ABSTRACT
Aims: The aim of the study was to determine whether the time to progression (TTP) or time to untreatable progression (TTUP) is an appropriate surrogate endpoint for overall survival (OS) in patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE). Materials and Methods: Eighty-four patients with Barcelona clinic liver cancer (BCLC) stage B or C HCC underwent TACE. The correlations of TTP and TTUP with OS were evaluated after a log transformation of the indicated values. After identifying independent prognostic factors of TTP, TTUP, and OS, the partial correlations of TTP and TTUP with OS were analyzed in all patients and subgroups. Subsequently, the prognostic value of TTP and TTUP was compared by the multivariate survival analysis of OS. Results: Both the BCLC stage and tumor number were correlated with TTP and TTUP. In addition, the BCLC stage, initial treatment failure, and sorafenib administration were associated with OS. In all patients, the correlation coefficients of TTP and TTUP with OS were 0.559 and 0.789, respectively. Adjustment for independent prognostic factors yielded partial correlation coefficients which were 0.433 and 0.697, respectively. Furthermore, OS was found to be associated with TTUP (P = 0.003; hazard ratio: 0.253; 95% confidence interval: 0.10–0.63) but not with TTP. Conclusion: Untreatable progression is more representative of clinical progression in patients with HCC who underwent TACE. In the current study, TTUP is a more appropriate surrogate endpoint for OS than TTP. Future studies should explore whether untreatable progression is a valuable endpoint event in clinical trials or an indicator of the need for second-line therapy
ABSTRACT
OBJECTIVE: To figure out the regulatory models and concepts of FDA in drug review process that promotes surrogate endpoints development. METHODS: This paper made a thorough research to the FDA regulations, guidance documents and guidelines and literatures, and through historical retrospective of surrogate endpoints used in clinical drug trials and regulatory acceptance, interpretation of FDA's established development model in scientific use of surrogates, combined with the status quo surrogate endpoints in the field of serious diseases as cancer, AIDS, diabetes. RESULTS AND CONCLUSION: Then conclusion of FDA's experience in promoting regulation and utility of surrogate endpoints is summed up, including the development of guidelines to promote common understanding of specific use of surrogates; combining a variety of programs promote the development of surrogate endpoints; and using a risk-based classification in favor of the allocation of resources.