Children of a lesser god: exclusion of chronic kidney disease patients from clinical trials

Abstract

The exclusion of chronic kidney disease (CKD) patients from clinical trials—particularly cardiovascular trials—remains a long-standing, unsolved problem, which prevents the optimization of clinical care in these patients. The situation recalls the insufficient recruitment of women in cardiovascular trials until the 1980s, a problem that was only resolved following regulatory interventions. Regulatory agencies are in a unique position to promote recruitment of CKD patients in clinical trials. The main stakeholders, namely patients’ associations and scientific societies, should make major lobbying efforts to persuade these agencies that the issue is an absolute public health priority.

cardiovascular, CKD, clinical trial, diabetes mellitus, guidelines

Chronic kidney disease (CKD) is a rising cause of mortality worldwide. In 1993, this disease was the 36th cause of mortality in the general population, rising to the 19th position in 2013 [1] and then to 13th in 2016 [2]. In high-income countries, CKD is now the 10th cause of mortality [2]. The issue is of major concern as, according to a recent estimate jointly made by the ERA-EDTA, the American Society of Nephrology (ASN) and the International Soceity of Nephrology (ISN), over 850 million people worldwide have some form of kidney disease [3], a figure twice as high as that of diabetes and 20 times higher than that of cancer or AIDS/HIV. From 2006 to 2016, mortality attributable to CKD through nephropathies by diabetes and by diseases other than diabetes has increased by 29 and 30%, respectively [2], which is a significant increase compared with those registered over the same decade for several major diseases including communicable, maternal and neonatal, nutritional, respiratory and cardiovascular diseases, cancer, cirrhosis and liver disease (increases range from 5 to 18%). According to recent projections by the Institute of Health Metrics and Evaluations, in 2040, CKD is expected to become the fifth cause of life-years lost on a world scale [4].

The clinical complexity of CKD (as defined by the number of comorbidities and other markers of disease severity) [5] matches the pathophysiological complexity of the same disease [6] and is the highest among internal medicine diseases [5]. CKD is bidirectionally linked to cardiovascular disease in that CKD engenders a high risk of cardiovascular complications and, vice versa, heart disease may induce or aggravate CKD [7]. CKD is per se one of the strongest risk factors for cardiovascular death. In 2013, there were 1.2 million cardiovascular deaths attributed to CKD [8]. CKD is also bidirectionally linked to neoplasia because, independently of other factors, cancers or treatments targeting cancers may engender CKD and, vice versa, CKD may predispose to cancer [9]. Furthermore, chronic liver diseases are associated with primary and secondary CKD, which are having a significant impact on mortality rates among these patients [10]. Thus, CKD is a public health priority and an increasing threat to global health on a worldwide scale.

Due to the almost unique complexity of CKD [5], treatments for cardiovascular disease, cancer and liver disease need to be appropriately profiled in CKD patients. However, the assumption that the ‘complex CKD patient’ may react differently to a given intervention than non-CKD patients cannot be evenly applied to all drugs and clinical situations. Systematically excluding such patients on the basis of the so-called safety considerations may be inappropriate. In a recent randomized, placebo-controlled trial with the dipeptidyl-peptidase 4 (DPP4) inhibitor, linagliptin, in a cohort of patients with type 2 diabetes and an estimated glomerular filtration rate (GFR) of as low as 15 mL/min/1.73 m² the drug proved to be quite safe [11]. Prior cardiovascular outcome trials with the DPP4 inhibitors sitagliptin, saxagliptin and alogliptin excluded such patients.

The fact that patients with CKD are most frequently excluded from clinical trials is a persistent cause for concern. A meta-analysis in 2006 revealed that >80% of trials focusing on coronary heart disease excluded patients with end-stage kidney disease and 75% excluded patients with pre-dialysis CKD [12]. Ten years later, an updated meta-analysis that extended to the whole range of cardiovascular interventions reported little progress on this issue, and in 2016 the exclusion rate of CKD patients remained at 58% [13]. In a very recent reanalysis of the problem based on 305 randomized trials with 696 935 participants, Maini et al. [14] noted that in the period 2006–14 randomized trials were less likely than those in 1985–2005 to exclude individuals with kidney diseases (46% versus 56%). However, this apparently favourable trend was mainly attributable to a decrease in the proportion of renin–angiotensin–aldosterone inhibitors trials, because no increase in CKD patients’ participation was observed in trials testing other cardiovascular drugs. Many reasons are given for this phenomenon including (i) the severity of cardiovascular damage that appears non-modifiable by treatment and the uniqueness of emerging risk factors in CKD, (ii) the peculiar pharmacokinetics of CKD and (iii) the high risk of mortality due to events (infections, lung disease and other) that compete with cardiovascular disease because of the high death rate of this population. As a matter of fact, a class of drugs like statins, which has a major impact upon cardiovascular outcomes in patients with other diseases and in the general population, exerts a progressively smaller protective effect on cardiovascular outcomes and death as the GFR declines, with almost no benefit in patients on dialysis [5].This exclusion scenario is not restricted to trials for cardiovascular disease, but encompasses trials of patients with cancer [15] and patients with liver disease [10].

