What tox package did approved small molecules have, from first-in-human to approval?

“Overall, 22 (58%) patients were treated at study sites in Europe, 11 (29%) patients were treated at study sites in the US, and 5 (13%) patients were treated at study sites in Asia.”

“and choroid plexus edema in the brain occurred in dogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1 or 0.4 times the human exposure based on AUC at the 25 mg, 200 mg or 300 mg dose, respectively), but were not observed in a 9-month study at 5 mg/kg/day.”

“Dedicated fertility and pre- and post-natal development studies were neither conducted nor necessary to support the development of avapritinib in patients with advanced cancer.”

“The Applicant did not conduct studies investigating the carcinogenic potential of avapritinib as such studies are not needed to support a marketing application for patients with advanced cancer.”

“A first-in-human, Phase 1/2, dose-selection, PK/PD, safety, and efficacy study in adult patients with relapsed/refractory or treatment-naïve B-cell malignancies conducted in Australia, New Zealand, Italy, South Korea, United Kingdom (UK), and USA (N = 385).”

“39-Week Repeat ed Oral Dose Toxicity and Toxicokinet ics Study in Beagle Dogs with 6-Week Recovery Period”

“In a pre- and postnatal development (PPND) study in rats, pregnant females were administered zanubrutinib at 30, 75, or 150 mg/kg/day from GD6 to lactation day (LD) 17.”

“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”

“the IND for etripamil was opened on November 10, 2014, with a phase 1 first-in-human dose-escalation study (MSP-2017-1096) conducted in Australia with MSP-2017 administered intranasally at doses of 3.5, 7, 14, 30, 60, 105, and 140 mg in healthy adult male subjects (N=56).”

“MSP-2017-1212/Etripamil: A 6-Month Intranasal Toxicity Study Followed by a 4-Week Recovery Period in Cynomolgus Monkeys”

“In the pre- and postnatal toxicity study in rats, intravenous administration of etripamil at doses of 0, 0.05, 0.15, and 0.374 mg/kg/day from GD 7 through lactation period (Postpartum Day 20) did not show any adverse effects on pre- and postnatal development”

“Considering the intermittent clinical dosing and exposure profile, lack of obvious pharmacology- and toxicology-based concerns, and the technical challenges of conducting long-term studies in rodents with the intended nasal route of administration, the Division agreed that rodent carcinogenicity studies are not warranted for the proposed clinical indication and dosing regimen”

“80 centres/ 14 countries: Belgium, China France, Germany, Hong Kong, Italy, Korea, Netherlands, Singapore, Spain, Switzerland, Taiwan, UK, USA”

“Recovery was not assessed in the 13-week studies, but increased physeal thickness in the femur and incisor degeneration did not show evidence of complete recovery in the 28-day rat study.”

“Studies on reproductive function, early embryonic development, pre- and postnatal development, and effects in juvenile animals were not conducted in accordance with ICH S9 guideline.”

“FDA agrees that carcinogenicity studies are not needed to support the use of pralsetinib in the currently proposed indication per ICH S9.”

“The IND for fedratinib was opened in October 2007 by TargeGen with a first-in-human (FIH) Phase 1 dose-escalation study in patients with MF”

“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”

“In the PPND study, fedratinib‐related effects were limited to decreased body weight parameters.”

“In a 6-month carcinogenicity study in transgenic Tg.RasH2 mice, there were no neoplasms that were attributed to treatment with fedratinib. No 2-year carcinogenicity study in rats was performed.”

“13 sitesc 5 countrie s (US, Spain, Canada, UK, France)”

“Duration: 13 Weeks GLP compliance: Yes Drug, lot#, and % purity: GDC-0077, lot # 68878-287, 98.9% purity Methods Doses: 0, 0.3, 1.5/1.0 mg/kg/day Frequency of dosing: Once daily Number/Sex/Group: 3 (terminal); 3 (recovery at 0 and 1.5/1.0 mg/kg/day only)”

“The ICH S9 guidance (ICH 2009) states that studies on (1) fertility and early embryonic development and (2) pre- and postnatal toxicology are not warranted to support marketing authorization applications for pharmaceuticals intended for the treatment of patients with advanced cancer, such as inavolisib. Accordingly, such studies were not performed.”

“FDA agrees that carcinogenicity studies are not warranted to support the proposed indication in patients with advanced cancer in accordance with ICH S9 guidance.”

“The initial IND included the protocol titled PHX111427: A Phase I, Randomized, Single-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of GSK1278863A in Healthy Subjects.”

“GSK1278863A: A 39-week Oral (Gavage) Toxicity Study in the Cynomolgus Monkey with a 6-week Recovery Period”

“In a pre- and postnatal development study, pregnant rats were dosed orally with daprodustat from implantation until weaning (gestation day 6 to lactation day 21)”

“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males)/ 7 mg/kg/day (females) in rats and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”

“Efficacy data supporting this NDA were generated in Study 849-001, an open-label, multi-center, first-in-human (FIH), Phase 1/2, multiple expansion cohort study of adagrasib in patients with advanced solid tumors malignancies with KRAS G12C mutation. Study 849-001 was designed and conducted in accordance with FDA draft guidance issued in August 2018 (FDA 2018) and conducted in the United States.”

“Study Title: A 13-Week Study of MRTX849 by Oral Gavage in Rats with a 28-Day Recovery Period”

“DRF and definitive EFD studies were performed in Wistar rat and NZW rabbits. No fertility, early embryonic development or PPND studies were performed. This is considered acceptable as adagrasib is intended for treatment of advanced cancer, and the ICH S9 guideline applies.”

“The FDA’s Assessment: The FDA agrees that carcinogenicity studies are not needed to support the use of adagrasib in the currently proposed indication per ICH S9.”

“Study INCB 54828-101 was an open-label, dose-escalation and expansion study of pemigatinib administered alone or in combination with another cancer therapy in participants with advanced malignancies.”

“In the 13-Week GLP study by oral gavage in Cynomolgus Monkeys with a 6-week recovery period, target organs were bone (physis) and cartilage plates of the sternum with a phosphorus increase.”

“No studies on pre-postnatal development have been conducted with pemigatinib. The lack of pre-postnatal developmental studies is acceptable in view of the intended indication for Pemazyre and is in line with the ICH S9 guideline.”

“Carcinogenicity studies were not conducted or needed to support the use of pemigatinib in the currently proposed indication per ICH S9.”

“Study X2101 was a multicenter, Phase IA, dose-escalation/expansion study of oral alpelisib in adult subjects with advanced solid malignancies.”

“13-week oral administration toxicity study in the dog followed by a 4-week treatment-free period/ Study 1070416”

“As per ICH S9, pre-and postnatal and juvenile toxicology studies are generally not warranted to support marketing of pharmaceuticals for the treatment of patients with advanced cancer.”

“The FDA agrees that no carcinogenicity studies are required for the proposed indication.”

“CABL001X2101 Countries: Australia, France, Germany, Italy, Japan, Singapore, South Korea, Spain, The Netherlands, United States”

“Prolonged administration of asciminib (3, 15, and 50 mg/kg/day) for 39 weeks in cynomolgus monkeys induced comparable findings to those observed in the 13-week study”

“Pre- and postnatal development: A pre- and postnatal development study has not been performed and is not considered necessary to support the proposed indication.”

“Carcinogenicity studies have not been conducted in accordance with ICH S9.”

“Study PRN1008-001 (FIH study in HV): Mean apparent volume of distribution (Vz/F) ranged from 6720 to 4890 L.”

“For the 9-month dog study with a 4-week recovery period (study DVR0377) Beagle dogs were treated”

“In a pre- and postnatal developmental toxicity study, pregnant rats were given rilzabrutinib by oral gavage at doses of 50, 150, or 300 mg/kg/day during the periods of gestation, parturition, and lactation (gestation day 7 to lactation day 21).”

“In this submission the sponsor included reports of two animal carcinogenicity studies, one in rats and one in mice.”

“FFP formulation was initially developed used in the FIH dose escalation study 001, Phase 2 efficacy study MK-6482-004, and food effect study MK-6482-002.”

“PT2977: A 13-week oral gavage toxicity study followed by 28-day and 26-week recovery periods in Sprague-Dawley rats / TT187809”

“Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”

“The study was a phase 1, first-in-human, randomized, placebo-controlled, double-blinded, single-site, sequential Cohort design in healthy subjects.”

“13-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of Zidebactam (WCK 5107) with a 4-Week Recovery Period in Beagle Dogs.”

“The study report for a WCK 5107 (zidebactam) pre-postnatal study in rats is reviewed below.”

“Long-term carcinogenicity studies have not been performed with cefepime or zidebactam.”

“The general conclusions from these studies were that oral administration of maltol in the context of the maximum daily intake of the proposed drug product are not toxicologically significant or are not appreciably different than the results of the 28-day repeat dose toxicology study in dogs administered iron maltol described above.”

“The NDA contains a study report for a mouse 18-month carcinogenicity study of maltol at doses of 0, 100, 200 or 400 mg/kg/day by dietary administration (Report 75009).”

“After cessation of vamorolone administration, compensatory lymphocyte hyperplasia was observed in thymus and spleen of mice, whereas the lymphoid depletion did not completely reverse in the recovery periods of the 28 days and 39 weeks toxicity studies in dogs.”

“Because the intended patient population is almost exclusively male, a standard battery of reproductive and developmental toxicology studies was not needed to support a marketing application”

“given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”

“In a GLP study, Beagle dogs (4 animals/sex/group) were administered VNZ by oral gavage once daily at 0 (vehicle), 1.5, 4, or 10 mg/kg for 39 weeks with additional animals included in the control and 10 mg/kg/day groups for a 6-week recovery period.”

“In a GLP pre- and postnatal development study (Study VX-121-TX-017), pregnant rats were administered VNZ at oral doses of 0 (vehicle), 2.5, 5, and 10 mg/kg/day”

“However, since the 2-year rat study for VNZ is not yet completed, the carcinogenicity potential cannot be determined at the moment for the VNZ, TEZ, and D-IVA co-administration.”

“In nine-month oral dose toxicity study with a three-month recovery period the highest dose level of 3.0 mg/kg was reduced to 1.5 mg/kg from week 24 of the dosing period due to serious skin lesions and dosing was withdrawn from week 26 (week 1 of the recovery period) to investigate the reversibility of any toxicity during a 13-week recovery period.”

“A pre- and postnatal development study was conducted in rats.”

