Implementing the FDA’s draft guidance on core PROs in cancer trials: the challenge of a modular approach

Tim Luckett, PhD¹; Brendan Mulhern, PhD¹; Carrie-Anne Ng, PhD¹; and Jessica Roydhouse, PhD^1,2

¹Cancer Quality of Life Expert Service Team (CQUEST), University of Technology Sydney (UTS), Australia
²Menzies Institute for Medical Research, University of Tasmania, and ISOQOL representative on the CQUEST Steering Committee

ISOQOL’s perspective (https://doi.org/10.1007/s11136-023-03396-z) on the FDA’s 2021 draft guidance (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/core-patient-reported-outcomes-cancer-clinical-trials) summarises many of the daily challenges we face as a ‘technical service’ funded by the Australian government to provide PROMs advice to 14 Australasian Collaborative Cancer Clinical Trials Groups. The guidance (and perspective) discusses a modular approach to choosing PROMs, which is a growing topic of interest in our conversations with stakeholders. While we agree with the ISOQOL authors that a questionnaire’s length should by no means be the only factor for selecting PROs for a given trial, burden from too many items is THE most common PROM-related complaint expressed by cancer patients and clinical triallists alike.

Over the past couple of decades, two ‘suites’ of PROMs have developed a near duopoly on cancer clinical trials: EORTC and FACIT. Both suites offer a ‘core’ or ‘general’ measure for use across cancer types plus further measures that capture disease- and/or treatment-specific impacts. Trials typically combine the general/core measure and relevant treatment/disease measure, commonly resulting in 50 or more items repeated at multiple time-points. Hardly ever will all sub-scales from a given measure be required to address a PRO objective, but administering complete measures has become the standard “least risky” approach. Unfortunately, this poses other risks in the form of demotivation for staff and patients that might increase missing data and reduce data quality. Neither the EORTC nor FACIT have endorsed the FDA’s modular approach. Yet both organisations have produced online tools that invite users to customise PROM selection from the suite’s full range of single and multi-item scales according to the needs of a given trial.

Attractive as it may be for reducing burden, encouraging triallists to use only parts of existing PROMs must be accompanied by several caveats. We know of few head-to-head studies that examine the trade-off between burden and validity for the use of selected PROM sub-scales, but we suspect that results will depend on which sub-scales are involved and their ordering in the original measure. The final sub-scales of the QLQ-C30 and FACT-G are especially vulnerable to an order effects because they contain items on overall quality of life that, for some participants, may represent a summation of reflection across preceding items. It’s also worth noting that items outside of the FDA’s core sub-scales may be needed to enable health economic analyses for key stakeholders, such as those engaged in health technology assessment. There may be unexpected effects that a modular approach fails to capture. And studies using a modular or custom approach may encounter difficulties when comparing to older studies that used measures in their entirety.

The above considerations significantly complicate the decision of choosing a PROM, which should take account of the overall trial objectives and context, as emphasised by international consensus initiatives by ISOQOL, SPIRIT-PRO and SISAQOL. Further discussion and guidance are needed to help researchers and services such as ours ensure that patient voices are heard in trials while minimising burden and ensuring that all stakeholders get the information they need.   

This newsletter editorial represents the views of the author and does not necessarily reflect the views of ISOQOL. 

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