Luca Richeldi, MD, PhD, speaking at the European Respiratory Society (ERS) Congress 2024, presented an analysis of recent failures in idiopathic pulmonary fibrosis (IPF) clinical trials, offering key lessons for future research. He emphasized that understanding the reasons behind these setbacks is crucial for improving trial designs and ultimately finding effective treatments for IPF.
Questioning Negative Trial Outcomes
Richeldi challenged the assumption that a negative randomized controlled trial is always a failure. He cited a 2012 study that, despite initial negative results, significantly impacted clinical practice and has been widely referenced. This highlights the potential for even unsuccessful trials to provide valuable insights.
Recent Phase 3 Trial Challenges
Over the past decade, there has been a surge in phase 2 and phase 3 trials for IPF, involving over 8500 patients. However, recent phase 3 trials of ziritaxestat, zinpentraxin alfa, and pamrevlumab have encountered significant challenges. These trials, despite promising phase 2 results, failed to demonstrate efficacy in larger, longer-term studies.
- Ziritaxestat: A phase 2 trial showed statistically significant improvements in forced vital capacity (FVC) over 12 weeks. However, the phase 3 trial, involving 1300 patients over 52 weeks, was terminated early due to a lack of efficacy and increased mortality.
- Zinpentraxin alfa: Similar to ziritaxestat, phase 2 results suggested slowed disease progression. However, the phase 3 trial failed to replicate these findings over a 52-week period with a larger patient cohort.
- Pamrevlumab: This monoclonal antibody demonstrated a statistically significant reduction in FVC in a phase 2 trial with less than 400 patients. The subsequent phase 3 trial did not produce similar results, potentially due to the concurrent use of antifibrotic therapies, which was not permitted in phase 2.
Common Pitfalls in Trial Design
Richeldi identified several common issues contributing to these failures:
- Small Sample Sizes in Phase 2 Trials: Smaller cohorts can lead to overestimations of efficacy, which may not translate to larger phase 3 studies.
- Short Study Durations: Short study durations in phase 2 trials may fail to capture the long-term effects of treatments, leading to optimistic results that do not hold up in longer-term studies.
- Outliers and Statistical Anomalies: The presence of outliers can skew results, particularly if not adequately accounted for in the statistical analysis. Distinguishing between true biological phenomena and statistical anomalies is a significant challenge.
- Concurrent Therapies: The use of concurrent therapies in phase 3 trials that were not present in phase 2 can confound results, as seen with the pamrevlumab trial.
Strategies for Improvement
To address these issues, Richeldi proposed several key strategies:
- Adaptive Trial Designs: Incorporate interim analyses and allow for adjustments based on emerging data. This approach can help identify issues early and adapt the study protocol accordingly.
- Rigorous Statistical Methods: Employ more rigorous statistical methods to handle outliers and missing data, including sensitivity analyses and better imputation methods.
- Patient-Relevant Outcomes: Focus on patient-relevant outcomes, such as quality of life and survival, rather than solely relying on FVC changes. Only a small fraction of current phase 2 studies on IPF prioritize cough as a primary endpoint, highlighting a need for change.
Richeldi concluded with optimism, stating, "I think that we can do better. We did a lot, and hopefully we'll be learning from our mistakes and will do better in the future."
