Thank you for joining us for another episode of the Guidance Recap Podcast. My name is Kylie Haskins, and I am today’s host. In this episode, I am excited to be talking with Dr. An Massaro, Lead Neonatologist for the Neonatology Program in the Office of Pediatric Therapeutics and Dr. Gerri Baer, a neonatologist in the Center for Drug Evaluation and Research. They will be sharing some thoughts with us on the newly published draft guidance titled, “Considerations for Long-Term Clinical Neurodevelopmental Safety Studies in Neonatal Product Development.” Welcome, Drs. Massaro and Baer! Thank you for speaking with us today.

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Dr. Massaro, for listeners less familiar with this topic, can you provide some background about medical product development for neonates and why long-term neurodevelopmental safety studies are important to consider in neonatal product development?

First, I think it is important to underscore that neonates are a both a very heterogeneous and a vulnerable population. We use the term “neonate” to refer to newborns during the first 28 days of life. In the case of pre-term newborns, the neonatal period includes the time from when they were born until 28 days after their expected date of delivery. The neonatal period encompasses a wide range of developmental stages across organ systems. Neonates can have a wide variety of medical conditions, some of which may be related to their stage of development, and may have specific acute and long-term treatment needs.

When you think about the important changes that need to occur after birth as a newborn transitions into a world in which they must now breathe, circulate blood, feed and digest on their own, you can begin to imagine what makes this population so unique and why developing medical products for neonates is so complex. Because neonates are undergoing rapid changes in all their organ systems and tissues, the absorption, distribution, metabolism, and excretion characteristics of a drug may differ in important ways for neonates compared to older children and adults, underscoring the importance of studying therapies specifically for use in the neonatal population. Similarly, designing a medical device for neonates requires consideration for their small size, growth, activity and physiologic changes that may impact the device design, settings, or algorithms.

These rapid changes in growth and development may affect the safety of a product when used in newborns, so it’s important to assess the potential short and long-term adverse effects of an investigational product in neonatal clinical trials. Such adverse effects may involve many developing body systems, but this guidance focuses specifically on the nervous system and assessing long-term neurodevelopmental safety. Patient safety is the FDA’s top priority. There are unique concerns related to exposing a neonate’s developing central and peripheral nervous systems to a medical product, as we need to keep in mind that adverse effects on neurodevelopment, whether of drugs, biologics, or devices, may not manifest clinically until well after exposure.

Past experience has underscored the potential consequences of not assessing long-term adverse effects of products that are used in neonates, and there have been instances where products that initially appeared safe and effective in this population were associated with serious adverse consequences as the child grew older. For example, short-term clinical improvement has been observed with use of high-dose corticosteroids for neonates with bronchopulmonary dysplasia, a lung disease associated with preterm birth, but later studies showed that this treatment may be associated with long-term neuromotor impairment. In this guidance, we provide recommendations to help sponsors consider the appropriate evaluation of long-term neurodevelopmental safety for their products for use in neonates.

Medical product development for neonates can be quite complex. Can you tell us more about what FDA is doing to help?

We continue to face challenges ensuring medical products are adequately studied for the neonatal population. In addition, development of new medical products specifically designed to treat neonatal conditions is lacking. For many reasons, sponsors have been hesitant to initiate medical product development programs in neonates, and thus many treatment interventions used in neonatal intensive care units are “off-label,” meaning the products used have been developed, evaluated and approved for adults or older children and not specifically for newborns.

By setting clear expectations for neonatal product development, our intention with this guidance and the previous guidance on clinical pharmacology considerations for neonatal studies is to help sponsors as they consider how to develop safe and effective medical products for neonates.

In addition to developing guidance for sponsors, FDA promotes the development of safe and effective medical products for neonates by encouraging sponsors to include neonates, when appropriate, in product development programs. We also work with experts across the agency to help ensure we take a consistent approach as we address the unique opportunities and challenges involved in evaluating products in neonates.

Dr. Baer, can you tell us a little about this guidance and provide a few key recommendations included in the guidance for long-term clinical neurodevelopmental safety studies?

This guidance provides a framework for considering clinical, long-term neurodevelopmental safety studies for neonatal product development that applies to drugs, biologics and medical devices. The framework will help sponsors plan the appropriate long-term clinical neurodevelopmental safety assessments and have conversations with FDA about these plans early in product development.

The guidance outlines factors that should be considered by sponsors as they assess whether a long-term neurodevelopmental safety evaluation needs to be conducted for neonates enrolled in clinical studies. These factors include the extent of body exposure, especially to the nervous system, the extent of exposure to the medical product, the timing of exposure relative to a vulnerable stage of organ or tissue development, and the duration of the exposure. We also highlight various population and product characteristics that may increase the likelihood that long-term neurodevelopmental safety evaluations will be needed.

