December 18, 2019

That would be crazy, right? But it is exactly what has been happening to patients with kidney disease for a long time, even though around 37 million people (14% of the population) in the U.S. have chronic kidney disease (CKD). Reasons for this exclusion are complex. Nonetheless, the research community must come together and find a way to ensure these patients are included in clinical trials.

Importance of Trials for Cardiovascular Disease (CVD) Treatments

Not only is renal disease common, but it often occurs alongside other ailments. For example, the association between CKD and CVD is well-known, so CVD therapies are likely to be prescribed for individuals with kidney disease. But renal patients are often excluded from safety and efficacy testing for such therapies, though in some cases, post-approval studies may expand the label to include them.

Exclusion of Renal Patients From CVD Clinical Trials

For example, an analysis of 22 major journals published between 2006 and 2014 showed that nearly half of randomized clinical trials targeting patients with chronic stable heart failure, acute myocardial infarction, atrial fibrillation, and stable coronary artery disease excluded patients with kidney disease. (Maini, Wong, Addision, et al. J Am Soc Nephrol. 2018.) This analysis covered 305 randomized trials with 696,935 participants. The authors concluded, “Given the increasing prevalence of kidney disease among patients presenting with CVD, the judicious broadening of trial eligibility is warranted.”

Another systematic review looked at 371 trials for CVD interventions, with 590,040 participants, between 2006 and 2013. (Konstantinidis, Nadkarni, Jacoub, et al. JAMA Intern Med. 2016.) Of these trials, 57% excluded patients with kidney disease. A table from this report shows the criteria used to determine exclusion. It also shows how often trials analyzed data from patients with renal disease as a subgroup — in other words, whether the studies took full advantage of including renal patients to correlate CVD and CKD data. Unfortunately, for the most part, they didn’t.

Why Sponsors May Not Include Renal Patients — and Why Renal Patients Might Not Participate

Including patients with kidney disease in research is challenging. Physical and social barriers can make it difficult for kidney patients to take part in clinical trials.

At the same time, the science is complex because kidney disease affects practically every organ system, and often, many organ systems all at once. Researchers may worry about controlling for confounding factors or about adverse effects, given low glomerular filtration rate (GFR) may alter the safety profiles of certain drugs and devices. (Decker, Kendrick. Adv Chronic Kidney D. 2014.)

Initiatives to Foster Inclusion of Renal Patients in Clinical Trials

Whatever the challenges, ensuring this growing patient population participates in clinical studies will benefit many people. A few initiatives exist to make this happen. Cardiologists and nephrologists are discussing the inclusion of patients with kidney disease in cardiovascular trials through efforts of the Kidney Health Initiative.

At the same time, the FDA has issued a new draft: Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry. This guidance encourages researchers to increase diversity in enrollment by broadening eligibility criteria so that clinical trials better reflect the populations most likely to use the drugs under consideration. To this end, the section on trial design and methodological approaches includes the following language encouraging sponsors to characterize metabolism and clearance in various subpopulations early (lines 140-147):

Consider characterizing — in early clinical development — drug metabolism and clearance across populations that may metabolize or clear the drug differently (e.g., across the elderly and patients with liver or kidney dysfunction). Early characterization of drug metabolism and clearance across groups will help avoid later exclusions. Alternatively, an expansion cohort may also allow dose modification and may be used to assess a reasonably safe dose in specific populations in which there may be significant differences in the systemic exposure to the investigational drug (e.g., pediatric or elderly participants or participants with organ impairment).

Inclusion of Renal Patients Is Feasible — and Help Is at Hand

If we work together, including renal patients in clinical trials can become more commonplace. While there are sometimes valid reasons to exclude some patients, including the renally impaired, following the FDA guidance in characterizing drug metabolism and clearance for special populations, may enable patients with renal disease to be included more often, possibly as separate cohorts. And Frenova can help. With our understanding of renal patients and their care, we can streamline the clinical trial process, ensure the collection of useful data, prevent surprises as trials progress — and bring a little balance to the world of clinical trials.

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