INC Resources and FAQs

Parent Key Messages

Laboratory Values in Neonates

• Age-appropriate reference ranges for laboratory values helps clinicians compare the response to treatments, improve safety monitoring, and clinical management.
• Age-appropriate reference ranges are needed to improve the critical knowledge gap.
• Why is this important?
  • Adding age-appropriate reference ranges for laboratory values in neonatal research may help a) increase parental confidence in the safety and accuracy of neonatal research b) reduce parental anxiety during clinical research c) decrease parental fear during clinical research and d) increases parental buy-in for clinical research.

Neonatal Adverse Event Severity Scale (NAESS)

• The scaling of the NAESS model clarifies safety reporting criteria, therefore reducing subjectivity in severity assessments and increasing the overall safety of each baby enrolled in a clinical trial.
• Parents may recognize a change in their infant’s baseline condition. Engaging parent participation in clinical care and clinical trial reporting of adverse events further increases the overall safety of all infants, including those enrolled in a clinical research trial.

Long-term Outcomes

• It is important to include long-term outcomes that are relevant to all stakeholders, including clinicians, regulators, and families.
• The most relevant long-term outcomes might differ across stakeholder groups, but all perspectives are of value to each study.
• It is important to involve families in clinical study design so that researchers/clinicians can determine if the study is relevant, acceptable, and feasible thereby optimizing the risk, benefit, and burden of the trial.

Neonatal Seizure

• New parents may be surprised to hear that there are very few clinical trials designed specifically for neonates and even fewer for neonatal seizures.
• Clinical trials for new ASDs are essential to lower the safety risks imposed on future neonates. These trials will help reduce the number of medications used in older children and adults that are administered off-label to sick newborns and instead encourage the development of medications that are effective to specifically treat neonatal seizures.
• NICU graduate parents provided various points of input that were included in the recommendations for the design of neonatal seizure trials. Parent opinions and shared experiences regarding trial safety, long-term outcomes and caregiver burden were incorporated into each area of study recommendations.

Culture of Research Communication in NICUs

• We should encourage the neonatal communities to regard research as a core mission in their specific NICUs.
• NICU staff should better communicate to parents why clinical research is needed, how research is operationalized, how it creates benefits for patients and families, and how parents can contribute.
• Parents and other involved NICU stakeholders should begiven the opportunity to receive research results upon study closures.
• There is an opportunity for further education around timing of approach and research consent.
• There is an opportunity for a refinement in standardization so that all the stakeholders are aware of how research is done at their own facilities.

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Neonatologists Key Messages

Laboratory Values in Neonates

• This INC literature search determined that there are no well accepted, age-appropriate reference ranges for laboratory values in neonates.
• Lack of well accepted age-appropriate reference ranges for laboratory values in neonates is a significant knowledge gap for clinical care, clinical research, and drug development.
• In neonatal research, safety reporting relies on well-accepted laboratory reference standards applied uniformly across multiple study sites to allow identification of drug-related laboratory values that are above or below normal ranges.
• INC is committed to creating a robust dataset that can be used to establish reference ranges for laboratory values in term and preterm infants and setting publication standards for neonatal laboratory data.

Neonatal Adverse Event Severity Scale (NAESS)

• Infant safety is critically important in both clinical care and research.
• The Neonatal Adverse Event Severity Scale (NAESS) is the first tool to provide a standardized, infant-specific framework to consistently assess severity of the most commonly reported events experienced among critically ill infants.
• Parents, nurses, pharmacists, neonatologists, and clinical research team members all play important roles in recognizing changes to an infant’s baseline condition, identifying possible AEs, and promoting safety culture
• Establishing tools that promote consistent, reproducible assessment of the safety of an intervention is critically important in clinical care, research and safety surveillance

Long-term Outcomes

• C-Path International Neonatal Consortium publication conceptualizes recommendations for outcome assessments in neonatal therapeutic trials.
• Investigational medicinal products (IMP) for neonates can impair or improve long-term outcomes through direct effects on the brain or indirect effects on other developing organ systems.
• Identification of reliable and impactful outcome assessments is a critical step in early protocol design that requires input from parents, health care providers, regulators, and sponsors.
• Assessments need to be tailored to the expected harms and benefits of the investigational medicinal product without excluding the assessment of unexpected impacts.
• Outcome assessments may occur at different time points throughout childhood; plans should balance of benefits costs, and burdens of assessments to the researcher and families thereby enhancing family participation and achieving high quality, meaningful data. (supplemental materials outline specific assessments at different ages)
• The involvement of parents, the use of harmonized global assessment instruments, and the collection of high-quality, standardized electronic health data can minimize the burden and costs of long-term outcome assessments.

