How Assessment-Schedule Matching Limits Bias When Comparing Progression-Free Survival in Single-Arm Studies: An Application in Second-Line Urothelial Carcinoma Treatments

• Published in: Value in health 2021-08, Vol.24 (8), p.1137-1144
• Main Authors: Kapetanakis, Venediktos, Prawitz, Thibaud, Schlichting, Michael, Ishak, K. Jack, Phatak, Hemant, Yu, Ting, Bharmal, Murtuza
• Format: Article
• Language: English
• Subjects: Aged; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents, Immunological - therapeutic use; assessment-schedule matching; assessment-time bias; Bias; Bladder cancer; Cancer; Carcinoma, Transitional Cell - drug therapy; Chemotherapy; Clinical outcomes; Clinical trials; Cost analysis; Evaluation; Female; health technology assessment; Humans; Immunotherapy; Male; Matching; matching-adjusted indirect comparisons; Metastases; Patients; population-adjusted indirect comparisons; Progression-Free Survival; Solid tumors; Survival; Technology Assessment, Biomedical; Tumors; Urinary Bladder Neoplasms - drug therapy; Urothelial carcinoma
• ISSN: 1098-3015; 1524-4733
• DOI: 10.1016/j.jval.2021.03.004

Population-adjusted comparisons of progression-free survival (PFS) from single-arm trials of cancer treatments can be derived using matching-adjusted indirect comparisons (MAICs); however, results are still susceptible to bias, particularly if the trials had different tumor assessment schedules. This study aims to assess the effects of assessment-schedule matching (ASM) on the relative effectiveness on the PFS of avelumab versus approved comparator immunotherapies or chemotherapy after population matching in the second-line (2L) setting for metastatic urothelial carcinoma. The MAIC used patient-level data for avelumab from the JAVELIN Solid Tumor trial (NCT01772004). PFS was compared with published curves for other treatments to obtain population-adjusted hazard ratios (HRs). The MAIC was repeated after conducting ASM for differences in tumor assessment scheduled first at 6 weeks for avelumab and durvalumab and at 8 or 9 weeks for other treatments. MAIC adjustment alone altered the HR estimates up to 23%, whereas MAIC plus ASM resulted in up to 32.7% reductions from naive comparisons. Even in cases in which MAIC had little effect, ASM brought an additional change of 11.1% to 15.4%. Overall, the HR range of avelumab versus other treatments changed from 0.83 to 1.25 for naive comparisons to 0.76 to 0.99 after ASM plus MAIC, numerically favoring avelumab. Small variations in assessment schedules can introduce bias in unanchored indirect treatment comparisons of interval-censored time-to-event outcomes. In this study, adjusted PFS was comparable across second-line urothelial carcinoma treatment options, numerically favoring avelumab versus immunotherapies and chemotherapy agents. Correcting this bias is especially important when HRs are applied in cost-effectiveness models to transition patients between states. •Indirect treatment comparisons based on single-arm studies may be biased by differences in schedules for tumor imaging, favoring the treatment with visits scheduled with longer intervals.•After assessment-schedule matching and population matching by matching-adjusted indirect comparisons, there were no differences in progression-free survival between immunotherapeutic agents in the setting of second-line treatments for metastatic urothelial carcinoma.•The size of bias owing to differences in assessment schedules can be higher than the bias-adjusted for by population matching.•In the context of unanchored comparisons in health technology assessments, as