For example, if we are considering a product with high systemic exposure that easily crosses the blood-brain barrier that will be used for several weeks in preterm neonates during a stage of rapid neurologic development, it is likely that comprehensive evaluation of long-term neurodevelopmental safety will be needed.

Some of our general recommendations when planning neurodevelopmental safety evaluations include:

• Controlled studies should be conducted whenever feasible. Having a concurrent comparator group that did not receive the investigational product helps us to compare the two groups and differentiate effects of the drug or device from many other factors that could be influencing neurodevelopment.
• Development of a long-term safety study plan should include an assessment of family perceptions to help identify early on if there may be barriers to study participation.
• Sponsors should consider how various factors that can affect neurodevelopmental outcomes, for example other medical conditions and socioeconomic, perinatal and environmental factors, may influence the interpretability of study results and they should collect that information accordingly.

Does the guidance address the actual clinical evaluations themselves in terms of when they should be done, what measurement tools are appropriate, and the scope of the assessments?

Yes, in the guidance we recommend sponsors conduct a general evaluation of all key neurodevelopmental domains, with additional evaluations if there are specific domains of concern. We also emphasize that overall physical, mental and social health should be evaluated as well.

We recommend that for the evaluation of neurodevelopmental safety, outcomes should be evaluated up to a minimum of two years of age, adjusted for prematurity, if appropriate.

We also outline key characteristics of the measurement tools that should be used. Evaluations should be reliable and relevant to the population and sponsors should use validated tools, when those are available. It is also important to identify and account for potential factors that may compromise the validity of an assessment and ability to interpret the result. Again, it’s important that sponsors discuss the study design and measurement tools with FDA early in the product development program.

Dr. Massaro, can you discuss some challenges with enrolling neonates in clinical trials and how sponsors can improve participation, particularly for studies like those described in the guidance that will require long-term follow-up?

Some challenges for enrolling neonates in clinical trials can include negative public perceptions of clinical trials, feasibility of participation and retention of patients once they are enrolled. Enrolling sick newborns in a research study is especially challenging given that we recognize that these discussions occur during a highly stressful time for families and caregivers, and considering long-term outcomes may be difficult during the acute period of illness. The guidance provides recommendations for sponsors to engage early in the medical product development process with relevant stakeholders, including patients and caregivers, to solicit their suggestions for trial design and clinically meaningful outcomes. Engaging patient families and community leaders early in development and at the protocol development stage may help promote participation, particularly for historically underrepresented communities, and improve overall study recruitment and retention.

Sponsors should also consider ways to make trials less burdensome, including streamlining evaluations, integrating community-level services and utilizing mobile technologies to collect information. Sponsors should provide families with the long-term follow-up plans during study enrollment, explain the importance of long-term follow-up and stay in touch with patient families throughout the entire clinical trial process.

FDA is working to improve understanding about clinical trials involving children to help ensure our stakeholders, including patients and families, know the importance of these trials and what safeguards are in place for children. FDA issued a draft guidance on ethical considerations for involving children in clinical trials² that discusses safeguards in place to ensure pediatric studies, including neonatal studies, are scientifically and ethically sound. We also recently published a consumer update³ with information for parents when considering enrolling their child in a clinical trial.

How do you anticipate this guidance will affect external stakeholders?

FDA is already working with sponsors to develop plans for long-term clinical neurodevelopmental safety studies in neonatal product development. This guidance is an important step toward helping sponsors with planning these studies and addressing approaches to minimize burden for families and sponsors. FDA is open to different approaches that improve feasibility and will consider all public comments on the draft guidance when finalizing the guidance.

Thank you very much for giving us insight into the impetus for the guidance and some of its key recommendations. Before we close today’s episode, is there anything else you would like to emphasize?

We realize evaluating long-term clinical neurodevelopmental safety is a highly challenging undertaking. We strongly encourage sponsors to consult with FDA early in product development so together we can help ensure medical products meet the unique needs of neonates and are effective and safe in the long-term.

Dr. Massaro and Dr. Baer, thank you for speaking with us today about the draft guidance on long-term clinical neurodevelopmental safety studies in neonates. We have learned so much from your informative discussion on the document. We would also like to thank the guidance working group for writing and publishing this draft guidance.

To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the guidance.

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¹ We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
² When final, this guidance will represent the FDA’s current thinking on this topic.
³ See Consumer Update titled, “Should your Child Participate in a Clinical Trial” web page at https://www.fda.gov/consumers/consumer-updates/should-your-child-participate-clinical-trial.