Reporting of master protocols towards a standardized approach: A systematic review

Abstract

Background: In September 2018 the FDA provided a draft guidance on master protocols reflecting an increased interest in these designs by industry. Master protocols refer to a single overarching protocol developed to evaluate multiple hypotheses and may be further categorized as basket, umbrella, and platform trials. However, inconsistencies in reporting persist in the literature. We conducted a systematic review to describe master protocol reporting with the goal of facilitating the further development and spread of these innovative trial designs.

Methods: We searched MEDLINE, EMBASE, and CENTRAL from inception to April 25, 2019 for English articles on master protocols. This was supplemented by hand searches of trial registries and of the bibliographies of published reviews. We used the FDA's definitions of master protocols as references and compared them to self-reported master protocols.

Results: We identified 278 master protocol publications, consisting of 228 protocols and 50 reviews. Sixty-six records provided unique definitions of master protocol types. We observed considerable heterogeneity in definitions of master protocols, and over half (54%) used oncology-specific language. The majority of self-classified master protocols (57%) were consistent with the FDA's definitions of master protocols.

Conclusion: The terms 'master protocol', 'basket trial', 'umbrella trial', and 'platform trial' are inconsistently described. Careful treatment of these terms and adherence to the definitions set forth by the FDA will facilitate better understanding of these trial designs and allow them to be used broadly and to their full potential in clinical research. We encourage trial methodologists to use these trial designations when applicable.

Keywords: Basket trials; Master protocols; Nomenclature; Platform trials; Umbrella trials.

Fig. 1

Master protocol definition characteristics. A summary of key characteristics of the definitions of ‘master protocol’. In this figure, the 20 definitions of master protocols identified were compared based four key attributes of common infrastructure, scope (i.e. oncology focused), centralized data monitoring, and shared ethics review structure.

Fig. 2

Key characteristics of basket trial, umbrella trial, and platform trial definitions. Theree were 35 definitions of basket trials identified, 26 umbrella trial definitions and 25 for platform trial definitions. These different definitions are summarized based on the number of interventions, diseases, and biomarkers involved are illustrated in the left panel (2a), and features of trial designs included in these definitions are mentioned in the right panel (2b). Basket trials are illustrated in color blue, color red for umbrella trials, and color green for platform trials. . (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Proportion of trials classified consistently with FDA definitions. The proportion of master protocols consistent with the FDA definitions are shown in this figure. We compared all self-classified master protocols with the FDA definitions and their attributes (outlined in Table 1). In total, this review identified 89 self-classified master protocols (34 basket trials, 17 umbrella trials, 25 platform trials). 13 protocols self-identified as master protocols and therefore were included under ‘all master protocols’ only.