Efficacy gap between phase II and subsequent phase III studies in oncology.

AIMS: There is a trend for more flexibility in timing of evidence generation in relation to marketing authorization, including the option to complete phase III trials after authorization or not at all. This paper investigated the relation between phase II and III clinical trial efficacy in oncology. METHODS: All oncology drugs approved by the European Medicines Agency (2007-2016) were included. Phase II and phase III trials were matched based on indication and treatment and patient characteristics. Reported objective response rates (ORR), median progression-free survival (PFS) and median overall survival (OS) were analysed through weighted mixed-effects regression with previous treatment, treatment regimen, blinding, randomization, marketing authorization type and cancer type as covariates. RESULTS: A total of 81 phase II-III matches were identified including 252 trials. Mean (standard deviation) weighted difference (phase III minus II) was -4.2% (17.4) for ORR, 2.1 (6.7) months for PFS and -0.3 (5.1) months for OS, indicating very small average differences between phases. Differences varied substantially between individual indications: from -46.6% to 47.3% for ORR, from -5.3 to 35.9 months for PFS and from -13.3 to 10.8 months for OS. All covariates except blinding were associated with differences in effect sizes for at least 1 outcome. CONCLUSIONS: The lack of marked average differences between phases may encourage decision-makers to regard the quality of design and total body of evidence instead of differentiating between phases of clinical development. The large variability emphasizes that replication of study findings remains essential to confirm efficacy of oncology drugs and discern variables associated with demonstrated effects.

Optimization of the recovery of high-value compounds from pitaya fruit by-products using microwave-assisted extraction.

A green microwave-assisted extraction of high value-added compounds from exotic fruits' peels was optimized by Box-Behnken design using 3 factors: solid/solvent ratio, X1, temperature, X2, and extraction time, X3. By using Derringer's desirability function, optimum extraction yields are obtained with X1=1/149.95g/mL, X2=72.27°C and X3=39.39min (white-fleshed red pitaya) and X1=1/148.96g/mL, X2=72.56°C and X3=5.02min (yellow pitaya) and a maximum betacyanin content is achieved with X1=1/150g/mL, X2=49.33°C and X3=5min. None of the factors influenced the extraction of phenolic compounds. Eighteen cinnamoyl derivatives, 17 flavonoid derivatives and 4 betacyanins were identified by HPLC-DAD-ESI/MSn, 23 and 15 new compounds being described in yellow and white-fleshed red pitayas, respectively. These results indicate that it is possible to reuse these by-products to recover compounds for food and pharmaceutical industries.