From novel drug targets for chronic kidney disease (CKD)[i] to advances in multifunctional drugs promising better efficacy, recent developments in the nephrology therapy area reflect an active and fast-moving landscape.

Cell and gene therapies are progressing, with research on human induced pluripotent stem cell therapies and genetically reprogrammed renal cells offering hope for new ways to restore kidney function.[ii] At the same time, the latest findings show that GLP-1 receptor agonists could have a major part to play in reducing the risk of serious kidney outcomes in patients with Type 2 diabetes and CKD[iii] – another potential gamechanger in the field.

According to GlobalData’s Clinical Trials Intelligence, there are currently 888 planned or ongoing studies for CKD. Although the majority are single-country trials, many of which are taking place in Asia-Pacific, the data shows at least 56 multinational CKD trials where Europe and North America lead the charge.  

Global studies are essential for capturing true biological and demographic diversity, as well as boosting enrollment rates through access to untapped patient populations. However, multinational studies often carry more operational risks – even strong biology might fail to show its value if site selection, global execution, and trial design aren’t precisely aligned to the disease biology being studied.

“Strong science doesn’t necessarily lead to a decisive trial outcome,” explains Jonathan Kornstein, VP of Rare Disease and Pediatrics at Caidya. “Your biology succeeds or fails based on how it’s translated into development decisions. Many nephrology programs fail, not because the drug is wrong, but because the assumptions went unchallenged – underpowered Phase IIs masquerading as proof-of-concept, unrealistic enrollment and feasibility planning, misaligned assumptions… I see these challenges all the time.”

On a recent webinar, nephrology experts at Caidya discussed common reasons why renal drug programs fail and how to de-risk programs with decisive global execution. This article explores four key learnings from the webinar, spanning geographic strategies and diversity considerations to protocol complexity and patient-centric design.

Lesson 1: Go where the patients are, not where history takes you

Nephrology indications such as lupus nephritis, IgA nephropathy, and rare glomerular diseases are frequently overcrowded. While patient populations can be small, many sponsors chase the same sites repeatedly, often following a traditional US or central European approach that has worked in the past but is becoming increasingly stretched in today’s environment.

In lupus nephritis, for example, data from GlobalData reveals 58 trials conducted in Europe since the start of 2019, including 27 with a site/s in Germany, 27 in Spain, 26 in the UK, and 24 in Italy. Other countries, such as many in Eastern Europe, have had just a few sites activated, including Greece and Bulgaria with 3 each over the seven years.

“Global strategies are critical in renal studies,” says Kornstein. “It’s largely about access to patients and potentially getting higher enrollment rates by going to some of those untapped regions, as opposed to going where past studies have been.”

By diversifying geography and exploring regions where prevalence is high and competition low, sponsors not only increase recruitment speed but can also reach diverse genetic backgrounds and patient populations that better mirror real-world disease heterogeneity.

Lesson 2: Diversity is an imperative, with operational implications

Across the board, sponsors have a responsibility to ensure diversity in clinical trial participation. In nephrology, data consistently demonstrates a high prevalence of kidney failure amongst Black and Hispanic populations, with the US African American population nearly four times more likely to experience kidney failure than white Americans.[iv] Genetic risk factors such as the APOL1 gene variant, common in people of African ancestry, play a huge role, but a range of social and economic factors and the presence of underlying conditions such as diabetes and hypertension also contribute.

As the FDA pushes for trials to mirror the demographic reality of diseases, sponsors must choose sites and geographies that can recruit under-represented groups. This may mean supporting less experienced sites that are closer to the real patient population. It also creates further impetus for global trials with geographic diversity, offering differences in genetics, disease expression, background therapy, and progression patterns.

“Heterogeneity is not noise for you to avoid – it’s about biological stress testing,” argues Henry Cremisi MD, Executive Medical Director, Medical Affairs, Caidya. “A mechanism that truly engages disease biology will do this across all geographies. When we see a demonstrated directional consistency across regions, even when the environments differ, we are strengthening our confidence and reinforcing the credibility of our data.”

