Patient-Reported Tolerability in Oncology: Expert Insights on Measuring What Matters Across Development Phases

As patient-reported outcomes (PROs) become increasingly central to oncology drug development, sponsors face a critical question: Should your approach to measuring tolerability differ between early-phase and late-phase trials?  

In our recent webinar, a panel of industry experts examined this question and shared practical strategies for capturing patient-reported tolerability data throughout the clinical development lifecycle. 

The panel brought together diverse perspectives from academia, industry, and clinical technology experts:

• Professor John Devin Peipert of the University of Birmingham discussed methodologies for measuring overall side effect burden and its relationship to tolerability
• Dr. Joshua Biber of Takeda shared industry insights on navigating evolving regulatory expectations
• Dr. Todd Everhart led discussions around key methodological challenges facing sponsors today 

Understanding the Shift From Toxicity to Tolerability 

One of the webinar's central themes was the distinction between toxicity and tolerability and why that distinction matters for regulatory success. While toxicity profiles describe what adverse events occur and how frequently, tolerability captures something more nuanced: the patient's holistic experience of their treatment's side effect burden. 

Dr. Everhart presented research showing that patients consistently report more symptoms, and at higher severity, than clinicians capture through traditional adverse event collection. Professor Peipert reinforced this with a striking observation: even low-grade adverse events can be highly bothersome and lead to early treatment discontinuation. A long list of low-grade AEs might look “well tolerated” on paper, but when a patient experiences ten of those symptoms simultaneously, the cumulative burden tells a very different story. 

The Evolving Regulatory Landscape

Dr. Biber provided valuable context on how regulatory expectations around patient-reported tolerability data continue to evolve. Sponsors who wait until Phase 3 to think seriously about tolerability assessment may find themselves scrambling to meet evidence requirements that could have been addressed earlier in development. 

Key regulatory considerations discussed included: 

• How to effectively leverage PRO data to strengthen submissions and support labeling claims
• The growing importance of demonstrating that treatments are not just effective, but also tolerable from the patient's perspective
• Concrete ways sponsors are preparing now for tomorrow's regulatory expectations

Phase-Specific Strategies: One Size Does Not Fit All 

The panel explored whether tolerability assessment strategies should differ between early-phase and late-phase trials, and the consensus was clear: context matters. 

Early-phase trials present unique opportunities and challenges: 

• Smaller sample sizes require careful consideration of which tolerability measures will be most informative
• Dose-finding decisions benefit from real-time understanding of patient-reported tolerability
• Flexibility in assessment approaches can help refine your strategy before pivotal trials

Late-phase trials demand different considerations and greater rigor: 

• Assessment approaches need to support regulatory submissions and potential label claims
• Consistency in measurement becomes critical for interpretability
• The evidence generated must meet increasingly rigorous regulatory standards

Methodological Challenges: Interpreting Tolerability Data 

One of the most thought-provoking discussions centered on the methodological challenges of translating profiles of individual adverse events into coherent tolerability interpretations. This remains an area where the science is still evolving. 

Dr. Everhart highlighted several outstanding questions that sponsors grapple with: 

• How do you weight different adverse events in an overall tolerability assessment?
• What's the best way to capture treatment burden over time versus at discrete timepoints? Traditional pre-cycle assessments may miss the worst inter-cycle symptoms; the PRO-CTCAE’s seven-day recall window means timing matters for accurate data capture.
• How do you account for individual patient differences in what they find tolerable? He cited data showing 26% of kinase inhibitors approved over a decade received post-marketing commitments or requirements to study lower doses, suggesting earlier tolerability assessment could have led to better dosing from the start. 

While perfect solutions don't exist yet, the panel emphasized that acknowledging these challenges and building flexibility into your data collection strategy can help you adapt as methodologies continue to mature. 

Practical Takeaways for Sponsors 

The webinar concluded with actionable guidance for sponsors at any stage of oncology development: 

1. Start early. Don't wait until Phase 3 to think about patient-reported tolerability. Early-phase data can inform dose selection and help you refine your assessment strategy.
2. Engage with regulators. Proactive conversations about your tolerability assessment plan can prevent costly surprises later in development.
3. Think holistically. Individual adverse event data is important, but capturing the patient's overall treatment experience provides critical context for interpreting that data. Measures like the FACT-GP5 capture overall treatment burden that individual AE lists cannot.
4. Plan for missing data. Capture reasons for missingness and consider inter-cycle assessments to capture the full treatment experience.
5. Make PRO data actionable. Define how it will be reviewed and used in clinical decision-making - in the protocol.
6. Leverage technology thoughtfully. Branching logic, adaptive testing, and BYOD can reduce burden while expanding what you capture.
7. Partner with experts. The complexity of tolerability assessment - from selecting appropriate measures to interpreting data - benefits from specialized expertise in clinical outcomes.

Looking Ahead 

The FDA has signaled clearly that tolerability assessments without patient-reported data will be considered incomplete. Sponsors who invest in robust strategies now – validated instruments, longitudinal PRO strategies across phases, and technology-enabled collection – will be better positioned to demonstrate not just that their treatments work, but that they offer meaningful benefits in ways that matter most to patients.