Incorporating and interpreting regulatory guidance on estimands in diabetes clinical trials: The PIONEER 1 randomized clinical trial as an example

Abstract

Regulatory guidelines describe the use of estimands in designing and conducting clinical trials. Estimands ensure alignment of the objectives with the design, conduct and analysis of a trial. An estimand is defined by four inter-related attributes: the population of interest, the variable (endpoint) of interest, the way intercurrent events are handled and the population level summary. A trial may employ multiple estimands to evaluate treatment effects from different perspectives in order to address different scientific questions. As estimands may be an unfamiliar concept for many clinicians treating diabetes, this paper reviews the estimand concept and uses the PIONEER 1 phase 3a clinical trial, which investigated the efficacy and safety of oral semaglutide vs placebo, as an example of the way in which estimands can be implemented and interpreted. In the PIONEER 1 trial, two estimands were employed for each efficacy endpoint and were labelled as: (a) the treatment policy estimand, used to assess the treatment effect regardless of use of rescue medication or discontinuation of trial product, and provides a broad perspective of the treatment effect in the population of patients with type 2 diabetes in clinical practice; and (b) the trial product estimand, used to assess the treatment effect if all patients had continued to use trial product for the planned duration of the trial without rescue medication, thereby providing information on the anticipated treatment effect of the medication. Both approaches are complementary to understanding the effect of the studied treatments.

Keywords: Diabetes; GLP-1 receptor agonists; PIONEER; estimand; oral semaglutide; regulatory guidance.

Conflict of interest statement

V. R. A. has served as a consultant for Adocia, AstraZeneca, BD, Novo Nordisk, Sanofi and Zafgen; has received research grant support to her employing institution from AstraZeneca/BMS, Calibra, Eisai, Janssen, Novo Nordisk, Sanofi and Theracos; and declares that her spouse is an employee of Merck.

J. B. has received contracted consulting fees that are paid to the University of North Carolina from Adocia, AstraZeneca, Dance Biopharm, Dexcom, Elcelyx Therapeutics, Eli Lilly, Fractyl, GI Dynamics, Intarcia Therapeutics, Lexicon, MannKind, Metavention, NovaTarg, Novo Nordisk, Orexigen, PhaseBio, Sanofi, Senseonics, Shenzhen HighTide, Takeda, vTv Therapeutics and Zafgen; has received grant support from AstraZeneca, Eli Lilly, GI Dynamics, GlaxoSmithKline, Intarcia Therapeutics, Johnson & Johnson, Lexicon, Medtronic, Novo Nordisk, Orexigen, Sanofi, Scion NeuroStim, Takeda, Theracos and vTv Therapeutics; has served as a consultant to Neurimmune AG; holds stock options in Mellitus Health, PhaseBio and Stability Health; and is supported by a grant from the National Institutes of Health (UL1TR002489).

M. J. D. has served as a consultant, advisory board member and speaker for Novo Nordisk, Sanofi‐Aventis and Lilly; has served as an advisory board member for Servier and Janssen; has served as a speaker for Boehringer Ingelheim and Takeda Pharmaceuticals International Inc; has received grants in support of the investigator and investigator‐initiated trials from Novo Nordisk, Sanofi‐Aventis, Lilly, Boehringer Ingelheim and Janssen.

T. S., M. D. and J. Z. are employees of Novo Nordisk A/S. T. S. and M. D. also hold shares in Novo Nordisk A/S.

© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1

Illustration of estimands used in the PIONEER 1 trial. HbA1c, glycated haemoglobin

Figure 2

Estimand description and results from the PIONEER 1 trial. Change from baseline in A, HbA1c and B, body weight for the treatment policy estimand and the trial product estimand at Week 26.9 ETDs [95% CI] are shown. American Diabetes Association PIONEER 1: Randomized Clinical Trial Comparing the Efficacy and Safety of Oral Semaglutide Monotherapy with Placebo in Patients with Type 2 Diabetes, American Diabetes Association, 2019. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association. CI, confidence interval; ETD, estimated treatment difference; HbA1c, glycated haemoglobin. aRescue medication criteria: confirmed fasting blood glucose greater than 240 mg/dL (13.3 mmol/L) from week 8 to 13, or greater than 200 mg/dL (11.1 mmol/L) from week 14 onwards. bIn PIONEER 1, trial product discontinuation rates were 2.3% to 7.4% with oral semaglutide and 2.2% with placebo

Figure 3

Frequency and timings of intercurrent events in the PIONEER 1 trial9