Quantitative Analysis to Support Full Extrapolation of Efficacy in Children for Partial Onset Seizures in Adjunctive Setting: FDA-PEACE Initiative Shailly Mehrotra Center for Translational Medicine, UMD; ORISE Fellow, FDA Division of Neurology Products, FDA Office of Clinical Pharmacology, FDA M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Disclaimer Disease is similar The views expressed in this presentation do not necessarily represent the policies of the Food and Drug Administration or the Department of Health and Human Services. M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Evidence to Support Disease is similar “Full Extrapolation” of Efficacy Full Extrapolation M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Disease Similarity Between Adults & Children • PEACE/DNP provided the clinical expertise to describe: – the pathophysiology of partial onset seizures (POS) • After excluding children under age 4 and those with POS associated with epileptic encephalopathies such as Lennox-Gastaut, the pathophysiology of POS is similar in children (≥ 4year old) and adults. M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
List of Drugs Investigated Drug Population Mechanism of Action Blocks voltage dependent Na channels, increase K ≥ 2 year Oxcarbazepine (Trileptal) conductance and modulate high voltage activated Ca channels ≥ 1 month Levetiracetam (Keppra) Acts by binding to SV2A protein Inhibits voltage sensitive Na channels, stabilize ≥ 2 year Lamotrigine (Lamictal) neuronal membranes and modulates presynaptic release of excitatory neurotransmitter Blocks voltage dependent Na channels, augments GABA activity, antagonize AMPA/Kainate subtype ≥ 2 year Topiramate (Topamax) of glutamate receptor, inhibits carbonic anhydrase enzyme Not known; binds with α2δ subunit of voltage ≥ 3 years Gabapentin (Neurontin) activated calcium channel but therapeutic effects of binding are unknown Noncompetitive antagonist of AMPA glutamate ≥12 year Perampanel (Fycompa) receptor Not known, enhances the activity of GABA an ≥12 year Tiagabine (Gabitril) inhibitory neurotransmitter ≥10 year Vigabatrin (Sabril) Not known, increase levels of GABA in CNS M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Trial Design and Primary Endpoint in Approval of AEDs in Adjunctive Setting Double Blind (DB) Phase 3X mg 3X mg Concomitant AEDs 2X mg Primary Endpoint X mg Median %CFB in Seizure Frequency/28 days PB Placebo (PB) in the DB Phase Baseline Phase Concomitant AEDs PB 8-12 weeks CFB: Change PB 1-3 Concomitant from baseline AEDs Titration Phase Maintenance Phase 2-6 weeks 12-24 weeks Randomization End of the trial Plasma samples are collected in the maintenance phase M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Evidence to Support Disease is similar “Full Extrapolation” of Efficacy Full Extrapolation M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Observed Efficacy of Approved AEDs in Adults & Children from Registration Trials Placebo Corrected Median % CFB in Seizure Frequency/28 days Children : Children : Children : Children Adult Source: Labels for oxcarbazepine, perampanel and levetiracetam M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Observed Efficacy of Approved AEDs in Adults & Children from Registration Trials Placebo Corrected Median % CFB in Seizure Frequency/28 days Children : Children : Children : Children Adult Source: Labels for topiramate, lamotrigine and gabapentin 9 M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Evidence to Support Disease is similar “Full Extrapolation” of Efficacy Full Extrapolation M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Concentration Metric Utilized for Comparing Exposures in Adults and Children • Cmin: trough concentration at steady state • Cavg: average concentration at steady state • Same metric utilized between adults and children for a given drug 11 M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Concentrations at Approved Doses in Adults & Children Drug B Drug A Doses Doses Concentration Concentration Drug C Drug D Doses Doses Concentration Concentration Adults Children *Doses in the boxes denote highest recommended maintenance doses M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Evidence to Support Disease is similar “Full Extrapolation” of Efficacy Full Extrapolation M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Methodology a) Graphical Analysis b) Model Based Analysis M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Drug A Exposure-Response in Adults & Children Log ( % CFB in Seizure Log (% CFB in Seizure Frequency/28 days) Frequency/28 days) Mean % CFB in Seizure Frequency/28 days Doses Concentration Concentration Children Adults M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Drug B Exposure-Response in Adults & Children Frequency/28 days % CFB in Seizure Frequency/28 days % CFB in Seizure Mean % CFB in Seizure Frequency/28 days Doses Concentration Concentration Children Adults M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Drug G Exposure-Response in Adults & Children Drug G Predicted seizure rate during maintenance phase Normalized Dose (mg) Children Adults M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Evidence Gathered from AEDs Approved Between 1960-1980 • Generally acceptable therapeutic range of total Carbamazepine carbamazepine in plasma (i.e. 4-12 µg/mL) is the same in adult and children • Dose in pediatrics was selected such that it produces plasma concentration within the generally accepted Phenytoin therapeutic target of 10-20 µg/mL, which is same for adults • Approved in ≥ 10 years age, same dose and the same Valproic acid target therapeutic plasma concentration range (50 -100 µg/mL) are recommended. Source: Labels for carbamazepine, phenytoin and valproic acid 18 M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Quantitative Assessment of Response, Exposures and Exposure-Response Supports Disease is similar “Full Extrapolation” of Efficacy Full Extrapolation M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Required information to Support an Indication for the Treatment of POS in Patients ≥ 4 years Approved indication for the treatment of POS in adults. A pharmacokinetic analysis to determine a dosing regimen that provides similar drug exposure (at levels demonstrated to be effective in adults) in pediatric patients 4 years of age and older and in adult patients with POS. This analysis will require pharmacokinetic data from both the adult and children (4 years of age and older) populations. Long-term open-label safety study(ies) in pediatric patients 4 years of age and older. M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
Acknowledgements • UMD: • FDA: Tao Liu (ORISE Fellow) – OCP: – Joga Gobburu • Angela Men – • Atul Bhattaram PEACE: • Mehul Mehta • • Ramana Uppoor – Jack Pellock • Michael Bewernitz – Neil D’Cruz • Vikram Sinha* – Jackie French • Kevin Krudys • Joo Yeon Lee • Epilepsy Foundation: DNP: – Angela Ostrom – • Billy Dunn • Sponsors for providing data • Eric Bastings • FDA review teams • Norman Hershkowitz • Philip Sheridan • Cathleen Michaloski • DPMH: • Donna Snyder • Hari Sachs * Currently at Merck M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016
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