Extrapolating evidence of antiepileptic drug efficacy in adults to children ≥2 years of age with focal seizures: The case for disease similarity

Pellock, John M.; Arzimanoglou, Alexis; D’Cruz, O’Neill F.; Holmes, Gregory L.; Nordli, Douglas R.; Shinnar, Shlomo

doi:10.1111/epi.13859

Cited by 58 publications

(54 citation statements)

References 100 publications

(168 reference statements)

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“…Regulatory agencies realize that, under certain conditions, efficacy and safety data obtained in adults can be extrapolated to children with the same disease . A convincing case has been made that, at least for patients with focal epilepsies, efficacy data can be extrapolated from adults to children down to the age of 2 years, provided careful pharmacokinetic and tolerability studies are conducted beforehand to permit appropriate dose adjustments in relation to age . It might be argued that efficacy data could be extrapolated from adults to children also for generalized tonic–clonic seizures associated with idiopathic (genetic) generalized epilepsies, even though for this seizure type there is little historical evidence from previous trials to support the contention that AED responsiveness for this seizure type in children younger than 12 years of age is comparable to that for older children or adults.…”

Section: Regulatory Trialsmentioning

confidence: 99%

“…21-23 A convincing case has been made that, at least for patients with focal epilepsies, efficacy data can be extrapolated from adults to children down to the age of 2 years, provided careful pharmacokinetic and tolerability studies are conducted beforehand to permit appropriate dose adjustments in relation to age. 24 It might be argued that efficacy data could be extrapolated from adults to children also for generalized tonic-clonic seizures associated with idiopathic (genetic) generalized epilepsies, even though for this seizure type there is little historical evidence from previous trials to support the contention that AED responsiveness for this seizure type in children younger than 12 years of age is comparable to that for older children or adults. Obviously, for epilepsies of infancy and childhood, such as West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, or childhood absence epilepsy, no extrapolation is possible and specific efficacy studies need be conducted in the pediatric populations of interest.…”

Section: Should Trial Designs Be Adjusted To Facilitate Generalizabilmentioning

confidence: 99%

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From clinical trials of antiepileptic drugs to treatment

Perucca

2018

Epilepsia Open

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SummaryRational prescribing should be based on the assessment of high‐quality evidence about the benefits and risks of available treatment options. Because clinical trials, particularly randomized controlled trials (RCTs), provide the best source of evidence, their design and results need to be carefully scrutinized. The majority of RCTs of antiepileptic drugs (AEDs) have been designed to address regulatory requirements, and generally they involve restrictive eligibility criteria, rigid dosing schemes, short duration of follow‐up, and comparison with placebo rather than standard treatments. Although these studies have high internal validity, they are conducted in a setting that is distant from routine clinical practice and therefore their usefulness in guiding treatment decisions is limited. Information more directly applicable to clinical practice can be derived from a relatively small number of comparative effectiveness monotherapy RCTs, although the design of some of these studies was probably biased in favor of the sponsor's product. Alarmingly, there is a paucity of well‐designed trials in epilepsy syndromes other than focal epilepsies, and no RCTs at all in most of the less common epileptic syndromes of infancy and childhood. In the light of these shortcomings, there is scope for re‐assessing regulatory requirements to facilitate generation of data more directly applicable to the routine clinical setting. Likewise, research‐funding organizations should be sensitized about the lack of adequate evidence to guide therapeutic practice in epilepsy, and the need to promote high‐quality comparative effectiveness trials. Future prospective pragmatic trials may benefit from the increasingly widespread availability of electronic health records.

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Section: Regulatory Trialsmentioning

confidence: 99%

Section: Should Trial Designs Be Adjusted To Facilitate Generalizabilmentioning

confidence: 99%

From clinical trials of antiepileptic drugs to treatment

Perucca

2018

Epilepsia Open

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“…The possibility of extrapolation from the addon to the monotherapy setting is also mentioned in the latest EMA draft guidelines, which state that 'on a case by case basis, it may be justified that a monotherapy trial is not necessary to support a monotherapy indication' (European Medicines Agency, 2018). The principle of extrapolation is also accepted by regulatory authorities to extend the indication of an AED from adults to children, at least for focal seizures, based on the concept of similarity of disease (Pellock et al, 2017;Perucca, 2018). Of course, when extrapolation of an indication is made from adults to children, the recommended dose regimen takes into account age-related pharmacokinetic differences.…”

