Which nonclinical studies did approved small molecules skip?

“Ferric maltol was mutagenic in vitro in bacterial reverse mutation (Ames) assays. Ferric maltol increased revertant frequency in the absence and presence of metabolic activation. Fertility studies have not been conducted with ferric maltol. Maltol was mutagenic in the Ames assay and increased micronuclei in an in vivo clastogenicity assay in mice.”

“Maltol was not carcinogenic in a 18-month study in mice at doses up to 400 mg/kg (approximately 5.6 times the human daily dose). Maltol was not carcinogenic in a 2-year study in rats at doses up to 400 mg/kg (approximately 11.2 times the human daily dose).”

“In a multi-generation animal reproduction study in male and female rats, there were no effects on mating, fertility, or early embryonic development at doses up to 400 mg/kg/day (approximately 11.2 times the human daily dose).”

“Difamilast was negative in a standard battery of genotoxicity tests, including the Ames test, the mouse lymphoma assay, and an in vivo micronucleus study in rats.”

“In 2-year dermal carcinogenicity studies in rats and mice, no test article-related neoplastic findings were observed in rats or mice that received difamilast at dermal doses up to 3% (3.7 to 10 times the MRHD based on AUC comparison).”

“In embryofetal development studies, fewer live fetuses, decreased fetal weight, retarded ossification, and increased membranous ventricular septum defect were noted in rats at the high dose of 100 mg/kg/day.”

“Vamorolone was negative in an adequately conducted battery of genotoxicity studies that consisted of an in vitro bacterial reverse mutation assay, an in vitro mammalian gene mutation assay in mouse lymphoma cells, and an in vivo micronucleus assay in mouse.”

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

“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”

“Vanzacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene variant, in vitro micronucleus assay in TK6 cells, and in vivo rat micronucleus assay.”

“In the case of VNZ, the studies consisted of a 6-month Tg.rasH2 transgenic mouse carcinogenicity study and a 2-year rat carcinogenicity study. VNZ did not demonstrate a carcinogenic potential at the doses evaluated in the Tg.rasH2 mouse up to 30mg/kg/day.”

“In animal embryo fetal development (EFD) studies, oral administration of vanzacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 30 times the exposure at the maximum recommended human dose (MRHD) in rats and 22 times the MRHD in rabbits.”

“Delgocitinib was not mutagenic in the Ames assay. Delgocitinib had the potential to induce polyploidy in human peripheral blood lymphocytes, but not chromosomal structural aberrations in vitro. Delgocitinib did not induce chromosomal aberrations (structural or numerical aberrations) in rat bone marrow cells in vivo.”

“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”

“Adverse effects were seen at higher doses in each of the reproductive and developmental toxicology studies, but a NOAEL was established in each study with acceptable margins of exposures.”

“Levacetylleucine was non-mutagenic in vitro (in bacterial cells) and non-clastogenic in vitro (in cultured human peripheral lymphocytes) and in vivo (in bone marrow cells of the CD rats).”

“We are requiring juvenile toxicity, fertility, and early embryonic development, pre- and postnatal development, and carcinogenicity studies to be conducted postapproval.”

“In pregnant rats, increases in resorptions, post-implantation loss, and skeletal malformation were seen due to exposure to levacetylleucine at doses of 600 mg/kg/day and at the human-equivalent dose of 97 mg/kg/day.”

“In studies conducted by the Applicant, artesunate was negative in the Ames test, mammalian chromosome aberration assay (CHO), and in vivo micronucleus assay (up to 500 mg/kg, highest concentration tested).”

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

“Oral administration of artesunate during organogenesis caused a significant increase in post-implantation loss in pregnant rats, rabbits and cynomolgus monkeys at significantly less than clinically relevant doses based on body surface area comparisons.”

“Acoramidis showed no mutagenic or clastogenic activity in a standard battery of genotoxicity studies, which included a bacterial reverse-mutation study and rat micronucleus and alkaline comet assays (Table 70).”

“A two-year oral carcinogenicity study in rats did not identify any carcinogenic potential at doses up to 50 mg/kg/day (males) or 350 mg/kg/day (females), doses producing exposures that approximated the clinical AUC or were 11-times the clinical AUC, respectively, at the MRHD. No acoramidis-related tumors were observed in a 26-week oral carcinogenicity study in Tg rasH2 mice.”

