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An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention-to-treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment-policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross-industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation.
Assuntos
Neoplasias , Troca de Tratamento , Interpretação Estatística de Dados , Humanos , Oncologia , Neoplasias/tratamento farmacológico , Projetos de PesquisaRESUMO
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INTRODUCTION: ABP 798 is being developed as a biosimilar to rituximab reference product (RP), a CD20-directed cytolytic antibody that is approved in the US and EU for the treatment of non-Hodgkin lymphoma (NHL). METHODS: This randomized, double-blind, comparative clinical study (JASMINE) evaluated the efficacy and safety of ABP 798 compared with rituximab RP. Adult, anti-CD20 treatment naïve patients diagnosed with grade 1, 2, or 3a follicular B-cell NHL expressing CD20 were randomized 1:1 to receive a 375 mg/m2 infusion of either ABP 798 or rituximab RP once weekly for 4 weeks and at weeks 12 and 20. Tumor assessments were performed at baseline and weeks 12 and 28. Primary endpoint was the risk difference (RD) of overall response rate (ORR) of complete response, unconfirmed complete response, or partial response by week 28 based on data from central, independent, and blinded assessments of disease. RESULTS: Of the 256 randomized patients, 254 were treated with ABP 798 (n = 128; 100%) or rituximab RP (n = 126; 98.4%); 96 (78.0%) patients in the ABP 798 group and 87 (70.2%) in the rituximab RP group had a best ORR by week 28. The point estimate of RD in ORR between ABP 798 and rituximab RP from the adjusted generalized linear model for stratification factors was 7.7%. Clinical equivalence was based on sequential testing of the one-sided 95% lower confidence limits and one-sided 95% upper confidence limits of RD in ORR (- 1.4% and 16.8%, respectively) which was within the prespecified non-inferiority margin (- 15%) and non-superiority margin (35.5%), respectively. Results of sensitivity analyses were consistent with the primary efficacy analysis. ABP 798 was also comparable to rituximab RP across additional secondary endpoints, further supporting the conclusion of similarity, and including: RD of ORR at week 12; trough serum concentrations; percent of patients with complete depletion of CD19+ cell count at day 8; safety; and immunogenicity. CONCLUSIONS: These results support a conclusion of similar clinical efficacy between ABP 798 and rituximab RP in patients with follicular lymphoma. NCT NUMBER: NCT02747043; first posted April 21, 2016. EUDRACT NUMBER: 2013-005,542-11; submitted 14 October, 2014.