Kidney Compass: Addressing Skepticism Around HCEs in Nephrology

Welcome to Kidney Compass: Navigating Clinical Trials!

In the third installment of our 4-part episode of Kidney Compass, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, are joined by special guests Dustin Little, MD, and Niels Jongs, PhD, as they discuss the implications of hierarchical composite endpoints (HCEs) for kidney disease trials, regulatory considerations, and patient-centered outcomes.

Wadhwani raises concerns about fixed follow-up requirements in clinical trials, particularly when studies are terminated early due to efficacy, as seen in the FLOW and DAPA-CKD trials. Jongs explains how follow-up variability can be statistically managed by adjusting pairwise comparisons to a minimum follow-up period, ensuring fair assessment across different trial durations. While acknowledging theoretical concerns, he emphasizes that empirical analyses suggest this approach does not significantly alter trial conclusions.

The conversation then shifts to skepticism surrounding HCEs, including how event prioritization is determined and how win odds should be interpreted. Little highlights the flexibility of HCEs, noting that they incorporate only validated clinical and surrogate endpoints, making them suitable for regulatory approval.

A key advantage of HCEs, the panel agrees, is their ability to enhance statistical power, potentially reducing required sample sizes—an especially critical benefit for rare kidney diseases. Wadhwani and Little further explore the potential to integrate patient-reported outcomes, such as symptom burden and quality of life, into HCE frameworks. While acknowledging the complexity of arranging hierarchies that blend clinical and PRO measures, they highlight polycystic kidney disease as a prime example where factors like cyst pain and kidney volume could be incorporated alongside traditional renal endpoints.

The episode concludes with a discussion on future applications of HCEs in nephrology. The panel emphasizes that while methodological refinements are ongoing, HCEs offer a promising strategy to improve trial efficiency, capture a broader range of clinically meaningful outcomes, and ultimately accelerate therapeutic advancements for patients with kidney disease.

For ease of viewing, we've divided this episode into 4 sections and highlighted them below.

Kidney Compass: Hierarchical Composite Endpoints in Nephrology

Part 1: Introductions, HCEs in Nephrology

Part 2: HCEs in Nephrology Clinical Trials

Part 3: Addressing HCE Skepticism, Potential Limitations (Current Segment)

Part 4: Applying HCEs in Kidney Disease Trials

Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas, and Travere Therapeutics. Relevant disclosures for Little include AstraZeneca.