The new article highlights the aspects related to the key considerations related to the study design. 

The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a draft guidance document dedicated to neonatal product development. In particular, the document describes in detail the considerations for long-term clinical neurodevelopmental safety studies. By the virtue of the guidance, the authority explains the importance of ensuring long-term safety of healthcare products intended to be used in neonates, and provides recommendations to be followed. 

It is important to mention that FDA guidance documents are non-binding in their legal nature, nor are intended to introduce new rules or impose new obligations, but rather to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be considered by medical device manufacturers and other parties involved in order to ensure compliance thereto. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the current regulatory framework and has been agreed with the authority in advance. 

Neurodevelopmental Follow-Up 

The scope of the guidance covers, inter alia, the aspects related to the neurodevelopmental follow-up for product development programs that include neonates. According to the guidance, long-term neurodevelopmental safety should be considered as part of neonatal product development plans, while sponsors should communicate as early as possible with the relevant FDA review division to reach alignment on the appropriate approach for long-term safety evaluations. The guidance further describes in detail the key points related to the matter. 


Determining the Need for Long-term Neurodevelopmental Safety Evaluations 

When developing a plan for clinical studies involving neonates, a sponsor should ensure the long-term neurodevelopmental safety evaluation is included as a part of it. The authority recommends considering this at the early product development stages and making changes to the applicable approach based on the new information becoming available. The document further outlines the main considerations, dividing them into several categories. 

According to the guidance, general considerations include:

  • Systemic Exposure associated with the routes of administration. As it is stated by the authority, higher levels of systemic exposure are usually associated with higher central nervous system (CNS) exposure and potential risk for long-term sequelae. 
  • Timing of Exposure stands for a specific stage when the patient is exposed to the product subject to review.
  • Duration of Exposure, which stands for the period of time the patient (study subject) is exposed to the effect caused by a product in question.


Patient and population-specific considerations include the following ones:

  • Neurodevelopmental vulnerability, stands for the anticipated rates of developmental, behavioral, and sensory impairments associated with a specific age or condition. 
  • Disease characteristics are important in terms of assessing the effects of the treatment and potential long-term consequences thereof. 


The guidance also outlines product-specific considerations which, as described by the authority, include:

  • Nonclinical toxicity;
  • Clinical pharmacology;
  • Clinical experience; and 
  • Product components.

Factors for Consideration 

The document further outlines the key factors to be considered when developing a plan to evaluate long-term neurodevelopmental safety. Should, upon evaluation of the criteria outlined hereabove, the sponsor determines that a long-term neurodevelopmental safety evaluation is required, the design of a study should be based on scientific rationale. In particular, the authority encourages study sponsors to conduct controlled investigations whenever possible. The authority mentions that although a single-arm study may be useful for collecting some types of safety information, the absence of a concurrent control is difficult, if not impossible. Thus, the authority encourages the involvement of several groups – in such a control group will ensure easier discrimination of drug or device-related patient outcomes from outcomes caused by other factors, including underlying disease and developmental progression, especially if the natural history of the condition in the patient population is not well-established. With respect to the above, the document also outlines the main considerations divided into groups. 

According to the document, general considerations include:

  • Standardization: in order to ensure the accuracy and reliability of the study results, the party responsible for the trial should consistency in administration and scoring across all the sites participating in the investigation. 
  • Community acceptance and inclusivity: a plan to be developed by the sponsors should include the aspects related to potential barriers. 
  • Multidisciplinary input: when developing a study plan, study sponsors should engage key stakeholders including, inter alia, patients, parents, and healthcare professionals since their feedback is important for identifying meaningful outcomes. 
  • Patient recruitment and retention: when recruiting the study participants, a sponsor should consider long-term follow-up evaluation. Hence, it is important to develop plans for keeping families engaged in order to be able to obtain the necessary information. For example, the authority additionally emphasizes the importance of staying in touch and keeping contact even if the family participating in the investigation changes its location. 
  • Patient burden. According to the guidance, sponsors developing long-term safety evaluations should consider and mitigate barriers to follow-up study enrolment as well as minimize the short-term and long-term burdens of study participation to the subjects and their families. 
  • Data quality. A sponsor should take all the measures necessary to ensure the proper quality of data collected since it impacts the accuracy and reliability of study results. 


In summary, the present FDA guidance outlines the key considerations related to the clinical investigations addressing long-term effects in neonates. The document describes in detail the approach to be followed by study sponsors when developing an investigation plan in order to make sure the study covers all the important aspects that are specific to this patient group. 



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