“Decreased body weight gain from the neonatal period to weaning and learning deficits were observed in the offspring of dams given 1,000 mg/kg/day. No adverse effects on pre- and postnatal development were observed at 350 mg/kg/day, approximately 18-times the clinical exposure at the MRHD based on AUC.”

“Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action. Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.”

“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”

“In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses ≥6 mg/kg, fetal malformations of malrotated hindlimbs and lower fetal body weights at doses ≥12 mg/kg”

“Defactinib was not mutagenic in the bacterial reverse mutagenesis (Ames) assay and was not clastogenic in an in vitro Chinese hamster lung cell chromosome aberration assay. Defactinib was positive in the in vitro micronucleus assay through an aneugenic mechanism and in the in vivo rat bone marrow micronucleus assay.”

“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.”

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

“Avapritinib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). Avapritinib was positive in the in vitro chromosome aberration test in human peripheral blood lymphocytes but negative in the in vivo rat bone marrow micronucleus test, and overall non-genotoxic.”

“Avapritinib was not mutagenic in a 6-month transgenic mouse study up to the highest dose evaluated at 20 mg/kg/day.”

“Daily oral administration of avapritinib to pregnant rats resulted in decreased fetal body weights, post-implantation loss, and increases in visceral (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) and skeletal (sternum) malformations at doses ≥ 10 mg/kg/day (a dose resulting in exposures approximately 2.7 times the exposure based on AUC at the 300 mg human dose).”

“Serdexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mammalian cell micronucleus assay using human peripheral blood lymphocytes, in the in vivo rat bone barrow micronucleus assay, or in the in vivo rat alkaline comet assay.”

“Carcinogenicity studies were not conducted with SDX. The Applicant is relying upon the carcinogenicity data in the referenced product labeling.”

“In the embryo-fetal development study in rabbits, there were no findings of maternal or fetal development toxicity at exposures up to 49 times (400 mg/kg) the MRHD.”

“Erdafitinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro micronucleus or an in vivo rat bone marrow micronucleus assay.”

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

“Doses ≥4 mg/kg/day (at total maternal exposures <0.1% of total human exposures at the maximum recommended human dose based on AUC) produced embryo-fetal death, major blood vessel malformations and other vascular anomalies, limb malformations (ectrodactyly, absent or misshapen long bones), an increased incidence of skeletal anomalies in multiple bones (vertebrae, sternebrae, ribs), and decreased fetal weight.”

“Amisulpride was negative in the Ames test, the in vitro mammalian chromosome aberration assay in human peripheral blood lymphocytes and the in vivo micronucleus assay in rats by oral gavage.”

“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.”

“Most female animals (90% to 95%) at each dose level remained in diestrus and failed to mate. However, this effect on mating reversed following cessation of treatment.”

“Baxdrostat was not genotoxic when tested in a battery of in vitro and in vivo assays.”

“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies. There was no evidence of carcinogenicity with oral doses up to 45 mg/kg/day in mice (264-fold), and up to 10 mg/kg/day in male rats (105-fold) and up to 3 mg/kg/day in female rats (62-fold).”

“In embryofetal development studies, reduced maternal body weight gain and fetal toxicities were observed in rats (adverse skeletal malformations of skull: mandible/zygomatic arch fusion) and rabbits (decrease in fetal body weight) at exposures >54-fold and >29-fold relative to the clinical exposures at the MRHD.”

“No genotoxic potential was identified in the standard battery of genotoxic toxicology, including in vitro Ames and chromosomal aberration assays, and in vivo bone marrow micronucleus assay in mice (Module 4.2.3.3).”

“No carcinogenicity studies were conducted. These studies were not required for an oncology drug intended for treatment of patients with severe or life-threatening malignancies per ICH S9 guidance.”

“Abnormalities included external, visceral, and skeletal malformations observed in the high dose group.”

“Gepotidacin was positive in an in vitro micronucleus test in human peripheral blood lymphocytes and in an L5178Y mouse lymphoma assay, consistent with the known in vitro clastogenic effects of topoisomerase inhibitors in in vitro mammalian cell assays. Gepotidacin was negative in an in vivo micronucleus test or Comet assay in rat.”

