Amplifying the Patient's Voice in Oncology Early-Phase Clinical Trials: Solutions to Burdens and Barriers.

Dose-finding oncology trials (DFOTs) provide early access to novel compounds of potential therapeutic benefit in addition to providing critical safety and dosing information. While access to trials for which a patient is eligible remains the largest barrier to enrollment on clinical trials, additional direct and indirect barriers unique to enrollment on DFOTs are often overlooked but worthy of consideration. Direct barriers including financial costs of care, travel and time investments, and logical challenges including correlative study designs are important to bear in mind when developing strategies to facilitate the patient experience on DFOTs. Indirect barriers such as strict eligibility criteria, washout periods, and concomitant medication restrictions should be accounted for during DFOT design to maintain the fidelity of the trial without being overly exclusionary. Involving patients and advocates and incorporating patient-reported outcomes (PROs) throughout the process, from initial DFOT design, through patient recruitment and participation, is critical to informing strategies to minimize identified barriers to offer the benefit of DFOTs to all patients.

Patient and public involvement and engagement in the development of innovative patient-centric early phase dose-finding trial designs.

BACKGROUND: In light of the FDA's Project Optimus initiative, there is fresh interest in leveraging Patient-reported Outcome (PRO) data to enhance the assessment of tolerability for investigational therapies within early phase dose-finding oncology trials. Typically, dose escalation in most trial designs is solely reliant on clinician assessed adverse events. Research has shown a disparity between patients and clinicians when assessing whether an investigational therapy is tolerable, leading to the recommendation of potentially intolerable doses for further investigation in subsequent trials. It is also increasingly recognized that patient and public involvement and engagement (PPIE) plays a pivotal role in enriching trial design and conduct. However, to our knowledge, no PPIE has explored the optimal integration of PROs in the development of advanced statistical trial designs within early phase dose-finding oncology trials. METHODS: A virtual PPIE session was held with nine participants on 18th October 2023 to discuss the incorporation of PROs within a dose-finding trial design. This cross disciplinary session was developed and led by a team of statisticians, clinical specialists, qualitative experts, and trial methodologists. Following the session, in-depth perspectives were provided by two patient advocates who actively engaged in the PPIE session. We discuss the importance of PPIE in shaping advanced dose-finding trial designs, share insights from patients on integrating PROs to inform treatment tolerability, and present a template for meaningful patient involvement in trial design development. RESULTS: Participants generally supported the introduction of PROs within dose-finding trials but showed some apprehensiveness as to how PROs may reduce the size of the recommended dose (and potentially efficacious effect). Some participants shared that they may be reluctant to record the real severity of their symptoms via PROs if it would mean that they would have to discontinue treatment. They discussed that PROs could be used to assess tolerability rather than toxicity of a dose. CONCLUSIONS: Amplifying patient voice in the development of patient-centric dose-finding trial designs is now essential. This paper offers an exemplary illustration of how trialists and methodologists can effectively incorporate patient voice in the future development of advanced dose-finding trial designs.

The aim of dose-finding oncology trials is to make sure a treatment is safe, understand its side effects, and recommend the right dose (or doses) for future clinical trials. Traditionally, a patient's tolerance to treatment is assessed by doctors who evaluate toxicities (side-effects) using established grading guidelines. Research has shown that doctors might not identify all the side effects that patients actually experience during a trial.There is growing interest in the introduction of patient-reported outcomes (PROs) within dose-finding trials. PROs are reports of a patient's health and well-being experiences which come directly from the patient themselves, usually assessed using a questionnaire.In a dose-finding trial, we start with a low dose of a drug and increase it until too many patients have severe side effects. The highest safe dose is then investigated in a later phase trial.   We are suggesting a new way to do these trials. We want to look at both what doctors see as severe side effects and what patients say. This enables us to recommend a dose that balances both perspectives. We would also like to ask patients what level of risk they are comfortable with regarding severe side effects.In this paper, we highlight the importance of involving patients in creating advanced dose-finding trial designs, particularly with PROs to help decide whether a dose is tolerable for patients. We also share findings of a patient and public involvement and engagement session and provide a guide for meaningful patient involvement in developing trial designs.