The role of the estimand framework in the analysis of patient-reported outcomes in single-arm trials: a case study in oncology
Doranne Thomassen, Satrajit Roychoudhury, Cecilie Delphin Amdal, Dries Reynders, Jammbe Musoro, Willi Sauerbrei, Els Goetghebeur, Saskia le Cessie, SISAQOL-IMI Work Package 3, Rajesh Kamalakar, Kavita Sail, Ethan Basch, Jaap C. Reijneveld, Karen Keating, Yun Su, Ahu Alanya, Gerhard Rumpold, Maxime Sasseville, Jennifer A. Black, Geert Molenberghs, Khadija Rantell, Michael Schlichting, Antoine Regnault, David Ness, Silène Ten Seldam, Tove Ragna Reksten, Anja Schiel, Ragnhild Sørum Falk, Alicyn Campbell, Joseph C. Cappelleri, Alexander Russell-Smith, Melanie Calvert, Samantha Cruz Rivera, Olalekan Lee Aiyegbusi, Limin Liu, Kelly Van Lancker, Claudia Rutherford, Vishal Bhatnagar, Ting‐Yu Chen, Mallorie H. Fiero, Paul G. Kluetz
Abstract
BACKGROUND: Patient-reported outcomes (PROs) play an increasing role in the evaluation of oncology treatments. At the same time, single-arm trials are commonly included in regulatory approval submissions. Because of the high risk of biases, results from single-arm trials require careful interpretation. This benefits from a clearly defined estimand, or target of estimation. In this case study, we demonstrated how the ICH E9 (R1) estimand framework can be implemented in SATs with PRO endpoints. METHODS: For the global quality of life outcome in a real single-arm lung cancer trial, a range of possible estimands was defined. We focused on the choice of the variable of interest and strategies to deal with intercurrent events (death, treatment discontinuation and disease progression). Statistical methods were described for each estimand and the corresponding results on the trial data were shown. RESULTS: Each intercurrent event handling strategy resulted in its own estimated mean global quality of life over time, with a specific interpretation, suitable for a corresponding clinical research aim. In the setting of this case study, a 'while alive' strategy for death and a 'treatment policy' strategy for non-terminal intercurrent events were deemed aligned with a descriptive research aim to inform clinicians and patients about expected quality of life after the start of treatment. CONCLUSIONS: The results show that decisions made in the estimand framework are not trivial. Trial results and their interpretation strongly depend on the chosen estimand. The estimand framework provides a structure to match a research question with a clear target of estimation, supporting specific clinical decisions. Adherence to this framework can help improve the quality of data collection, analysis and reporting of PROs in SATs, impacting decision making in clinical practice.