Epilepsy therapy development: Technical and methodologic issues in studies with animal models

Abstract

SUMMARY The search for new treatments for seizures, epilepsies and their comorbidities faces considerable challenges. Partly, this is due to gaps in our understanding of the etiology and pathophysiology of most forms of epilepsy. An additional challenge is the difficulty to predict the efficacy, tolerability and impact of potential new treatments on epilepsies and comorbidities in humans, using the available resources. Here we provide a summary of the discussions and proposals of the Working Group 2 as presented in the Joint American Epilepsy Society and International League Against Epilepsy Translational Workshop in London (September 2012). We propose methodological and reporting practices that will enhance the uniformity, reliability and reporting of early stage preclinical studies with animal seizure and epilepsy models that aim to develop and evaluate new therapies for seizures or epilepsies, using multi-disciplinary approaches. The topics considered include: (a) implementation of better study design and reporting practices, (b) incorporation in the study design and analysis of covariants that may impact outcomes (including species, age, sex), (c) utilization of approaches to document target relevance, exposure and engagement by the tested treatment, (d) utilization of clinically relevant treatment protocols, (e) optimization of the use of video-EEG recordings to best meet the study goals, and (f) inclusion of outcome measures that address the tolerability of the treatment or study endpoints apart from seizures. We further discuss the different expectations for studies aiming to meet regulatory requirements to obtain approval for clinical testing in humans. Implementation of the rigorous practices discussed in this report will require considerable investment in time, funds and other research resources, which may create challenges for academic researchers seeking to contribute to epilepsy therapy discovery and development. We propose several infrastructure initiatives to overcome these barriers.

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

“…10,11 Therefore, this model has been incorporated as a late-stage differentiation assay in a pharmacoresistance screening workflow utilized by the Epilepsy Therapy Screening Program (ETSP). 17 Although carbamazepine, valproate, and ezogabine have been evaluated in the lamotrigine-resistant amygdala-kindled rat model, 1,10,11 a comprehensive assessment of ASD prototypes has not been reported. 14,15 Newer ASDs have provided specific advantages over previously existing therapies, but substantial gains in efficacy and tolerability are still needed.…”

The challenge and promise of anti-epileptic therapy development in animal models

“…The disadvantages are that acute seizure models typically will not select drugs (or therapies) that affect or prevent the underlying epilepsy or associated comorbidities; cannot discriminate drugs on the basis of their relative capability to treat seizures; could miss potentially efficacious therapies; 26 and might not predict certain adverse or toxic effects noted in human beings. 8 …”

“…The advantage of chronic models over other models is that they might better represent the human disorder, model the development of epileptogenesis including drug-sensitive and drug-resistant spontaneous seizures (enabling testing of antiepileptogenic drugs), and enable better testing of potential for adverse events in the populations of interest. 22,8 The disadvantage is that a specific insult (eg, stroke, status epilepticus) might not produce results that are generalisable to epilepsy resulting from other types of injury (eg, traumatic brain injury). Moreover, most human epilepsies do not result from a known insult, and therefore these models might not be fully representative.…”

“… These recommendations are based on or modified from references 2, 8, 12 , and 14 . For specific recommendations relevant to epilepsy research, see also reference 8 .…”

A companion to the preclinical common data elements and case report forms for rodent EEG studies. A report of the TASK3 EEG Working Group of the ILAE/AES Joint Translational Task Force

“…If EEG is continuous, with no interruptions, the element “EEG recording start to end date Interval” (EEGLogRecStartEndDateInt) is used instead. Logging the total duration of the EEG or vEEG recordings is important to report (priority set at moderate here) so as to compare the duration of monitoring between experimental and sham control groups as well as to help place the recorded frequency of seizures in the context of how intensive the EEG monitoring was …”