Assessment-Schedule Matching in Unanchored Indirect Treatment Comparisons of Progression-Free Survival in Cancer Studies
The timing of efficacy-related clinical events recorded at scheduled study visits in clinical trials are interval censored, with the interval duration pre-determined by the study protocol. Events may happen any time during that interval but can only be detected during a planned or unplanned visit. Disease progression in oncology is a notable example where the time to an event is affected by the schedule of visits within a study. This can become a source of bias when studies with varying assessment schedules are used in unanchored comparisons using methods such as matching-adjusted indirect comparisons.
We illustrate assessment-time bias (ATB) in a simulation study based on data from a recent study in second-line treatment for locally advanced or metastatic urothelial carcinoma, and present a method to adjust for differences in assessment schedule when comparing progression-free survival (PFS) against a competing treatment.
A multi-state model for death and progression was used to generate simulated death and progression times, from which PFS times were derived. PFS data were also generated for a hypothetical comparator treatment by applying a constant hazard ratio (HR) to the baseline treatment. Simulated PFS times for the two treatments were then aligned to different assessment schedules so that progression events were only observed at set visit times, and the data were analysed to assess the bias and standard error of estimates of HRs between two treatments with and without assessment-schedule matching (ASM).
ATB is highly affected by the rate of the event at the first assessment time; in our examples, the bias ranged from 3 to 11% as the event rate increased. The proposed method relies on individual-level data from a study and attempts to adjust the timing of progression events to the comparator’s schedule by shifting them forward or backward without altering the patients’ actual follow-up time. The method removed the bias almost completely in all scenarios without affecting the precision of estimates of comparative effectiveness.
Considering the increasing use of unanchored comparative analyses for novel cancer treatments based on single-arm studies, the proposed method offers a relatively simple means of improving the accuracy of relative benefits of treatments on progression times.
VK and JI conceived the method; MS, HP, MB and JWS contributed to the method inception; TP analysed the data and wrote the first draft of the manuscript; MB led the project team from inception to completion; VK, MS, JI, HP, MK, JWS, AB and MB contributed to the interpretation of results and revision of the manuscript. All authors have read and approved the final manuscript; VK is the guarantor of the manuscript.
Compliance with Ethical Standards
This research was funded by Merck KGaA, Darmstadt, Germany, and is part of an alliance between Merck KGaA and Pfizer Inc., New York, NY, USA.
Conflict of interest
Venediktos Kapetanakis, Thibaud Prawitz, Jack Ishak and Agnes Benedict are employees of Evidera, which was hired by the sponsor, Merck Healthcare KGaA, to conduct this research. John W. Stevens served as a consultant to Evidera. Michael Schlichting and Mairead Kearney are employees of the sponsor, Merck Healthcare KGaA. Hemant Phatak and Murtuza Bharmal are employees of EMD Serono, a business of Merck KGaA, Darmstadt, Germany.
- 6.Phillippo DM, Ades T, Dias S, Palmer S, Abrams KR, Welton NJ. NICE DSU technical support document 18: methods for population-adjusted indirect comparisons in submissions to NICE. Sheffield: NICE Decision Support Unit; 2016.Google Scholar
- 9.NICE Single technology appraisal: atezolizumab for treating metastatic urothelial bladder cancer after platinum-based chemotherapy [ID1327]. London: NICE; 2017.Google Scholar
- 11.Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10111):2461–71.CrossRefGoogle Scholar
- 13.Apolo AB, Ellerton J, Infante JR, Agrawal M, Gordon MS, Aljumaily R, et al. Avelumab treatment of metastatic urothelial carcinoma (mUC) in the phase 1b JAVELIN Solid Tumor study: updated analysis with ≥ 12 months of follow-up in all patients [poster no. 856P]. 42nd ESMO Annual Congress; 8–12 Sep 2017; Madrid.Google Scholar