“In the dermal carcinogenicity study in mice, delgocitinib ointment (1%, 3% and 5%) was administered once daily for 104 weeks. No drug-related neoplastic findings were noted at topical doses up to 5% delgocitinib ointment. In the 2-year oral carcinogenicity study in rats, increased incidence of benign thymoma was noted in females at 30 mg/kg/day”

“Levacetylleucine (0, 100, 200, and 600 mg/kg/day) administered by oral gavage in dogs in a 39-week toxicity study followed by a 4-week treatment-free period was without adverse effects with NOAEL of 600 mg/kg/day.”

“A rodent pre- and postnatal development toxicity study will be required as a PMR.”

“A 26-week carcinogenicity study in the transgenic rasH2 mouse will be required as a PMR, along with a 2-year rat carcinogenicity study.”

“A 28-day Repeated Intravenous Dose Toxicity and Toxicokinetic Study of Artesunate in Beagle Dogs Followed by a 28-day Recovery Period”

“The extent of embryolethality and fetal malformations observed in the oral embryo-fetal development studies indicate that pre-and postnatal development study(ies) conducted with artesunate, by any route of administration route, would not yield any clinically meaningful information.”

“No carcinogenicity studies have been conducted with artesunate. Given the short duration of treatment (up to 7 days) carcinogenicity studies are not indicated.”

“A 39-Week Study of AG10 by Oral Gavage in Dogs With a 28-Day Recovery Period”

“In a pre- and postnatal developmental toxicity study, pregnant rats received oral administration of acoramidis at doses of 0, 50, 350, or 1,000 mg/kg/day throughout pregnancy and lactation (Gestation Day 6 to Lactation Day 20).”

“Both studies were reviewed previously under the IND and were concluded to be negative.”

“Study Title (study # H58-0008): Defactinib: 13-Week repeated oral dose toxicity and toxicokinetics study in rats with a 4-week recovery period Study Title (study # H58-0009): Defactinib: 13-Week repeated oral dose toxicity and toxicokinetics study in Beagle dogs with 4-week recovery period”

“The Applicant did not conduct any reproductive toxicology studies with avutometinib and defactinib.”

“The Applicant did not conduct carcinogenicity studies with avutometinib; it is also not warranted to support the marketing application of AVMAPKI FAKZYNJA CO-PACK for the proposed indication.”

“A 6-Month Study of KP415 Administered by Oral (Stomach Tube) Administration in Juvenile Rabbits with a 1-Month Recovery Period/Study No. 20144952”

“A pre- and postnatal development study was not conducted with SDX. As noted above, further studies to characterize the effect of SDX and unique metabolites were not deemed warranted”

“Therefore, considering the weight-of-evidence, we agree that carcinogenicity studies are not needed for SDX.”

“In the pivotal 1-month (data not shown) and 3-month dog toxicology studies, no mortality was observed during the treatment window or in the recovery period.”

“In accordance with ICHS9 and ICHS5 (R3) guidelines no studies on fertility and early development and on pre- and postnatal development have been performed.”

“Carcinogenicity Not conducted or required to support this NDA application of erdafitinib for patients with advanced cancer.”

“Amisulpride: Intravenous (Slow Bolus) 28-Day Toxicity Study in the Rat with a 14 Day Treatment Free Period (Study # BGX0002).”

“In a prenatal and postnatal development study in rats, amisulpride was administered daily by oral gavage (0, 60, 100 and 160 mg/kg/day) to pregnant rats from gestation day 6 to lactation day 20.”

“Carcinogenicity studies of amisulpride were not conducted. Carcinogenicity studies are not required for this indication for which the drug will be administered as a single dose.”

“Monkey Studies: In a 39-week oral gavage toxicity study in cynomolgus monkeys with a 4-week recovery phase, baxdrostat was administered at doses of 0, 1, 3, or 6 mg/kg/day.”

“Prenatal and Postnatal Development (PPND) Study Eighty F0 generation time-mated female Wistar-Han rats were assigned to 4 groups (20 animals each).”

“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies.”

“Study #2013N160007 /GSK2140944E: A 13-week Oral (Gavage) Toxicity in Rats Followed by a 28-day Recovery Period”

“In a pre- and postnatal development mouse study, 0 (vehicle), 200, 500, or 1000 mg/kg/day gepotidacin was administered by oral gavage to female mice from GD6 to lactation day 20 (LD20).”

“13.1.4.3. Carcinogenicity No studies were available.”

“Daily administration of oral ibrexafungerp for 26 weeks in rats, at the highest dose of 80 mg/kg/day (approximately 10 times the RHD based on AUC comparison), was associated with marked, but reversible, phospholipidosis and foamy histiocytes in alveolar tissue in the lung and labored breathing”

“A Developmental and Perinatal/Postnatal Reproduction Study of SCY-078 by Oral Gavage in Rats, Including a Postnatal Behavioral/Functional Evaluation/ SCY078- TOX-029”

“Carcinogenicity studies were not performed for ibrexafungerp due to the limited duration of its intended use for the treatment of VVC.”

“a second chronic toxicity study (with 9 months of administration) was conducted in dogs with a lower maximum dose of 8 mg/kg/day and a recovery period of 26 weeks (similar duration to the previous study).”

“The potential effect of brensocatib on pre- and postnatal development was investigated in rats after once daily oral dosing from GD6 to LD21 at dose levels of 0, 3, 9 and 20 mg/kg/day.”

“The carcinogenic potential of brensocatib was assessed in a 6-month Tg Ras mouse study and in a 104- week carcinogenicity study in rats.”

“Pivotal 4-week repeat-dose toxicity studies with 2-week recovery groups in minipig and monkey are reviewed in detail in sections 6.2.1 and 6.2.2.”

“Conduct a pre-and post-natal development study testing the drug product formulation that evaluates all standard endpoints including learning, memory, and reproductive function of the F1 offspring and obtains adequate toxicokinetic data in a species and provides adequate exposures to support the proposed clinical exposures for the proposed maximum duration of use based on the clinical indication.”

“Carcinogenicity studies were not conducted or required to support the safety of the proposed acute indication with remimazolam.”

“Table 56. Study Information, 39-Week Oral (Gavage) Administration Toxicity Study in the Dog Followed by a 4-Week Recovery Period (8348308)”

“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”

“In the 2-year carcinogenicity studies, odevixibat was not tumorigenic in rats or mice at oral doses up to 100 mg/kg/day.”

“Exposure was consistent with that observed in 52-week dog study with 5 mg/kg/day oral administration of TMC278 LA (study reviewed under NDA 202022).”

“Reproductive toxicology studies with CAB consist of a male fertility study in rats, a combined female fertility and embryo-fetal development study in rats, an embryo-fetal development study in rabbits, and PPND studies in rats.”

“Two-year carcinogenicity studies were conducted in mice and rats.”

“6.2.8. 39-Week oral toxicity study in dogs with a 17-week recovery”

“In segment III pre- and post-natal development study in rats, MVA at doses up to 1.5 mg/kg/day did not cause F0 maternal systemic toxicity, F1 neonatal/developmental toxicity, F1 parental systemic toxicity, F1 reproductive toxicity, and F2 embryonic toxicity.”

“The Division has agreed the 2-year rat carcinogenicity study can be completed post-approval and the study is currently ongoing.”

“Study title/ number: 9-Month Oral Toxicology and Toxicokinetic Study of ITI-007 in Beagle Dogs”

“When pregnant rats were administered lumateperone during the period of organogenesis through lactation, the number of perinatal deaths of pups was increased at 4.9 times the MRHD, with no adverse effects on pups at 2.4 times the MRHD”

“The nonclinical study reports for the carcinogenicity studies were submitted on April 19, 2018 and April 26, 2018. The Applicant submitted the final portion of the NDA on September 27, 2019.”

“Study title/ number: A 9-Month Oral Gavage Toxicity and Toxicokinetic Study of PF-04965842 in Cynomolgus Monkeys with a 12-Week Recovery Phase / 13MA055”

“In an oral pre- and postnatal development study in rats, abrocitinib (doses: 0, 10, 30, and 60 mg/kg/day) caused a high rate of total litter loss and markedly decreased F1 survival at 60 mg/kg/day”

“Carcinogenicity studies were conducted in mice (6-month study in Tg rasH2 mice) and rats (104-week study).”

“Table 92. Study: 1-Year Toxicology Study in the Monkey (GLP) Study Parameters Details Doses and RoA 0 (water control), 1(LD), 5 (MD), and 12.5 (HD) mg/kg/day; nasogastric intubation Species/strain Rhesus monkey (Macaca Mulatta) Number/sex/group Main study: n=4/sex/group Recover: n=2/sex for HD only”

“pre- and postnatal toxicity study with an additional follow-up pre- and postnatal study with xanomeline alone in the rat. Most of the nonclinical studies, including all pivotal safety studies, were submitted, and reviewed under the IND.”

“Nonetheless, in the rat and mouse carcinogenicity studies, oral administration of xanomeline via the diet did not cause necrotic lesions or progress into neoplastic tumors in the liver at doses up to 1.5 and 3 times the MRHD (125 mg BID) of xanomeline.”

“Rats were treated with 0, 1, 3, or 10 mg/kg trilaciclib in 5% dextrose by oral gavage (5 mL/kg) for 28-days followed by a 3-week drug-free recovery period.”

“No developmental or reproductive toxicity (DART) studies were conducted, consistent with the short duration of clinical use and therapeutic needs of the patient population”

“Importantly, trilaciclib clinical dosing is in patients who are receiving chemotherapy to target existing small cell lung cancer so there was little to be gained”

“12-Month Oral Toxicity Study in Dogs With an 8-Week Recovery Period, Study TXC1204”

“A pre- and postnatal development study was conducted with daily oral administration of crinecerfont free base to pregnant rats during the period of organogenesis to weaning from GD7 to lactation day 20 at 0, 15, 150 or 250 mg/kg/day.”

“The Applicant evaluated the oncogenic potential of crinecerfont by conducting 2-year rat and 6-month transgenic mouse carcinogenicity studies.”

“The Applicant conducted 14- and 28-day repeat-dose toxicology studies in rats and dogs with administration of the test article every other day.”

“In the prenatal and postnatal development (PPND) study in rats, there were no test article-related adverse effects observed on parturition and lactation of F0 females;”

“Carcinogenicity studies are not required to approve a drug product indicated for acute use.”

“Dog: in the 39-week (+ 4-week recovery) study, trofinetide was administered at doses of 0, 25, 150, and 500 mg/kg BID (0, 50, 300, and 1000 mg/kg/day).”

“In the pre- and postnatal development study in rat, trofinetide was administered orally throughout pregnancy and lactation at doses of 0, 150, 450, and 1000 mg/kg BID (0, 300, 900, and 2000 mg/kg/day).”

