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Tumor Discovery Practice and consideration of master protocol design

Administration (FDA) released guidance about master protocols in various disease fields, along with the reasons
protocols in oncology drugs in 2022 and COVID-19 for these phenomena by the characteristics of the diseases,
[1]
in 2019 , representing the concerns and support of the the mechanism of therapeutic products, and the principles
[2]
regulatory authorities for master protocols. So far, over 100 of various types of master protocols. Finally, we also
master protocol trials have been initiated, leading to the propose practical considerations, including design, ethical,
marketing of several therapies, such as vemurafenib and statistics, and funding aspects, to assist practitioners in
[3]
entrectinib . better designing and identifying potentially valuable
[4]
therapies using protocols.
In recent years, master protocol trials have proven to be
more efficient in evaluating new targeted therapies, with 2. Definition and types of master protocol
a substantial increase in the number of clinical trials and trial design
research [5-10] . Woodcock et al. initiated the definition of
master protocols and illustrated it with two examples in A master protocol aims to explore or evaluate multiple
[6]
cancer . Janiaud et al. reviewed the investigational drug therapies or multiple subpopulations in parallel under a
clinical trials with master protocols in ClinicalTrials.gov single overarching protocol, with the characteristics of
and briefly summarized the advantages and limitations in improving efficiency and establishing uniformity through
oncology . In contrast, only a few master protocol trials standardization of procedures in clinical trials. In addition,
[11]
and research have been conducted in radiation oncology the master protocols can be designed adaptively to modify
devices (RODs). Bitterman et al. summarized the examples the protocol flexibly, such as incorporating or terminating
with master protocols in RODs and demonstrated the individual sub-studies, which are often classified into
shortcomings and challenges of clinical evaluation of basket trials, umbrella trials, and platform trials (Figure 1).
RODs . Couwenberg et al. explored the feasibility of a 2.1. Basket trial design
[12]
master protocol in techniques/software development for
magnetic resonance (MR)-guided adaptive radiotherapy A basket trial is a type of clinical trial that tests how well
with the MR-Linac . Due to the regulatory requirements a new drug or other substance works in patients who have
[13]
for Class I and Class II devices , these devices often different types of cancer that all have the same mutation or
[14]
undergo less rigorous prospective assessment and have biomarker (Figure 1A). In basket trials, all patients receive
fewer clinical research studies conducted. the same treatment that targets the specific mutation
or biomarker found in their cancer. In practice, the
Despite the increasing number of clinical trials utilizing nonrandomized sub-studies within basket trials may be
master protocols in both investigational drugs and medical preferred because of their feasibility and close connection
devices, there are still a lot of challenges and varying degrees to the conventional single-arm Phase II designs. However,
of insularity in the field. Published reviews have primarily due to the absence of a comparator, non-randomized
focused on oncology drugs and devices, respectively, with basket sub-studies should select an objective response as
limited comparisons and discussions across different the primary endpoint for its interpretability. In addition,
fields, hindering a comprehensive understanding of basket trials may also be useful for studying rare cancers
master protocols. Besides, given the heightened scrutiny of and cancers with rare genetic changes. For example,
medical devices, the application of the master protocols to the prevalence of many targets is too low to analyze by
identify the most high-value technologies more efficiently each target type with enough subjects, while pooling all
is necessary [12,15] . In addition, the development of in vitro subpopulations with homogeneity might be considered .
[16]
diagnostics parallel to their corresponding therapeutic
products in master protocols needs further investigation, as 2.2. Umbrella trial design
they can help identify populations with a higher likelihood An umbrella trial endeavors to study multiple therapies
of response and safety. within a single disease (Figure 1B), in which patients
To synthetically understand how to identify the most with targets of interest are allocated to mutually exclusive
valuable innovative drugs and medical devices more therapeutic sub-studies. In terms of the allocation of
efficiently based on limited health-care resources using patients, it is a necessity to prespecify and evaluate an
master protocols, this paper provides an overview of the explicit rule governing how to match subpopulations
master protocol framework, unifying definitions and and candidate regimens, especially for patients who are
illustrating essential design elements from representative positive for multiple biomarkers. Umbrella trials can
example trials in both drugs and medical devices. Besides, employ either randomized or nonrandomized designs. For
to understand the master protocols deeply, it is also a randomized umbrella sub-studies, FDA recommends a
need to summarize the commonly-used types of master common control arm of the standard of care (SOC), which

Volume 2 Issue 2 (2023) 2 https://doi.org/10.36922/td.342