Patient-Focused Drug Development in Kidney Disease

Drug development in kidney disease has exploded within the past decade, resulting in major advancements in CKD management, including sodium-glucose cotransporter 2 inhibitors, endothelin receptor antagonists, and nonsteroidal mineralocorticoid receptor antagonists.¹ For rare kidney diseases, interventional studies for new therapies have increased in some indications by over 150%, with monoclonal antibodies, endothelin angiotensin receptor antagonists, and other treatments providing targeted approaches to treating diseases such as FSGS and IgA nephropathy.² Although drug development in pediatrics has lagged behind that of adults, global efforts are now accelerating for this group as well.³ End points to capture meaningful treatments effects are needed to reveal the true benefit of emerging treatments to patients. Although reduction in proteinuria and improvement in kidney function are promising end points, it is necessary that new treatments are evaluated for their ability to reduce disease-related symptoms and functional impairments (e.g., physical function, cognitive function).⁴

Regulators increasingly request inclusion of patient-centered end points during clinical trial development. Although there are challenges in identifying and justifying well-developed patient-centered end points, recent methodologic guidance can ease this process. In particular, the US Food and Drug Administration's (FDA) Patient Focused Drug Development (PFDD) program has articulated a key regulatory framework to leverage patient-centered outcomes in support of drug evaluation, which includes a four-part methodologic guidance series. The aim of this article was to highlight key themes from PFDD guidance and other key resources with recommendations for clinical trial design in kidney disease.

Clinical Outcome Assessments to Reflect the Patient's Experience

Patient-reported outcome (PRO) measures have been a focus of attention in CKD, with notable advancements made by the Standardised Outcomes in Nephrology initiative in collecting input from patients on prioritized outcomes and developing several key PROs.⁴ The FDA PFDD guidance focuses extensively on capturing meaningful aspects of health, or “aspect[s] of feeling or functioning in daily life that [are] important to patients.”⁵ While PROs are critical for capturing meaningful aspects of health, these are sometimes best assessed by other reporters. For example, in general, older children may be able to report for themselves, while for younger children or those with intellectual/developmental disabilities, observer-reported outcomes may be preferable. To help overcome this challenge, PFDD frameworks acknowledge a range of clinical outcome assessments (COAs) that can reflect the patient's experience.⁵ In addition to PRO measures, these include observer-reported outcomes, clinician-reported outcomes, and performance outcomes. The acknowledgment of multiple types of COAs reflects opportunities to elicit information on meaningful aspects of health using different methods and different reporters (Figure 1). Multiple COAs addressing the same concept may be useful to include in the same trial to capture different aspects of the patient's experience, such as using both PROs and performance outcomes to assess mobility.

Figure 1.

Overview of a process to use COAs in kidney disease drug development. Includes information from Fiero et al. Lancet Oncol. 2020;21(10):e488–e494. COA, clinical outcome assessment; MAH, meaningful aspects of health.

Building a Rationale for COA Selection: Fitness for Purpose

Drug developers are faced with a challenge of building the rationale for COA selection to ensure fitness for purpose or “the level of validation associated with a medical product development tool that is sufficient to support its context of use,” derived from the Biomarkers, Endpoints, and Other Tools Resource.⁵ The focus should be on supporting the use of the most appropriate COA for a particular trial objective and clinical population. The FDA PFDD roadmap offers a practical process for sponsors to follow when deciding which COAs are fit for purpose.⁵ Sponsors will need to determine: (1) is there an available COA that meets the needs identified, (2) is there an available COA that can be modified to meet these needs, or (3) does a new COA need to be developed? An additional FDA PFDD guidance document outlines the essential role that direct patient input plays in capturing the patient's experience.^6,7 This is often obtained by rigorous qualitative interviews (e.g., concept elicitation), although this can be done by other methods such as focus groups, facilitated discussions, or patient surveys.⁷ Patient input is necessary early in a drug development program to justify why a COA has been selected.

Sponsors must make the case for a clearly established context of use for the COA within the trial, which needs to specify: (1) how the COA will be used to support end points in addressing trial objectives; (2) the target population, linked to the trial's eligibility criteria; (3) how the COA fits within the study design; (4) timing of COA assessment; and (5) practical elements of COA implementation regarding where (e.g., remote, in clinic), how (paper, electronic), and by whom the COA will be administered. With increasing opportunities for digital COA administration, we call attention to recent international guidance around the importance of inclusivity and equity in COA use in trials, which must be considered throughout the drug development process to ensure all research participants benefit from patient-centered trial design.⁸

In addition, fit-for-purpose COAs must yield scores that are not overly influenced by irrelevant factors, are appropriate for the health concept, and are directly linkable to patients' health experiences (e.g., a PRO measuring physical function includes questions about activities that the patient is likely to perform). Similarly, the COA score must be sensitive enough to reflect clinically meaningful changes. Selected COAs will likely require significant psychometric evaluation to provide this evidence, including both qualitative (content validity) and quantitative (e.g., reliability, construct validity, responsiveness to change) investigations.

Moving from Outcomes to End Points

Once a selected COA is deemed fit for purpose, it must be operationalized into an end point to meet the trial objectives.⁹ A fit-for-purpose COA can be incorporated into the kidney trial's hierarchy of end points. The recent Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Consortium provided accessible guidance on formation and analysis of common PRO end points that have relevance to emerging kidney-focused COA end points, including changes from baseline in symptoms, time to event, or symptom/function steady state.¹⁰

FDA PFDD guidance emphasizes approaches to determine how much change, either improvement or deterioration, is considered meaningful to patients.⁹ This often is determined through quantitative analyses of the change in a COA score and its relationship to the change in an anchor or external variable that is recognized to capture meaningful change in the disease state.

We also recommend that sponsors use well-developed resources to support including COAs in trials. These are compiled in the PROTEUS-Trials Consortium (Patient-Reported Outcomes Tools: Engaging Users & Stakeholders) Handbook (www.TheProteusConsortium.org) and include guidance for trial protocol development (Standard Protocol Items: Recommendations for Interventional Trials—PRO Extension Statement), analysis guidance and result visualization guidance (Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints), and trial reporting standards (Consolidated Standards of Reporting Trials PRO Extension Statement).

Conclusions

A new era of drug development in kidney disease presents an opportunity to embed a culture of patient-focused outcomes. Recent efforts show significant promise in this topic, such as the PREPARing a clinical outcomes assessment set for Nephrotic Syndrome project, which is creating a core set of COAs for the effect of swelling in nephrotic syndrome,¹¹ and the Standardized Outcomes in Nephrology initiative has generated new COAs capturing pain, fatigue, and life participation in selected kidney diseases.⁴ In addition, the Kidney Health Initiative's elicitation of patient-preference information around innovative alternatives to KRT (Kidney Health Initiative|Current Projects) represents another way the patient's voice can support regulatory decision making, and this approach may have relevance in drug development as well. Patient-driven approaches like these are required to determine if emerging kidney disease treatments are beneficial to patients.

Supplementary Material

jasn-37-610-s001.pdf ^{(1.4MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F550.

Author Contributions

Conceptualization: Louise Oni, John D. Peipert, Eloise Salmon.

Writing – original draft: Louise Oni, John D. Peipert.

Writing – review & editing: Olalekan Lee Aiyegbusi, Nicola Anderson, Melanie Calvert, Laurel Damashek, Louise Oni, John D. Peipert, Eloise Salmon, Libby Thomas, Howard Trachtman.

Funding

J.D. Peipert: US Food and Drug Administration, Center for Drug Evaluation and Research (UH3FD007308). E. Salmon: Center for Drug Evaluation and Research (UH3FD007308).