Translating regenerative medicine therapies in neonatal necrotizing enterocolitis | Pediatric Research – Nature.com

Empowering neonatal intensive care unit (NICU) teams and enhancing parent/caregiver engagement

The success of regenerative medicine trials for NEC hinges significantly on the empowerment of NICU teams and the active engagement of parents and caregivers.29 Comprehensive training for NICU team members that focuses on the informed consent process and includes a trauma-informed approach to addressing concerns of parents/caregivers is pivotal for trial success. Effective training strategies ensure that parents/caregivers are adequately informed and supported, thereby facilitating their engagement and mitigating follow-up losses. Many parents/caregivers learn about NEC after diagnosis. The overwhelming psychological burden may hinder their understanding of intervention benefits/risks, and active participation in the trial. Providing clear, accessible information about NEC, including risk factors and proposed interventions before diagnosis can foster informed decision-making. Technological tools (e.g. animated videos) can help to inform parents/caregivers about regenerative medicine interventions and trial procedures.31 We have partnered with the NEC Society, the only patient-led nonprofit organization working to advance research, advocacy, and education to improve treatment strategies and outcomes for the most vulnerable infants at risk for NEC. The perspectives and lived experiences of parents/caregivers affected by NEC significantly contribute to translational research trial design and improve consent processes.

Building upon the foundation of empowered NICU teams and engaged parents/caregivers, the next logical step is to address the recruitment challenges that frequently impede the progress of pediatric and neonatal trials, especially in NEC.32,33 Slow recruitment is a critical issue that can lead to early discontinuation of pediatric and neonatal trials. This is exacerbated by complicating factors such as rarity of the disease, restrictive eligibility criteria, concerns about stem cell interventions, inadequate risk/benefit assessment, limited partner engagement, and lack of institutional support.31 These factors are especially pertinent in NEC, an acute, rare, life-threatening condition affecting the most vulnerable patients. To navigate these challenges, a stepwise and evidence-based approach is essential. This approach relies on empirical evidence gathered at each of the steps below, which inform and refine the subsequent step(s):

Designing eligibility criteria, adverse events, and outcomes based on historical cohort studies such as the Canadian Neonatal Network34;

Conducting observational studies and trial feasibility studies to refine eligibility criteria, pre-specified adverse events, pilot patient and patient-family inclusion strategies, intervention delivery, and outcome measurements;

Developing protocols for phase I/II safety and feasibility interventional trials;

Developing protocols for phase II/III efficacy trials, which will evaluate the effectiveness of interventions.

Careful planning, resource allocation, and a methodological approach informed by empirical evidence is the key to addressing recruitment challenges, allowing advancement into the critical phases of trial development.

The large heterogeneity in outcome selection, measurement, and reporting in NEC trials hinders successful interpretation and implementation of findings. Following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Guidelines for Reporting Outcomes in Trial Protocols,35 outcomes should address five core elements: outcome domain (title or concept), measurement variable and tool, specific metric (unit of measurement), method of aggregation (procedure for estimating treatment effect), and time point of outcome data collection. A harmonized core outcome set for NEC treatment trials involving stem cell-based interventions considering the most relevant outcomes for clinicians, patients, and parents/caregivers is required to guide the development of evidence-based regenerative medicine interventions.

Early involvement of trial statisticians using modern frameworks can address challenges related to small sample sizes and heterogeneous patient populations, minimizing recruitment time and improving trial efficiency through adaptive trial designs and interim data analysis. Adaptive trial designs allow for preplanned modifications to the trial based on interim data analyses, including changes to sample size, treatment allocation, and even the inclusion/exclusion criteria. Techniques like Bayesian statistics36 and response-adaptive randomization37 incorporate prior and accumulating knowledge to adjust trial parameters dynamically, reducing the time required to get effective, safe combination therapies to the most vulnerable patients. Furthermore, adaptive trial designs offer a strategic advantage with the potential for substantial cost savings. The high cost of running trials, driven by the extensive time and resources needed for trial activation and to meet accrual targets, poses a significant barrier to their long-term feasibility and impacts the scope and scale of clinical research undertaken.38 The rarity of NEC necessitates the inclusion of multicenter trials to gather sufficient number of participants, further escalating costs. Moreover, the vulnerability of the patient population, predominantly premature infants, adds layers of complexity in trial design and implementation, requiring rigorous safety protocols and extended monitoring periods. Adaptive designs can mitigate these financial challenges by reducing unnecessary expenditure on ineffective treatments or overly large sample sizes.