Neonatal Seizures

Two general messages regarding neonatal drug development not specific to seizures:

• Neonatal clinical trials and drug development programs are needed to ensure that safe and effective therapies are available for critically ill newborns. Clinical care can be complicated by an absence of treatment options or inadequately studied treatments.
• Neonates are a unique, vulnerable population in whom clinical trials are difficult to perform. The advocacy and input of parents can enhance trial design and potential success of a trial.

Four key messages related to therapeutic trials for neonatal seizures:

• Seizures, one of the most common neurologic emergencies in neonates, are associated with significant mortality and neurodevelopmental disability. In fact, seizures are more common in neonates than any other age group. There is a critical need for safe and effective treatments for seizures in neonates.
• Phenobarbital, often the first-line medication for neonatal seizure management, is efficacious in only 40-50% of neonates with seizures.
• The INC published comprehensive recommendations for clinical trial design components of anti-seizure medications in neonates with valuable input from clinical care providers, researchers, nurses, industry, regulatory agencies, and parent advocacy groups. They specifically provide recommendations for inclusion/exclusion criteria, choice of comparator arms for treatment, consent, and outcome measures to facilitate the conduct of trials evaluating anti-seizure drugs or treatments for neonates. The supplement provides a literature review and drug specific discussion regarding formulations. This paper provides essential guidance to efficiently develop a regulatory clinical trial of anti-seizure treatments in neonates to determine which medications are safe and effective.

Culture of Research Communication in NICUs

The INC survey asked neonatologists, nurses, and parents about their personal perspectives on research-related education and communication practices in the NICUs across the globe (https://www.nature.com/articles/s41372-021-01220-5.pdf).

• Neonatologists surveyed felt that existing drugs routinely used in the Neonatal ICU are not adequate to meet the needs of neonates. Further efforts to communicate the need for new medications and research on the safety and efficacy of new and “off label” medications is critical for achieving the partnership of neonatologists, NICU nurses, and parents and the advancement of neonatal care.
• Neonatologists, nurses, and parents all reported that research should be integral to Neonatal ICU clinical care.
• Communications about research opportunities, safety measures, and results should be visible and accessible to nurses, health care providers, and families in the NICU.
• Physicians, nurses and parents all agreed that study results should be made available to families whose neonates participated in research when the study is completed.
• Parents may benefit from ongoing contact with research teams in order to ask further questions during a study and also to receive reminders of how to obtain study results once the study is completed.
• Nurse and parent input is essential to all stages of research. A parent perspective editorial is available here.

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Nurse Key Messages

Laboratory Values in Neonates

• This large literature review demonstrated that there are no well accepted, age-appropriate reference ranges for neonatal laboratory values.
• The absence of laboratory standards can impact nursing care at the bedside and undermines clinical decision making, shared decision processes, and safety reporting during clinical trials.
• Large real-word datasets are necessary to determine laboratory reference ranges for newborns.

Neonatal Adverse Event Severity Scale (NAESS)

• Education for nurses caring for research patients on the use of the NAESS will lead to clear communication for AE identification and evaluation. (The NAESS implementation plan includes a training module.)
• Application of nurses’ clinical expertise in AE identification and documentation is critical.
• The NAESS will support nurses to concurrently identify changes in baseline to better identify the occurrence and severity of AEs, thereby contributing to the overall safety of clinical care and trials.
• NAESS, when used consistently by all stakeholders, including nurses, will strengthen the research culture shared by the multidisciplinary team.

Long-term Outcomes

• The benefits or adverse effects of investigational medicinal products may not appear until after a study’s completion making long-term follow-up imperative. Nurses value the results of long-term outcome studies.
• Nurses support long-term follow-up studies that balance benefits, costs, and burden of specific assessments, particularly for the participants and their families.
• Maintaining participation throughout long-term follow-up is critical. Nurses support efforts to optimize retention and minimize disparities with drop-out over long-term studies, particularly among children with adverse outcomes and those from socially disadvantaged backgrounds.
• There are important benefits to long-term follow-up since the safety and efficacy of a drug or interventions may not be evident for many years.
• Suitable tracking and retention strategies are needed to ensure families are adequately informed of the study’s expectations. Nurses could help families understand the importance of long-term follow-up assessments.