Section: Clinical Trials In An Evolving Regulatory Scenariomentioning

confidence: 99%

Antiepileptic drugs: evolution of our knowledge and changes in drug trials

Perucca

2019

Epileptic Disorders

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Clinical trials provide the evidence needed for rational use of medicines. The evolution of drug trials follows largely the evolution of regulatory requirements. This article summarizes methodological changes in antiepileptic drug trials and associated advances in knowledge starting from 1938, the year phenytoin was introduced and also the year when evidence of safety was made a requirement for the marketing of medicines in the United States. The first period (1938–1969) saw the introduction of over 20 new drugs for epilepsy, many of which did not withstand the test of time. Only few well controlled trials were completed in that period and trial designs were generally suboptimal due to methodological constraints. The intermediate period (1970–1988) did not see the introduction of any major new medication, but important therapeutic advances took place due to improved understanding of the properties of available drugs. The value of therapeutic drug monitoring and monotherapy were recognized during the intermediate period, which also saw major improvements in trial methodology. The last period (1989–2019) was dominated by the introduction of second‐generation drugs, and further evolution in the design of monotherapy and adjunctive‐therapy trials. The expansion of the pharmacological armamentarium has improved opportunities for tailoring drug treatment to the characteristics of the individual. However, there is still inadequate evidence from controlled trials to guide treatment selection for most epilepsy syndromes, particularly in children. Second‐generation drugs had a very modest impact on drug resistance, and a change in paradigm for drug discovery and development is needed, focusing on treatments that target the causes and mechanisms of epilepsy rather than its symptoms. Testing potential disease modifying agents will require innovative trial designs and novel endpoints, and will hopefully lead to introduction of safer and more effective therapies.

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“…This complexity requires organization of scale to evaluate the interdependence and integration of these components. The excitability and inhibition balance required for homeostasis can be compromised by signaling cascades, genetics, or system failure across multiple neuronal circuits [7]. Therefore, selecting three diverse forms of electrophysiologic dysfunction: stroke, traumatic brain injury, and temporal lobe epilepsy - this review will discuss their commonality of electrophysiologic dysfunction, the limitations of the tools for evaluating electrophysiologic dysfunction, and the benefit of focused analysis with a hyperpolarized (HCN) channel, a depolarized calcium (CaV) channel and the sodium-potassium-chloride-one/potassium-chloride-two (NKCC1/KCC2) co-transporters.…”

Section: Introductionmentioning

confidence: 99%

Temporal Lobe Epilepsy, Stroke, and Traumatic Brain Injury: Mechanisms of Hyperpolarized, Depolarized, and Flow-Through Ion Channels Utilized as Tri-Coordinate Biomarkers of Electrophysiologic Dysfunction

Sizemore

Lucke‐Wold²,

Rosen³

et al. 2018

obm neurobiol

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The brain is an integrated network of multiple variables that when compromised create a diseased state. The neuropathology of temporal lobe epilepsy (TLE), stroke, and traumatic brain injury (TBI) demonstrate both similarity and complexity that reflects this integrated variability; TLE with its live human tissue resection provides opportunity for translational science to demonstrate scale equivalent experimentation between the macroscopic world of clinical disease and the microscopic world of basic science. The extended value of this research is that the neuroinflammatory abnormalities that occur throughout astrocytes with hippocampal sclerosis and damaged or even reversed signaling pathways (inhibition to excitation such as with gaba-aminobutyric acid) are similar to those seen in post-stroke and TBI models. In evaluation of the epilepsy population this interconnectedness of pathology warrants further evaluation with collaborative efforts. This review summarizes patterns that could shift experimentation closer to the macro level of humanity, but still represent the micro world of genetics, epigenetics, and neuro-injury across etiologies of physiologic dysfunction such as TLE, stroke, and TBI with evaluation of cell function using electrophysiology. In conclusion we demonstrate the plausibility of electrophysiologic voltage and current measurement of brain tissue by patch clamp analysis to specify actual electrophysiologic function for comparison to electroencephalography in order to aid neurologic evaluation. Finally, we discuss the opportunity with multiscale modeling to display integration of the hyperpolarization cyclic-nucleotide gated channel, the depolarized calcium channels, and sodium-potassium-chloride-one/potassium-chloride-two co-transporter channels as potential mechanisms utilized as tri-coordinate biomarkers with these three forms of neurologic disease at a molecular scale of electrophysiologic pathology.

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Extrapolating evidence of antiepileptic drug efficacy in adults to children ≥2 years of age with focal seizures: The case for disease similarity

Cited by 58 publications

References 100 publications

From clinical trials of antiepileptic drugs to treatment

From clinical trials of antiepileptic drugs to treatment

Antiepileptic drugs: evolution of our knowledge and changes in drug trials

Temporal Lobe Epilepsy, Stroke, and Traumatic Brain Injury: Mechanisms of Hyperpolarized, Depolarized, and Flow-Through Ion Channels Utilized as Tri-Coordinate Biomarkers of Electrophysiologic Dysfunction

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