Estimand Framework in AML Based on a Randomized, Placebo-Controlled, Phase 3 Study Investigating the Effect of Adding Midostaurin to Standard Chemotherapy in Patients with Newly Diagnosed AML without a FLT3 Mutation
Authors: Bengoudifa Bourras-Rezki , Weber Hans , Gathmann Insa , Hoenekopp Albert , Berkowitz Noah 
Published: October 2019

Abstract
In the ongoing randomized, placebo-controlled, phase 3 study in patients with newly diagnosed FLT3-mutation-negative acute myeloid leukemia (AML; NCT03512197) investigating the effect of adding midostaurin to standard chemotherapy, event-free survival (EFS) is the primary endpoint. EFS is a standard endpoint in clinical studies in AML. In a recent FDA submission, EFS was confirmed by an advisory committee to be clinically meaningful in AML (https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM570800.pdf. Accessed August 1, 2018). With the release of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E9 draft addendum, we describe EFS in the estimand framework to address the scientific question of interest and illustrate the power of this concept to transparently define the relevant population, the variable of interest, and the management of relevant incidents that can occur in a clinical trial ("intercurrent events").
The objective is to determine the benefit of adding midostaurin to the whole standard chemotherapy sequence, consisting of induction, consolidation therapy, hematopoietic stem cell transplant (HSCT; if applicable), and postconsolidation therapy, in patients with newly diagnosed AML without a FLT3 mutation. The main interest is the interventional effect of the whole treatment sequence and not the contribution of an individual part of it.
The study population includes all randomized patients following the treatment policy approach. Patients can be randomized only if there is confirmation from the central laboratory that there is no FLT3 mutation.
EFS is a composite endpoint defined as the time from randomization until death, relapse, or induction failure. Induction failure is defined as no achievement of remission until end of the induction period. The definition of induction failure also includes instances in which HSCT is conducted as salvage therapy in nonresponding patients. Per convention, the EFS event date of induction failure is set to the randomization date.
The option to receive HSCT can be an outcome of the treatment. Therefore, clinical benefit is assessed regardless of whether patients received HSCT. This treatment policy approach mandates collection of disease assessments after HSCT has been completed. In the same consideration, the option to receive consolidation and postconsolidation treatment is also an outcome of the induction treatment as only patients achieving remission with induction qualify to continue with consolidation and postconsolidation treatment. As such, the benefit is assessed regardless of treatment duration.
The analysis plan defines a supportive estimand to assess the treatment effect of midostaurin, excluding potential benefit from HSCT. Another supportive estimand assesses the effect of discontinuation of induction treatment due to toxicities. This approach addresses a hypothetical scenario in which patients did not receive HSCT, for instance, to estimate the midostaurin-only effect. However, the outcome of the treatment is not limited to the direct effect of an experimental compound but also includes which new treatment option the compound allows for the patients (eg, HSCT).
The estimand framework is an efficient tool to ensure consistency between the scientific question and the definition of the study objectives. It ensures transparency in unfavorable yet unavoidable situations in clinical trials ("intercurrent events"). It facilitates communication within the clinical team and with health authorities. The outcome of studies that are following the estimand framework can be interpreted in a consistent manner.

Disclosures
Bengoudifa: Novartis: Employment. Weber:Novartis: Employment. Gathmann:Novartis: Employment. Hoenekopp:Novartis: Employment. Berkowitz:Novartis: Employment.