Pediatric dosing aims to produce similar drug exposure to that of adults, provided that children and adults have similar exposure‐response (ER) relationships. We examined ER similarities between adult and pediatric populations using in‐house NDA data. All NDAs that included pediatric uses were screened, from which 10 NDAs that contained the following parameters and indices (P&I) were analyzed: pharmacokinetics (PK), ER, drug‐related adverse events (ADR), and efficacy (E) after administration of various formulations/dosage regimens. Pediatric‐to‐adult ratios (PTA) of these P&I were calculated for various pediatric age groups (3 mo‐16 yrs). Trend analysis did not reveal a consistent pattern relating drug exposure to ADR or E P&I. Pediatric exposure levels were higher than adults (Cmax ratios = 0.33 ‐ 2.58, AUC ratios = 0.43 ‐ 2.25) but resulted in less than comparable response (E ratios = 0.18 ‐ 1.36). Although the PTA ADR ratios were comparable to adults, ranging from 0.25 to 4.24, 3 drugs manifested serious adverse events (SAE) in children only. In general, the difference in ADR and E P&I are inversely related to age. Detailed age‐group analysis will be presented. PTA E or ADR ratios among therapeutically‐similar drugs could not be extrapolated. The lack of PTA similarity observed in this study implies that pediatric PK studies may provide key information for dose adjustment but incorporation of ADR and E data is critical. Clinical Pharmacology & Therapeutics (2004) 75, P75–P75; doi:
The Division of Antiviral Drug Products of the US FDA has regulatory authority over the investigational new drugs under development by various sponsors to treat HIV-infected populations. The FDA and the sponsors of investigational new drugs use the Code of Federal Regulations to guide the entire drug development process, in order to ensure that safe and efficacious drugs are brought to market. To achieve this goal, diligent monitoring for safety during the pre-approval phase of new drug development is particularly crucial. When deciding what adverse experiences on clinical trials should be expeditiously reported, the Division recommends a conservative interpretation of the Code of Federal Regulations, where an adverse experience in a clinical trial of advanced HIV-infected patients is considered to be 'associated with the use of the drug' when the relationship cannot be ruled out with objective evidence. Fatal adverse experiences for subjects on clinical trials should be especially scrutinised. Safety reporting should be expedited when death occurs during clinical trials of advanced HIV-infected populations. The three components of an expedited reportable death occurrence, namely 'serious', 'unexpected' and 'associated with the drug use' as they relate to advanced HIV-infected populations, are discussed in this article. An occurrence of death is by definition serious. Unexpected experiences are unlisted adverse experiences, but need to be put into the context of specificity and severity. 'Associated with the drug use' has been clarified as 'relationship to the drug cannot be ruled out'. Because death in the advanced HIV-infected/AIDS population is usually a complex event, the possible contribution of the study drug is difficult to rule out. Thus, if the three components of the reporting requirement are met or insufficient information is available to make a firm determination of causality by the seventh day of the reporting period, the Division of Antiviral Drug Products expects expedited death reports on subjects participating in investigational new drug clinical studies.
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