On February 15, 2018, FDA issued draft guidance to sponsors on the clinical development of drugs for the treatment of partial onset seizures (POS), which can support extrapolation of the effectiveness of such approved drugs in adults to pediatric patients four years of age and older. The draft guidance does not address seizures other than POS, and does not apply to pediatric patients less than four years of age.
Since evidence to support an extrapolation approach was not previously available, FDA required sponsors to establish effectiveness of treatments in pediatric patients with POS in one or more adequate and well-controlled clinical trials under section 505(d) of the FDCA. Doses in these pediatric trials were generally based on patient’s body weight and age in order to achieve blood concentrations of drug similar to those found to be effective in adults. Dosages were also determined by safety and tolerability data from open-label pediatric studies.
FDA proposes that efficacy data can be extrapolated from adults to pediatric patients when it is reasonable to assume that children, as compared with adults, have (i) a similar progression of disease, (ii) a similar response of the disease to the treatment, and (iii) a similar exposure-response relationship. Citing to current studies, FDA states that pediatric patents four years and older with POS (except in children with POS associated with epileptic encephalopathies, such as Lennox-Gastaut syndrome) satisfy all of these criteria. In particular, based on systemic and quantitative analysis conducted by FDA, both adults and this pediatric population show similar progression of POS, similar reduction in seizure frequency in response to treatment, and similar relationship between treatment and reduction in seizure frequency. In light of these studies, FDA concludes that it is appropriate to extrapolate efficacy data from adults with POS to children four years of age and older.
To support extrapolation, FDA recommends obtaining blood concentrations of active drug/metabolites from patients four to sixteen years of age receiving single or multiple doses of the drug. The goal in these adequately designed pharmacokinetic and tolerability studies is to select doses that are expected to achieve similar exposure in adults.
Unlike efficacy data, safety data generally cannot be extrapolated from adults to children. Accordingly, FDA states that further studies are needed to establish the safety of a drug in pediatric patients with POS.