“Carcinogenicity studies have not been conducted (with agreement from the Division) prior to submission of the NDA, but these studies will be required as a PMR.”

“Dosing began on Day 0 and animals were sacrificed on Day 14 (one day after the final dose was given).”

“Reproductive and developmental toxicology studies were waived for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”

“Carcinogenicity studies were not needed for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”

“In the dietary administration of UX007 to male and female juvenile minipigs at doses of 0%, 10%, 30%, or 50% DCI for 9 months with a 4-week recovery and a 3-month interim sacrifice”

“In the pre- and postnatal development study, the effects of oral dietary administration of triheptanoin (10%, 30%, and 50% DCI) to female rats and their offspring were studied.”

“Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug.”

“Bile duct, thymus, and bone marrow histopathology remained present after recovery periods of 4 or 8 weeks in the 13 and 39-week studies, respectively, but appeared to be resolving.”

“In a pre- and postnatal development study in rat, administration of givinostat (0, 40, 80, and 160 mg/kg) from GD 6 to postnatal day (PND) 20 resulted in reduced number of litters with liveborn pups, increases in stillborn pups, total litter loss, and decreases in pups surviving to PND 21.”

“PMR 4575-1 Conduct a carcinogenicity study of givinostat in mouse. • Final Protocol Submission: 12/2022 (submitted) • Study Completion: 12/2024 • Final Report Submission: 12/2025 PMR 4575-2 Conduct a 2-year carcinogenicity study of givinostat in rat.”

“TCBZ was administered as a diet admixture to rats and beagle dogs at doses of 10, 100 and 1000 ppm daily, for 13 weeks.”

“In a 2-generation, combined fertility and pre- and postnatal developmental toxicity study in rats, decreases in body weight gain of second generation pups (F2) were observed at the highest dose”

“KVD900: A 26-Week Intermittent Oral (gavage) Administration Toxicity Study with an 8-Week Recovery Period in Non-Human Primates (Cynomolgus Monkeys)”

“In a GLP pre- and postnatal development study, Crl:WI(Han) pregnant female rats (20 animals/sex/group) received sebetralstat at daily oral doses 0, 100, 200, 450 mg/kg from GD 6 to Lactation Day 20.”

“While the NDA includes appropriate preapproval nonclinical and clinical pharmacology studies, a post-marketing requirement will be issued to complete an ongoing 2-year carcinogenicity study in rats receiving sebetralstat.”

“Skin changes fully recovered within the 22-week recovery phase in monkeys treated for 39 weeks with the high dose of risdiplam.”

“In the pre- and postnatal development study in rats in which the highest dose tested (3 mg/kg) was limited by apparent effects on parturition (dystocia), gestation was lengthened at the HD”

“A two-year carcinogenicity study in rats is planned to be conducted post-approval. This is acceptable and in agreement with feedback received from CHMP and PDCO. Reference to the ongoing carcinogenicity study in rats is presented in SmPC section 5.3.”

“AAI101, cefepime and AAI101 + cefepime: 13-week intravenous toxicity study in beagle dog followed by an 8-week recovery period”

“In the pre-postnatal development study in rats with enmetazobactam, maternal body weights and the body weights of first-generation offspring were reduced, and pinna detachment in first-generation offspring was delayed with maternal doses of 500 mg/kg/day.”

“Carcinogenicity studies of enmetazobactam have not been conducted and are not planned based on the intended duration of therapy (≤ 14 days).”

“5/sex/group were dosed for 12 months, with 3/sex/group necropsied after 12 months of dosing and the remaining 2/sex/group given a 3-month, drug-free recovery period before necropsy.”

“A Segment III reproductive toxicology study with orally administered BMY 13805-1 in rats.”

“More importantly, there was no evidence of carcinogenic potential in the completed two-year mouse and rat bioassays.”

“Satellite groups/ unique design: 5/sex in control and high dose groups for 4-week recovery; 4/group for TK”

“The NOAEL for parturition, maternal function, and pre-/postnatal development and viability of the pups was the high dose of 1000 mg/kg/day.”

“Carcinogenicity studies were not conducted. CHMP agreed that carcinogenicity studies were not needed as the SmPC states that the duration of dosing will be generally 14 days or less (not exceeding 21 days).”

“Methods of 28-Day Oral Toxicity Study in the Dog, Study # 0505-2007 Parameter Details Dose and frequency of dosing: 0, 50, 200, 800 mg/kg Route of administration: Oral gavage Formulation/vehicle: 5% Tween 80/0.5% Methyl cellulose 400 cP (Methocel) suspension, water for injection Species/strain: Dog/beagle Number/sex/group: 3/sex/group Age: 1 year old Satellite groups/unique design: 2/sex/group (2-week recovery group)”

“The NOAEL for maternal toxicity and pre- and postnatal development was 200 mg/kg, similar to the clinical dose based on AUC comparisons.”

“Carcinogenicity studies are not indicated for fexinidazole and were not conducted. However, structurally related compounds such as metronidazole have exhibited carcinogenic potential in lifetime animal studies.”

“Study title: PS433540: 39- Week Toxicity Study in Cynomolgus Monkeys with an 8-Week Recovery”

“In the pre- and postnatal developmental toxicity study, administration of sparsentan at doses of 5, 20 and 80 mg/kg/day to pregnant rats caused toxicity in offspring”

“Long-term carcinogenicity studies were conducted in mice (26 -week duration) and one in rats (104- week duration).”

“In a 39-Week Oral Toxicity Study (1458-006) in Cynomolgus Monkeys With a 6-Week Recovery tivozanib hydrochloride was well tolerated when administered daily to both male and female cynomolgus monkeys at all dose levels evaluated.”

“As it is intended for advanced Renal Cell Carcinoma, in accordance with ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, carcinogenicity studies are not required.”

“Thereafter, decreases in body weight gain were observed throughout the duration of the study leading to a ~ 37% decrease in body weight at Month 9. Body weight loss and decreased weight gain were reversible upon dosing cessation.”

“No effects were noted at any dose tested in the pre- and post-natal development study in rats up to the maximum feasible dose of 200 mg/kg.”

“Carcinogenicity assessments were conducted in a 26-week study in Tg.RasH2 transgenic mice and a 2-year study in rats.”

“Three pivotal repeat dose toxicity studies were conducted in Beagle dogs with fruquintinib in National Shanghai Center for New Drug Safety Evaluation and Research (4 and 39-weeks non-GLP, 2009 and 2012) and Covance Pharmaceutical R&D (Shanghai) Co., Ltd (Covance - Shanghai; 13-week GLP study, 2021).”

“Carcinogenicity studies were not warranted to support marketing of fruquintinib for the current indication.”

“Mirdametinib was administrated for 13 weeks at dose of 0.1, 0.3 and 1 mg/kg/day (same doses used in the 4-weeks study). Only rat exposures at the highest dose were demonstrated to be in the range of the clinical exposure at the intended recommended dose (as per the indication). The exposures at low and mid dose are below the clinical range exposure. No recovery period was added.”

“This justifies the absence of further DART studies and that the SmPC section 5.3 mentions that the EFD studies were exploratory studies and that definitive EFD studies and PPND studies were not conducted with mirdametinib.”

“The Applicant is currently conducting a 2-year carcinogenicity study in rats and a post-marketing requirement (PMR) will be issued for the submission of the final study report.”

“A 7-month chronic-dose study conducted in Wistar rats revealed dose-dependent fertility impairment in males and females (i.e. arrested spermatogenesis and absent corpora lutea and follicles).”

“A potential for an influence on reproductive performance and intrauterine development in humans can be assumed based on the cytotoxic and genotoxic properties of treosulfan. Therefore, no dedicated reproductive and developmental toxicity studies for treosulfan according to current regulatory guidance were conducted.”

“Due to sufficient evidence in humans, treosulfan was considered by International Agency for Research on Cancer (IARC) Working Groups as “carcinogenic to humans (Group 1)”. (IARC, 2012) Therefore, carcinogenicity studies in animals were deemed not necessary.”

“In a 9-month toxicology study in dogs, tenapanor was administered orally to beagle dogs at doses of 50, 300 and 1000 mg/kg/day.”

“In a pre- and postnatal development study in mice, tenapanor had no treatment-related effects on the maternal animals, including gestation lengths, parturition or the mean number of implantation sites.”

“Tenapanor was not tumorigenic in 2-year rat and 6- month Tg rasH2 mouse carcinogenicity bioassays.”

“Nine-month oral toxicity study in rhesus monkeys / Study No. TT #14-1068 Key Study Findings • Dose-limiting toxicities were observed at 100 mg/kg, leading to early termination of dosing and euthanasia of seven animals. All findings were reversible and absent at the end of the recovery period.”

“Pre- and postnatal development studies in rats showed no effects on maternal parameters or F₁ offspring development, behavior, or reproductive performance at doses up to 10 mg/kg/day”

“Consistent with this profile, ISL was non-carcinogenic in a 2-year study in rats and in a 26-week study in rasH2 transgenic mice.”

“26-week repeat dose study (with 4 weeks recovery) in the rat, and 39-week repeat dose study (with 4 weeks recovery) in the dog.”

“In a prenatal and postnatal development study in pregnant and lactating rats, sotagliflozin was administered at oral doses up to 100 mg/kg/day from gestation Day 6 through to lactation Day 20 (weaning).”

“The carcinogenic potential of sotagliflozin was evaluated in a 26-week transgenic RasH2 mouse carcinogenicity study and a 2-year rat carcinogenicity study. The Executive Carcinogenicity Committee (ECAC) concluded that both studies adequately addressed the carcinogenicity of sotagliflozin”

“A 92 Day Toxicity Study of E7727 Administered via Oral Gavage in Cynomolgus Monkeys Followed by a 21 Day Recovery”

“Cedazuridine and decitabine are genotoxic, and decitabine targets rapidly dividing cells in general toxicology studies; per ICH S9, reproductive and developmental toxicity studies are not needed for this class of drugs.”

“Per ICH S9, we agree that carcinogenicity studies are not needed to support the approval of ASTX727 for the proposed indication.”

“52-Week Toxicity Study by the Oral Route (Gavage) in Cynomolgus Monkeys Followed by an 8-Week Treatment-Free Period (GFT505_TOX3_009)”

“A pre- and postnatal development study was performed using oral administration of 10, 30, or 100 mg/kg/day elafibranor in female rats during organogenesis through lactation.”