Neonatal Seizures

Nurses played a key role in the development and review of this document, and nurses are often the initial members to recognize neonatal seizures, thus nurses support the following:

• Seizures in neonates present a significant burden with occurrence of seizures at about 3/1000 live births.
• Seizures in neonates have multiple etiologies making a single treatment less likely to be effective and must be considered in relationship to neurologic outcomes.
• Alternative trial designs that serve to answer the research question are preferred as these alternative designs will require the enrollment of fewer subjects reaching the outcome in a timely manner.
• Several specific challenges exist in researching ASDs in neonates. While these challenges exist, they must be balanced with exposure to non-validated therapies.
• It is recognized that there are consent challenges to trials designed to study seizures in neonates. Nurses agree that parental consent is critical and support remote consenting that will accomplish timely enrollment while adequately informing parents.
• Nurses support avoiding unnecessary/excessive blood sampling in this population and support the use of non-invasive biomarkers to establish drug safety whenever possible.
• Nurses support clear dosing administration guidelines and dose formulation as outlined in Appendix 2 of the supplementary materials.​

Culture of Research Communication in NICUs

Nurses played a key role in the development of the culture of research survey and were the majority respondents to the survey. Based on those responses this paper and nursing key messages were developed. We would like to highlight the following messages that relate to the nursing community:

1. Neonates are routinely exposed to multiple drugs that have not been adequately researched specifically for neonates nor approved by regulatory agencies for this population. (thus off label)
2. All nurses responding were very likely to say that research should be central to NICU work, however, fewer nurses felt that research was indeed actually central.
3. The majority of nurse respondents feel free to advocate for their patients during decision-making processes.
4. Nurses suggested that direct contact or face to face meetings were the most effective communication method to be informed of ongoing or future research in their NICU.
5. Nurses expressed a lack of very effective education to prepare them for competent participation in neonatal research.
6. Nurses support improved engagement to meet the unique challenges of neonatal research given the lack of evidence to support many NICU therapies/drugs.
7. It is essential to increase the involvement of NICU nurses and parents in all stages of research.

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Regulators Key Messages

Laboratory Values in Neonates

• A structured literature search concluded that there are no well-established, evidence-based age-appropriate reference ranges for laboratory values in neonates.
• This is a critical knowledge gap for neonatal drug development as laboratory values are often monitored in clinical trials as a part of the assessment of safety, and sometimes efficacy, of medical products used in neonates.
• INC plans to generate publication recommendations on how to report neonatal laboratory data and, ultimately, work to define actionable age-appropriate laboratory reference ranges in neonates.
• Availability of reliable, evidence-based laboratory reference ranges in neonates can help guide not only clinical care, but also the assessment of safety and efficacy of new drugs aimed for use in neonates..

Neonatal Adverse Event Severity Scale (NAESS)

• NAESS emphasizes that neonates are different and describes neonatal morbidity helping to differentiate disease and intervention-related events.
• NAESS defines a better language, common to all parties involved in the care of the neonate and their enrollment in a study/trial.
• NAESS is aligned with MedDRA and NIH to meet regulatory needs for submissions. This provides more complete picture of risk, benefit, and causality assessment and informs pharmacovigilance, pediatric safety reports/summaries, benefit/risk discussion, and labeling.

Long-term Outcomes

• The publication puts forth an expert consensus on the neurodevelopmental safety assessments recommended following neonatal trials of medicinal products.
• It provides a framework for the planning of long-term neurodevelopmental safety and efficacy evaluations associated with neonatal medicinal product trials.
• The document provides expert consensus on the minimum time for follow-up of neonates following clinical trials for medicinal products.
• Promoting retention without undue burden to research participants and parents must be considered, while ensuring systematic, interpretable, and adequate safety follow.

Neonatal Seizures

• The publication puts forth multidisciplinary consensus on the design of neonatal therapeutic trials for anti-seizure drugs (ASD) to facilitate development of a Master Protocol.
• It specifies key study population considerations including enrollment of neonates with EEG-confirmed seizures, addressing various etiologies of neonatal seizures in analysis plans, and inclusion of preterm infants only when supported by available safety and pharmacokinetic data.
• The document provides expert consensus on the recommended efficacy endpoints for neonatal seizure trials including reduction of seizure burden (primary), seizure recurrence (co-primary or secondary), administration of rescue ASDs (secondary), and demonstration of improved long-term neurologic outcomes (secondary).
• Other key design elements include defining study procedures to ensure that timing to administration of study drug does not delay anti-seizure treatment, use of a usual care (phenobarbital) comparator, incorporation of neonatal-specific adaptive trial designs, and inclusion of neurodevelopmental assessment at a minimum age of 18-24 months as both, a safety and an efficacy measure.

