Pediatric Developmental Safety and the ICH E11A Extrapolation of Safety

Introduction

Safety assessment remains a fundamental component of pediatric drug development and could not be extrapolated to pediatric patients from another patient population until ICH E11A.¹ The concept of a safety evaluation in a pediatric patient is more complex than in adults because of the developmental process which remains a continuous concern throughout all ages of pediatric patients. Drug effects on developmental systems are very much dependent on the stage of development at the time of exposure, so the evaluation process must consider multiple systems that may be affected at different periods of development. Adult surveillance of adverse effects should not solely dictate surveillance in pediatrics.

Previously, extrapolating safety data from reference populations (patient populations that data is being taken from) to pediatric target populations (pediatric population data is being extrapolated to) was deemed inappropriate due to concerns about potential population-specific differences in drug safety profiles. The complexity of assessing the safety of drugs in pediatric patients led to important limitations regarding the extrapolation of safety information from the adult population to pediatric patients. The original inclusion of pediatric extrapolation of efficacy information in the 1994 final US FDA regulation on pediatric labeling stated that, when needed, additional pediatric safety information is necessary.²

Our scientific understanding and experience with pediatric drug development trials has since advanced considerably, enabling the development of a more advanced framework for pediatric extrapolation and including extrapolation of both efficacy and safety. The ICH E11A Pediatric Extrapolation Guidance for Industry¹ sets forth a comprehensive framework that outlines key considerations for developing pediatric safety extrapolation strategies. Pediatric efficacy extrapolation operates along a continuum that reflects the degree of certainty regarding disease similarity, drug pharmacology, and expected treatment response across populations. The extrapolation of safety should be considered separately as part of a Safety Extrapolation Plan (Section 4.1.7 in the Guidance).

The ICHE11A Safety Extrapolation Plan:

The pediatric safety extrapolation plan should address the eight questions listed in the Extrapolation of Safety section of the ICH E11A Guidance (Section 3.4.1; see Figure 1). Of particular relevance are the questions and additional considerations (Section 3.4.2 of the Guidance) relating to

• developmental “on- and off-target effects relevant to pediatric safety,” and

• “significant safety findings noted in the reference population that would be of special importance in pediatrics.”

Figure 1.

Graphical representation of the safety-related ICH E11A questions on the left, the available tools for answering those questions in the middle, and the integrated prediction of pediatric adverse events with a benefit-risk analysis on the right.

The on- and off-target effects of a new drug that are relevant to pediatric development cannot always be discerned from the adult population. Even when extrapolating efficacy and safety from an older pediatric reference patient population to a younger pediatric population, the developmental effects of a drug could be considerably different depending on the maturational stage of the organ system affected. Juvenile animal studies are triggered when there is a safety concern, and a weight-of-evidence approach is outlined in the ICH S11 Nonclinical Safety Testing in Support of Development of Pediatric Pharmaceuticals Draft Guidance for Industry.³ Juvenile animal studies may not reflect human development, and less than 10% of these studies result in changes in the clinical development program.⁴ Additionally, the pharmaceutical industry routinely screens for on and off-target effects during drug development using a panel of secondary pharmacology screening programs,⁵ and some screened targets are associated with developmental toxicities.⁶ The positive links between off-target activity and a potential relationship with a pediatric developmental toxicity should be adjudicated in relation to the age group being treated, the benefit-risk assessment for drug use in that pediatric population, and the quantitative assessment of risk for this developmental toxicity.

The incidence of adverse effects in the pediatric population is particularly important where safety findings of special importance have been observed in the reference population. For example, if an adverse event is frequent in the pediatric population and could have an important developmental effect, such as on learning or the development of motor skills, then a more complete assessment of this adverse effect would likely be necessary in the pediatric population. One example is the difference in sedation from antidepressant and antipsychotic drugs between the pediatric and adult populations. Six of the 10 antidepressant/antipsychotic drugs assessed had higher sedation rates in pediatric patients than adults with risk differences ranging from 9.6 to 36.6 %.⁷ Therefore, if an adverse effect like sedation is observed in the reference population, a further assessment of the incidence of this side effect in the pediatric population should be ascertained. Some adverse effects of these drugs occurred less frequently in the pediatric population.