The transition from methodologically robust trial designs to the clinical implementation of new treatments, once proven effective through high quality clinical trials, is often delayed or never occurs. This is due to various factors including intervention complexity. Important determinants of implementation include attitudes of medical staff and parents/caregivers towards stem cell-based interventions, and the impact of evidence from evaluative studies on decision-making. A hybrid effectiveness-implementation design could address the delay in implementation by assessing the intervention safety and effectiveness while also exploring implementation barriers.39 Empirically investigating these factors during the safety/efficacy trial phase, especially understanding parent attitudes towards interventions, could be a novel approach.

A multinational consortium is essential for incorporating diverse NEC patients and management practices and evaluating stem cell-based interventions. Our international NEC consortium involving 12 centers across Canada, US, UK, Netherlands, Sweden, and Spain,40 unifies resources, expertise, input from Partners, and patient populations for effective large-scale trial design, conduct, and analysis. The consortium standardizes trial procedures, raises NEC awareness, and advocates for policy and public support, fostering advancement in stem cell-based NEC interventions. Additionally, collaboration with the Neonatal Research Network (NRN), a network of neonatal intensive care units across the United States, will further enhance the capacity for rigorous patient evaluation. Leveraging the NRNs infrastructure and extensive experience in multi-center neonatal trials, including in NEC,41 in combination with the strength of our consortium, will accelerate the development and testing of innovative interventions.

In trials involving small, heterogeneous, and critically ill groups like neonates with NEC, assessing the generalizability of stem cell-based interventions is challenging. Innovative methods like risk and effect score analyses42 can address this by grouping patients based on predicted health outcomes or treatment effects, offering personalized treatment opportunities.43 This novel approach to treatment effect heterogeneity demands multidisciplinary expertise for effective implementation. This nuanced approach underscores the necessity for multidisciplinary expertise and collaboration in overcoming the inherent challenges of neonatal clinical trials, particularly in NEC.

A main task of the dedicated research consortium is the development of NEC-specific adverse event (AE) frameworks and safety endpoints across collaborating centers. These frameworks will categorize AEs by type and severity and link them to stem cell-based interventions, ensuring patient safety, accurate reporting, and effective safety monitoring. Instruments for grading of unexpected AEs44 are essential for quantifying the severity and impact of AEs with enhanced objectivity. A Delphi consensus approach can be employed to develop a comprehensive harmonized AE framework. The Delphi method is a structured communication technique, involving the systematic collection of expert opinions.45 This process involves iterative rounds of questionnaires sent to a panel of selected experts and patient-families. Feedback is aggregated and shared with the panel after each round, allowing for the refinement of opinions and convergence towards a consensus. By gathering insights from key trial Partners (Table1), including parents/caregivers, the Delphi method facilitates the creation of a harmonized AE framework most relevant to neonates with NEC in stem cell trials, enhancing the safety, efficacy, and transparency of interventions in this vulnerable population. Developing these frameworks in the early planning stages of phase I safety trials will allow for consistent safety assessment of these interventions in various trials and settings.

Following the establishment of frameworks to evaluate the safety of interventions, it is crucial to recognize that conducting neonatal stem cell-based intervention trials embodies significant ethical challenges, including minimizing risks and maximizing the value of knowledge gained. Key to both is rigorous preclinical evidence assessment and implementation of a robust consent process to avoid therapeutic misconception and misestimation by the parents/caregivers of these vulnerable, critically ill newborns.

Industry partners are crucial in selecting standardized, clinical-grade stem cell products for NEC treatment. They facilitate the evaluation of product quality standards, scale, costs, labeling, packaging, storage, timely distribution, and regulatory compliance. Furthermore, early involvement of industry partners facilitates the navigation of regulatory compliance with Good Manufacturing Practices.

Early health economic evaluation, which is underutilized in neonatology, is a tool to support product investment decision making, provide guidance in (economic) data collection and support prioritization of future research. Estimation of the economic burden of NEC, as the first step, could highlight its societal and healthcare impact, and guide policy makers in prioritizing treatments. Early engagement of health economics experts to ascertain financial viability is crucial to identify whether and under which conditions, once proven effective, stem cell-based therapies for NEC are economically viable and accessible.

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Translating regenerative medicine therapies in neonatal necrotizing enterocolitis | Pediatric Research - Nature.com