“In a 2-year study in Sprague-Dawley rats, elafibrinor produced hepatocellular adenoma in males and females at a dose of 30 mg/kg/day”

“39-Week Oral Gavage Chronic Toxicity and Toxicokinetic Study with LCI699 in Dogs with a 4-Week Recovery Period”

“An Oral (Gavage) Pre and Postnatal Developmental Toxicity Study in the Rat”

“Sponsor submitted safety report regarding observations from rat and mouse carcinogenicity studies”

“A 39-Week Study of BI 1015550 by Oral Gavage in Minipigs with a 28-Day Recovery Period Doses: 0, 3, 10, or 25/20 mg/kg/day Yes 17R062 4520258 Cynomolgus Monkeys BI 1015550: A 39-Week Oral Gavage Toxicity and Toxicokinetic Study in Cynomolgus Monkeys with an 8-Week Recovery”

“In an oral PPND study, four groups of virgin-mated female Wistar Han rats (F0 generation) were treated by oral administration with 0 (vehicle), 0.3, 1, and 3 mg/kg/day BI 1015550 from GD6 through Lactation Day 20.”

“Nerandomilast showed no evidence of carcinogenic potential when administered for 26 weeks to transgenic mice (Tg.rasH2) or for 104 weeks to rats up to dose levels of 60 (male)/ 100 (female) and 2 mg/kg/day, respectively.”

“Repeat-dose toxicology studies of up to 3 months were conducted in rats and dogs”

“For the reproductive toxicity assessment, the absence of fertility and PPND studies is in line with ICH guideline S9.”

“No carcinogenicity studies with pirtobrutinib were submitted as these studies are not warranted for advanced cancer indications (ICH S9).”

“13-Week Oral Toxicity Study of NVL-520 with a 4-Week Recovery Period in Wistar Han Rats/ ID # NVL-520-NCTX-001”

“FDA agrees that fertility, early embryonic development, and pre- and postnatal development studies were not warranted to support the use of zidesamtinib in the proposed indication per ICH S9.”

“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”

“Leniolisib has been administrated in monkeys by oral gavage for 2 weeks, 13 weeks and 39 weeks with 4-week recovery period.”

“Requirement Conduct a pre- and post- natal development study in rats. Table 50. PMR-3 Milestones Schedule, Pre- and Postnatal Development Study in Rats Milestone Status Study completion date 12/2022 Final report submission date 04/2023”

“The 6-month transgenic (Tg-RasH2) mouse carcinogenicity study and 2-year carcinogenicity study with rats are ongoing under Special Protocol Assessments with ECAC concurrence. The final study reports will be submitted as post-marketing requirements.”

“In a 13-week monkey study, animals were treated with SUZ at 0, 20, 50, and 150 mg/kg via oral gavage. Of note, no recovery group was included in this study.”

“Reproductive and developmental toxicities of SUZ were assessed in male and female fertility and early embryonic development studies in rats, embryo-fetal development (EFD) studies in rats/rabbits, and a pre- and postnatal development (PPND) study in rats.”

“Long-term animal studies have not been completed to evaluate the carcinogenic potential of suzetrigine.”

“The finding was only identified in the 39-week study, was considered adverse by the study pathologist and had limited margins to clinical exposure at NOAEL and LOAEL. Further, as no recovery group was used in the study, the potential for recovery is not known.”

“a full battery of reproductive toxicology studies (including a fertility and early embryonic development study in rat, embryofetal developmental toxicity studies in rat and rabbit and a pre-and postnatal development study in rat), and two 2-year carcinogenicity studies in mouse and rat.”

“a full battery of reproductive toxicology studies (including a fertility and early embryonic development study in rat, embryofetal developmental toxicity studies in rat and rabbit and a pre-and postnatal development study in rat), and two 2-year carcinogenicity studies in mouse and rat.”

“4-Week Oral Gavage Toxicity and Toxicokinetic Study with KX2-391 in Rats with a 2-Week Recovery Sprague-Dawley rats, study No. 7709- 102. Study title: 4-Week Oral Gavage Toxicity and Toxicokinetic Study with KX2-391 in Dogs with a 2-Week Recovery, study No. 7709-103.”

“Tirbanibulin was evaluated for effects on prenatal and postnatal development, including maternal function, in a study that involved administration by oral gavage to female rats from day 6 of gestation until day 20 of lactation”

“Not applicable, as the proposed use does not involve chronic exposure.”

“The reversibility of selumetinib-related findings was evaluated in 1-month studies in mice and monkeys as well as in the 26-week study in mice. All pivotal toxicology studies were appropriately designed in accordance with ICH guidelines and were conducted in compliance with GLP regulations. Study Title/Number: 26-week Oral Toxicity Study in the Mouse with Assessment of Effects on Male Fertility Followed by a 13 Week Recovery Period (VKS/0211)”

“Because of these characteristics, the Applicant conducted a full battery of reproductive toxicology studies as well as carcinogenicity studies to support the development of selumetinib.”

“The Applicant’s Position: Selumetinib showed no evidence of carcinogenicity in 6-month CByB6F1/Tg rasH2 transgenic mouse and 2-year Han Wistar rat studies.”

“The nonclinical safety program supporting the clinical development and approval of doxecitine and doxribtimine included repeat-dose oral toxicity studies in mice (up to 4 weeks), rats (up to 6 months), and dogs (up to 3 months)”

“Based on the negative findings in the EFD and juvenile toxicity studies in rats at high exposure margins, a rat PPND study is considered unwarranted.”

“Postmarketing Requirement #1 Conduct a 26-week carcinogenicity study in Tg-rasH2 mice to identify and evaluate the carcinogenic risk of dC/dT.  Draft Protocol Submission: 11/2026”

“Oral Toxicity Study in Purebred Dogs Repeated Dosage for One Year/Study No. 3048/69/474; Study Report No.: 3048-69-474 Also described in: Toxicological Investigations on the Tolerability of Nifurtimox (Hoffmann 1972) Reviewer Comment: This non-GLP study was conducted in 1970, and did not include a recovery period.”

“In a pre-postnatal study in rats, maternal findings included reduced maternal body weights in mid- and high-dose dams during dosing, but no changes in uterine content parameters.”

“Because the proposed treatment duration of nifurtimox is less than 6 months, a carcinogenicity assessment is not required.”

“Histologic findings in the kidney of other high dose dogs in the 13-week study included slight tubule degeneration/regeneration and marked infarct, which were not present after an 8-week recovery period.”

“Prenatal and postnatal development studies were not conducted or needed to support the use of lazertinib in the currently proposed indication (NSCLC) per ICH S9.”

“The Applicant did not conduct carcinogenicity studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”

“52-Week oral gavage toxicity and toxicokinetic study of CTP-543 in Beagle dogs with an 8-week recovery”

“In a pre- and postnatal developmental study in rats, decreased pup survival, decreased F1 animal body weight, and adverse effects on reproductive outcome in the F1 females were noted at 75 mg/kg/day.”

“Deuruxolitinib was not carcinogenic in a 6-month oral transgenic mouse carcinogenicity study or a 2-year oral rat carcinogenicity study.”

“Once daily oral gavage administration of relacorilant to cynomolgus monkeys was well tolerated for 39 weeks at dose levels of 0, 3, 10, and 30 mg/kg/day.”

“In a pre-/postnatal toxicity study in rats (Study 950-125, Table 57), relacorilant was administered to pregnant rats from GD 6 through lactation day (LD) 20 at doses of 0 (vehicle), 1, 2.5, or 10 mg/kg/day.”

“there was no evidence of drug-related neoplasms in rats in the 2-year study or in mice in the 26-week study.”

“In the second 39-week oral RDT study in dogs with 6-month recovery (doses: 0, 10, 20, 10 [BID, 6 hours apart] and 40 mg/kg/day), ritlecitinib exposure was similar between sexes and increased dose-proportionally”

“Developmental and reproductive studies were completed in rats and rabbits. These included a fertility and early embryonic development study in male and female rats, DRF and pivotal EFD studies in pregnant rats and rabbits, and a pre- and postnatal development study in rats.”

“The potential for carcinogenicity was assessed in a 6-month study in transgenic rasH2 (tg/wt) mice and a 2-year study in rats in accordance with ICH Guidelines M3(R2), 2009.”

“52-Week Oral Gavage Toxicity and Toxicokinetic Study With MBX-8025 in Cynomolgus Monkeys With an 8-Week Recovery Phase (Study #8308417)”

“Reproductive and developmental toxicology studies using oral administration of seladelpar included a fertility study in male and female rats, EFD studies in rats and rabbits, and a pre- and postnatal development study in rats.”

“The carcinogenicity of seladelpar was evaluated in 2-year studies in mice and rats”

“4-week recovery period was allowed after the initial 6 months of treatment; 8-week recovery period was allowed after the 1 year of treatment.”

“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and post-natal development study in rats.”

“Therefore, submission of the 2-year rat carcinogenicity study should be a Postmarketing Requirement. The study results will be included in subsection 13.1 of the labeling, in addition to the results of the completed carcinogenicity study in Tg.RasH2 mice.”

“Following 52 weeks of dosing, all surviving main group animals in the control, 100, and 200 mg/kg/day groups were euthanized. Recovery animals, 2/sex in the control group and 1 male and 2 females in the 200 mg/kg/day dose group, were maintained off dose for an 8-week recovery period.”

“In the pre-and postnatal developmental toxicity study maribavir was administered to pregnant rats at oral doses of 50, 150, or 400 mg/kg/day from GD 7 to postnatal day (PND) 21.”

“Two-year carcinogenicity studies were conducted in mice and rats administered oral doses up to 150 and 100 mg/kg/day, respectively.”

“A 39-Week Oral Toxicity Study in Cynomolgus Monkey Followed by a 28­ Day Recovery Period (Study # ISA02-01)”

“In a prenatal and postnatal development study with mix-ISA247 in rats, dystocia (observed as prolonged parturition) was observed at 25 mg/kg/day.”

“Two-year studies were conducted in rats and mice.”

“Both the 13-week and 9-month repeat-dose studies with 4-week recovery periods also evaluated doses of 1, 3, and 10 mg/kg/day.”

“In a pre- and postnatal development study, pregnant rats were administered SAM at oral doses of 10, 30, and 100 mg/kg/day from gestation day 6 through lactation day 20.”

“SAM is also non-carcinogenic as it did not induce tumors in male and female rats administered SAM for up to 95 weeks at exposures which are approximately 32 and 237 times the MRHD based on AUC, respectively and did not induce tumors in rasH2 transgenic mice administered SAM for 6-months.”

“Recovery groups were included in one of the 13- week rat studies but unfortunately not in Cynomolgus monkeys.”

“A pre- and postnatal developmental study was conducted in the rat.”

“Elinzanetant’s potential for carcinogenicity was assessed in a six-month carcinogenicity transgenic mouse model (tg RasH2) study in addition to one long-term two-year rat study.”

