Development of Early-Stage CKD Treatments: NKF-FDA Workshop

Approximately 30 million individuals in the United States are living with chronic kidney disease (CKD); worldwide, the number is estimated to be 700 million. The most serious manifestation of CKD is kidney failure; however, those at earlier stages of CKD are at increased risk of other adverse outcomes that include cardiovascular disease and mortality. Caring for patients with CKD and related complications in the United States is estimated to cost $120 billion annually.

In the past 10 years there has been significant progress in identifying surrogate end points that can be used to evaluate the efficacies of therapies to slow CKD progression. There has also been increased interest in the development of treatments for early stages of CKD.

In December 2020, the National Kidney Foundation (NKF) sponsored a scientific workshop in collaboration with the US FDA. The meeting was titled the NKF-FDA Conference on Clinical Trial Considerations in Developing Treatments for Early Stages of Common, Chronic Kidney Diseases.

The workshop was designed to examine perceptions of the value of treating early CKD among patients, providers, and payers. More than 90 individuals representing a range of stakeholders, including faculty experts in clinical trials, nephrology, cardiology, and endocrinology, patient advocacy organizations, patients, payers, health economists, regulators, and policy makers took part in the virtual meeting. Results of the meeting were outlined by Lesley A. Inker, MD, MS, and colleagues on behalf of the workshop advisory group in a special report in the American Journal of Kidney Diseases [2022;80(4):513-526].

The report opened with a brief overview of CKD and its progression. Patients with CKD face increased risk for cardiovascular disease and death not related to kidney failure as well as other complications, including cognitive impairment and infections. There are robust associations between decreased glomerular filtration rate (GFR) and elevated albuminuria and cardiovascular disease, heart failure, hospitalizations, and mortality; more than 50% of deaths in CKD are the result of cardiovascular causes. Conversely, cardiovascular disease can precipitate decline in GFR.

Assessing Risk Factors for CKD Progression

Specific parameters are needed when estimating risk for inclusion in clinical trials as well as in clinical-decision making. Absolute risk, or the probability of an event occurring over a specific period, is most relevant to patients. For patients with CKD, the relevant time frame for the development of a serious adverse outcome may be a lifetime. For sponsors or investigators designing clinical trials, the relevant time frame is often the length of time needed to show the efficacy of an intervention.

Identification of the specific end point of interest is also a key parameter. The common end point of studies aimed at developing risk tools for CKD progression is kidney failure with the need for kidney replacement therapy (KFRT). This has two major limitations: (1) many patients, particularly older adults and those in settings with limited resources, may never receive KRT; and (2) progression of CKD in the relevant time horizon is not captured by kidney failure. More appropriate end points may be GFR slope, 30% and 40% declines in GFR, and reaching CKD GFR category 4 (G4; GFR <30 mL/min/1.73 m²). In addition, cardiovascular disease could be an end point of interest in CKD trials, and incidence or progression of CKD could be an outcome of interest in cardiovascular trials.

Risk Factors and Tools

Traditional risk factors for CKD progression are level of GFR and albuminuria, and the presence of hypertension, diabetes, hyperlipidemia, smoking, and variably, obesity. The most widely used tool to predict progression of CKD is the Kidney Failure Risk Equation that predicts risk of KFRT over 2-year and 5-year periods in individuals with GFR <60 mL/min/1.73 m². The risk tools can be used to inform patient counseling, referral to nephrology and multidisciplinary care, evaluation for transplant, and place of vascular access.

There are three tools for patients with higher GFR: (1) estimated risk of KFRT over 15 years and the lifetime; (2) 5-year risk of developing GFR <60 mL/min/1.73 m²; and (3) 2- to 3-year risk of developing 40% decline in GFR. The first model was designed for potential kidney donors and is not useful in people with CKD; the second and third models are most appropriate in the identification of high-risk populations for trials designed to evaluate efficacies of therapies for development or prevention of CKD progression in early CKD.

Cost Versus Benefit

Cost-effectiveness assessments require consideration value that is apparent in the immediate time frame as well as anticipated costs and savings. For treatment of early CKD, the potential costs and cost savings are key, because the benefits of treatment will likely be achieved after years, and due to the large number of individuals potentially eligible for treatment. In addition, due to uncertainties in clinical course, not all patients treated will derive benefit.

The two main sources of cost are direct and indirect. Direct costs are incurred by the health care system and include those related to prescriptions, outpatient appointments, visits to the emergency department, and inpatient episodes. In the US Medicare CKD population, following adjustment for age, sex, and relevant comorbidities, the annual direct spending cost per patient increased with worsening CKD stage ($8091 for stage 2; $46,128 for stage 4/5; and $87,399 for KFRT). Indirect costs are those incurred by patients and caregivers, as well as those related to absenteeism, presenteeism, unemployment, and lost productivity. Thus, higher direct costs in early CKD should be balanced by lower direct and indirect costs associated with late-stage disease.

Summary

The workshop attendees agreed that there is value in preventing the development of and treating the progression of early-stage CKD in those at high risk for progression. End points in trials designed to examine the efficacy of such interventions are likely to be intermediate or surrogate end points. Cost analyses of early-stage CKD treatments should be holistic and include more than costs of the drug; savings on health care delivery and on treatment of kidney failure should be considered. Safety of treatment of early-stage CKD is crucial and will require additional assessment beyond that available during study periods.

“Successful drug development and implementation of effective therapies will require collaboration across sponsors, patients, patient advocacy organizations, medical community, regulators, and payers,” the authors said.

Takeaway Points

1. The National Kidney Foundation in collaboration with the FDA held a workshop to examine patient, provider, and payer perceptions regarding treatment of early stage chronic kidney disease (CKD).
2. The virtual meeting included more than 90 people, including experts in clinical trials, nephrology, cardiology, and endocrinology, patient advocacy organizations, patients, payers, health economists, regulators, and policy makers.
3. The attendees agreed that successful drug development and implementation of effective therapies for early-stage CKD will require collaboration across that broad spectrum of stakeholders.