For this reason, Dr Cremisi recommends pursuing geographic diversity before Phase III capital is committed, since regional variability exposes false positives or hidden confounders. “We see programs in Phase II where a signal looked compelling in a single region, but not when expanded globally,” he notes. “This isn’t failure, it was clarity arriving early when it was still affordable.”

Lesson 3: Design around the patient, not the data

Renal patients often suffer from multiple overlapping conditions, with one paper revealing that 98.2% of CKD patients have at least one comorbidity versus 51.8% in controls.[v] This has many implications for nephrology studies, one being that participants often suffer higher rates of pill burden, frequent clinic visits, travel costs, and invasive procedures.

When designing a new study, it’s essential to consider these factors and simplify visit schedules and procedures where possible. According to GlobalData’s Enrollment Module, the average duration for a Phase II IgA nephropathy study is almost 30 months. If the protocol is overly demanding, with frequent visits and follow-up biopsies, for example, retention is likely to become a source of delay.

“Understanding the patient, what that patient journey is, and thinking about ways to make it easier for the patient is really critical when designing studies,” says Kornstein. “Getting early feedback on protocol feasibility is crucial; you can even involve advocacy groups to give you a better understanding of the patient journey.”

The beauty of designing trials around the patient is that it benefits everyone. Patients are more likely to enroll and less likely to drop out. Delays are avoided, costs minimized, and attrition bias prevented.

Lesson 4: Prioritize clarity over speed

Renal trials are often slow-moving, with endpoints that only become clear over long timeframes. Because of this, small misalignments can amplify over time, with issues concerning dose, population, geography, endpoints, or interpretations stacking up and echoing over the trial’s duration and across its regions. One pitfall is to prioritize speed and efficiency over clarity and conviction. The real opportunity in this competitive market is not to run trials faster but to align and learn earlier.

“Phase II trials need to be designed to answer questions, not just to run,” says Dr Cremisi. “Too many renal programs use the same sites, same network, same playbook. On the surface that feels efficient, but we risk fatigue, recycled assumptions, and data that looks comparable but isn’t truly differentiated. Efficiency should never replace intention.”

As part of this, it’s wise to avoid protocol over-complexity, which does not equate to rigour. Overburdened renal sites suffer with complicated designs, causing delays. Instead, focus on precision, screening accuracy, trigger-based monitoring, and careful selection of biomarkers. Not all biomarkers are decision-enabling, and over-implementation in smaller trials can create more noise than insight. Nephrology sponsors must choose biomarkers that inform concrete decisions rather than adding complexity and drowning teams in data. Specifying how the data will be interpreted and how that will influence the program is essential for accelerating decision-making with confidence.

In conclusion, success in modern renal trials often comes down to how precisely and independently programs are designed and operationalized, with ‘template-driven’ approaches a common source of failure. When biology, design, operations, and interpretation are intentionally aligned, global studies gain the clarity and conviction needed to challenge assumptions early and de-risk development before it’s too late.

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References: [i] https://medicine.missouri.edu/news/possible-therapeutic-targets-kidney-disease-identified [ii] https://www.aftau.org/news_item/tau-achieves-breakthrough-in-regenerative-kidney-medicine/ [iii] https://www.nejm.org/doi/abs/10.1056/NEJMoa2403347 [iv] https://centerforhealthjournalism.org/our-work/insights/health-divide-blacks-are-four-times-more-likely-develop-kidney-failure-whites [v] MacRae C, Mercer SW, Guthrie B, Henderson D. Comorbidity in chronic kidney disease: a large cross-sectional study of prevalence in Scottish primary care. Br J Gen Pract. 2021 Feb 25;71(704):e243-e249. doi: 10.3399/bjgp20X714125. PMID: 33558333; PMCID: PMC7888754.