Estimation methods for estimands using the treatment policy strategy; a simulation study based on the PIONEER 1 Trial

Estimands using the treatment policy strategy for addressing intercurrent events are common in Phase III clinical trials. One estimation approach for this strategy is retrieved dropout whereby observed data following an intercurrent event are used to multiply impute missing data. However, such methods have had issues with variance inflation and model fitting due to data sparsity. This paper introduces likelihood-based versions of these approaches, investigating and comparing their statistical properties to the existing retrieved dropout approaches, simpler analysis models and reference-based multiple imputation. We use a simulation based upon the data from the PIONEER 1 Phase III clinical trial in Type II diabetics to present complex and relevant estimation challenges. The likelihood-based methods display similar statistical properties to their multiple imputation equivalents, but all retrieved dropout approaches suffer from high variance. Retrieved dropout approaches appear less biased than reference-based approaches, resulting in a bias-variance trade-off, but we conclude that the large degree of variance inflation is often more problematic than the bias. Therefore, only the simpler retrieved dropout models appear appropriate as a primary analysis in a clinical trial, and only where it is believed most data following intercurrent events will be observed. The jump-to-reference approach may represent a more promising estimation approach for symptomatic treatments due to its relatively high power and ability to fit in the presence of much missing data, despite its strong assumptions and tendency towards conservative bias. More research is needed to further develop how to estimate the treatment effect for a treatment policy strategy

Measurement error is often neglected in medical literature: a systematic review.

OBJECTIVES: In medical research, covariates (e.g., exposure and confounder variables) are often measured with error. While it is well accepted that this introduces bias and imprecision in exposure-outcome relations, it is unclear to what extent such issues are currently considered in research practice. The objective was to study common practices regarding covariate measurement error via a systematic review of general medicine and epidemiology literature. STUDY DESIGN AND SETTING: Original research published in 2016 in 12 high impact journals was full-text searched for phrases relating to measurement error. Reporting of measurement error and methods to investigate or correct for it were quantified and characterized. RESULTS: Two hundred and forty-seven (44%) of the 565 original research publications reported on the presence of measurement error. 83% of these 247 did so with respect to the exposure and/or confounder variables. Only 18 publications (7% of 247) used methods to investigate or correct for measurement error. CONCLUSIONS: Consequently, it is difficult for readers to judge the robustness of presented results to the existence of measurement error in the majority of publications in high impact journals. Our systematic review highlights the need for increased awareness about the possible impact of covariate measurement error. Additionally, guidance on the use of measurement error correction methods is necessary

Visualizing the target estimand in comparative effectiveness studies with multiple treatments

Aim: Comparative effectiveness research using real-world data often involves pairwise propensity score matching to adjust for confounding bias. We show that corresponding treatment effect estimates may have limited external validity, and propose two visualization tools to clarify the target estimand. Materials & methods: We conduct a simulation study to demonstrate, with bivariate ellipses and joy plots, that differences in covariate distributions across treatment groups may affect the external validity of treatment effect estimates. We showcase how these visualization tools can facilitate the interpretation of target estimands in a case study comparing the effectiveness of teriflunomide (TERI), dimethyl fumarate (DMF) and natalizumab (NAT) on manual dexterity in patients with multiple sclerosis. Results: In the simulation study, estimates of the treatment effect greatly differed depending on the target population. For example, when comparing treatment B with C, the estimated treatment effect (and respective standard error) varied from -0.27 (0.03) to -0.37 (0.04) in the type of patients initially receiving treatment B and C, respectively. Visualization of the matched samples revealed that covariate distributions vary for each comparison and cannot be used to target one common treatment effect for the three treatment comparisons. In the case study, the bivariate distribution of age and disease duration varied across the population of patients receiving TERI, DMF or NAT. Although results suggest that DMF and NAT improve manual dexterity at 1 year compared with TERI, the effectiveness of DMF versus NAT differs depending on which target estimand is used. Conclusion: Visualization tools may help to clarify the target population in comparative effectiveness studies and resolve ambiguity about the interpretation of estimated treatment effects

Applicability and added value of novel methods to improve drug development in rare diseases

The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports. The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were 'innovative trial designs' (six methods), 'level of evidence' (one method), 'study endpoints and statistical analysis' (four methods), and 'meta-analysis' (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters. Direct applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters. Novel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes. The online version of this article (10.1186/s13023-018-0925-0) contains supplementary material, which is available to authorized users

Estimands in clinical drug development: from design to regulatory assessment

In this thesis, I investigated the (implicit) use of estimands in the pre-estimand era in clinical trials for regulatory evaluation and approval to understand what estimands may correspond to efficacy investigations and common efficacy analyses. Additionally, I developed data-generating models (DGMs) that take into account the association between clinical outcomes and intercurrent events

Julius Symposium 2017 - Mitroiu M.

Julius Symposium 2017 - Mitroiu M

Measurement error in medical research: a systematic review of current practice

In medical research, covariates (e.g. exposure and confounder variables) are often measured with error. While it is well accepted that this introduces bias and imprecision in exposure-outcome relations, it is unclear to what extent such issues are currently considered in research practice. The objective was to study common practices regarding covariate measurement error via a systematic review of general medicine and epidemiology literature. Original research published in 2016 in 12 high impact journals was full-text searched for phrases relating to measurement error. Reporting of measurement error and methods to investigate or correct for it were quantified and characterized. 247 (44%) of the 565 original research publications reported on the presence of measurement error. 83% of these 247 did so with respect to the exposure and/or confounder variables. Only 18 publications (7% of 247) used methods to investigate or correct for measurement error. Consequently, it is difficult for readers to judge the robustness of presented results to the existence of measurement error in the majority of publications in high impact journals. Our systematic review highlights the need for increased awareness about the possible impact of covariate measurement error. Additionally, guidance on the use of measurement error correction methods is necessary

Measurement error is often neglected in medical literature : a systematic review

Objectives: In medical research, covariates (e.g., exposure and confounder variables) are often measured with error. While it is well accepted that this introduces bias and imprecision in exposure-outcome relations, it is unclear to what extent such issues are currently considered in research practice. The objective was to study common practices regarding covariate measurement error via a systematic review of general medicine and epidemiology literature. Study Design and Setting: Original research published in 2016 in 12 high impact journals was full-text searched for phrases relating to measurement error. Reporting of measurement error and methods to investigate or correct for it were quantified and characterized. Results: Two hundred and forty-seven (44%) of the 565 original research publications reported on the presence of measurement error. 83% of these 247 did so with respect to the exposure and/or confounder variables. Only 18 publications (7% of 247) used methods to investigate or correct for measurement error. Conclusions: Consequently, it is difficult for readers to judge the robustness of presented results to the existence of measurement error in the majority of publications in high impact journals. Our systematic review highlights the need for increased awareness about the possible impact of covariate measurement error. Additionally, guidance on the use of measurement error correction methods is necessary

Applicability and added value of novel methods to improve drug development in rare diseases

BACKGROUND: The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports. METHODS: The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were 'innovative trial designs' (six methods), 'level of evidence' (one method), 'study endpoints and statistical analysis' (four methods), and 'meta-analysis' (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters. RESULTS AND DISCUSSION: Direct applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters. CONCLUSION: Novel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes