CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 206709Orig1s000 207223Orig1s000 OTHER REVIEW(S) Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research | Office of Surveillance and Epidemiology (OSE) Epidemiology: ARIA Sufficiency Memo: Diacomit (stiripentol) Version: 2018-01-24 Date: August 1, 2018 Reviewer Elisa Braver, PhD Division of Epidemiology I Team Leader: Kira Leishear, PhD, MS Division of Epidemiology I Associate Division Wei Hua, PhD, MHS, MS Director: Division of Epidemiology I Subject: Active Risk Identification and Assessment (ARIA) Sufficiency Memo for Pregnancy Safety Concerns Drug Name: Diacomit (stiripentol) Application Type/#: NDA 206709 and NDA 207223 Applicant/Sponsor: Biocodex SA OSE RCM #: 2018-1274 Page 1 of 5 Reference ID: 4301704 Expedited ARIA Sufficiency Template for Pregnancy Safety Concerns 1. BACKGROUND INFORMATION 1.1. Medical Product Stiripentol is a derivative of α -ethylene alcohol and has a chemical structure that is completely different from other currently marketed antiepileptic agents. It mechanism is thought to be acting as an allosteric modulator of the c-aminobutyric acid (GABA)A receptor.a Stiripentol is designated as an orphan drug. Diacomit (stiripentol) has a proposed indication for (b) (4) treatment of (b) (4) (b) (4) seizures associated with Dravet syndrome in patients (b) (4) . Dravet syndrome is a rare form of epilepsy that begins during infancy with frequent seizures that can be prolonged; the condition generally is associated with a mutation in SCN1A genes. Based on an incidence rate of 1 per 37,000 children, there may be nearly 2,000 children with this disease in the United States, according to the clinical reviewer.b The seizures can result in developmental delays and even sudden death and do not respond to first-line epilepsy drugs. The drug is already approved for use in Canada and Europe. 1.2. Pregnancy Exposure Registry There are no adequate data on the developmental risks associated with the use of stiripentol in pregnant women. Instead of requiring a separate pregnancy exposure registry, stiripentol will be included in the North American Antiepileptic Drug (NAAED) Pregnancy Registry, which monitors pregnancy outcomes in women exposed to anti-epileptic drug during pregnancy (http://www.aedpregnancyregistry.org/). 1.3. Describe the Safety Concern – Pregnancy Risk Only limited human data are available to establish whether stiripentol poses a risk of adverse pregnancy outcomes. The following information is from the draft clinical review.c The Integrated Summary of Safety submitted by the Sponsor did not identify any reports of exposure during pregnancy during the clinical trials or in the published literature. The Sponsor reported a search in the Biocodex pharmacovigilance database through June 2016 for any pregnancy event recorded with stiripentol either during the clinical development of the drug or during the commercialization of the drug and identified 3 cases. All 3 cases were non-Dravet patients in which the drug was added to carbamazepine; no adverse pregnancy or infant outcomes were a Steven Dinsmore. Division of Neurology Products, CDER. Draft clinical review. May 29, 2018. b Ibid.. c Steven Dinsmore. Division of Neurology Products, CDER. Draft clinical review. May 29, 2018. Page 2 of 5 Reference ID: 4301704 reported for 2 of the 3 cases and the outcome for the third case was unknown. (b) (4) the following information about what is known about the drug in terms of reproduction.d In a three-generation study, stiripentol was tested on the development of the progeny of Sprague-Dawley rats up to maturity. Stiripentol was administered daily orally at dose levels of 0, 50, 200, and 800 mg/kg to groups of 24 females over a period of 15 days prior to mating, during the mating period, and throughout pregnancy and lactation. The high dose level of 800 mg/kg caused a significantly increased incidence of delayed ossification of fetuses. No other treatment-related effects were seen on pup bodyweights and their physical behavior development as well as on auditory and visual functions. The pups developed normally without any drug-related effects until adulthood. The no-effect observed dose level for maternal and embryo-fetal toxicity was 200 mg/kg/day which is 4 times the clinical human dose of 50 mg/kg/day. No drug-related teratogenicity was observed. The effects of stiripentol on embryo-fetal development also were determined in mice and rabbits.e Groups of 25 pregnant mice received stiripentol at dose levels of 0, 50, 200, or 800 mg/kg on days 6-16 of gestation daily by oral gavage. No effects were seen on the number of live and dead fetuses, but the number of resorptions was increased at the two higher dose levels. Possible teratogenic effects of stiripentol were also evaluated in the rabbit. Groups of 18-28 pregnant rabbits were given stiripentol on days 8-21 of gestation daily by oral gavage at dose levels of 0, 50, 200, or 800 mg/kg. No effect was seen on fetal bodyweight. The drug did not induce gross, visceral, or skeletal malformations. 