Table 1.
Challenges with involving patients with kidney disease in cardiovascular trials and proposed solutions
| Challenges | Solutions |
| Building the business case | |
| Trial sponsor concerns | |
| Finite resources and competing priorities | Consider existing FDA programs (e.g., Orphan Designation, Breakthrough Therapy and Fast Track Designation, Accelerated Approval, and Priority Review Designation) |
| Inclusion of patients with advanced kidney disease could potentially skew efficacy and safety results and affect regulatory approval and product labeling | Financial incentives, such as market exclusivity extensions |
| Engage CMS and other payers early in the development process | |
| Incorporate feedback from patients throughout the development process | |
| Study design and implementation | |
| Safety concerns | |
| Higher risk of adverse events, drug interactions, nonadherence to the intervention, withdrawal from the trial | Develop strategies to mitigate safety concerns (e.g., novel study design, prohibit or restrict medications that interact with investigational product, understand effect of investigational product on eGFR, manage risks of exacerbating complications of kidney disease, such as hyperkalemia) |
| Financial and logistical burden of safety monitoring and reporting | |
| Potential reduction in data quality due to poor adherence and dropout from the study due to adverse events | |
| Concern that investigational product may affect kidney function or exacerbate complications of kidney disease | |
| Efficacy concerns and lack of innovative protocol designs | |
| Lack of efficacy or smaller effect size in subgroup with kidney disease, which could skew overall result toward the null | Consider whether there is adequate justification to exclude patients with advanced kidney disease |
| End points used in the general population may not be as relevant for patients with advanced kidney disease | Sponsor could be offered the option of enrolling patients with an eGFR below a certain threshold in a broader study but exclude them from key efficacy analyses |
| Use of protocol templates that excluded patients with kidney disease | Conduct dedicated cardiovascular trial for patients with advanced kidney disease in parallel with a cardiovascular trial in general population that excludes patients below a certain eGFR cutoff |
| Protocols designed without nephrologist input | Select appropriate end points and develop standardized cardiovascular outcome definitions for patients with advanced kidney disease and kidney failure |
| Include nephrologists in the development of cardiovascular trial protocols | |
| Recruitment concerns | |
| Prevalence of patients with advanced kidney disease is relatively low and may be a barrier to trial recruitment and enrollment | Seek guidance from patients with kidney disease on study materials (e.g., protocols) and how to optimize recruitment strategies |
| Create registries for patients with kidney disease in order to have “virtual” pool of potential participants | |
| Leverage best practices from trials that have successfully enrolled patients with advanced kidney disease and kidney failure | |
| Clinical trial culture in nephrology | |
| Lack of “on-study” culture and trial infrastructure in nephrology | |
| Lack of awareness and incentives for nephrologists to participate in trials | Offer financial and other incentives to physicians for participation in trials |
| Limited number of established sites and investigators with experience enrolling patients with advanced kidney disease | Enhance government (e.g., NHLBI, NIDDK), subspecialty society, and industry-sponsored funding |
| Challenges with communicating the value of trial participation to health systems | Provide training in trial planning and execution to trainees and junior investigators |
| Develop resources (e.g., papers, presentations) to support nephrologists’ participation in trials | |
| Encourage cross-specialty collaboration between cardiologists and nephrologists, leveraging existing organizations (e.g., ERA-EDTA, HFSA, KCVD, CRSA, INI-CRCT) and attendance at multidisciplinary meetings (e.g., CVCT, KDCT) | |
| Enrollment challenges | |
| High number of expected reportable adverse events may serve as a disincentive to site coordinators to enroll patients with advanced kidney disease | Compensation to sites to incentivize enrollment of patients with advanced kidney disease |
| Financial and logistical barriers to enrolling patients receiving dialysis | Build provider networks and partnerships to support trial conduct among patients receiving dialysis |
| Patient involvement | |
| Patients unaware of clinical trials or how to participate Patients with kidney disease are unaware that they are at risk for cardiovascular disease | Increase patient knowledge about the link between cardiovascular and kidney disease via educational campaigns coordinated by NIH and specialty organizations (e.g., ASN, NKF, ISN, ERA-EDTA) with support from dialysis providers and patient groups |
| Educate patients on trial participation via physicians, patient advocacy groups, social media, and other patients with kidney disease | |
| Develop registry of ongoing trials and provide mechanism for patients to determine eligibility and connect with study coordinator | |
| Patient concerns include fear of the unknown, risk of receiving placebo, polypharmacy, painful testing, inconvenience, and lack of time, sufficient compensation for participation, and communication of research results | Communicate trial results back to participants |
FDA, Food and Drug Administration; CMS, Centers for Medicare & Medicaid Services; NHLBI, National Heart, Lung, and Blood Institute; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; ERA-EDTA, European Renal Association–European Dialysis and Transplant Association; HFSA, Heart Failure Society of America; KCVD, Council on the Kidney in Cardiovascular Disease; CRSA, Cardio-Renal Society of America; INI-CRCT, Investigation Network Initiative–Cardiovascular and Renal Clinical Trialists; CVCT, CardioVascular Clinical Trialists Forum; KDCT, Kidney Disease Clinical Trialists; NIH, National Institutes of Health; ASN, American Society of Nephrology; NKF, National Kidney Foundation; ISN, International Society of Nephrology.