Methods for indirect comparisons and network meta-analysis use aggregate level data from multiple studies. A very common, and closely related, scenario is where a company has individual patient data ...(IPD) from its own trial, but only has published aggregate data from a competitor's trial, and an indirect comparison of the treatments evaluated in these two trials is required. Matching-Adjusted Indirect Comparison (MAIC) has been developed for this situation, where we use the available IPD to adjust for between-trial imbalances in the distributions of observed baseline covariates between the two trials. We extend the current MAIC methodology, where we compute the weights that satisfy the conventional method of moments and result in the largest possible effective sample size (ESS). We show that the approach proposed by Zubizarreta in a previous study can be used for this purpose. We derive a new analytical result that shows why this alternative approach provides a larger ESS than a conventional MAIC. We also derive a new formula for the maximum ESS that can be achieved, even when permitting negative weights, when adjusting for one covariate. This can be used as an easily computed new metric that quantifies the difficulty in adjusting for covariates.
Purpose
Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with deteriorating health and health-related quality of life (HRQoL) among people with COPD during and after ...events. HRQoL data are key to evaluating treatment cost-effectiveness and informing reimbursement decisions in COPD. EuroQoL 5-dimension 5-level (EQ-5D-5L) utility scores, based on various HRQoL measures, are used in economic evaluations of pharmacotherapy. These analyses estimated associations between EQ-5D-5L utility scores and exacerbations (new and previous) in patients with moderate-to-very severe COPD.
Methods
Longitudinal mixed models for repeated measures (MMRM), adjusted for time and treatment, were conducted using data from the ETHOS study (NCT02465567); models regressed EQ-5D-5L on current and past exacerbations that occurred during the study, adjusting for other patient reported outcomes and clinical factors.
Results
Based on the simplest covariate adjusted model (adjusted for current exacerbations and number of previous exacerbations during the study), a current moderate exacerbation was associated with an EQ-5D-5L disutility of 0.055 (95% confidence interval: 0.048, 0.062) with an additional disutility of 0.035 (0.014, 0.055) if the exacerbation was severe. After resolving, each prior exacerbation was associated with a disutility that persisted for the remainder of the study (moderate exacerbation, 0.014 0.011, 0.016; further disutility for severe exacerbation, 0.011 0.003, 0.018).
Conclusion
An EQ-5D-5L disutility of 0.090 was associated with a current severe exacerbation in ETHOS. Our findings suggest incorporating the effects of current, recently resolved, and cumulative exacerbations into economic models when estimating benefits and costs of COPD pharmacotherapy, as exacerbations have both acute and persistent effects.
Objective To characterise failure of antibiotic treatment in primary care in the United Kingdom in four common infection classes from 1991 to 2012.Design Longitudinal analysis of failure rates for ...first line antibiotic monotherapies associated with diagnoses for upper and lower respiratory tract infections, skin and soft tissue infections, and acute otitis media.Setting Routine primary care data from the UK Clinical Practice Research Datalink (CPRD).Main outcome measures Adjusted rates of treatment failure defined by standardised criteria and indexed to year 1 (1991=100).Results From 58 million antibiotic prescriptions in CPRD, we analysed 10 967 607 monotherapy episodes for the four indications: 4 236 574 (38.6%) for upper respiratory tract infections; 3 148 947 (28.7%) for lower respiratory tract infections; 2 568 230 (23.4%) for skin and soft tissue infections; and 1 013 856 (9.2%) for acute otitis media. In 1991, the overall failure rate was 13.9% (12.0% for upper respiratory tract infections; 16.9% for lower respiratory tract infections; 12.8% for skin and soft tissue infections; and 13.9% for acute otitis media). By 2012, the overall failure rate was 15.4%, representing an increase of 12% compared with 1991 (adjusted value indexed to first year (1991) 112, 95% confidence interval 112 to 113). The highest rate was seen in lower respiratory tract infections (135, 134 to 136). While failure rates were below 20% for most commonly prescribed antibiotics (amoxicillin, phenoxymethylpenicillin (penicillin-V), and flucloxacillin), notable increases were seen for trimethoprim in the treatment of upper respiratory tract infections (from 29.2% in 1991-95 to 70.1% in 2008-12) and for ciprofloxacin (from 22.3% in 1991-95 to 30.8% in 2008-12) and cefalexin (from 22.0% in 1991-95 to 30.8% in 2008-12) in the treatment of lower respiratory tract infections. Failure rates for broad spectrum penicillins, macrolides, and flucloxacillin remained largely stable.Conclusions From 1991 to 2012, more than one in 10 first line antibiotic monotherapies for the selected infections were associated with treatment failure. Overall failure rates increased by 12% over this period, with most of the increase occurring in more recent years, when antibiotic prescribing in primary care plateaued and then increased.