1.4. FDAAA Purpose (per Section 505(o)(3)(B)) Purpose Assess a known serious risk Assess signals of serious risk Identify unexpected serious risk when available data indicate potential for X serious risk 2. REVIEW QUESTIONS 2.1. Why is pregnancy safety a safety concern for this product? Check all that apply. ☐ Specific FDA-approved indication in pregnant women exists and exposure is expected ☐ No approved indication, but practitioners may use product off-label in pregnant women d (b) (4) e (b) (4) A study by Finnell et al. (1999) provided additional information on mice. Finnell RH, Bennett GD, Mather GG, Wlodarczyk B, Bajpai M, Levy RH. Effect of stiripentol dose on phenytoin-induced teratogenesis in a mouse model. Reprod Toxicol. 1999 Mar-Apr;13(2):85- 91. Page 3 of 5 Reference ID: 4301704 ☒ No approved indication, but there is the potential for inadvertent exposure before a pregnancy is recognized ☒ No approved indication, but use in women of childbearing age is a general concern 2.2. Regulatory Goal ☒ Signal detection – Nonspecific safety concern with no prerequisite level of statistical precision and certainty ☐ Signal refinement of specific outcome(s) – Important safety concern needing moderate level of statistical precision and certainty. ☐ Signal evaluation of specific outcome(s) – Important safety concern needing highest level of (b) (4) A study by Finnell et al. (1999) provided additional information on mice. Finnell RH, Bennett GD, Mather GG, Wlodarczyk B, Bajpai M, Levy RH. Effect of stiripentol dose on phenytoin-induced teratogenesis in a mouse model. Reprod Toxicol. 1999 Mar-Apr;13(2):85- 91. APPEARS THIS WAY ON ORIGINAL statistical precision and certainty (e.g., chart review). 2.3. What type of analysis or study design is being considered or requested along with ARIA? Check all that apply. ☐ Pregnancy registry with internal comparison group ☐ Pregnancy registry with external comparison group ☐ Enhanced pharmacovigilance (i.e., passive surveillance enhanced by with additional actions) ☐ Electronic database study with chart review ☒ Electronic database study without chart review ☐ Other, please specify: 2.4. Which are the major areas where ARIA not sufficient, and what would be needed to make ARIA sufficient? ☒ Study Population ☐ Exposures ☒ Outcomes ☐ Covariates ☒ Analytical Tools For any checked boxes above, please describe briefly: Study Population and Outcomes: ARIA is insufficient to identify the study population (babies that experienced in utero exposure or postpartum exposure through lactation) because the mother and baby records are not currently linked in Sentinel. Thus, the exposure Page 4 of 5 Reference ID: 4301704 corresponding to the mother and potential outcomes corresponding to the infant cannot be connected. This lack of linkage between mother and baby records renders ARIA insufficient for both the study population and outcome identification. Analytical Tools: ARIA analytic tools are not sufficient to assess the regulatory question of interest because data mining methods have not been tested for birth defects and other pregnancy outcomes. We did not formally assess the other parameters given that the mother-infant linkage is not currently available in ARIA. 2.5. Please include the proposed PMR language in the approval letter. The following language (still in draft form) has been proposed for PMRs related to pregnancy outcomes: Conduct a pregnancy outcomes study using a different study design than provided for in the North American Antiepileptic Drug (NAAED) Pregnancy Registry (for example, a retrospective cohort study using claims or electronic medical record data or a case control study) to assess major congenital malformations, spontaneous abortions, stillbirths, preterm births, and small-for-gestational-age births in women exposed to Diacomit (stiripentol) during pregnancy compared to an unexposed control population. The finalized PMR language will be issued upon approval. 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