Luca Richeldi, MD, PhD, outlined crucial lessons from recent idiopathic pulmonary fibrosis (IPF) trial failures, advocating for adaptive trial designs, rigorous statistical methods, and a focus on patient-relevant outcomes to enhance future research.
Luca Richeldi, MD, PhD, professor of respiratory disease at the Catholic University of the Sacred Heart, presented a thought-provoking analysis on the failures of idiopathic pulmonary fibrosis (IPF) clinical trials during the European Respiratory Society (ERS) Congress 2024.1 His insights provide crucial lessons for the future of IPF research, emphasizing the need to learn from past setbacks to improve future trial designs.
Richeldi began by addressing a fundamental question: "Do we know if a negative randomized controlled trial is always a failure?"
Richeldi emphasized the need to learn from past setbacks to improve future clinical trial designs in IPF | Image credit: photon_photo – stock.adobe.com
He noted that not all negative trials are without merit, citing a landmark 2012 study that, despite its initial negative results, had a profound impact on clinical practice and has since been cited over 1300 times.2
Over the past decade, there has been an increase in phase 2 and phase 3 trials for IPF, with more than 8500 patients enrolled overall.1 However, there were 3 major phase 3 trials published in the past year that encountered challenges, offering valuable lessons in Richeldi’s eyes: the ziritaxestat, zinpentraxin alfa, and pamrevlumab studies.3-5
The phase 2 trial of ziritaxestat included 23 patients with just 12 weeks of treatment, demonstrating statistically significant improvements in forced vital capacity (FVC).3 However, in the phase 3 trial involving 1300 patients over 52 weeks, the study was terminated early due to a lack of efficacy and a signal of harm, specifically increased mortality. Phase 2 results also appeared encouraging forzinpentraxin alfa, demonstrating significantly slowed disease progression.4 However, phase 3 results again failed to replicate these findings as the patient cohort multiplied by 6 and the study period extended to 52 weeks.
Third time’s a charm, right? Once again, monoclonal antibody pamrevlumab showed a statistically significant reduction in FVC in a phase 2 trial with less than 400 patients, but failed to produce similar results in a larger phase 3 trial, partly due to the concurrent use of antifibrotic therapies, which was not permitted in phase 2.5
So, what do these studies have in common?
First, the small sample sizes in phase 2 trials.1 Having a smaller cohort can lead to overestimations of efficacy and does not always translate well to larger phase 3 studies. The short study duration in phase 2 can also fail to capture the long-term effects of treatments, again leading to optimistic results that may not hold up in longer-term studies.
As seen with the pamrevlumab trials, the presence of outliers can skew results, particularly if not adequately accounted for in the statistical analysis. Richeldi highlighted the challenge of distinguishing between true biological phenomena and statistical anomalies. Additionally, the use of concurrent therapies in phase 3 trials that were not present in phase 2 can confound results.
To address these issues, Richeldi proposed 3 key strategies to improve future trial design and execution. He advocated for adaptive trial designs that incorporate interim analyses and allow for adjustments based on emerging data. This approach can help identify issues early and adapt the study protocol accordingly. He also recommended adopting more rigorous statistical methods to handle outliers and missing data. This includes sensitivity analyses to assess the impact of removing outliers and better imputation methods for missing data.
Finally, he highlighted the importance of focusing on patient-relevant outcomes, such as quality of life and survival, rather than solely relying on FVC changes. Of the 12 active and recruiting phase 2 studies on IPF he mentioned, only 2 of them had cough as a primary end point rather than FVC. According to Richeldi, this shift could provide a more comprehensive understanding of a treatment’s impact on patients’ quality of life.
“I think that we can do better,” Richeldi closed with optimism. “We did a lot, and hopefully we'll be learning from our mistakes and will do better in the future.”
References
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