“Long term carcinogenicity studies have not been conducted with gepotidacin.”

“In embryo‑fetal development studies in mice and rats, decreased fetal weights and increased fetal mortality (late resorptions) were observed at exposures less than the maximum recommended human dose (MRHD). In a mouse pre- and postnatal development study, there were no adverse developmental effects at exposures approximately equal to the MRHD”

“Bexagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro CHO cell assay, an in vivo micronucleus assay in rats, and an in vivo unscheduled hepatic DNA synthesis study in rats.”

“The carcinogenic potential of bexagliflozin was evaluated in 2-year studies in Sprague-Dawley (SD) rats and CD-1 mice. There were no neoplastic findings in mice and rats up to the highest doses tested (150 mg/kg/day for mice and 30 mg/kg/day for rats, representing approximately 135 and 54 times the clinical dose of 20 mg based on AUC, respectively).”

“Bexagliflozin produced no adverse effects on fertility in rats, on embryofetal toxicity in rats or rabbits, or on pre- and postnatal development in rats at clinically relevant exposures.”

“Ibrexafungerp was negative for genotoxicity in both nonclinical in vitro assays (Ames assays and a chromosome aberration assay in mammalian cells) and in vivo studies (micronucleus study in rat bone marrow cells).”

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

“In pregnant rabbits, oral ibrexafungerp administered during organogenesis was associated with fetal malformations including absent forelimb(s), absent hindpaw, absent ear pinna, and thoracogastroschisis at dose exposures greater or equal to approximately 5 times the human exposure at the RHD.”

“Brensocatib was found to be negative for genotoxic potential in the in vitro bacterial reverse mutation (Ames) assay, an in vitro mouse lymphoma cell thymidine kinase locus assay, and in vivo micronucleus assay in rats.”

“No neoplastic findings were observed in a 6-month Tg Ras mouse study and a 104-week carcinogenicity study in rats up to the highest doses tested yielding AUC-based (unbound brensocatib fraction) safety margins of > 60-fold (mice) and > 50-fold (rat) to the MRHD.”

“Drug-related adverse skeletal malformation of bent scapula was observed in fetuses from pregnant dams administered 100 mg/kg/day brensocatib (4 of 110 fetuses, 3.7%).”

“Zanubrutinib was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in either the in vitro chromosomal aberrations assay or in the in vivo bone marrow micronucleus assay in rats.”

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

“In an embryo-fetal development study in female rats, once daily administration of zanubrutinib at 30, 75, or 150 mg/kg/day on GD 6-17 resulted in fetal heart malformations in the form of 2- or 3-chambered hearts.”

“Genetic toxicology battery for the API was negative in the Ames assay, mouse lymphoma assay, and in vivo rat micronucleus test.”

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

“Regardless of these adverse effects to the pregnant female, in surviving animals, remimazolam had no adverse effects on embryo-fetal development up to 30 mg/kg/day in rat”

“Odevixibat tested negative in the bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma cell forward mutation assay, and the in vivo rat micronucleus test.”

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

“No adverse findings were observed in the fertility study in male and female Wistar rats, the embryo-fetal development study in rats, or the juvenile toxicity study in rats. In an embryo-fetal development study in pregnant rabbits, fetuses from all maternal groups treated orally with odevixibat showed an increase in cardiovascular malformations”

“CAB was negative for mutagenesis and clastogenicity in the in vitro bacterial reverse mutation assay and the in vivo micronucleus assay in rats.”

“CAB has demonstrated a lack of carcinogenic potential in conventional oral 2-year studies in mouse and rats at doses corresponding 7 and 19-fold the clinical AUC exposure in patients.”

“In the pivotal rat PPND study, an increase in the number of F1 stillbirths and early postnatal deaths by PND 4 was observed at 1,000 mg/kg/dose (27.9× higher than human exposure at the proposed human dose).”

“Mavacamten was not genotoxic in a bacterial reverse mutation test (Ames test), a human in vitro lymphocyte clastogenicity assay, or a rat in vivo micronucleus assay.”

“There was no evidence of carcinogenicity seen in a 6-month rasH2 transgenic mouse study at mavacamten doses of up to 2.0 mg/kg/day in males and 3.0 mg/kg/day in females, or in a 2-year rat study at mavacamten doses up to 0.6 mg/kg/day.”