This article discusses the generalization of the local influence measures for normally distributed responses to local influence measures for generalized linear models with random effects. For these ...models, it is shown that the subject‐oriented influence measure is a special case of the proposed observation‐oriented influence measure. A two‐step diagnostic procedure is proposed. The first step is to search for influential subjects. A search for influential observations is proposed as the second step. An illustration of a two‐treatment, multiple‐period crossover trial demonstrates the practical importance of the detection of influential observations in addition to the detection of influential subjects.
•Chronic obstructive pulmonary disease drugs were assessed in UK medical practice.•Confounding by indication represents a considerable challenge for real-world data.•Inhaled corticosteroid (ICS) ...versus non–ICS treatment was compared.•A cox marginal structural model was evaluated to assess comparative effectiveness.•The main results were inconsistent with previous demonstrated benefits of ICS.
To evaluate the potential of a Cox marginal structural model (MSM) to estimate the time-varying causal inference of a known clinical trial association where the effectiveness of inhaled corticosteroid- (ICS-) versus non–ICS-containing treatments has been compared in patients with chronic obstructive pulmonary disease (COPD).
This retrospective study from 2006–2016 used linked data from Clinical Practice Research Datalink-GOLD, Hospital Episode Statistics, and Office for National Statistics mortality. A Cox MSM, incorporating a new-user design, was deemed capable of replicating a clinical trial-like pathway. Repeated outcomes for exacerbation events and stabilized weights were used to include time-varying and fixed covariate exposures.
Of 45,958 patients, 55% were male; 52% had moderate COPD. ICS-treated patients had a higher incidence of comorbid asthma than non–ICS-treated patients. Adjusted hazard risk ratios for any exacerbation event: ICS and/or long-acting β2-agonist (LABA) versus long-acting muscarinic antagonist (LAMA), 1.07 (95% confidence interval 1.04–1.10); ICS/LABA versus LABA and/or LAMA, 1.05 (1.00–1.10); ICS and/or LABA and/or LAMA versus LAMA, 1.04 (1.01–1.06); ICS and/or LABA and/or LAMA versus LABA and/or LAMA 1.02 (0.97–1.07).
The Cox MSM was not able to fully demonstrate results consistent with the previously established benefits of ICS-containing treatments seen in clinical trials. Future studies should continue to investigate causal inference methods and their capability to estimate the long-term outcomes of treatment in COPD.
Survival extrapolation of trial outcomes is required for health economic evaluation. Generally, all-cause mortality (ACM) is modeled using standard parametric distributions, often without ...distinguishing disease-specific/excess mortality and general population background mortality (GPM). Recent National Institute for Health and Care Excellence guidance (Technical Support Document 21) recommends adding GPM hazards to disease-specific/excess mortality hazards in the log-likelihood function (“internal additive hazards”). This article compares alternative extrapolation approaches with and without GPM adjustment.
Survival extrapolations using the internal additive hazards approach (1) are compared to no GPM adjustment (2), applying GPM hazards once ACM hazards drop below GPM hazards (3), adding GPM hazards to ACM hazards (4), and proportional hazards for ACM versus GPM hazards (5). The fit, face validity, mean predicted life-years, and corresponding uncertainty measures are assessed for the active versus control arms of immature and mature (30- and 75-month follow-up) multiple myeloma data and mature (64-month follow-up) breast cancer data.
The 5 approaches yielded considerably different outcomes. Incremental mean predicted life-years vary most in the immature multiple myeloma data set. The lognormal distribution (best statistical fit for approaches 1-4) produces survival increments of 3.5 (95% credible interval: 1.4-5.3), 8.5 (3.1-13.0), 3.5 (1.3-5.4), 2.9 (1.1-4.5), and 1.6 (0.4-2.8) years for approaches 1 to 5, respectively. Approach 1 had the highest face validity for all data sets. Uncertainty over parametric distributions was comparable for GPM-adjusted approaches 1, 3, and 4, and much larger for approach 2.
This study highlights the importance of GPM adjustment, and particularly of incorporating GPM hazards in the log-likelihood function of standard parametric distributions.
•Survival extrapolations based on standard parametric distributions do not differentiate between disease-specific/excess mortality and general population background mortality (GPM).•Recent National Institute for Health and Care Excellence guidance (Technical Support Document 21) recommends adding GPM hazards in the log-likelihood function (“internal additive hazards”).•In this article, the internal additive hazards approach is compared to 4 alternative survival extrapolation approaches with and without GPM adjustment.•This study confirms the importance of GPM adjustment, and particularly of incorporating GPM hazards in the log-likelihood function of standard parametric distributions.
