Time to Abandon Renalism
Year: 2023
Type: article
Abstract: Conscious exclusion of patients with kidney disease from drug trials is a commonly accepted practice.1 This must change. In the United States, 37 million adults, 15% of the population, have CKD.2 Patients with CKD are at a higher risk of mortality from a wide range of causes, including cancer, infection, and cardiovascular disease, among others. Improving therapies for patients with CKD is poised to have a significant effect on mortality and quality of life for a large portion of patients. Yet, for over two decades, exclusion has been the norm. Why is renalism happening, and what can be done to facilitate broader inclusion in future clinical trials? Bringing a new drug from a concept to market is a lengthy and expensive process. It is understandable that drug manufacturers would aim to structure trials to maximize the likelihood of success for any new therapeutic. Excluding patients with significant comorbidities, such as CKD, becomes a strategy to move drugs ahead in the clinical trial process. Although logical, this strategy fails to visualize a longer-term view of how drugs will be used once approved for clinical use. CKD is common among patients with cancer. Twelve percent to 53% of patients with cancer have CKD at the time of cancer diagnosis.3 Cancer patients with an eGFR <60 ml/min per 1.73 m2 have a significantly higher risk of death from cancer, especially breast and urologic malignancies.4 In part, the higher risk is suspected to be related to limited access to chemotherapeutic drugs and clinical trials.5 The Food and Drug Administration (FDA) has issued multiple guidance documents directed toward inclusion of patients with kidney disease in randomized clinical trials with the goals of expanding access and standardizing the process for drug evaluation in the CKD patient population. In this issue of CJASN, Butrovich et al. aim to assess the effect of FDA guidance on inclusion of patients with CKD in clinical trials.6 Their results are enlightening. The authors identified 74 pivotal drug trials evaluating 55 anticancer drugs approved by the FDA during 2015–2019. Ninety-five percent of the trials had kidney-related exclusion criteria. Defining kidney function for inclusion was variable, with only 68% of trials using GFR-based criteria. When GFR was used, the methods varied significantly between trials. Pharmacokinetic studies were commonly performed for CKD stages 1–3 but were rarely performed for patients with CKD stages 4–5 and extremely rarely for patients on dialysis despite recommendations from the FDA indicating pharmacokinetic studies should be considered. Kidney-related adverse events were reported for 78% of drugs. However, guidance for clinicians regarding safe dosing in patients with impaired kidney function was limited and inconsistent. The authors conclude that despite FDA guidelines, patients with kidney disease continue to be excluded from anticancer clinical trials and there is limited and inconsistent reporting of information to guide clinicians for appropriate drug use in patients with impaired kidney function. The rationale for excluding patients with kidney disease is thin. While safety of patients who participate in clinical trials is of major concern, methods have been described enabling enrollment of patients with impaired organ function in a way that minimizes risk.7 The most obvious example is exclusion of patients with CKD from trials of drugs that have no significant change in excretion through the kidneys. This approach is overly conservative and likely contributes to the limited availability of anticancer drugs for patients with CKD. The American Society of Clinical Oncology (ASCO) has published guidelines to assist clinical trial design and execution by outlining methods for inclusion of patients with kidney disease.7 Appropriate dosing modifications and standardized determination of GFR optimize study design and minimize toxicity. Conducting clinical trials including patients with CKD may be performed safely when the FDA and ASCO guidelines are followed. The continued lack of thought given to considering how trials might include patients with CKD is unacceptable and fully inconsistent with America's renewed, consensus commitment to improve the lives of all patients with kidney disease. Engaging nephrologists early in the clinical trial design process, careful consideration of the ASCO and FDA guidelines, and engagement with patients with kidney disease are straightforward strategies to move the field forward. As a two-time kidney transplant recipient and a prior hemodialysis patient, I would argue in favor of engaging with the nephrology and kidney disease patient communities as part of a strategy to tackle this problem. Instead of conducting trials using historical protocols, simply asking how we include patients with CKD will go a long way to generate safe, standardized, and effective protocols for the future and end renalism currently embedded in the trial design.
Author: Joseph P. Gaut
Institution: Washington University in St. Louis
Language: English
Subfield: Statistics and Probability
Field: Mathematics
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W4324017670