Raising the bar for antineoplastic agents: how to choose threshold values for superiority trials in advanced solid tumors
A partir de données portant sur 43 essais cliniques (35 419 patients, 12 types de cancer, 23 agents thérapeutiques), cette étude analyse les conséquences de l'utilisation de diverses valeurs-seuils pour déclarer qu'un critère de jugement (ici, la survie globale) est "cliniquement" significatif
Purpose. To establish the concept of minimum clinically meaningful outcome (mCMO) of treatment in advanced solid tumors, to establish its threshold and evaluate how many superiority trials of new antineoplastic agents pass this threshold.
Experimental design. We chose overall survival (OS) as the primary indicator of patient benefit. Four conceptually different types of treatment effect can be identified in OS curves: hazard ratio (HR), gains in median OS, proportional and absolute increases at long-term OS. We postulated threshold levels for these 4 parameters defining the mCMO and set the bar at 3 different levels of required benefit : high, medium and low. The postulated values were then studied by comparing our thresholds with the actual results of the pivotal superiority phase III trials on new drugs reporting on mature OS data.
Results. 43 trials on 35,419 patients in 12 cancer types on 23 novel agents met these criteria. Only 2 trials reached the postulated "high" thresholds for HR and median OS. The number of "positive trials" increased to 8 and 15 when the bar was lowered to the "medium" and "low" levels, respectively. The same analysis was done for proportional and absolute increases in long-term OS. No trial satisfied the criteria for long term benefit, whereas only 2 and 9 trials satisfied both parameters for the "medium and low" required benefit levels, respectively.
Conclusions. All 4 OS-related parameters contribute to define the mCMO. If the bar for the mCMO is raised too much , positive trials are exceptional.
Clinical Cancer Research , résumé, 2014