“In the pivotal 4-week and 13-week toxicology studies in rats and dogs, no mortality was observed during the treatment window or in the recovery period.”

“In line with ICH S9, no fertility, PPND or juvenile animals studies were performed.”

“The FDA’s Assessment: Carcinogenicity studies are not recommended for the proposed indication.”

“Study №: 0770339. A 52-week toxicity study of BAF312 administered orally via nasal gavage to Cynomolgus monkeys, with an 8-week recovery period.”

“In the pre- and postnatal development study in rat, siponimod was administered at doses of 0, 0.05, 0.15, and 0.5 mg/kg from GD 6 to lactation day 20.”

“Two-year carcinogenicity studies were conducted in mice and rats.”

“The toxicity profile of orally administered dordaviprone was defined in GLP-regulated studies with once or twice (on 2 consecutive days) weekly administration for up to 13 weeks in both rodents (Sprague-Dawley rats) and nonrodents (Beagle dogs)”

“Dordaviprone is intended for the treatment of patients with advanced cancer; therefore, studies on fertility and pre- and postnatal development have not been conducted, as they are not required per ICH S9 guidelines for the nonclinical evaluation for anticancer pharmaceuticals (ICH 2010).”

“The FDA agrees that carcinogenicity studies are not warranted for the current indication of pediatric and adult patients with H3 K27M-mutant diffuse glioma.”

“Study Number/Title: Nonclin-0056/CK-3773274: A 39-Week Oral Gavage Toxicity Study in the Beagle Dog Followed by a 2-Month Recovery Period”

“Pre- and post-natal development effects of aficamten were evaluated in rats.”

“There were no aficamten-related tumor findings in a 26-week carcinogenicity study in transgenic rasH2 mice at doses up to 2.0 mg/kg/day or in a 2-year carcinogenicity study in Sprague Dawley rats”

“Considering that all findings were resolved following the recovery period, no other histopathological findings indicative of hepatic or renal injury were observed, and there were no findings indicative of renal function impairment, the toxicological significance of the liver, thyroid, and kidney findings was considered limited.”

“a complete battery of reproductive toxicity studies including a combined fertility, early embryonic development, and embryo-fetal development study in rats, an embryo-fetal development study in rabbits, and a pre- and postnatal development study in rats”

“the 6-month carcinogenicity study in transgenic mice, and the 2-year carcinogenicity study in rats were submitted to IND 141315.”

“In the 52-week monkey toxicity study, histological change in liver was limited to periportal or diffuse vacuolation consistent with positive staining Oil Red O (lipids) at ≥20 mg/kg/day.”

“In a rat pre- and postnatal development study, treatment with bempedoic acid was associated with adverse delivery outcomes, including increases in stillborn pup and reductions in numbers of live pups, pup survival, pup growth, and slight delays in learning and memory at ≥10 mg/kg/day (below the clinical exposure at human dose of 180 mg, based on AUC).”

“the IND was put on Partial Clinical Hold on November 19, 2009, for clinical studies in excess of 6 months until draft repo1ts from completed 2-year rat and mouse carcinogenicity studies were submitted.”

“39-week toxicity study by the oral route (gavage) in adult female cynomolgus monkeys followed by a 6-week treatment-free period (Study ES-T20, GLP)”

“In a pre- and post-natal development study in rats, E4 caused maternal toxicity (reduced body weight and food consumption), parturition difficulties or absence of delivery”

“The tumor findings from the rat and mouse final carcinogenicity studies were reviewed and agreed upon by the Division and ECAC on November 24, 2020.”

“KW-6002 Toxicity to dogs by repeated oral administration for 52 weeks with a 12-week recovery period”

“Therefore, it seems evident that KW-6002 treatment of dams had an effect on viability and body weights of rat pups whether due to prenatal or lactational exposure.”

“The Exec CAC concluded that the 2-year carcinogenicity studies in mouse and rat were adequate and negative, pending confirmation of the sponsor’s statistical analysis by the Agency.”

“ODM-201-39-week oral (gavage) toxicity study in the Beagle dog followed by an 8-week treatment-free period/Study number AB19526.”

“Not conducted or warranted to support this NDA submission for a therapeuticintended to treat male patients with advanced prostate cancer”

“The applicant should provide the results of the 6-month Tg-rasH2 mouse carcinogenicity study by 30 June 2022 (see RMP).”

“A 9-Month Intravenous Toxicity Study in Juvenile Beagle Dogs With a 3-Month Recovery Period”

“Pre- and postnatal development (PPND) study in mice. • 104-Week carcinogenicity study in mice. • Thorough QT/QTc Study. We are not requiring these studies pre-approval so as not to further delay approval of Nulibry”

“A two-year carcinogenicity study in mice is however planned as a post-marketing requirement from FDA.”

“9-Month Repeat Dose Toxicity and Toxicokinetic Study of BHV-3000 Hemisulfate in Cynomolgus Monkeys with a 28-Day Recovery Period”

“Overall, the nonclinical data support approval of NDA 212728 (ODT) however, a pre- and postnatal development study, to include an adequate number of offspring for evaluation and a more rigorous neurobehavioral assessment, should be a post-marketing requirement (PMR).”

“Based on a review by the CDER Division of Biometrics, BHV-3000 did not induce tumor formation in the 26-week and 2-year carcinogenicity studies”

“histopathology assessments in a 4-week repeat dose rat study with a 3-month recovery period, histopathology assessments in a 4-week repeat dose dog study with a 3-month recovery period”

“In a pre- and postnatal development study, gravid female rats were administered 0, 50, 100, or 200 mg/kg/day zoliflodacin by oral gavage from GD 6 until weaning on lactation day 20.”

“Carcinogenicity studies have not been conducted with zoliflodacin.”

“Nirogacestat was administered to rats and dogs in repeat dose general toxicology studies up to 3 months in duration followed by a 1‐month recovery.”

“Based on the severity of the embryo‐fetal development (EFD) effects of nirogacestat observed in the dose‐range finding study in rats (Study 01214026) and the importance of the gamma‐ secretase pathway in embryo implantation and development, SpringWorks requested a waiver for conducting the definitive EFD study in rat, the range finding and definitive EFD studies in rabbits, as well as the pre‐ and post‐natal development (PPND) study in rats.”

“In the 6‐month carcinogenicity study (Study 20174162), a significant increase in hemangiosarcomas was noted in both male and female transgenic mice with the incidence above historical control values of the test facility. Therefore, SpringWorks requested a waiver for the 2‐year carcinogenicity study in rats”

“In males, the 3-month study highlighted decreased testes and epididymal weights with associated microscopic findings of seminiferous tubules degeneration/atrophy and reduced epididymal luminal sperm at all doses (≥ 50 mg/kg Q2D, 0.3-fold human exposure); lower testes weight persisted after 2 weeks of recovery.”

“The 2-year rat carcinogenicity study is ongoing. The carcinogenicity evaluation is considered adequate considering the ongoing 2-year study.”

“GS-0387: 39-Week Oral Toxicity Study in Dogs With a 6-Week Recovery Period”

“In a pre- and postnatal development study, pregnant rats (F0) were orally treated daily with 0, 2, 6 or 12 mg/kg/day of momelotinib from GD6 to lactation day (LD) 20.”

“In the 26-week carcinogenicity study in transgenic mice, there were no MMB-related neoplasms in animals administered up to 100 mg/kg/day, although there was a clear carcinogenic response in animals administered the positive control article.”

“The nonclinical program supporting clinical development of Oliceridine included a pharmacology, ADME, general toxicology studies (28 days duration in rats and 14 days duration in monkeys), genetic toxicology, and reproductive toxicity studies.”

“In a pre- and post-natal development study in rats, maternal dosing of oliceridine between Gestation Day 6 (GD 6) and Lactation Day 21 (LD 21) resulted in an overall increase in pups found dead or sacrificed moribund from birth to weaning.”

“Long-term animal studies have not been completed to evaluate the carcinogenic potential of oliceridine.”

“A 39-week ocular toxicity study of DE-117 ophthalmic solution in cynomolgus monkeys with a recovery period of 4 weeks”

“The Applicant submitted one fertility and early embryonic development (FEED) study (rat), two embryofetal development (EFD) studies (rat and rabbit), and one pre-/post-natal development (PPND) study (rat).”

“Carcinogenicity testing has not been performed with omidenepag isopropyl or omidenepag.”

“Study title: 52-week oral (gavage) toxicity study in the Cynomolgus monkey with an 8-week recovery period.”

“In the reproductive and developmental toxicology studies in rat, opicapone was tested at oral doses up to 1000 mg/kg/day, using standard study designs. No adverse effects on fertility or on embryofetal (EFD) or pre- and postnatal development (PPND) were observed.”

“Two long term carcinogenicity studies have been completed with Opicapone. Mice were dosed with oral opicapone at 100, 500/375 and 1000/500 mg/kg/day and rats were dosed with 100, 500 and 1000 mg/kg/day).”

“Study Title/Number: A 9-Month Study of BCX7353 by Oral Gavage in the Cynomolgus Monkey with a 13-Week Recovery Period (#806-162)”

“Berotralstat was nonteratogenic in pregnant rats and rabbits dosed with the drug during the organogenesis period. Berotralstat did not affect the fertility or PPND of rats.”

“No evidence of tumorigenicity was found in mice or rats. The carcinogenicity potential of berotralstat was evaluated in a 2-year traditional bioassay in rats and a 26-week study in B6F1 Tg.RasH2 mice.”

“Animals were dosed once per day for 30 days in doses of 0 (vehicle), 50, 400, and 1000 mg/kg/day. Route of administration: Oral gavage Formulation/Vehicle: 0.5% methylcellulose Species/Strain: Cynomolgus monkeys Number/Sex/Group: 3/sex/group Age: 3 to 3.5 years of age Satellite groups/ unique design: No separate toxicokinetic animals or recovery animals were included in the study.”

“developmental and reproductive toxicology studies (male and female fertility study in rats, embryo-fetal development studies in mice, rats, and rabbits, a pre-postnatal development study in rats and a juvenile toxicology study in rats).”

“No carcinogenicity studies have been conducted for sulopenem etzadroxil or sulopenem.”

“Study Title/Number: 39-Week Oral Gavage Toxicity Study of TAK-861 in Monkeys/B-8934”

“In the pre- and postnatal development (PPND) study in rats, there were no drug-related effects on maternal endpoints or reproductive function, or on offspring development (survival, growth, behavior, and reproductive function).”

“Oveporexton was also found to be non-carcinogenic in a GLP 2-year rat and a GLP 6-month transgenic mouse carcinogenicity study.”