Even though two recent major trials [16, 17] focusing on cardiovascular outcomes in hypertensive patients and in patients with type 2 diabetes included a considerable number of CKD patients, hypertensive patients with a GFR <20 mL/min/1.73 m² [18] and patients with type 2 diabetes with a GFR <30 mL/min/1.73 m² [17] were excluded from these trials. The same applies to other major contemporary cardiovascular trials. For example, patients with severe CKD (GFR <30 mL/min/1.73 m²), a high-risk category that may benefit from intensive LDL cholesterol therapies, has been systematically excluded from clinical trials with PCSK9 inhibitors [19].

For decades, the exclusion of CKD patients from cardiovascular trials has remained a litany in the nephrology literature [20]. Clinical investigators, irrespective of their standing and commitment to the fight against CKD, cannot modify the status quo by simply persuading funding bodies and the industry to allow the participation of CKD patients in clinical trials. The situation recalls the insufficient recruitment of women in cardiovascular trials until the 1980s [21], a problem that was only resolved following regulatory interventions. In 1993, the FDA issued a guideline (58 FR 39406, 22 July 1993) regarding its expectation that drug manufacturers should include both males and females in clinical studies undertaking drug development. In 1993, the US congress demanded that there be an adequate number of women included in the NIH-sponsored clinical trials. A 1997 FDA rule (62 FR 49946) further stated that the FDA may put on hold the trials testing drugs for severe, life-threatening conditions if otherwise eligible men and women are excluded. Regulatory agencies are in a unique position to promote recruitment of a meaningful proportion of patients with impaired kidney function in cardiovascular trials. Solutions are possible to circumvent the concern of cardiovascular investigators and, particularly so, of the industry that the protective effects of cardiovascular drugs are attenuated or abolished in CKD. Trial sponsors are eager to have as few adverse events and serious adverse events as possible. Yet, CKD patients will generate more such adverse events. With the proviso that the ideal solution remains that of combining two adequately powered trials, one of which is in CKD patients, in a transition phase like the present one, less ambitious solutions can be foreseen to promote cardiovascular trials in CKD patients. For example, by design, the patients with CKD can be omitted from the primary analysis and then be separately analysed for efficacy and safety. Even though this solution is not a panacea, it may set the stage for meta-analyses of similar trials and hence for more robust conclusions. Another important opportunity is warranting priority or exclusivity for the use of drugs in CKD whose efficacy has been proven specifically in this population. Finally, involving patients and patient associations in lobbying regulatory agencies so that these agencies promote the inclusion of CKD patients in trials on cardiovascular drugs and other drugs may be a fruitful strategy. Neoplasia is a major cause of mortality in HIV. However, until recently, trials of new anti-neoplastic drugs excluded patients with HIV. A joint effort by the American Society of Clinical Oncology–Friends of Cancer Research HIV Working Group produced sound recommendations on immunological and pharmacological criteria for eligibility of HIV patients in oncology trials considering safety, access to experimental agents and trial integrity [22]. Also because of this well-conceived initiative, opportunities for patients with HIV to participate into clinical trials are now a reality for at least some types of cancer [23].

Major nephrology societies have put the issue of persuading regulatory agencies of the impellent need to involve CKD patients in clinical trials high in their agenda. Establishing quotas of CKD patients in relationship to specific trials and target clinical outcomes is a problem of paramount importance that needs to be defined. The ERA-EDTA has already established a channel of communication with the European Medicines Agency [24], and the inclusion of CKD patients in clinical trials is set as a priority in ongoing discussions. In the framework of the Kidney Health Initiative, the ASN has started a specific project aimed at understanding and overcoming the challenges for involving CKD patients in cardiovascular trials [25], the ultimate goal of this project being that of forming a solid rational basis for constructively interacting with the FDA. Hopefully in the near future, these efforts will solve this long-standing problem and significantly improve knowledge based on CKD-specific studies, which will eventually bring into the evidence-based realm the treatment of cardiovascular complications, cancer and infectious disease in this high-risk population.

ACKNOWLEDGEMENTS

All authors except M.K. are active members of the ERA-EDTA Council.

CONFLICT OF INTEREST STATEMENT

None declared.