“Mavacamten was shown to be teratogenic in both rats and rabbits in embryo-fetal developmental studies. In rats, mavacamten increased post-implantation loss, lowered mean fetal body weight, slightly reduced fetal skeletal ossification, induced heart malformations (total situs inversus), and increased the incidence of skeletal malformations relative to control.”

“Lumateperone was positive for mutagenic potential in the Ames test in the presence of metabolic activation in the TA1537 tester strain and the mouse lymphoma test. Lumateperone was negative for clastogenic activity in the in vivo micronucleus assay in rats and was not genotoxic in the in vivo Comet assay in rats”

“Lifetime carcinogenicity studies were conducted in rats and mice, and results showed no carcinogenic potential in either species.”

“Oral administration of lumateperone to male and female rats adversely affected male and female fertility and caused estrus cycle irregularities at doses approximately equal to the MRHD of 42 mg lumateperone on a mg/m2 basis.”

“Etripamil was not genotoxic in a bacterial reverse mutation assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, and an in vivo micronucleus study in rats (IV administration).”

“Given the intermittent clinical dosing, lack of obvious pharmacology-based concerns, and the technical challenges for conducting long-term studies in rodents with the intended intranasal route of administration, rodent carcinogenicity studies are not warranted for the proposed clinical indication and dosing regimen.”

“In pregnant rats, intravenous administration of etripamil throughout the period of organogenesis did not result in any adverse effects on embryofetal development at doses up to 0.375 mg/kg/day, approximately 3x the C max and 0.4x the AUC at the MRHD.”

“Abrocitinib was not mutagenic in an in vitro reverse bacterial mutation assay. Abrocitinib was positive in an in vitro micronucleus assay and determined to be an aneugen in a follow-up study; however, it was not genotoxic in an in vivo micronucleus assay in rats.”

“At doses ≥10 mg/kg/day, abrocitinib significantly increased the incidence of benign thymoma in the thymus of female rats. No abrocitinib-related tumor findings were noted in males.”

“Abrocitinib increased the incidence of skeletal variations at doses ≥30 mg/kg/day, including the incidence of short 13th ribs, thickened ribs (HD only), and cervical arches with reduced ventral processes (HD only). Abrocitinib increased embryofetal lethality at the HD.”

“Xanomeline was not mutagenic or clastogenic in a battery of genetic toxicity tests. These tests included in vitro bacterial reverse mutation (Ames), mouse lymphoma TK, unscheduled DNA synthesis in rat hepatocytes, in vitro chromosome aberration in mammalian (CHO) cells and in vivo bone marrow micronucleus assay in mice.”

“Xanomeline did not increase the incidence of tumors in rats treated for 2 years via the diet at doses up to 37 mg/kg/day in males and 46/mg/kg/day in females, respectively, which is slightly higher than the xanomeline dose at the MRHD of 125 mg/30 mg xanomeline/trospium, BID, based on body surface area (BSA).”

“At these maternally toxic doses, embryofetal and developmental toxicities included decreased fetal and neonatal weight, stillborn pups, and/or neonatal deaths.”

“Trilaciclib was negative for mutagenic potential in the Ames assays and negative for clastogenic potential in primary human fibroblasts. Trilaciclib increased micronucleus formation in human peripheral blood lymphocytes in vitro, suggesting clastogenic activity.”

“Carcinogenic potential of trilaciclib has not been assessed in animals.”

“No fertility, developmental, or reproductive toxicity studies were conducted in animals.”

“Crinecerfont was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.”

“Crinecerfont did not show oncogenic effects in transgenic mice. In the 2-year rat study, crinecerfont increased the incidence of thyroid gland follicular cell adenoma and carcinoma in females at 100 mg/kg crinecerfont (4-fold MRHD exposure).”

“No developmental toxicity was observed in rats at 4-fold higher than human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC). Crinecerfont was associated with a low incidence of poly-malformations (craniofacial defects) in rabbits at 2-fold higher than human exposure at the MRHD.”

“Cipepofol was not genotoxic in a standard battery of genotoxicity assays, testing negative in an in vitro Ames assay, in the in vitro chromosomal aberration assay, and in the in vivo bone marrow micronucleus test in mice.”