“PRC-16-007, GLP Monkey, Cynomolgus, 6/sex/dose (controls and high-dose – 4/sex/dose terminated immediately after dosing, 2/sex/dose recovery group), 4/sex/dose (low- and mid-dose) 0, 15, 30 and 60 mg/kg/day, oral or nasogastric gavage 39 weeks with 4 weeks recovery”

“In the pre- and post-natal developmental toxicity study reduced pup viability index and reduced F1 generation body weight (in males until post-pairing day 55, in females until maturation day 7) was seen at the dose level of 250 mg/kg/day.”

“Carcinogenicity of voxelotor was studied in the 2-year study with rats study (PRC-16-009) and the 26-week study with transgenic mice (study PRC-17-006).”

“CRN00808-HCL: 39-Week Repeated Oral Dose Toxicity and Toxicokinetic Study in Beagle Dogs with 4-Week Recovery/ 2018-TX-051”

“DART program is composed with a GLP fertility and early embryonic development study in rats, embryo-foetal development studies in rats and rabbits and a pre- and postnatal study in rats.”

“Paltusotine did not elicit any treatment-related increase in the incidence of tumors in a 2-year study in rats or a 26-week study in Tg.rasH2 transgenic mice.”

“One-Month BID Oral Gavage Toxicity Study of PF-07321332 in Cynomolgus Monkeys with a Two-Week Recovery (Study# 21GR125)”

“The pre- and postnatal development study was ongoing; the interim report has been provided. The final study report for the PPND (21GR149) is requested by 30/04/2022 (LEG).”

“No carcinogenicity studies have been performed. Considering that the duration of treatment is limited to 5 days, the absence of carcinogenicity studies is in-line with the recommendations of ICH S1A.”

“In a 52-week oral toxicity study with 9-week recovery period in beagle dogs, animals were administered lactitol at 250, 1250 and 6250 mg/kg/day (Onishi M, et al., 1994).”

“To support the NDA, FDA stated that the Applicant should conduct the required carcinogenicity and reproductive toxicity nonclinical studies. These studies were submitted and reviewed by Tamal Chakraborti, PhD.”

“In a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice at 225, 675 and 2000 mg/kg/day, there were no drug-related neoplasms in either males or females. The 104-week oral carcinogenicity study in rats was initiated in February 2017, and the study report will be submitted post approval, as per agreement with the Agency.”

“studies of 2 weeks, 3 months, and 9 months duration were conducted in cynomolgus monkeys. In all studies, doses were administered daily by oral or nasogastric gavage corresponding to the proposed clinical oral dosing regimen. In the chronic studies, post-treatment assessments continued for 3 months to evaluate reversibility, progression, or delayed toxicity.”

“repeat dose toxicity studies (in mice, rats, and monkeys, for up to 39 weeks), fertility and pre- and post-natal developmental studies in rats; embryo-fetal developmental studies in rats and rabbits”

“The applicant states that a 2-year oral carcinogenicity study in the rat is ongoing. A genotoxic concern based on the positive mutagenicity results of the M50 metabolite cannot at this point be excluded. However, based on the absence of pre-neoplastic or neoplastic findings in the chronic toxicity studies in the rat, or in the 26-week carcinogenicity study in transgenic mice”

“During the 9-month study in monkey, mitapivat increased the incidence of emesis at all doses. A reversible white area in liver was observed in females at 200 mg/kg.”

“NOAEL is 10 mg/kg/BID (3.5× MRHD) for maternal toxicity and 25 mg/kg/BID (exposure 13× MRHD, based on AUC) for postnatal development.”

“Mitapivat was not carcinogenic in a 2-year rat study at doses up to 150 mg/kg/BID in males and 100 mg/kg/BID in females (47× and >100× MRHD, respectively), or in transgenic ras H2 mice up to the highest doses tested at 500 mg/kg/day in males and 250 mg/kg/day in females when given orally for 26 weeks.”

“18-month main study: n=22/sex/group, from which n=5/sex in the control and HD groups were evaluated after a 6-week recovery”

“Viloxazine caused maternal toxicity of decreased body weight, weight gain, and food consumption at doses ≥87 mg/kg/day and maternal death at 217 mg/kg/day.”

“One Two Year Oral Gavage Carcinogenicity Study in Wistar Rats and One Six-Month Oral Gavage Carcinogenicity Study in rasH2 Transgenic Mice.”

“Ripretinib was evaluated in repeat dose toxicity studies in rats and dogs (14 days, 4 weeks with 4 weeks recovery, 13 weeks with 4 weeks recovery).”

“The reproductive toxicity program is in accordance with ICH S9 guideline which states that studies on fertility and early embryonic development, and pre-and postnatal toxicology studies are generally not warranted to support marketing of pharmaceuticals for the treatment of patients with advanced cancer.”

“The Regulatory Authorities agree that carcinogenicity was not warranted for the proposed indication.”

“Study TT #13-1074: Nine-Month Oral Toxicity Study in Rhesus Monkeys with a Three-Month Interim Necropsy”

“In the GLP pre- and postnatal developmental toxicity study in rats, atogepant was administered at dose levels of 0 (vehicle), 15, 45 or 125 mg/kg/day.”

“Based on the FDA statistical analysis of the 2-year mouse and rat carcinogenicity studies, atogepant was not carcinogenic.”

“Daridorexant - 39-Week Toxicity Study by the Oral (Gavage) Route in the Beagle Dog Followed by an 8-Week Treatment-Free Period (Study T-16.017)”

“Daridorexant was administered orally to pregnant rats during gestation and lactation at doses of 50, 100, and 300 mg/kg/day, which are approximately 1, 3, and 9 times the MRHD of 50 mg, respectively, based on AUC.”

“2-year and 6-month carcinogenicity studies in the rat and Tg.rasH2 mouse, respectively”

“Reports of intravenous bolus and continuous infusion studies in rats and dogs up to 4-week duration were available. Four-week i.v. bolus study in rats with 4-week recovery period (Yamaguchi 1997c)”

“The same doses that were tested in rat fertility and EFT studies were tested in the rat pre/postnatal developmental study (Nishimura, 1997d).”

“The applicant has not conducted carcinogenicity study because of short-term clinical use (consistent with the reference drug) nor juvenile studies.”

“Relebactam was evaluated in repeat-dose toxicity studies in rats (4 weeks with 4 weeks recovery, and 12 weeks with no recovery phase) and in monkeys (4 weeks with 4 weeks recovery, and 12 weeks with no recovery phase).”

“Relebactam: The study report for a MK-7655 (relebactam) pre-postnatal study in rats is reviewed below.”

“In the absence of genotoxicity, and as the proposed treatment duration is relatively short, no carcinogenicity tests have been conducted.”

“ECG was evaluated prior to the initiation of dosing, Dosing Day 269, and on Recovery Day 23.”

“Drug effects on pre- and postnatal development (PPND) were assessed in SD rats administered up to 1500 mg/kg/day (BID) AMX0035 from GD 6 to postnatal day (PND) 20.”

“If the NDA is approved, carcinogenicity studies in two species (mouse and rat) should be conducted as post-marketing requirements, as previously agreed to by the Division and communicated to the sponsor.”

“Repeat-dose toxicity studies were conducted with gedatolisib in Sprague Dawley rats and Beagle dogs up to approximately 1-month duration using an every 4-day dosing schedule (8 total doses) and up to approximately 3-month duration using the clinical dosing schedule of once weekly for 3 weeks on followed by 1 week off; both durations were followed by a 12-week recovery period.”

“Animal reproductive toxicity studies have not been conducted with REVTORPYK.”

“In accordance with ICH S9 on the Nonclinical Evaluation for Anticancer Pharmaceuticals, no carcinogenicity studies have been conducted with gedatolisib.”

“In the 13-week dog toxicology study, animals were dosed daily at doses of 0, 12.5, 25, or 40 mg/kg/day for 13 weeks followed by a 13-week recovery period.”

“a pre- and post-natal toxicology study is generally not warranted for marketing of pharmaceuticals for the treatment of patients with advanced cancer.”

“The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”

“General Toxicology: the oral toxicity of lasmiditan was tested in Sprague-Dawley rat (4-week + 2-week recovery, 13-week + 4-week recovery, and 26-week + 8-week recovery) and Beagle dog (2-week, 4-week + 2-week recovery, 13-week + 4-week recovery, and 39-week + 8-week recovery).”

“Pre- and postnatal development: Oral administration of lasmiditan (0, 100, 150, or 225 mg/kg/day) to rats throughout pregnancy and lactation resulted in increases in stillbirth and neonatal mortality at the highest dose tested, which was associated with maternal toxicity.”

“A 26-week study in transgenic RasH2 mice and a 2-year study in Sprague-Dawley rats were conducted.”

“A 9-Month Oral Toxicity Study With MGL-3196 in Dogs With a 4-Week Recovery Period, Study 0472DM72.001”

“Reproductive and developmental toxicology studies of resmetirom included a fertility study in male and female rats, EFD studies in rats and rabbits, and a pre- and postnatal development study in rats.”

“2-year carcinogenicity studies were conducted with resmetirom in CD-1 mice and in SD rats.”

“39 Week Oral Toxicity Study in Dogs with a 13 Week Interim Sacrifice and an 8 Week Recovery Period”

“Additionally, targeted ROCK2 receptor knockdown in homozygous knockout mice showed placental dysfunction, intrauterine growth retardation, and foetal death. Consequently, a PPND study is not considered necessary based on current knowledge.”

“PMR #9 Conduct a rodent carcinogenicity study in mice to evaluate the potential for carcinogenicity.”

“All pivotal studies included recovery periods; these were of 6 or 12 months duration in the 26-week studies in rats and cynomolgus monkeys, respectively.”

“The study revealed no effects on pre-and postnatal development up to the reproduction of the F1 generation, and, therefore, the NOAEL for pre- and postnatal development was set at 45 mg/kg/day.”

“No carcinogenicity studies have been conducted. Considering the proposed therapeutic indication and the proposed duration of treatment, this was considered a satisfactory approach.”

“In a 39-week GLP oral repeat-dose toxicity study in beagle dogs, animals (4/sex/group) were administered doses of 0 (vehicle), 10, 50, and 300 mg/kg/day remibrutinib. No recovery groups were included in the study.”

“In a pre- and postnatal development study, pregnant rats received daily oral doses of remibrutinib at 0 (vehicle), 100, 300, and 1000 mg/kg/day from GD 6 to Lactation Day 21.”

