Use of External Comparators for Health Technology Assessment Submissions Based on Single-Arm Trials

Abstract

Background: Single-arm trial (SAT) data is increasingly reviewed for drug approvals by regulators and Health Technology Assessment (HTA) bodies. Supplementary data in the form of external comparators (ECs) can be used to provide clinical context to support these drug evaluations. In this study we characterized HTAs for SAT-based submissions, the use of supplementary EC data and outcomes from HTA review.Methods: HTA Accelerator database was used to describe SAT-based HTA submissions with decisions (2011-2019).Results: A total of 433 SAT-based HTA submissions were identified between 2011 and 2019 with a 13-fold increase during this period. Around 65%(283/433) were in oncology or hem-oncology. Around 52%(226/433) of submissions contained some type of EC data, including prior clinical trials (24%, 104) and real-world data (RWD) (20%, 87), but 40%(175) contained no EC data. The overall acceptance rate for SAT-based submissions was 48% and with RWD EC data acceptance was 59%. In the latest 5year period (2015-2019), use of RWD ECs increased 22% as a proportion of submissions per year, whereas, prior trial ECs decreased (-14%) and use of no EC remained stable (-2%). Between 2015 to 2017 and 2018 to 2019, acceptance rate for RWD ECs increased by 20% (41% in 2015-2017 to 61% in 2018-2019) whereas prior trial EC use decreased by 10% and no EC submissions decreased 16%. Of 226 submissions using ECs, only 29%(66) used an adjusted indirect treatment comparison method.Conclusions: SAT-based submissions to HTA bodies are rapidly evolving in terms of composition and acceptance. Types of EC and methodological approach used are important determinants of positive outcomes.

A Proposal for Value-Based Managed Entry Agreements in an Environment of Technological Change and Economic Challenge for Publicly Funded Healthcare Systems

“…According to Hatswell et al ( 46 ), between January 1999 and May 2014, the EMA issued 795 approvals, including 44 solely on evidence from SATs, while the US Food and Drug Administration (FDA) issued 774 and 60, respectively in the same period. The interest is increasing in designs that use non-randomized control patients external to the CT for comparison reasons, to strengthen the evidence of a SAT or RCT ( 47 , 48 ). The external comparator patients are not part of the same trial as those receiving the investigational product.…”

“…They may be receiving the best standard of care treatment or be untreated, and may be sourced from previous trials, observational studies, registries or databases of routine healthcare. External comparators are increasingly used in regulatory decision making ( 47 ).…”

“…It is a natural next step that RWD should be proposed for use in establishing an external comparator arm in clinical trials ( 47 , 49 ). Consequently, studies using RWD (now standard practice in post-authorization safety or effectiveness studies) can be more representative of the population requiring treatment in clinical practice (i.e., externally valid) ( 50 ).…”

Gene Therapy Evidence Generation and Economic Analysis: Pragmatic Considerations to Facilitate Fit-for-Purpose Health Technology Assessment

“…However, such limited data have created larger-than-usual gaps for GT evidence needs ( 16 ), and strategies to improve the strength of evidence for GTs have been recommended ( 21 ). First, the inclusion of other types of non-randomized study designs could provide complementary evidence to single-arm trial data.…”

“…DAF considerations : Although numerous approaches to reduce payer uncertainties with single-arm studies have been published, HTA guidance on assessing evidence from single-arm trials remains scant ( 21 ). In addition, HTA bodies are more likely to accept indirect comparisons for demonstrating non-inferiority but are cautious to accept such evidence for demonstrating superiority ( 28 ).…”