Background. The rank-preserving structural failure time model (RPSFTM) is used for health technology assessment submissions to adjust for switching patients from reference to investigational ...treatment in cancer trials. It uses counterfactual survival (survival when only reference treatment would have been used) and assumes that, at randomization, the counterfactual survival distribution for the investigational and reference arms is identical. Previous validation reports have assumed that patients in the investigational treatment arm stay on therapy throughout the study period. Objectives. To evaluate the validity of the RPSFTM at various levels of crossover in situations in which patients are taken off the investigational drug in the investigational arm. Methods. The RPSFTM was applied to simulated datasets differing in percentage of patients switching, time of switching, underlying acceleration factor, and number of patients, using exponential distributions for the time on investigational and reference treatment. Results. There were multiple scenarios in which two solutions were found: one corresponding to identical counterfactual distributions, and the other to two different crossing counterfactual distributions. The same was found for the hazard ratio (HR). Unique solutions were observed only when switching patients were on investigational treatment for <40% of the time that patients in the investigational arm were on treatment. Limitations. Distributions other than exponential could have been used for time on treatment. Conclusions. An HR equal to 1 is a necessary but not always sufficient condition to indicate acceleration factors associated with equal counterfactual survival. Further assessment to distinguish crossing counterfactual curves from equal counterfactual curves is especially needed when the time that switchers stay on investigational treatment is relatively long compared to the time direct starters stay on investigational treatment.
In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic antagonist (LAMA)/long-acting β
2
...-agonist (LABA) or inhaled corticosteroid (ICS)/LABA therapies, triple ICS/LAMA/LABA therapy is recommended. A previous network meta-analysis showed comparable efficacy of the ICS/LAMA/LABA, budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) 320/18/9.6 µg, to other fixed-dose and open combination triple therapies at 24 weeks in COPD. Subsequently, the ETHOS study was published, including data for 8509 patients, assessing the efficacy and safety of BUD/GLY/FOR over 52 weeks. This network meta-analysis (NMA) was conducted to compare the relative efficacy, safety, and tolerability of BUD/GLY/FOR 320/18/9.6 µg with other fixed-dose and open combination triple therapies in COPD over 52 weeks, including data from ETHOS. A systematic literature review was conducted to identify ≥ 10-week randomized controlled trials, including ≥ 1 fixed-dose or open combination triple-therapy arm, in patients with moderate-to-very severe COPD. The methodologic quality and risk of bias of included studies were assessed. Study results were combined using a three-level hierarchical Bayesian NMA model to assess efficacy and safety outcomes at or over 24 and 52 weeks. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Nineteen studies (
n
= 37,741 patients) met the inclusion criteria of the review; 15 contributed to the base case network. LAMA/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes for exacerbations, lung function, symptoms, health-related quality of life, safety, and tolerability, the efficacy and safety of BUD/GLY/FOR were comparable to those of other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium bromide/formoterol fumarate) and open combinations at or over 24 and 52 weeks. Sensitivity analyses and meta-regression results for exacerbation outcomes were broadly in line with the base case NMA. In this NMA, BUD/GLY/FOR 320/18/9.6 μg showed comparable efficacy versus other ICS/LAMA/LABA fixed-dose or open combination therapies in terms of reducing exacerbation rates and improving lung function, symptoms and health-related quality of life in patients with moderate-to-very-severe COPD, in line with previously published meta-analysis results of triple combinations in COPD. The safety and tolerability profile of BUD/GLY/FOR was also found to be comparable to other triple combination therapies.
To synthesize the current literature on the use of surrogate end points, including definitions, acceptability, and limitations of surrogate end points and guidance for their design/reporting, into ...trial reporting items.
Literature was identified through searching bibliographic databases (until March 1, 2022) and gray literature sources (until May 27, 2022). Data were thematically analyzed into four categories: (1) definitions, (2) acceptability, (3) limitations and challenges, and (4) guidance, and synthesized into reporting guidance items.
After screening, 90 documents were included: 79% (n = 71) had data on definitions, 77% (n = 69) on acceptability, 72% (n = 65) on limitations and challenges, and 61% (n = 55) on guidance. Data were synthesized into 17 potential trial reporting items: explicit statements on the use of surrogate end point(s) and justification for their use (items 1–6); methodological considerations, including whether sample size calculations were informed by surrogate validity (items 7–9); reporting of results for composite outcomes containing a surrogate end point (item 10); discussion and interpretation of findings (items 11–14); plans for confirmatory studies, collecting data on the surrogate end point and target outcome, and data sharing (items 15–16); and informing trial participants about using surrogate end points (item 17).
The review identified and synthesized items on the use of surrogate end points in trials; these will inform the development of the Standard Protocol Items: Recommendations for Interventional Trials–SURROGATE and Consolidated Standards of Reporting Trials–SURROGATE extensions.
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•Ninety documents were included: 79% (n = 71) had data on definitions, 77% (n = 69) on acceptability, 72% (n = 65) on limitations and challenges, and 61% (n = 55) on guidance for design/reporting of surrogate end points in trials.•There was heterogeneity in how surrogate end points were defined.•Key recommendation identified was the need to justify use of a surrogate end point using evidence of validation.•Another key recommendation of this review was increased involvement of patients and public in trials that use surrogate end points.•Synthesized items on the use of surrogate end points in trials from the review will inform the Standard Protocol Items: Recommendations for Interventional Trials–SURROGATE and Consolidated Standards of Reporting Trials–SURROGATE extensions.
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