Neonatal/Juvenile Animal Safety Studies Kenneth L. Hastings, Dr.P.H., D.A.B.T. Office of New Drugs, CDER

Specific Guidance Qualifying for Pediatric Exclusivity under Section 505A of the Federal Food, Drug, and Cosmetic Act (Sept. 1999) “FDA may request … nonclinical trials before completing pediatric studies in humans. Certain toxicology studies in immature animals may be necessary to evaluate the safety of…use in pediatric conditions. “

Specific Guidance (2) ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Population (December, 2000): “The decision to proceed with a pediatric development program…involves consideration of many factors, including: …unique…safety concerns…, including any nonclinical safety issues.” “The need for juvenile animal studies should be considered on a case-by-case basis and be based on developmental toxicology concerns” Refers to ICH M3 document for specifics

Specific Guidance (3) Nonclinical Safety Evaluation of Pediatric Drug Products Draft published February 2003 Provides guidance on “…the role and timing of animal studies in the safety evaluation of therapeutics intended for the treatment of pediatric patients.” “…provide[s] specific recommendations based on the available science and pragmatic considerations.”

Assessment of Drugs for Pediatric Use Basic assumption: under most circumstances, safety and efficacy of drugs approved for use in adults predicts pediatric use Relative body surface area good default measure for dose adjustment, but generally less informative than data from clinical pharmacology studies Clinical pharmacology studies support dose adjustments based on differences in pharmacokinetics

Neonatal/Juvenile Animal Studies to Enable Clinical Studies Determine if clinical pharmacokinetic studies in pediatric patients safe Origin of Guidance: to provide information (“triggers”) on need for nonclinical studies To provide advice on conduct of studies To provide information on how results of these studies would be used

Overview of Guidance on Juvenile Animal Studies Differences in Drug Safety Profiles between Mature and Immature Systems These include susceptibility to insult, differences in toxicity-related ADME parameters Recognition that some physiologic systems more vulnerable than others, esp. those that undergo extensive post-natal development

Utility of Juvenile Animal Studies Risk Assessment Risk Assessment Adverse effects observed in mature animals predict neonatal/juvenile effects: determine exposure parameters associated with increased/decreased risk Hazard Identification Adverse effects in mature animals not predictive of adverse effects in developing systems

Risk Assessment: Considerations (Humans) Distribution –Tissue binding (receptor, protein) differences with age Absorption –  V d (small size, large SA:Wt, body composition) –  Gastric pH (  basic  acid drug) – GI motility (infant/neonate low, child high) –Bioavailability unpredictable –Unique exposure routes (e.g. milk)

Risk Assessment: Considerations (2) Metabolism (Pediatric>Adult) –Phase I Maturation (0-3 Yr.) –Phase II Maturation (0-12 Yr.) –Enzyme activity varies with P450, substrate, age –Active metabolites Excretion –  GFR,  tubular secretion/reabsorption –Infant/Neonate slower CL, longer T 1/2 –Child rapid CL, shorter T 1/2

How Valuable are Animal Models for ADME Comparisons? Obvious Advantage: Experimental manipulations Not So Obvious Disadvantage: Lack of comparative information, esp. with respect to P450 isozymes However: valuable if PK parameters associated with adverse effects can be identified for use in clinical trials

Differential Susceptibility Relative maturation rates of physiologic systems probably better understood in animals If adverse effect observed in mature animals, neonatal/juvenile animals studies can be used to demonstrate increased/decreased susceptibility ADME parameters can be studied as well, but extrapolation to clinical trials less certain

Animal Studies for Short-Term Exposure Not Needed? May not be necessary to conduct nonclinical studies prior to conduct of clinical trials: depends on known adverse effects However: May need long-term follow-up studies, (e.g. fluoroquinolones)

Animal Studies for Long-term Use May shift to hazard identification depending on what is known about drug Begin dosing in neonatal/juvenile animals, continue through maturation: adverse effects observed may indicate need to determine “window of vulnerability” Risk assessment can be built into model Safety pharmacology studies can be incorporated (as with short term studies)

Efficacy Models Various animal tumor models may be used (transplanted tumors, genetically manipulated animal models, initiation-promotion models) May also be an opportunity to obtain safety information

The Animal Rule 21 CFR 314, subpart I ( ; ); subpart H Allows for use of animal studies to demonstrate efficacy where clinical trials would be unethical and/or not feasible Applies to new drug and biological products “used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances.” Drugs considered should have demonstrated safety in humans and, if possible, clinical activity in relevant disease (although lack of clinical efficacy data should not prejudice against consideration) Important to consider: in what way can this principle be applied to pediatric oncology drugs? (Similarity of disease - course and response to therapy)

Conclusions Juvenile animal studies can be useful for safety determinations, especially when a problem is suspected Juvenile animal studies are not prohibitively challenging to conduct Available data does not indicate that juvenile animal studies need to be conducted routinely to support clinical trials in pediatric patients, but might be needed under some circumstances Data base is limited, however, and this conclusion might change as more studies are submitted