How can the ICH E11A Guidance Safety Questions be Answered?

Figure 1 provides a synthesis of the ICH E11A Guidance questions related to safety extrapolation and the techniques to develop an extrapolation concept relating to safety. The ICH E11A Guidance includes a table (Table 1 in the Guidance) with examples of sources and types of data to evaluate disease, drug pharmacology, and response to treatment. The sources of data include clinical trial data, nonclinical data, real-world data and other sources. The nonclinical data includes in silico and in vitro data and is attractive given the FDA’s plan to minimize animal testing and institute new approach methodologies (NAMs) in their place.⁸

Secondary Pharmacology:

In vitro testing of secondary targets is routinely used by large pharmaceutical manufacturers. Secondary pharmacology studies are in vitro assays of small molecules’ reactivity with off-target receptors performed at the early stages of drug development by pharmaceutical manufacturers with the aim to find off-target receptors that can produce critical adverse drug events. While a number of targets currently screened are relevant for developmental toxicity,⁶ there are likely many other targets associated with developmental toxicity that could be screened. Once these targets are identified and the associations with developmental toxicity are validated, the addition of other pediatric-specific targets should not add a significant burden for the screening process. Adding pediatric secondary pharmacology targets could parallel the current program of molecular targets for pediatric oncology (https://www.fda.gov/about-fda/oncology-center-excellence/pediatric-oncology). One example of a pediatric target that is not routinely being tested is for cereblon (CRBN), a protein in the ubiquitin-proteasome system thought to be responsible for thalidomide teratogenesis.⁹

Importance of Quantitative Analysis:

An additional concern when extrapolating efficacy or safety from a reference population to the target pediatric population is finding an effective dose that minimizes adverse effects. As stated in the ICH E11A Guidance, a drug with a narrow therapeutic index is of special concern since matching the drug exposures observed in the adult population to exposures in the pediatric population may be difficult. In a review of 31 products (86 trials) in drug development where adult efficacy was being extrapolated to the pediatric population, pediatric exposures had mean Cmax and AUC ratios (pediatric/adult) ranging from 0.63 to 4.19 and 0.36 to 3.60 respectively.¹⁰ Therefore it is important to establish an acceptable range of exposure criteria for the pediatric target population prior to the study conduct.

The ICH E11A Guidance discusses the use of modeling and simulation to quantitatively derisk and reduce uncertainty, and multiple approaches can be used. Due to its quantitative and mechanistic nature and integration of factors such as development, maturation and ontogeny, quantitative systems pharmacology (QSP) models can be used in adjudicating the results of secondary pharmacology assays to predict potential developmental toxicity under pharmacologic concentrations.

Other means of testing:

Additional means of in silico and in vitro testing include quantitative structure-activity relationships (QSAR) and microphysiologic systems. The latter have been developed for a number of disease processes such as intestinal disease modeling, lung injury, and human cervical disease. Experience with each of these systems in relation to pediatric disease would need to be gained over time, but these methods hold promise and could be integrated into new drug screening protocols for pediatric developmental effects in the future.

In addition, considering the large number of pediatric studies that have been conducted in the past 25 years and the data from those studies, interrogation of the available pediatric study information through the use of informatics and artificial intelligence may allow for better predicting drug safety for developing pediatric patients.

Conclusion

It is important to stress that the pediatric extrapolation of efficacy and the pediatric extrapolation of safety should be considered as two related but separate issues. As discussed above, pediatric developmental toxicities that cannot be assessed in the adult population need to be directly considered, and the ICH E11A Guidance questions should be addressed. Additionally, concerns over adverse effects observed in the reference population that may have special importance to pediatric patients will likely require additional safety information in the pediatric population.

Therefore, the type, amount, and timing of the safety data that should be collected will depend on the gaps in knowledge identified as part of the pediatric extrapolation concept regarding safety in the target population. Whether there is a need for additional safety data (e.g., longer-term safety data) beyond that which has already been collected in the target pediatric population as part of the efficacy extrapolation approach should be evaluated as described in the ICH E11A Guideline. This evolution reflects both advancing regulatory framework and the ongoing commitment to advancing pediatric drug development without compromising the safety standards essential for a pediatric benefit-risk evaluation.