P313: Total Kidney Volume as a Prognostic Biomarker: A Use Case for a Regulatory Science Framework of Drug Development Tools
Poster Presenter
Anna-Marika Bauer
Regulatory Specialist II
Critical Path Institute United States
Objectives
To describe the utility of a Regulatory Science Framework for Drug Development Tools through use of a case study describing the regulatory qualification of Total Kidney Volume as a prognostic biomarker for the selection of patients in Autosomal Dominant Polycystic Kidney Disease clinical studies.
Method
Drug development tools (DDTs) include biomarkers, clinical outcome assessment measures and other methods such as clinical trial simulation tools that facilitate drug development. We conducted a review of qualified DDTs that used a framework for regulatory decision-making.
Results
The collaborative construct of a public-private partnership (PPP) has led to the generation of tangible DDTs that positively transform drug development process, resulting in safer and more effective treatment for patients. A review of DDTs developed by a PPP has culminated in a Framework and decision tree designed to provide detailed guidance on how the Critical Path Institute develops regulatory-ready solutions for unmet needs in medical product development. The Framework explores how an unmet need is identified, how context of use is defined, how supporting evidence is developed, and how regulatory science solutions and regulatory strategies are developed. An accompanying decision tree was developed to elucidate critical processes that should be considered and captures key questions and go/no-go decisions when generating novel DDTs.
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a debilitating genetic disease affecting more than 600,000 individuals. With only one drug approved as of January 2025, there is a need for earlier intervention and improved therapy due to adverse side effects. Total kidney volume (TKV) is a measure of kidney function and used to assess the risk of kidney disease progression. TKV is used as a case study to demonstrate the application of this Regulatory Science Framework for Drug Development Tools.
Collaborations within the Polycystic Kidney Disease Outcomes Consortium have created a clinical database of shared, aggregated and standardized PKD data. Through interrogation of the PKD data, a disease model was developed that evaluated the relationship between baseline TKV and progression of ADPKD. The disease model was used to support the regulatory qualification of baseline TKV as an enrichment prognostic biomarker for ADPKD TKV. The qualification of TKV as a prognostic biomarker contributed to the FDA Final Guidance for Industry in 2016 on the use of TKV for the selection of patients in studies for the treatment of ADPKD.
Conclusion
The qualification of TKV has had far reaching implications as an accelerator of drug development. In 2018, the FDA approved tolvaptan as the first treatment for ADPKD based on clinical evidence demonstrating a slowing of kidney function decline in adults at risk of rapidly progressing for ADPKD. With use of the data from the tolvaptan approval in combination with models used to support the qualification of TKV as a prognostic biomarker, the FDA designated TKV as a reasonably likely surrogate endpoint, which has stimulated a robust ADPKD drug development pipeline that now includes more than 10 drug candidates under evaluation from preclinical to the late-clinical stages of testing. Additionally, the STAGED-PKD trial used TKV as a primary endpoint and, following a prespecified interim analysis. The interim analysis showed that treatment had no effect on rate of change in TKV, allowing the study to end early due to futility and tangibly reducing patient burden by not administering an ineffective treatment.
The Framework was designed as an essential knowledge management tool to capture learnings from previously developed and validated solutions. Strategic considerations, standards and critical decision points were outlined to further reduce uncertainty when developing DDTs and ultimately accelerate drug development. The Framework can impact stakeholders across the drug development spectrum including but not limited to regulators, patients living with diseases with no therapies, and pharmaceutical industry members. The validation of a DDT such as TKV as a prognostic biomarker has built confidence for all drug development players in the tools and endpoints used in clinical trials while also providing a standard that can be consistently used across an indication.
