Box 25.

Exemplars on reporting item 20

Example 1. Use of surrogate outcome to inform adaptation “We chose change in the SOFA scores as a surrogate outcome based on strong correlations between this measure and 28-day mortality (33). Whether change in the SOFA scores and the timing of reassessment (48 h in this case) represents the “right” surrogate endpoint for nonpivotal sepsis trials remains unclear and is an area for future consideration, although the use of change in the SOFA score as a surrogate outcome is supported by a recent meta-analysis (34).” [142] Example 2. Duration of assessments to inform dose selection “The use of the adaptive seamless design is not without potential risk. The initial dose-finding period needs to be long enough for a thorough evaluation of effects. Two weeks was considered a fully adequate period in which to attain pharmacodynamic steady state….” [141] Example 3. Early stopping outside the scope of the pre-planned adaptation and possible explanation “The aim was to determine the minimum efficacious dose and safety of treatments in HIV-uninfected patients. However, the study had to be prematurely terminated due to unacceptably low efficacy in both the single and multiple dose treatment arms, with a cure rate of only 85% in the multiple-dose arm. Adverse effects of treatment in this study were in line with the current drug label. The overall low efficacy was unexpected, as total doses of 10 mg/kg and above resulted in DC rates of at least 90% in a trial in Kenya (13). The trial was not powered for data analysis by geographical location (centre) and the results may have been due to chance, but both the 10 mg/kg single dose and 21 mg/kg multiple dose regimens appeared to work very well in the small number of patients treated in Arba Minch Hospital (southern Ethiopia). We have little explanation for the overall poor response seen in this study or for the observed geographical variations. Previously, similar geographical variation in treatment response in these three sites was seen for daily doses of 11 mg/kg body weight paromomycin base over 21 days (7), a regimen which had also proven efficacious in India (18). Methodological bias is unlikely in this randomized trial, but differences in base line patient characteristics between the three trial sites could have possibly introduced bias, leading to variation in treatment response….” [143] Example 4. Limitations of biomarkers and RAR “Our study has some important limitations. First, and probably most important, our biomarker groups were less predictive than were individual biomarkers, which diluted the impact of strong predictors in determining treatment probabilities. For example, EGFR mutations were far more predictive than was the overall EGFR marker group. The unfortunate decision to group the EGFR markers also impacted the other marker groups and their interactions with other treatments, resulting in a suboptimal overall disease control rate as described. Second, several of the pre-specified markers (for example, RXR) had little, if any, predictive value in optimizing treatment selections. This limitation will be addressed in future studies by not grouping or prespecifying biomarkers prior to initiating these biopsy-mandated trials. In addition, adaptive randomization, which assigns more patients to the more effective treatments within each biomarker group, only works well with a large differential efficacy among the treatments (as evident in the KRAS/BRAF group), but its role is limited without such a difference (for example, in the other marker groups). Allowing prior use of erlotinib was another limitation and biased treatment assignments; in fact, the percentage of patients previously treated with erlotinib steadily increased during trial enrollment. Overall, 45% of our patients were excluded from the 2 erlotinib-containing arms because of prior EGFR TKI treatment. As erlotinib is a standard of care therapy in NSCLC second-line, maintenance, and front-line settings, the number of patients receiving this targeted agent will likely continue to increase.” [256]