This August (2025), the U.S. Food & Drug Administration (FDA) set out draft guidance that could significantly impact the future of clinical trials focused on oncology treatments.
Building on recent cross-industry discussions around endpoints, the 18 page document details several recommendations for sponsors undertaking randomised clinical trials in emerging cancer drugs. In all the detail, there is one line that arguably stands out as the key takeaway: “Overall survival should be prioritized as the primary endpoint when feasible.”[1],[2]
At first glance, this might not seem so significant. After all, overall survival (OS) is commonly accepted as the gold standard endpoint, reflecting the potential of a therapy to prolong life – an objectively desirable outcome that is entirely straightforward to evaluate and encapsulates the key goals of efficacy and safety. However, this comes in the context of the fact that oncology trials are not always designed with OS as the primary endpoint. In many Phase 2 trials, measures such as progression-free survival (PFS) are used instead, switching focus to the length of time that a patient lives with disease following treatment, without their condition getting worse.[3]
There is no question that PFS is a valuable marker of promising early-stage response to a therapy, highlighting where patients have benefited from a suppression of tumour growth, the inhibiting of new lesion growth, or no unequivocal increase non-measurable malignant disease. It does not necessarily follow, however, that meeting the threshold for PFS correlates to an improved chance of overall survival. Indeed, as the FDA points out, several drug development programs have demonstrated a discord between these measures, with evidence of anti-tumour activity counterbalanced by drug related toxicity and reductions in OS. In short, PFS might equate to patient benefits, but it does not necessarily equate to patients living longer – a situation that has even led some to propose retiring the term progression free survival in favour of progression free interval. [4]
While OS might be a more desirable endpoint, arriving at this gold standard is far from simple, and far from expedient. OS, by definition, is a longer-term measure of efficacy and safety, which, historically, has meant results are evaluated descriptively, with the FDA making assessments regarding safety on this basis. For its part, the FDA acknowledges these points of friction. In response, it advises employing OS as the primary endpoint for oncologic diseases with a short natural history, late-line disease settings, or in settings demonstrating retention or improvement on existing therapeutics known to already deliver survival advantage.
The FDA has also underlined the important caveat of feasibility in relation to OS. For some indolent diseases or where therapeutics are extremely efficacious, the regulator accepts that long survival times will result in impractical levels of follow up time. It also might not be feasible in single arm trials. Furthermore, the FDA recognises the complexity of measuring and interpreting OS led trial results, given the impact of crossover, the role of additional therapies and other potential intercurrent events.
But even where feasibility issues preclude OS as the primary endpoint, the FDA guidance recommends “collection and submission of overall survival data”, with OS potentially prespecified as a secondary endpoint. This serves to underline a direction of travel where treatment effect and safety can be better evaluated in relation to OS through closer consideration of this factor in trial design.
In summary, then, the draft guidance sets out a clear direction of travel from the FDA when it comes to placing greater emphasis on OS within oncology trials. And there is little doubt that such a shift will directly impact on the complexity and duration of oncology trials, leading to increased costs. In turn, this has the potential to reduce the appetite of sponsors to invest, leading to an overall reduction in the number of therapies progressing to trial.
For those that do, there are important considerations, particularly in light of the growing trend for self-administered dosage forms, including oral drugs and sub-cutaneous injections. Further considerations include the increased likelihood of intercurrent events, such as treatment discontinuation, in trials that have a longer timeframe. Together, these factors make it even more critical for participating patients to require close monitoring over an extended period to track real world behaviours and assess genuine treatment effects, both in terms of efficacy and safety.
It is surprising, then, that that FDA guidance does not place emphasis on the importance of adherence monitoring within its admirable vision of a new world order in oncology trials. And this is particularly pertinent in light of Project Optimus, the initiative led by the regulator’s Oncology Center of Excellence (OCE) which aims to improve characterisation of dosing for new therapies to optimise for efficacy, safety and tolerability – an ambition that inherently relies on close measurement of adherence within trials.
Proactive management of patients should be fundamental in trials targeting measurement of OS to ensure that the mechanisms for monitoring dosing activity is fully robust. Without it, there is a risk that better designed trials targeting more powerful results are let down by inherently weak understanding of the true relationship between exposure to a promising therapy and levels of efficacy and safety.
Cancer is a growing global health burden, with over 35 million new cases predicted in 2050, representing a 77% increase from the estimated 20 million cases in 2022.[5] The FDA is to be applauded for any steps that shift the conversation in trials towards delivering not just progression free survival but overall survival. This might have always been the aim of sponsors, but given extra impetus by the FDA, there is exciting potential to re-establish robust endpoint goals and secure improved outcomes.
If an underlying mechanism as important as adherence measurement is incorporated into the objectives, design and data collection model from the start of a trial, then sponsors stand a greater chance of establishing high quality, high integrity analysis on overall survival impact. If it is not part of that conversation, however, then trials are weakened and the intended shift towards OS driven endpoints could fail to deliver on its full potential in terms of advancing vital life extending and lifesaving treatments that are so desperately desired by cancer patients and their families.
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[1] https://www.fda.gov/regulatory-information/search-fda-guidance-documents/approaches-assessment-overall-survival-oncology-clinical-trials
[2] aacr.org/professionals/policy-and-advocacy/regulatory-science-and-policy/events/fda-aacr-asa-workshop-overall-survival-in-oncology-clinical-trials/
[3] https://www.cancer.gov/publications/dictionaries/cancer-terms/def/progression-free-survival
[4] https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00015-8/abstract
[5] https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing–amidst-mounting-need-for-services
