Evidence generation in the clinical development of medicines for leukaemia

Abstract

Leukaemia accounts for the highest age-standardised mortality rate among haematological malignancies in Europe. Evidence of efficacy for antineoplastic agents may be valued differently by regulatory and health technology assessment (HTA) bodies in the European Union (EU), impacting decision-making and access to novel medicines. The aims of the study were to analyse the evolvement of efficacy parameters studied in leukaemia clinical trials (CTs), to explore scientific expert opinions on evidence generated and clinical assessments for antineoplastic therapies and to determine core efficacy outcomes prioritised by EU decision-makers for leukaemia CTs. Part I data collection on trends in efficacy parameters involved the following: (1) Phase II to Phase IV leukaemia CTs were identified from the EU Clinical Trials Register database throughout an 11-year period (2007-2017), (2) CTs were screened against inclusion criteria, (3) efficacy endpoints were extracted and grouped according to type of measurement, (4) data mining of trends was performed using descriptive and inferential statistics. Part II data collection exploring scientific expert opinions consisted of these steps: (1) the Response Evaluation in Leukaemia (ReVALeu) surveying tool was developed and tested for validity and reliability, (2) the tool was disseminated in an e-Delphi process with two independent panels composed of regulatory and HTA oncology experts, (3) core efficacy outcomes reaching consensus were determined. Thirty-six unique efficacy endpoints were identified from the final dataset of CTs (N=431) and grouped into clusters of survival (n=5), time-to-event (n=6), response rates and biomarkers (n=16) and other (n=9). Complete response rate was the most studied primary endpoint (CTs: 19%, n=81), with progression-free survival (PFS) and minimal residual disease (MRD) registering the highest frequency change pre- and post-2012 (PFS: 8%, p=0.01; MRD: 8%, p=0.003). Thirty-six panellists were recruited in the eDelphi; 24 regulatory representatives from the European Medicines Agency (EMA) and 12 experts from HTA bodies in 9 EU countries. Opinions on the quality of pre- and post-authorisation evidence generated for antineoplastic agents were statistically different (pre-authorisation: p=0.01, post-authorisation: p=0.04). Six efficacy endpoints achieving consensus were common to both regulatory and HTA groups of decisionmakers and identified as the core outcomes. Biomarker-based endpoints are emerging as primary efficacy measures in leukaemia CTs. Decision-makers perceive the quality of evidence generated for antineoplastic therapy differently. The identification of core efficacy outcomes may potentially optimise CT data packages for regulatory and reimbursement approvals.