“A 104-week oral carcinogenicity study of remibrutinib in Wistar rats (50/sex/dose) showed no evidence of carcinogenicity at oral doses of 0 (water), 0 (vehicle), 30, 100, and 300 mg/kg/day remibrutinib once daily.”

“Upadacitinib was evaluated in repeat-dose toxicity studies in mice (4 weeks with no recovery), rats (4 weeks with 4 weeks recovery, and 26 weeks with no recovery), and dogs (4 weeks with 4 weeks recovery, and 39 weeks with no recovery).”

“In the oral PPND study with pregnant rats, UPA at doses up to 10 mg/kg/day produced no evidence of maternal toxicity, embryofetal toxicity, or postnatal toxicity.”

“The 26-week mouse and 104-week rat carcinogenicity studies were submitted and reviewed under IND 114,717”

“In the 39-week repeat-dose dog toxicology study (Study No. 8413879) with a 4-week recovery phase, vimseltinib was administered once daily by oral gavage at 0, 2, 4, or 8 mg/kg/day.”

“The Applicant also performed a pre- and post-natal study (Study No. DCC-3014-04-0029) to observe the effects of oral administration of vimseltinib from the period of implantation to lactation.”

“The Applicant is conducting a 104-Week rat carcinogenicity study of vimseltinib in Sprague Dawley rats (DCC-3014-04-0025, eCTD 2.6.7 Table 21).”

“No corneal findings were seen in the 13-week plus 8-week study in rats, nor in all toxicity studies in dogs.”

“No carcinogenicity studies have been submitted as part of the application.”

“A 39-week study was performed in marmoset monkeys with a 4-week recovery period.”

“The Agency provided a response on January 30, 2023, conveying their disagreement with the request and stating that a pre- and post-natal developmental study to assess postnatal effects following in utero and lactational exposure would be needed to support a marketing application.”

“Therefore, a postmarketing requirement for a 2-year carcinogenicity study in rats to evaluate the carcinogenicity risk is warranted.”

“In repeat-dose toxicology studies of up to 26-weeks in rats and 43-weeks in dogs, clinical signs related to CNS stimulation, reductions in food consumption, and lower body weight and/or body weight gain were observed dose-dependently across studies in both species.”

“Reproductive and developmental toxicity studies that were conducted included fertility studies in male and female rats, embryofetal development (EFD) studies in rats and rabbits, a pre- and post-natal development (PPND) study in rats, and a juvenile animal study (JAS) in rats.”

“In this submission the sponsor included reports of two animal carcinogenicity studies, one in rats and one in mice.”

“Male and female cynomolgus monkeys (9-10/sex/group) were administered doses of 0 (sesame oil), 10, 30, or 100 mg/kg RTA 408 by daily oral gavage for 39 weeks with 4 weeks recovery; an interim 13-week sacrifice was included.”

“PPND toxicity was investigated in rats and concentrations of omaveloxolone were determined in milk and in pup plasma samples.”

“Carcinogenicity studies (26-week study in Tg.rasH2 mice and 2-year study in SD rats) are to be conducted as post-marketing requirements.”

“Due to the lack of significant toxicity, the mid dose was increased from 25 to 120 μg/kg/day for at least 39 weeks (Week 13 through Week 52). Recovery was assessed for an additional 13 weeks in animals treated at 12 and 40 μg/kg/day.”

“As palovarotene adversely affected fetal development in pregnant rats, and retinoids as a class are known to carry a risk of affecting fetal development, neither an EFD study in pregnant animals of a second species nor a pre-/postnatal developmental toxicity study were warranted.”

“Therefore, rodent carcinogenicity studies in two species to assesses the carcinogenic potential from long-term oral exposure to palovarotene are being recommended as post marketing requirements.”

“The 9-month toxicity study in monkeys showed that liver-related findings were limited to mostly minimal to mild increases in total bilirubin throughout the study in females at doses ≥ 3 mg/kg/day and males at 10/5 mg/kg/day and that the bilirubin changes were reversible after the 2-month recovery period.”

“In a rat oral pre- and postnatal development study, deucravacitinib (0, 5, 15, and 50 mg/kg/day) had no adverse effects on maternal reproductive function or effects on survival, sexual maturation, neurobehavioral, and reproductive function of the offspring, when administered from GD 6 to lactation day (LD) 20.”

“Deucravacitinib did not cause increases of tumor incidences in a 6-month oral carcinogenicity study in transgenic rasH2 mice and a 2-year oral carcinogenicity study in rats.”

“Animals were dosed once every 4 weeks for up to 37 weeks then sacrificed after a 2- or 13-week recovery period.”

“For the assessment of long-term development toxicity effects from prenatal exposure, a prenatal and postnatal development (PPND) rat study was conducted.”

“A 6-month transgenic mouse (TgRasH2) and a 2-year rat carcinogenicity studies with lenacapavir are stated to be in progress becoming available between end of 2021 and early 2023).”

“Dogs: In a pivotal 12-month repeat-dose toxicity study with a 13-week recovery period, solriamfetol given in two divided daily oral doses of (total) 8, 21, or 42 mg/kg caused hyperactivity/agitation and transient weight loss at all dose levels”

“In the pre- and post-natal developmental toxicity study in the rat, at 3.5- and 11- times the MRHD based on mg/m2 body surface area, solriamfetol caused maternal toxicities of decreased body weight gain, food consumption, and hyperpnea.”

“The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”

“Cynomolgus monkeys were administered with capmatinib (0, 10, 30 and 75 mg/kg/day) by oral gavage for 13 weeks, followed by an 8-week recovery period.”

“In line with ICH guideline S9, neither fertility and early embryonic development nor pre- and postnatal toxicology studies have been conducted with capmatinib.”

“Carcinogenicity studies were not conducted for capmatinib or necessary for a drug intended for the treatment of patients with advanced cancer.”

“Avacopan has been evaluated in repeat-dose toxicity studies in hamsters (up to 13 weeks with 4 weeks recovery), rats (up to 26 weeks with 6 weeks recovery) and monkeys (up to 44 weeks with 6 weeks recovery).”

“In a pre- and post-natal development study with hamsters, there were no effects of CCX168-treatment of the F0 mothers at doses up to 1000 mg/kg/day on growth, physical, and neurological development as well as reproductive performance of the F1 generation.”

“The 2-year carcinogenicity studies in rat and hamster were reviewed under NDA 214487”

“VX-445: A 39-week Oral (Gavage) Toxicity and Toxicokinetic Study in Beagle Dogs With a 26-week Interim Sacrifice and 6-week Recovery Period”

“A peri- and postnatal development study with elexacaftor was conducted in rats.”

“negative in teratogenicity and carcinogenicity assays (based on the 6-month study in mouse only; the 2-year carcinogenicity study in rat will be completed as a post-marketing requirement)”

“it is acknowledged that cardiac effects were not noticed in the 9-months dog study and no safety signal in clinical studies were observed; however this study did not include a recovery group (similar to the long-term rat study).”

“Preliminary studies on embryonic and foetal development in rats and a pre- and postnatal study have been carried out.”

“Carcinogenicity studies with capivasertib were not warranted to support this NDA, as the proposed indication is for advanced cancer.”

“BGJ398: A 39‐Week Oral Gavage Toxicity Study in Dogs with a 13‐Week Recovery Period”

“Pre‐ and Postnatal Development: No pre‐ or post‐natal studies have been conducted with infigratinib.”

“Carcinogenicity studies are not warranted to support a marketing application for the proposed indication.”

“In 6-month repeat dose ocular GLP toxicity studies in the beagle dog and the New Zealand White rabbit with 14-day recovery periods”

“Fertility and pre- and postnatal development animal studies have not been performed because there is negligible clinical systemic exposure at the RHOD and lack of systemic toxicity.”

“The committee agreed with the Division that in the absence of systemic exposure for acoltremon ophthalmic solution, 0.003%, there is no need to conduct carcinogenicity studies.”

“Repeat dose toxicity studies were conducted in dogs for up to 39 weeks with oral dose levels from 5 to 1000 mg/kg/day. Key findings are summarized below. 39-Week (13-Week Recovery) Toxicology Study”

“In a pre- and postnatal developmental study in female rats, oral administration of 10, 50 or 250 mg/kg/day macitentan during the pregnancy and the lactational periods reduced pup survival and impaired male fertility of offspring at all doses.”

“Two-year carcinogenicity studies with macitentan did not identify any carcinogenic potential at doses up to 100 mg/kg/day and 250 mg/kg/day in mice and rats”

“A 9-month oral (gavage) toxicity study of PLX3397 with a 16-week recovery period in Beagle dogs”

“In a pre-and postnatal development study, female rats received pexidartinib once daily from GD 6 to lactation day (LD) 20 at doses up to 10 mg/kg/day (approximately 0.3 times the exposure at the 800 mg clinical dose).”

“The Applicant conducted a two-year (104-week) carcinogenicity study with pexidartinib in rats and a 26-week carcinogenicity study in rasH2 transgenic mice (See Appendix 19.3 for full review).”

“Study # LJT 2561. A 13-Week Repeated Oral Dose Toxicity Study on LJC 11,084 Using Cynomolgus Monkeys With a 4-Week Recovery Segment”

“In the pre- and postnatal development (PPND) study in rats, oral administration of tebipenem pivoxil resulted in adverse findings in offspring (stillborn litters, reduced postnatal survival, and decreased body weights through postnatal day 4) that were considered secondary to maternal toxicity.”

“A partial recovery was observed after 3 months of a treatment-free period in both the 3-month and 9-month dog studies.”

“AKB-6548: An Oral Study for Effects on Pre- and Postnatal Development including Maternal Function in Rats (Study No. 1817-037)”

“The carcinogenic potential of vadadustat was evaluated in a 2-year rat study and a 6-month transgenic mouse study, both under GLP compliance.”

“Repeat-dose toxicity studies were conducted in Sprague-Dawley rats, beagle dogs and cynomolgus monkeys given quizartinib dihydrochloride for up to 13 weeks, including a 4-week recovery period for all pivotal studies.”

“No pre- and postnatal studies were performed. Considering the patient population, this is agreed.”

“No carcinogenicity studies were conducted or are required to support the marketing of quizartinib for the current indication.”

“Methods: Animals were dosed by oral administration for 9 months. Dose and frequency of dosing: 10, 30, 100 mg/kg/day Route of administration: Oral Formulation/vehicle: Atrasentan HCl powder in gelatin capsules. Species/strain: Beagle dog Number/sex/group: Five/sex/dose group Age: 6.5 to 7.5 months old Satellite groups: Recovery: two/sex (control and high-dose group)”

“13.1.7.3. Pre- and Postnatal Developmental Study Study Number/Title: R&D/15/0589 Peri- and Postnatal Development in Rats GLP compliance: Yes”

“Two long-term studies were conducted to evaluate the carcinogenicity of atrasentan: a 26-week study in Model 001178-T (hemizygous) CByB6F1-Tg(HRAS)2Jic mice and a 104-week study in Sprague Dawley rats.”

