should have access to treatments that improve the chance of conception. There was also strong agreement with the idea that the desire for children is a basic human need. WTP questions showed that a majority of respondents supported a monthly contribution to fund a national ART programme, although there is some evidence of an acquiescence bias that may overstate support among specific samples.