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  5. Guidance Recap Podcast | General Clinical Pharmacology Considerations for Neonatal Studies for Drugs and Biological Products
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Guidance Recap Podcast | General Clinical Pharmacology Considerations for Neonatal Studies for Drugs and Biological Products

Thank you for joining us for another episode of the Guidance Recap Podcast. The Guidance Recap Podcast provides highlights for FDA guidance documents straight from the authors. My name is Kylie Haskins, and I am the host for today’s podcast. In today’s episode, I am excited to be talking with Dr. Elimika Pfuma Fletcher, a Policy Lead in the Office of Clinical Pharmacology, and Dr. Gerri Baer, the team lead for pharmacovigilance and neonatology in the Office of Pediatric Therapeutics. Dr. Fletcher and Dr. Baer will be sharing some thoughts with us on the newly published final guidance titled, “General Clinical Pharmacology Considerations for Neonatal Studies for Drugs and Biological Products.” Welcome, Dr. Fletcher and Dr. Baer! Thank you for speaking with us today.

Let’s begin with Dr. Baer. Can you explain to the audience why clinical pharmacology considerations for neonatal studies are important and provide some of the reasons that FDA issued this guidance?

Absolutely, Clinical pharmacology considerations for neonatal studies are critically important because this population has unique absorption, distribution, metabolism, and excretion characteristics that differ from older children and adults. Even within the neonatal population, there is also significant diversity, with respect to size, physiologic maturity, and the specific conditions of the neonate. All of these considerations need to be factored in when developing formulations, determining dosing strategies, and considering study designs so that the study has the best possible chance of meeting its objectives.

Another reason that we need this guidance are unique neonatal conditions that require treatments designed specifically for neonates. In this case there may not be much clinical pharmacology data that can be borrowed from other populations, and the neonatal studies are crucial.

Currently, many drugs are still used off-label in neonatal intensive care units, and there have been cases where adult drugs have been ineffective or even harmful to neonates. For example, years ago, gastric acid blockers developed for adult gastroesophageal reflux disease were widely used to treat preterm neonates who were spitting up. The practice wasn’t studied adequately prior to its adoption, and observational studies found that preterm neonates who had received these drugs were at higher risk of mortality and bowel complications.

FDA issued this guidance as part of an ongoing effort to support sponsors and investigators who are planning neonatal trials. The Agency wanted to provide recommendations for selecting appropriate designs for clinical pharmacology studies and identifying the correct neonatal dose to support the successful development of treatments specific for neonates, and this guidance was mandated by FDA Reauthorization Act of 2017 (also known as FDARA) as part of a continued public health response,.

Dr. Fletcher, for listeners less familiar with this area, can you provide a little background about clinical pharmacology considerations for neonatal studies?

Sure, one of the biggest considerations for neonatal studies is that neonates are a diverse population.  This guidance defines the neonatal period for the term and post-term newborn as the day of birth plus 27 days, and for the preterm newborn, as the day of birth, through the expected date of delivery plus 27 days. When designing studies, it is important to consider stratifying the neonatal population by gestational age and/or weight at birth to decrease heterogeneity related to maturation.

Pharmacokinetic information from older populations and from animal studies may be integrated into modeling and simulation approaches to predict dosing, but data from neonates are required to confirm this information. In general, traditional PK studies are not ethical or feasible due to limited blood volumes, so strategies like sparse sampling and opportunistic sampling  are particularly helpful and make the information amenable for population pharmacokinetic analyses.

Given the challenges associated with conducting neonatal studies, this guidance highlights alternative and innovative approaches that may improve study success and also discusses the potential limitations of these approaches.

Finally, it is important to note that this is a supplemental guidance to the FDA guidance titled General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products, as neonates are a subset of the pediatric population. For additional information, we also recommend that listeners read the pediatric guidance.

Dr. Baer, How do you anticipate this guidance will affect external and internal stakeholders?

For FDA staff, this guidance supports consistent practices across the agency for evaluating neonatal clinical pharmacology study plans and protocols and will be a valuable resource for reviewers. The guidance will also provide reviewers with specific recommendations to give sponsors when questions on neonatal clinical pharmacology arise.

This guidance also will help industry as it provides useful strategies for conducting neonatal studies. FDA frequently receives requests from external stakeholders for more information on best practices for conducting neonatal studies, and it is apparent there is a perception that studying these patients is too risky. Sponsors and investigators can view the guidance as assurance that FDA recognizes the importance of these studies and provides expectations and strategies for feasibility.

This guidance contains an incredible amount of useful and important information.  For our last question, Dr. Fletcher, can you provide the listeners with a couple of key items that you especially want them to remember?

Yes, that’s a great question. There is so much useful content in this guidance, and a few key items that I would like listeners to remember are:

Firstly, that adequate pharmacokinetic characterization of treatments in neonates is key for optimal dose selection. Neonates are a diverse population and careful consideration is needed for study planning to increase likelihood of clinical trial success to inform approval of drugs in this patient population.

Secondly, neonates are a vulnerable population with potentially unpredictable safety issues and in some cases unique conditions. The science to supplement our understanding of neonatal clinical pharmacology is growing, and the FDA issued this guidance to support the conduct of neonatal studies. Neonates have historically been treated with off-label treatments based on studies in adults and older children, in an attempt to protect babies from being included in clinical trials. Unfortunately, a number of the off-label therapies have been found to be harmful, and many show limited or no benefit. FDA would like to spread the message that therapies designed specifically for neonates need to be developed, and we can protect neonates through inclusion in clinical research.

Dr. Fletcher and Dr. Baer, thank you for taking the time to share your thoughts on the neonatal clinical pharmacology final guidance. We all have learned so much from your experience and insights in this area, and we appreciate the hard work that you have invested to inform safe and effective use of the drugs and biologics we regulate. We would also like to thank the guidance working group for writing and publishing this 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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