“2 animals/sex from the vehicle, 10, and 15 mg/kg/day groups were maintained for a 4-week recovery period after 273 consecutive days of dosing.”

“As part of the NDA package, the Applicant submitted three in vitro pharmacology studies and a pre- and postnatal development (PPND) study in rats with etrasimod, as well as genetic toxicology studies with two process-related impurities.”

“The NDA submission included the final study reports and corresponding SEND datasets for the 2-year carcinogenicity studies in mice and rats.”

“8331280*** (GLP) FEMALE Monkey, oral gavage @ 0, 10, 25, and 40 mg/kg/day fezolinetant for 39 weeks with 4- week recovery”

“The Sponsor submitted carcinogenicity study reports and pre-and post-natal developmental study report under IND 130277 eCTD 0115. The carcinogenicity studies and the pre-postnatal developmental study are being reviewed under the current NDA submission.”

“Carcinogenicity studies were done in rats and transgenic mice. The final study reports were presented at the 10/25/22 Executive Carcinogenicity Assessment (ECAC) meeting and both studies were considered negative.”

“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”

“In a pre-postnatal development study in rats, vericiguat was administered orally at doses of 7.5, 15 or 30 mg/kg/day from GD 6 through lactation day 21.”

“Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats.”

“The reversibility of findings in dogs was not assessed. The NOAEL (MD, 11.8 μg·h/mL, and 3.4 μg·h/mL AUC0­24, Day 270, in males and females) represents a 0.06× (M) and 0.02× (F) exposure margin to the anticipated clinical dose (200 mg BID, 213 μg·h/mL AUC).”

“Reproductive toxicology was assessed in mice in two fertility and early embryonic development studies (BALB/c and CD-1), an embryo-fetal development study (CD-1) and a pre- and postnatal development study (CD-1).”

“Pacritinib was not carcinogenic in either a 2-year rat study or during a 26-week hemizygous Tg(HRAS) transgenic mouse study, demonstrating low carcinogenic potential secondary to inhibition of JAK2/FLT3 activity.”

“5, 15, 50 mg/kg/day for 13 weeks, once daily followed by a 4-week recovery period”

“the applicant has committed to perform and submit a PPND study in rats post-approval with submission of the final study report by Q2 2026.”

“Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”

“Toxicity Study by Dermal Administration to Göttingen Minipigs for 9 Months Followed by a 1-Month Off-Dose Period”

“GSK2894512A: Subcutaneous Pre- and Postnatal Development Study in Rats / 2018N368233”

“Long-term carcinogenicity studies were conducted in mice (daily topical administration at doses of 0.5, 1.5 and 3% tapinarof cream) and in rats (subcutaneous administration at doses of 0.1, 0.3, and 1 mg/kg/day tapinarof).”

“Dogs were administered daily oral gavage doses of tafamidis meglumine at 0, 5, 15, or 45 mg/kg/day for 13 or 39 weeks in a pivotal subchronic/chronic toxicity study (Study SYI00013) that included a 4-week recovery phase after 13 weeks of dosing.”

“In pre- and postnatal study, pregnant rats received oral administration of tafamidis meglumine at doses of 0, 5, 15, or 30 mg/kg/day throughout pregnancy and lactation”

“Carcinogenicity were evaluated in Tg.rasH2 transgenic mice dosed at 10, 30, or 90 mg/kg/day for 26 weeks and in Sprague Dawley rats dosed at 3, 10 or 30 mg/kg/day for 2 years. Both studies were considered adequate and found to be negative for increases in tumor findings with the Executive CAC’s concurrence.”

“Study Title/Number: A 28-Day Study of ETX2514 by Intravenous Infusion in Beagle Dogs With a 28-Day Recovery Period. Study PC2514-2020-0001”

“Study Information for GLP Pre- and Post-Natal Development Study of ETX2514 by the Intravenous Route (2-Hour Infusion) in the Rat (Segment III), Study PC2514-2019-0004”

“Study title: YKP3089: a 52-week oral toxicity study, with 13-week and 26-week interim portions, including 4-week recovery (following 13 weeks of administration) or a 3-month recovery (following 52 weeks of administration), in cynomolgus monkeys”

“In the pre- and postnatal development study in rat, cenobamate was administered orally to female rat throughout gestation and lactation at doses of 0, 11, 22, and 44 mg/kg.”

“A 26-week study in transgenic RasH2 mice and a 2-year study in Sprague-Dawley rats were conducted. The executive carcinogenicity assessment committee concluded that the studies were adequate and that there were no drug-related neoplasms in either study.”

“1020-7122: Lotilaner: A 9-Month Repeat-Dose Topical Ocular Toxicity Study Followed by a 4-Week Recovery Period in the Beagle Dog”

“a 2-generation reproductive toxicity study in the rat to cover both male fertility and reproductive and developmental toxicity of the product.”

“No studies were performed. The Sponsor provided a rationale for not conducting carcinogenicity studies with Lotilaner that was found to be acceptable by this reviewer”

“Abametapir was administered to juvenile rats orally for 8 weeks at oral doses of 0 (vehicle control; ), 5, 12, or 30 mg/kg/day beginning on PND 7 (70658).”

“In a perinatal and postnatal development study in rats, oral doses of 10, 25, and 75 mg/kg/day were administered from the beginning of organogenesis (gestation day 6) through the end of lactation (lactation day 20).”

“No carcinogenicity studies were included in this NDA submission. Abametapir lotion is intended as a single use drug product. Re-infestation would require a second application, but the product is not intended for chronic use.”

“In the 39-week study in dogs, no recovery phase was included.”

“No prenatal and postnatal development (PPND) toxicity studies were conducted with mavorixafor. However, given the difficulties to perform animal reproduction toxicity studies with human relevant exposure and based on the results from CXCR4/SDF-1 knock out mice which showed high peri-postnatal lethality and adverse effects on developmental, this was acceptable to the CHMP.”

“Postmarketing requirements for the conduct of rat and mouse carcinogenicity studies will be issued.”

“Study title/ number: A 13-Week (13-Cycle) Oral Gavage Toxicity and Toxicokinetic Study of KPT-330 in Sprague Dawley Rats with a 4-Week Recovery Period/ KNC-G-13-001”

“No carcinogenicity study was conducted, and only maternal and embryo-foetal development toxicity were carried out, indicating a NOAEL value at 0.25 mg/Kg/day for rats.”

“Carcinogenicity studies were not conducted to support the use of selinexor for the proposed indication.”

“Note testicular toxicity was only observed in the 9-month study where recovery was not assessed.”

“The FDA confirms that carcinogenicity studies were not conducted and not warranted for the proposed indication.”

“A 39-week oral toxicity study of RPC1063 with a 6-week recovery period in Cynomolgus monkeys”

“However, the available data demonstrate that ozanimod, administered to pregnant animals, has clear adverse effects on the developing organism, including teratogenicity, which are consistent with the critical role of the S1P1 and S1P5 receptors in embryogenesis (including vascular and neural development) and should discourage use during pregnancy. Therefore, I do not believe the sponsor needs to conduct such a study.”

“Adequate coverage for ozanimod and the three major metabolites was achieved in the 6-month carcinogenicity study conducted in mouse. In the 2-year carcinogenicity study conducted in rat, adequate exposure (> 50% exposure at the MRHD) to the parent, RP101124, and CC112273 was achieved”

“In 2- 4- and 13-week studies in rats, marmosets, and dogs, injection site findings included thrombus formation, accumulation of inflammatory cells, thickening of the vascular wall in the periphery of the dosing catheter, granulomas, edema/hemorrhage and/or necrosis of tissues around the catheter.”

“BAP00640/ Study for Effects of BAL5788 (Prodrug of BAL9141) on Pre- and Postnatal Development Including Maternal Function by Intravenous Infusion in Rats”

“No studies were available and none are warranted for this relatively short treatment duration.”

“A 52-Week Oral (Gavage) Toxicity and Toxicokinetic Study of SCH 66336 in Cynomolgus Monkeys/ Study No. 96036”

“A Pre- and Postnatal Developmental Toxicity and Maternal Function Study of SCH 66336 Administered Orally by Gavage in Rats / Study No. 96047”

“As agreed at the pre-IND meeting held on August 22, 2018 (PIND 139923), the Applicant will conduct a carcinogenicity study postapproval.”

“Ganaxolone: A 1-Year Oral Toxicity Study in Dogs”

“A full battery of reproductive and developmental toxicology studies was conducted for ganaxolone: fertility and early embryonic development (FEED) study in SD rat, embryofetal development (EFD) study in CD-1 mouse, and a combined EFD/pre- and postnatal development (PPND) study in SD rat.”

“Carcinogenicity studies in two species (26-week study in TgRasH2 mouse and 2-year study in rat) are to be conducted as post-marketing requirements (PMR)”

“A 28-Day Study of SAGE-547 by Intravenous Infusion in Beagle Dogs with a 28-Day Recovery Period”

“A Continuous Intravenous Infusion Pre and Postnatal Study of SAGE-547 in the Rat”

“Brexanolone was not assessed for carcinogenicity because the treatment of PPD with brexanolone infusion is considered acute.”

“An additional GLP study was conducted to evaluate the potential toxicity in dogs when zuranolone was administered at dose levels up to 2.5 mg/kg/day once daily for 273 days, including a 28-day recovery period.”

“Oral administration of zuranolone (0, 1, 4, or 10 mg/kg/day) to rats throughout pregnancy and into lactation resulted in increased perinatal mortality and persistent bodyweight reductions in the offspring at the mid and high doses”

“The carcinogenic potential of zuranolone was tested in a 6-month Tg.rasH2 transgenic mouse assay and in a 2-year rat carcinogenicity study. Both studies were adequately conducted and, according to the Food and Drug Administration (FDA) statistical analyses, negative for drug-induced tumors.”

“A 14-day non-good laboratory practice dose-range-finding toxicity study in juvenile rats and a 13-week good laboratory practice toxicity study in juvenile rats using CuHis have been conducted by the Applicant.”

“DART studies, including FEED, EFD, and PPND studies to evaluate the reproductive toxicity potential of CuHis in patients with MD can be waived as MD manifests predominantly in male infants.”

“The limited life expectancy associated with classical MD is consistent with the International Council for Harmonisation S1A guidance criteria for waiving the requirement for carcinogenicity studies.”