Bridging the 13-Year Evidence Gap: A Time for Age-Inclusive Research
Authors: Louise Oni, Rona Smith, Alan D. Salama, Jonathan Barratt, Howard Trachtman, Moin Saleem
Journal: Journal of the American Society of Nephrology (2024)

The Evidence Gap In a rapidly expanding population of people living with CKD, children represent a vulnerable subgroup. There is poor recognition of their specific needs and inequalities in the systems that result in few clinical trials and prevent new treatments reaching them in a timely manner. IgA nephropathy is a disease seen in both children and adults that exemplifies the situation. It has excelled in clinical trial evaluation, with a recent detailed analysis reporting 104 registered clinical trials underway. However, only 13% of the protocols included children and only 1% were exclusively pediatric.1 The delay has been seen in the evaluation of the efficacy of renin–angiotensin–aldosterone system inhibition in patients with IgA nephropathy; in adults, there were seven randomized controlled trials involving 610 patients, with the first being published in 1994,2 in contrast to only two pediatric randomized controlled trials with 93 patients, published from 2007. This equates to a 13-year difference between the adult and pediatric first reported trial data. Decades later, the same evidence gap remains with the emergence of the sodium–glucose cotransporter 2 inhibitors. For adults with CKD, there has been a meta-analysis of 13 trials for sodium–glucose cotransporter 2 inhibitors involving 90,413 participants that were first reported from 2017,3 and there are no pediatric data to date. Fortunately, planning for such trials in children has commenced, despite the complex methodological challenges, and publication of pediatric data is expected around 2030. Once again, this is 13 years after the first reported adult data. If these agents prove similar efficacy in children with CKD, as they do in adults, thereby delaying kidney failure progression by 37% within 3.3 years (0.8–4.2 years),3 they give hope of significant gain in childhood years for our youngest population. The Current Situation In contrast to the improvements reported in upper age disparities that previously excluded older people from clinical research,4 children have not seen similar change. The current situation, with a well-defined threshold of 18 years, means that the latest treatments either never reach children, they are significantly delayed, or they creep into practice resulting in unlicensed use. Consequently, there is unregulated, unequal use of treatments in the young without the generation of high-quality evidence.5 The need for equity is clear. Beyond principles of fairness, in rare kidney diseases, approximately 75% of the >150 subtypes will have an onset in childhood, and therefore, changing the trajectory of rare disease outcomes is an age-dependent phenomenon. Moreover, most childhood-onset CKD is attributable to a rare kidney disease, and therefore, improvements will affect most of our young patients. Incentives for the pharmaceutical industry to invest in children, for example, the longer market exclusivity period and free regulatory advice, have been positive measures to support inclusion; however, the situation cannot be resolved by pharmaceutical efforts alone. Challenges facing the rare kidney disease field are complex, as captured by Kidney Disease Improving Global Outcomes, and include the need for accurate diagnoses, novel study designs, and translating scientific advances.6 The fact that the translational pipeline is skewed to benefit adults is an important additional consideration. Proposed Solutions There is a need for clinical trials to truly represent the population who experience the disease, including children.7 To generate fully age-inclusive evidence, an international effort is required to improve the systems and engage the community. Changing the Environment Regarding infrastructure, the core foundations of data, science, and guidelines need rejuvenating to aid age-inclusive trials. A coordinated, international data collaboration to harmonize core datasets that is inclusive of all ages would accurately inform the distribution of the target population and define the natural history of the disease. The strength of inclusive data was recently illustrated in a large prospective cohort of patients with IgA nephropathy participating in the UK National Registry of Rare Kidney Diseases, where data on 2299 adults and 140 children revealed that most patients, with a threshold level of proteinuria, regardless of age, reached kidney failure within 10–15 years from diagnosis, thus changing our understanding of the natural history of this important disease.8 Existing data registries, such as National Registry of Rare Kidney Diseases and European Rare Kidney Disease Reference Network, could be transformed into regulatory approved "trial ready cohorts" to rapidly identify phenotyped patients and add information on the degree of similarity between childhood and adult-onset disease to permit Bayesian borrowing. Regarding science, embedding routine biobanking would gain more precise understanding of diseases, especially in the young where the early evolution can be witnessed, uncomplicated by age-associated comorbidities. Implementation of accredited guidelines, like those established by Kidney Disease Improving Global Outcomes, would mean that the standard of care will be largely aligned to do large-scale trials. Rare disease clinical trial protocols could progress seamlessly from adults to children as safety and efficacy data evolve, thus not risking harm to children yet being inclusive. The existing age barrier, dictated by legal thresholds, should be blurred for postpubertal children, and studies should be designed with embedded bridging biomarkers and data extrapolation to ease progression into children. Further novel methodological ideas, such as the exploitation of the open-label extension phase and learning from off-label prescribing, could also be incorporated.9 A collaborative pediatric nephrology international trials network, linked to existing adult networks such as The George Institute for Global Health, would enable the efficient coordination of clinical trials. Changing the Mindset Another key to promoting age-inclusive research is to unite and engage all relevant stakeholders to drive change (Figure 1). There remains apprehension regarding clinical research in children that may exist due to historical legacy when research was deemed experimental. This is far from the current reality where research permits access to the latest treatments in a highly regulated manner. The entire kidney community needs to recognize, prioritize, and support overcoming the historical legacy facing young patients; this cannot be achieved by pediatricians alone. Adult and pediatric academic units should connect as cohesive hubs to expand capacity, broaden expertise, and support investment. Collaborative initiatives, such as the pediatric gateway initiative for glomerular disease, will create a critical mass to help drive change.10 Pediatric representation on all executive boards should be a measurable standard, for example, global pharmaceutical boards, international organizations, editorial committees, and funding associations. Drug regulators and ethical advisory boards should explore ways to communicate effectively with experts to find solutions, ensuring waivers preventing the development of evidence in children are an exception. Finally, world-leading journals could set a precedent by making age-inclusive evidence more accessible through permitted open access.Figure 1: An illustration of a proposed international framework (labeled A, B, C, D, E) to promote age-inclusive research. The ecosystem framework consists of aligning care guidelines, bridging datasets to span all ages, connecting discovery science from all opportunities, using trial accelerator platforms, and adopting templates for collaboration.There is no doubt that an age-inclusive approach will add complexities to conducting kidney research. However, in 1989, a historic commitment was made to the world's children through the United Nations Convention on the Rights of the Child. Children have a legal, moral, and ethical right to access safe and effective treatments, and this includes the right to be an equal part of a global effort to change the trajectory of kidney diseases.11 It is up to us, both adult and pediatric nephrologists, to champion nephrology as a fully inclusive specialty, advocate for children, and close the 13-year evidence gap.