Culture of Research Communication in NICUs

• The publication describes a survey of multistakeholder perspectives on research-related education and communication practices in the NICU.
• While there was general agreement across neonatologists, neonatal nurses and parents regarding the importance of research in the NICU, there were several disparate perspectives across stakeholder groups, particularly concerning engagement of nurses and parents in research planning, education, and dissemination.
• While the majority of neonatologists felt that current medications to treat critically ill neonates were insufficient and there is a need for more studies by pharmaceutical companies, parents and nurses were less likely to have this perspective.
• Understanding multistakeholder perspectives on the culture of research in the NICU can provide opportunities to optimize future neonatal clinical trials.

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Industry Key Messages

Laboratory Values in Neonates

• There are no well accepted age-appropriate reference ranges for laboratory values in neonates. Consequently, laboratory-related adverse events were not included in the first version of the Neonatal Adverse Event Severity Score (NAESS).
• Age-appropriate reference ranges for neonatal laboratory values not only matter for disease diagnosis, prognosis, and management, but are needed for drug development.
• Findings of a literature search to identify standards for publication of neonatal laboratory data indicated information was sparse, incomplete, and lacking a systematic approach, standards, or recommendations.
• INC intends to generate publication recommendations for reporting neonatal laboratory data. Recommendations can subsequently be applied to the ongoing INC effort to define actionable reference ranges of commonly used laboratory values, to improve the impact of publications.

Neonatal Adverse Event Severity Scale (NAESS)

• INC NAESS addresses a current gap for the conduct of neonatal trials (existing severity scales not appropriate for neonates).
• NAESS scale was developed by a diverse set of global stakeholders to enhance the quality of the data and assist data safety monitoring boards, sponsors, and regulators in safety reporting.
• Collaborated with the Medical Dictionary for Regulatory Activities (MedDRA) to create specific NAESS adverse event terminology by mapping of the AEs to MedDRA LLTs.
• There is a plan in place for validation and training module for successfully implementing this tool to enhance safety of infants in clinical trials.

Long-term Outcomes

• A framework has been developed by the C-Path International Neonatal Consortium to determine the need, nature, and duration of LTO assessments in trials involving newborn infants.
• The framework outlines assessments for outcomes as direct or indirect consequence of intervention.
• Materials were provided as a supplement to the article which may be useful in development of the study visit schedule, and CRF development.
• The framework calls for the strategic involvement of parents and patient advocates balance of benefits, costs, and burdens of assessments to the researcher and families.

Neonatal Seizures

• Consensus recommendations for design of therapeutic trials for neonatal seizures to inform industry trials were developed by INC global working group of experts and key stakeholders (academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups). These recommendations are intended to facilitate the development of a master protocol to evaluate anti-seizure drugs.
• The unique characteristics of neonatal seizures require special consideration with regard to trial design including: inclusion/exclusion criteria, endpoints, randomization, masking, safety, and statistical plan stopping rules and analyses.
• The experts’ recommendation is to use neonatal seizure burden, as measured via continuous video electroencephalography (cvEEG), to assess drug efficacy. An 80% reduction in seizure burden was identified through literature review as an optimal drug response.
• Linked Supplementary information include guidance on administration, dosing, and formulation, bioanalytical requirements for drug and biomarker analysis for population PK/PD studies, drug specific safety measures, permitted or prohibited drug specific concomitant care, and interventions for anti-seizure drugs.

Culture of Research Communication in NICUs

• INC Communications work group evaluated stakeholder perspectives on the role of research in advancing neonatal care in the NICU, the current clinical and research communication flow in the NICU, education and training of neonatal personnel about the value of neonatal research, the research consent process, and disclosure of study results to families.
• This is the first reported parallel survey across multiple domains, of NICU parent, nurse, and physician perceptions regarding communication relevant to the role of research in the NICU.
• Differences were noted between stakeholder groups with respect to whether current medications meet the needs of sick neonates, research as central to the mission of the NICU, availability of appropriate education/training for all members of the research team, and adequacy of information provided to parents before, during, and after a research study is completed.
• Opportunities identified were engagement of nurses and parents at all stages of NICU research, and education on the research process and protections for all stakeholders.
• A parent editorial accompanied this publication.

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