Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols

Abstract

Background Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation. Despite the many advantages of these designs, they are infrequently used. Methods We conducted a landscape analysis of master protocols using a systematic literature search to determine what trials have been conducted and proposed for an overall goal of improving the literacy in this emerging concept. On July 8, 2019, English-language studies were identified from MEDLINE, EMBASE, and CENTRAL databases and hand searches of published reviews and registries. Results We identified 83 master protocols (49 basket, 18 umbrella, and 16 platform trials). The number of master protocols has increased rapidly over the last five years. Most have been conducted in the US (n = 44/83) and investigated experimental drugs (n = 82/83) in the field of oncology (n = 76/83). The majority of basket trials were exploratory (i.e., phase I/II; n = 47/49) and not randomized (n = 44/49), and more than half (n = 28/48) investigated only a single intervention. The median sample size of basket trials was 205 participants (interquartile range, Q3-Q1 [IQR]: 500–90 = 410), and the median study duration was 22.3 (IQR: 74.1–42.9 = 31.1) months. Similar to basket trials, most umbrella trials were exploratory (n = 16/18), but the use of randomization was more common (n = 8/18). The median sample size of umbrella trials was 346 participants (IQR: 565–252 = 313), and the median study duration was 60.9 (IQR: 81.3–46.9 = 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6–4 = 2). The majority of platform trials were randomized (n = 15/16), and phase III investigation (n = 7/15; one did not report information on phase) was more common in platform trials with four of them using seamless II/III design. The median sample size was 892 (IQR: 1835–255 = 1580), and the median study duration was 58.9 (IQR: 101.3–36.9 = 64.4) months. Conclusions We anticipate that the number of master protocols will continue to increase at a rapid pace over the upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design methods to fields outside of oncology.

An overview of precision oncology basket and umbrella trials for clinicians

“…For both basket trials and umbrella trials, they may be conducted with or without a control group (ie, randomized vs single‐arm nonrandomized designs). A landscape analysis recently showed that it is more common for umbrella trials to use a control group (n = 8 of 18 trials; 44.4%) than basket trials (n = 5 of 49 trials; 10.2%) . For umbrella trials, the control group may be placebo if there is no established care, or the existing standard of care for the disease being studied may be used for all of the subgroups.…”

“…With these rising interests and efforts toward precision care, it is vital to recognize the importance of biomarkers and how they are used to develop targeted therapies in clinical research . Notable methodological advancements that have recently been made toward biomarker‐guided clinical trials include the development of basket and umbrella design trials under the master protocol framework . A master protocol refers to a single, overarching design developed to evaluate multiple hypotheses with the general goal of improving efficiency through standardized trial procedures .…”

“…Two types of master protocols are basket and umbrella trials. Basket trials refer to designs in which a targeted therapy is evaluated for multiple diseases that share common molecular alterations, and umbrella trials refer to designs in which multiple targeted therapies are evaluated for a single disease that is stratified into multiple subgroups . The US Food and Drug Administration (FDA) released its draft guidance document outlining recommendations for basket trials and umbrella trials on September 2018, highlighting their support for a wider dissemination of these master protocols .…”

“…The US Food and Drug Administration (FDA) released its draft guidance document outlining recommendations for basket trials and umbrella trials on September 2018, highlighting their support for a wider dissemination of these master protocols . A recent landscape analysis using a comprehensive literature search has found a rapidly increasing number of these master protocols, as the number increased from 2 (a basket trial and an umbrella trial) to 67 (49 basket trials and 18 umbrella trials) over 10 years between 2009 and 2019 …”

“…Despite these rapidly increasing numbers of basket and umbrella trials, currently, they are still poorly understood . Most basket and umbrella trials have been conducted in oncology and were led by investigators from the US National Cancer Institute (NCI), industry, and contract research organizations . Understanding of basket and umbrella trials is not widespread among clinicians and researchers outside of the NCI and the private sector.…”