Clinical Development of Antiepileptic Drugs for Children

Abstract

Summary:A clinical development plan specific to children is a necessary component of every development plan for a new antiepileptic drug (AED). In the last decade, considerable discussion has occurred in the medical and regulatory communities, resulting in specific pediatric drug development legislation. Ethical issues are a foremost consideration in the design and conduct of studies. The timing of clinical studies differs between adults and children. In general, studies in children will not be performed until efficacy and safety has been demonstrated in adults. Exceptions include development of AEDs for seizure types seen only in children. Formulation preparation and dosing selection are often more challenging in children.Clinical trials including pharmacokinetic studies will be conducted in patients. A relatively small number of children, given subdivision into age groups and seizure types, are available for study. Clinical trials must be designed with children in mind, adjusting the length of the trials and the choice of controls. Efficacy extrapolation from adults may be considered for partial seizures in children, but not in infants. Seizure counts remain an appropriate efficacy endpoint; however, ascertainment in infants and younger children may require EEG monitoring. Safety specific to growing and developing children must be evaluated and long-term effects monitored.

Adjunctive zonisamide therapy in the long‐term treatment of children with partial epilepsy: Results of an open‐label extension study of a phase III, randomized, double‐blind, placebo‐controlled trial

“…Consequently, there is still a need for additional treatment options. Regulatory requirements for pediatric epilepsy have become increasingly stringent , and relatively few well‐designed, randomized‐controlled trials have been performed in pediatric populations to date . A particularly important aspect of the evaluation of safety of a new agent in pediatric patients is the assessment of the effects of long‐term treatment on growth and development …”

Improving clinical drug development regulatory procedures for anticonvulsants

“…time which elapsed until the patient's condition worsened up to a predefined degree. While the FDA accepts this type of trials for the purpose of granting marketing approval to the investigational drug for withdrawal-to-monotherapy in refractory patients, the EMA still requires monotherapy trials with treatment-naïve patients 3,4,5 . In order to make withdrawal-tomonotherapy type of clinical trials more feasible, the FDA now accepts the results of previous studies as "historical controls" for establishing efficacy and safety of new drugs in patients who were stable, but not seizure-free on a single anticonvulsant.…”

“…According to EMA requirements, at least 100 pediatric patients should be followed for a year or longer in order to establish safety of new anticonvulsant in children. However, these requirements are not based on evidence of adverse consequences of enrolling children with age-nonspecific epilepsies in early clinical trials, and on the other hand, without pharmacokinetic data, optimal dosing information and tolerability data gathered from a pediatric clinical trial it is very difficult to administer antiepileptic drug optimally to this vulnerable population 5,21,22 . Regulatory documents should be less restrictive when trials of antiepileptic drugs in children are in question, the sponsors will then have more options for clinical development of their drugs and the trial results will be more useful for pediatric clinical practice.…”

“…Clinicians who have to prescribe new antiepileptic drug are frequently frustrated, because from the summary of product characteristics they cannot have clear understanding: is the drug effective as initial therapy, could it be used as mono-therapy, what is the optimal dosing regimen, what inter-individual differences could be expected in responsiveness to the drug, what are long-term effectiveness, tolerability and safety of the drug 4 . The situation is even more challenging when antiepileptic drugs are to be prescribed to children, especially in regard to the generalized seizures and epilepsy syndromes encountered only in childhood 5 . The aim of this review is to focus on the gaps in current knowledge about optimal use of new antiepileptic drugs in clinical practice, and to suggest changes in regulatory procedures for clinical development of these drugs which could result with improved treatment of patients with epilepsy.…”

Biblical Poetry, Spinozist Hermeneutics, and Critical Scholarship

“…Influenced by Horace, Garofalo had claimed that poetry's objects were theology and philosophy, and that poetry was a natural means to insinuate the true idea of God into the human intellect. 69 Knowledge of those sciences was a necessary requisite for a poet, to distinguish between good and evil and to explain the nature of passions. 70 To the contrary, Rabeni maintained that the object of poetry was not il vero (truth), inquired after by philosophy and theology; rather poetry aimed to conceal falseness under semblance of truth.…”