Avoidable waste of research related to outcome planning and reporting in clinical trials

Background Inadequate planning, selective reporting, and incomplete reporting of outcomes in randomized controlled trials (RCTs) contribute to the problem of waste of research. We aimed to describe such a waste and to examine to what extent this waste could be avoided. Methods This research-on-research study was based on RCTs included in Cochrane reviews with a summary of findings (SoF) table. We considered the outcomes reported in the SoF tables as surrogates for important outcomes for patients and other decision makers. We used a three-step approach. (1) First, in each review, we identified, for each important outcome, RCTs that were excluded from the corresponding meta-analysis. (2) Then, for these RCTs, we systematically searched for registrations and protocols to distinguish between inadequate planning (an important outcome was not reported in registries or protocols), selective reporting (an important outcome was reported in registries or protocols but not in publications), and incomplete reporting (an important outcome was incompletely reported in publications). (3) Finally, we assessed, with the consensus of five experts, the feasibility and cost of measuring the important outcomes that were not planned. We considered inadequately planned or selectively or incompletely reported important outcomes as avoidable waste if the outcome could have been easily measured at no additional cost based on expert evaluation. Results Of the 2711 RCTs included in the main comparison of 290 reviews, 2115 (78%) were excluded from at least one meta-analysis of important outcomes. Every trial contributed to 55%, on average, of the meta-analyses of important outcomes. Of the 310 RCTs published in 2010 or later, 156 were registered. Inadequate planning affected 79% of these RCTs, whereas incomplete and selective reporting affected 41% and 15%, respectively. For 63% of RCTs, we found at least one missing important outcome for which the waste was avoidable and for 30%, the waste was avoidable for all important outcomes. Conclusions Most of the RCTs included in our sample did not contribute to all the important outcomes in meta-analyses, mostly because of inadequate planning or incomplete reporting. A large part of this waste of research seemed to be avoidable

Simulation-Based Estimates of the Effectiveness and Cost-Effectiveness of Pulmonary Rehabilitation in Patients with Chronic Obstructive Pulmonary Disease in France

International audienceBackgroundThe medico-economic impact of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) is poorly documented.ObjectiveTo estimate the effectiveness and cost-effectiveness of pulmonary rehabilitation in a hypothetical cohort of COPD patients.MethodsWe used a multi-state Markov model, adopting society’s perspective. Simulated cohorts of French GOLD stage 2 to 4 COPD patients with and without pulmonary rehabilitation were compared in terms of life expectancy, quality-adjusted life years (QALY), disease-related costs, and the incremental cost-effectiveness ratio (ICER). Sensitivity analyses included variations of key model parameters.Principal FindingsAt the horizon of a COPD patient’s remaining lifetime, pulmonary rehabilitation would result in mean gain of 0.8 QALY, with an over disease-related costs of 14 102 € per patient. The ICER was 17 583 €/QALY. Sensitivity analysis showed that pulmonary rehabilitation was cost-effective in every scenario (ICER <50 000 €/QALY).ConclusionsThese results should provide a useful basis for COPD pulmonary rehabilitation programs

Differences in Treatment Effect Size Between Overall Survival and Progression-Free Survival in Immunotherapy Trials: A Meta-Epidemiologic Study of Trials With Results Posted at ClinicalTrials.gov

Purpose We aimed to compare treatment effect sizes between overall survival (OS) and progression-free survival (PFS) in trials of US Food and Drug Administration–approved oncology immunotherapy drugs with results posted at ClinicalTrials.gov . Methods We searched ClinicalTrials.gov for phase II to IV cancer trials of Food and Drug Administration–approved immunotherapy drugs and selected those reporting results for both OS and PFS. For each trial, we extracted the hazard ratios (HRs) with 95% CIs for both outcomes and evaluated the differences by a ratio of HRs (rHRs): the HR for PFS to that for OS. We performed a random effects meta-analysis across trials to obtain a summary rHR. We also evaluated surrogacy of PFS for OS by the coefficient of determination and the surrogacy threshold effect, the minimal value of HR for PFS to predict a non-null effect on OS. Results We identified 51 trials assessing 14 drugs across 15 conditions. Treatment effect sizes were 17% greater, on average, with PFS than with OS (rHR, 0.83; 95% CI, 0.79 to 0.88; I2 = 34.4%; P = .01; τ2 = 0.0129). Nearly one half of the trials (n = 23, 45%) showed statistically significant benefits for PFS but not for OS. Differences were great for trials of obinutuzumab (rHR, 0.21; 95% CI, 0.08 to 0.54), bevacizumab (rHR, 0.75; 95% CI, 0.67 to 0.84), and rituximab (rHR, 0.79; 95% CI, 0.64 to 0.98). The coefficient of determination was 38% and the surrogacy threshold effect was 0.50. Conclusion Treatment effect sizes in trials of immunotherapy drugs were greater for PFS than for OS, with important differences for some drugs, which is consistent with surrogacy metrics. Caution must be taken when interpreting PFS in the absence of OS data. </jats:sec

characteristics of the population without pulmonary rehabilitation (usual cares) and with pulmonary rehabilitation (PR); ⁺% non smokers/ex-smokers/smokers; ⁺⁺% of patients at least 1 exacerbation per year.

<p>characteristics of the population without pulmonary rehabilitation (usual cares) and with pulmonary rehabilitation (PR); ⁺% non smokers/ex-smokers/smokers; ⁺⁺% of patients at least 1 exacerbation per year.</p

Acceptability curve.

<p>Percent chances that PR is-cost-effective (as compared to standard care) as a function of the willingness to pay (€/QALY) for it.</p

Probabilistic sensitivity analysis.

<p>Incremental costs (€) of pulmonary rehabilitation intervention as a function of its incremental effectiveness (QALY).</p

Pharmacogenomic biomarkers as inclusion criteria in clinical trials of oncology-targeted drugs: a mapping of ClinicalTrials.gov

International audiencePurpose: To describe pharmacogenomics-based inclusion criteria (enrichment) and main characteristics of clinical trials involving oncology targeted therapies.Methods: Clinical trials of oncology targeted therapies approved after 2005 with pharmacogenomic testing required or recommended in their label were retrieved from a mapping of clinicaltrials.gov database. Results: We included 12 drugs and 858 trials. Overall, 434 trials (51%) were enriched on the biomarker first mentioned in the label and 145 (17%) on another biomarker whereas 270 (31%) trials included all patients. The median proportion of trials corresponding to both the drug's indication and drug's target was 35%. Among the 361 trials which tested drugs in another disease than the first one in the label, 219 (61%) were without enrichment and 87 (24%) were actually enriched but on another biomarker than the first one in the label. Conclusions: Several drugs have been tested in trials enriched on many different biomarkers. Nonetheless, most of targeted therapies have been developed only in biomarker-positive patients and, therefore, exclusion of biomarker-negative patients from treatment relies on only pre-clinical data and on biological understanding of the disease and target

Decision model.

<p>Four health states (GOLD2 to GOLD4 and death) defining the outcome of a patient with COPD. The arrows indicate the possibility of transition from one state to another. Transition from one state to another, based on GOLD criteria, is unidirectional. GOLD4 patients cannot transit to another stage, and « death » is an absorbing state in which transition to another state is not possible.</p