OTHER CONSIDERATIONS

5.1 Excipients

Dedicated JAS on excipients are generally not needed to qualify pediatric formulations. To assess the safety of the pediatric clinical formulation, available toxicity information on the excipients should be evaluated.

Pharmaceutical formulations used in pediatric indications can occasionally contain novel excipients or excipients not previously used in pediatric populations of a relevant age. If there are insufficient data to support the use of the excipient in the intended pediatric population, a JAS can be warranted. Although JAS that are primarily intended to assess the safety of active ingredients need not always be conducted with the clinical

formulation, an excipient could be assessed in a JAS along with the active ingredient, if such studies were being conducted.

659-672 5.2 Combination Pharmaceuticals

The development of combination pharmaceuticals for pediatric use should have a nonclinical evaluation consistent with the principles outlined in ICH M3 (R2) for combination products in general together with the WoE principles outlined in this guideline. For example, a combination JAS would generally not be recommended for a combination of two late stage

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entities for which there is adequate pediatric clinical experience with co-administration. Whereas, a combination JAS might be warranted for a combination of two early stage entities if a WoE evaluation suggests that a JAS would address identified concerns. If additional nonclinical information is needed, the study design should consider what assessment endpoints are appropriate to address any concerns of administering the particular combination. If a JAS is considered appropriate, assessment of the combination as it is to be used clinically is generally sufficient and testing of the individual active ingredients may not be critical. Alternatively, an extra group with the combination could be added to a JAS that is already being conducted with one of the single entities. This could eliminate the need to do a separate study with the combination product.

673-698

6. GLOSSARY

Enhanced Pre- and Postnatal Development Study (ePPND):

This study design is based on biopharmaceutical (NHP) experience and is a PPND study which includes elements of the embryofetal development (EFD) study in newborns and infants instead of the fetus.

Juvenile:

Any postnatal stage not fully matured in terms of morphology and function

Pediatric First:

Pediatric-first development is when the pharmaceutical is developed for pediatric patients before any clinical data are available in adults for any indication.

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Pediatric Only:

Pediatric-only development describes development for an indication requiring treatment 687 exclusively in pediatric ages (e.g., neonatal respiratory distress syndrome).

Weight of Evidence:

An approach that evaluates a combination of information from several independent sources to 691 determine if there is sufficient evidence to support pediatric clinical trials or whether 692 additional nonclinical assessments are recommended to address safety concerns that cannot be managed clinically.

The weight given to the available evidence depends on factors such as the quality of the data, consistency of results, nature and severity of effects, and relevance of the information. The weight of evidence approach requires use of scientific judgment and, therefore, should consider the robustness and reliability of the different data sources.

699-724

7. NOTES

Note 1

If the off treatment period begins prior to maturity, the capacity and character of the recovery can be influenced by the continued growth and development of some organ systems, and should be carefully interpreted.

Note 2

The propensity for mortality to occur is generally higher in juvenile animals compared to adult animals. Study-related procedures should be

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limited as much as possible before and at the time of weaning as they can contribute to mortality.

Note 3

Assessments on immature animals should be done with reference to age-matched control data (e.g. body weights, clinical pathology, organ weights, histology) either from concurrent control animals or from other reference background data. This is especially important to consider in cases of unscheduled assessment of endpoints. JAS animals are generally not screened prior to initiation of treatment. Therefore,

background rates of abnormalities in juveniles can differ from animals of the same age used in adult toxicity studies.

Note 4

Since growth happens in spurts, frequent assessments of bone length for ‘transient’ effects on growth is challenging to appropriately power and offers limited value. An assessment using data from the end of treatment is more useful. An effect solely on decreased body weight gain is not necessarily an effect on growth.

Note 5

Assessment of organ weight data should be done in the context of growth. For instance, if growth was restricted then absolute weights of most organs decrease in proportion to body weight; however, some organs have different sensitivity to growth effects.

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725-735

8. REFERENCES

1. ICH E11 Guideline: Clinical Investigation of Medicinal Products in the Pediatric 726 Population; 2017

2. ICH M3 Guideline: Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals; June 2009.

3. ICH S5 Guideline: Detection of Toxicity to Reproduction for Medicinal Products 731 and Toxicity to Male Fertility; 2000

4. ICH S6 Guideline: Preclinical Safety Evaluation of Biotechnology-Derived 733 Pharmaceuticals; 2011 5. ICH S9 Guideline: Nonclinical Evaluation for Anticancer

Pharmaceuticals; 2009

These tables reflect a high level overview of organ system development by species to illustrate similarities and differences between the commonly used toxicology species, as compared to humans, for the timing and relative duration of development. Specific milestones include birth, introduction of solid foods, weaning, puberty, and adulthood. The tables are intended to aid in the assessment of the relevance of existing

nonclinical data, as well as the selection of species, starting age, and dosing duration for a JAS. These summary tables are based on a review of current knowledge, but are not comprehensive. Species-specific and/or organ system reviews in the literature can provide additional detail and should be consulted for each specific situation.