Complex Cancer Trials: Group of UK Experts Offers Recommendations

Regulatory NewsRegulatory News | 08 January 2020 |  By 

As the use of complex innovative design (CID) trials for new cancer treatments continues, a group of UK professors from the University of Oxford, Birmingham and others, as well as representatives from the UK’s Medicines and Healthcare products Regulatory Agency and Pfizer have offered a series of recommendations on the flexible trials.

Published this week in the British Journal of Cancer, the consensus statement explains how unlike conventional trials in which patients are recruited by tumor of origin, patients enrolled in one kind of CID trial, known as “master protocol” trials, incorporate molecular biomarkers. One type of master protocol trial is known as the basket trial, which involves patients who have different tumor types, but all of whom have a common biomarker relevant to the investigational drug.

“By contrast, in umbrella trials, [which is another type of master protocol trial,] patients with a single-tumour type are stratified into multiple cohorts based on molecular markers defining each treatment arm. These stratifications allow parallel comparison of therapy/ies for an individual disease (or biomarker cohort) or enable overall assessment via a single stratified analysis,” the statement says.

One of the earliest examples of a CID trial was the international PROFILE 1001 non-small cell lung cancer (NSCLC) study designed to investigate crizotinib, which was first approved in the US in 2011. “EU Marketing Authorisation was obtained for crizotinib just 5 years after the discovery of the EML4-ALK fusion gene,” the authors note.

One of the UK group’s recommendations for future CID trials, in addition to meeting with regulators, HTA bodies and other stakeholders as early as possible before or during the trial design, is related to the use of risk-based monitoring, which they said “can lead to improvement in the efficiency of monitoring while preserving data quality. This approach has been endorsed by the EMA, and is particularly suited to CID trials given their complexity.”

Last March, the US Food and Drug Administration (FDA) also released new draft guidance on risk-based monitoring that built off a previous guidance from 2013, in addition to guidance on adaptive trial designs. The agency is also running a pilot program through 2022 to offer some sponsors increased interactions with the agency to discuss their proposed CID approach.

But the UK experts caution that although CID trials are designed to be flexible, “A clear trial end needs to be specified, e.g., a maximum study duration, a maximum number of arms or events that define the end of each study arm. This is to prevent the establishment of an endless study, with numerous additional arms or IMP combinations that were not considered in the original trial design.”

They also say that any changes made at the end of trial, “for whatever reason, should be notified as a substantial amendment, with prior regulatory discussions recommended.”

Statistical approaches and patient-facing documentation for CID trials are also discussed, including a recommendation for participants to receive a document explaining the technical and practical details of taking part in the trial and information on the storage and analyses of tissue biopsies, protection and sharing of the personal data.
They further make clear that there is a legal obligation in the EU and US for sponsors to report both negative and positive clinical trial results either in EudraCT or in

“Although there is no regulatory mandate to report interim trial data or make the results of completed arms of a CID trial available on public trial registries until the whole trial is completed, the prompt reporting of the results as they are obtained minimises the risk of duplication of effort whilst enabling early dissemination of important findings into the community,” they add. “It is our recommendation that reporting of trial data at robust and pre-specified time points when scientifically and clinically relevant should be supported as best practice and the most appropriate timing of data release must be predefined in the protocol. It will be crucial to ensure this practice extends beyond scientific publication and includes dissemination to trial participants and other interested groups and communities.”

And as more cancer drugs are approved via the accelerated approval pathway, the experts say it is “essential that regulators specify the appropriate post-marketing commitments to manufacturers, and that marketing authorisation is withdrawn if these are not met.”

Effective delivery of Complex Innovative Design (CID) cancer trials—A consensus statement


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