Association of Industry and Academic Sponsorship With Negative Phase 3 Oncology Trials and Reported Outcomes on Participant Survival: A Pooled Analysis
A partir d'une revue de la littérature publiée entre janvier 2016 et juin 2018 dans cinq grandes revues américaines, cette étude évalue la proportion d'essais cliniques négatifs de phase III financés par l'industrie et/ou des institutions académiques et évaluant un anticancéreux dont les résultats de l'essai de phase II ne sont pas concluants, puis analyse l'association entre le fait de conduire ces essais et la survie globale des patients
Importance : Only 3.4% of cancer drugs evaluated in phase 1 trials are approved by the US Food and Drug Administration, with most failing in phase 3 trials.
Objective : To investigate whether an association exists between the sponsorship and conduct of a negative phase 3 randomized clinical trial (RCT) investigating a cancer drug that lacked supporting phase 2 trial evidence for that drug, and to evaluate the association with overall survival among patients randomized to the experimental arm of such phase 3 trials.
Data Sources : Articles in the Lancet, Lancet Oncology, JAMA, JAMA Oncology, and Journal of Clinical Oncology published between January 2016 and June 2018 were searched.
Study Selection : Phase 3 RCTs of cancer drugs that failed to improve the primary end point were selected and any prior phase 2 trial of the same drug that supported the phase 3 trial was selected without any date or journal restrictions.
Data Extraction and Synthesis : Percentages of negative phase 3 RCTs of cancer drugs that lacked any phase 2 evidence, had a negative phase 2 trial, or had a positive phase 2 study were extracted. Associations were assessed using the Fisher exact test. Pooled hazard ratios and 95% CIs for the overall survival of patients enrolled in these negative phase 3 RCTs were estimated using a random-effects model.
Main Outcomes and Measures : Negative phase 3 RCTs with a lack of a phase 2 trial or the presence of a negative phase 2 trial and overall survival of enrolled patients in the phase 3 RCTs.
Results : In this meta-epidemiological study, 67 negative phase 3 RCTs on cancer drugs, which included 64 600 patients, met the criteria of being sponsored by industry or academic groups, of which 42 RCTs (63%) were industry sponsored and the remaining 25 RCTs (37%) were academic. A phase 2 trial was not available for 28 of these trials (42%). Of 29 trials (43%) with a phase 2 trial available, 8 trials (28%) failed to meet their primary end points and 5 of those were industry sponsored. There was no association with overall survival for patients participating in these negative phase 3 RCTs (pooled hazard ratio, 0.99; 95% CI, 0.96-1.02). When the pooled analysis was limited to the 27 RCTs with a hazard ratio above 1.00, the overall pooled hazard ratio for overall survival was 1.11 (95% CI, 1.06-1.16). No association between having a negative or undefined phase 2 trial and trial sponsorship was found using the Fisher exact test.
Conclusions and Relevance : More than 40% of the negative phase 3 RCTs in oncology published in these 5 journals were conducted without a supporting phase 2 trial and were sponsored by both academia and industry. Running such trials not only may risk loss of resources owing to a failed trial but also may be associated with decreased patient survival. Further research and regulations in this area appear warranted.
JAMA Network Open , article en libre accès, 2018