“The carcinogenic potential of cipepofol has not been evaluated.”

“It appears that the significantly increased post-implantation loss was mainly driven by increased resorption. Similar, but not significant and not dose-dependent, effects were observed in the FEED study in rats with every other day IV dosing. The reproductive effects observed in the FEED studies are likely related to maternal hypoxia secondary to anesthesia.”

“Trofinetide was negative in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.”

“The nonclinical data submitted to the NDA support approval of trofinetide for the proposed indication, with appropriate labeling and post-marketing requirements for carcinogenicity studies in mouse and rat.”

“Embryofetal development studies were conducted in rat and rabbit. Trofinetide was administered orally during the period of organogenesis at doses of 0, 150, 450, and 1000 mg/kg BID (0, 300, 900, and 2000 mg/kg/day) to rats and at doses of 0, 75, 150, and 300 mg/kg BID (0, 150, 300, and 600 mg/kg/day) to rabbits. No adverse effects on embryofetal development were observed in either species.”

“Lemborexant was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or in the in vitro mouse lymphoma thymidine kinase assay, and was not clastogenic in the in vivo rat micronucleus assay.”

“Lemborexant did not increase the incidence of tumors in a 6-month carcinogenicity study in Tg ras H2 transgenic mice or in a 2-year study in rats and therefore is considered non-carcinogenic.”

“Reproductive and developmental toxicity was assessed in fertility studies in male and female rats, embryo-fetal development studies in pregnant rats and rabbits, and a pre- and post-natal development study in rats. Irregular estrous cycles and decreased pregnancy rates were observed in female rats at doses ≥100 mg/kg/day.”

“Although taurolidine is positive for genotoxicity in vitro regardless of metabolic activation (mouse lymphoma and Ames tests), it is negative in vivo.”

“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.”

“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.”

“Triheptanoin was not mutagenic in the Ames assay up to 4800 µg/plate, did not induce chromosomal aberration in vitro in human peripheral blood lymphocytes up to 409 µg/ml, and it was negative in the in vivo rat micronucleus assay at up to 2000 mg/kg/day.”

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

“Administration of dietary triheptanoin to pregnant rats at doses approximately 2 times above, and pregnant rabbits approximately equal to the targeted clinical dose of 35% DCI resulted in increased incidence of skeletal malformations and decreased litter weights in both species and reduced number of viable litters in rabbits.”

“Givinostat was positive in a bacterial reverse mutation (Ames) assay, and negative in an in vitro mammalian cell (mouse lymphoma) mutation assay, an in vitro chromosomal aberration assay in mammalian (human lymphocytes) cells, and an in vivo gene mutation assay (with Pig-a endpoints) in Big Blue transgenic rats.”

“The Applicant was therefore informed in a Type C meeting (May 11, 2020) that, due to the nature of the proposed indication (i.e., DMD), carcinogenicity studies for givinostat may be deferred until post approval.”

“In animal studies, oral administration of givinostat during organogenesis resulted in decreased fetal body weight and increased structural variations; oral administration during pregnancy and lactation resulted in increased embryofetal and offspring mortality and neurobehavioral changes in the offspring.”

“No genotoxic potential was noted for triclabendazole tested in a battery of 6 genotoxicity in vitro and in vivo assays which include a bacterial reverse mutation assay, chromosome aberration assays, and a micronucleus assay.”

“Orally administered TCBZ did not have effects on fertility in rats. Oral administration of TCBZ was not embryotoxic in rats and rabbits up to 200 and 20 mg/kg/day, which is 1.6 and 0.3 times the clinical dose respectively, based on a body surface area comparison.”

“Sebetralstat was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation assay (Ames test), in vitro chromosomal aberration assay in mouse lymphoma cells, and in vivo rat micronucleus assay.”

“A statement regarding carcinogenicity has been implemented in SmPC in section 5.3. to reflect the lack of carcinogenicity based on a 26-week study in rasH2-Tg transgenic mice and a 104-week study in rats.”

“In an embryo-fetal development (EFD) study in pregnant rats, administration of sebetralstat during the period of organogenesis caused increased incidence of malformations in offspring, specifically cleft palate and incomplete interventricular septum of the heart, at 60 times the exposure at the maximum recommended human dose (MRHD) of 1,200 mg sebetralstat.”

“Ensartinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human lymphocyte chromosome aberration assay or an in vivo rat bone marrow micronucleus assay.”

“Carcinogenicity studies were not conducted or needed to support the use of ensartinib in the currently proposed indication per International Council for Harmonisation (ICH) S9.”

“Oral administration of ensartinib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural abnormalities. Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC”

“RIS was negative for mutagenicity in an in vitro Ames test but positive for clastogenicity (micronucleus (MN) formation) in vitro in mouse lymphoma cells and in vivo in a combined bone marrow micronucleus and comet assay in rat.”

“A 6-month carcinogenicity study in Tg.rasH2 mice showed no tumorigenic effects at oral doses up to 9 mg/kg/day”

“Embryofetal mortality (increased number of late resorptions) and increased incidences of fetal malformations (hydrocephaly) and variations were seen in the rabbit embryofetal development study at the HD (12 mg/kg), which was also maternally toxic.”

“Enmetazobactam was negative for genetic toxicity in vitro in a bacterial reverse mutation assay and a chromosomal aberration assay in Chinese Hamster ovary cells, and in vivo in a mouse micronucleus assay in bone marrow cells.”

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

“In embryo-fetal development (EFD) studies in rats and rabbits, enmetazobactam was not associated with fetal malformations, but did cause maternal toxicity in the form of reduced body weight gain and fetal toxicity as reduced fetal body weights in both studies.”

“Mobocertinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. Mobocertinib was not clastogenic in an in vivo bone marrow micronucleus test in rats.”

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

“Mobocertinib induced embryo-fetal mortality due to post-implantation loss (early resorptions) as well as decreased fetal weight at 10 mg/kg (approximately 1.7 times the exposure based on AUC at the human dose of 160 mg).”

“Gepirone HCl tested negative in 4 genotoxicity assays (Ames, in vivo rat micronucleus, hepatocyte DNA repair, and CHO/HGPRT mammalian gene mutation assays) and in a chromosome aberrations assay conducted in CHO cells with 5 hours treatment.”

“This reviewer agreed with the Sponsor that there were no gepirone-related tumors evident in either rats or mice up to maximum tolerated doses (MTD); concurrence by the Executive-CAC was given on January 8, 2002.”

“In embryo/fetal development studies, oral administration of gepirone to pregnant rats (75, 150, and 300 mg/kg/day) or pregnant rabbits (50, 100, and 200 mg/kg/day) during the period of organogenesis resulted in decreased embryo/fetal body weights and lengths, with accompanying skeletal variations, at the mid and high doses.”

“Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays.”

“Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential.”

“In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures 4- to 6-times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily did not induce embryo or fetal toxicity (see Data) .”

“non-mutagenic in Ames test, increased chromosomal aberrations in vitro but not considered clastogenic in the in vivo rat micronucleus assay and did not induce DNA damage in the Comet assay in rat hepatocytes”

“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).”

“Cefiderocol did not cause developmental toxicity in mice when administered to dams at daily subcutaneous doses up to 2000 mg/kg/day (twice daily 1000 mg/kg doses) from GD 6-15. It did not cause developmental toxicity in rats when administered intravenously to dams at doses up to 1000 mg/kg/day from GD 6-17.”

“Fexinidazole was mutagenic (positive in strains TA98, TA100, and TA1535 in the presence and absence of S9 and TA1537, and TA102 in the presence of S9) but was negative in the in vitro micronucleus assays in cultured human peripheral blood lymphocytes up to 180 µg/mL (+/-S9), and the in vivo micronucleus assay in the bone marrow of treated mice (2 oral doses up to 2000 mg/kg).”

“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.”

“Delayed ossification-reduced fetal weights and reduced placental weights were observed at 800 mg/kg in the presence of maternal toxicity (reduced maternal body weights).”

“There was no evidence of mutagenicity or clastogenicity for sparsentan in in vitro bacteria reverse mutation and chromosomal aberration assays or in an in vivo rat micronucleus study.”

“In the 2-year rat carcinogenicity study, there was no evidence of an increased incidence of neoplasia in male rats orally administered 15 mg/kg/day (dose limited by tolerability) and in female rats orally administered up to 240 mg/kg/day, which provides an exposure approximately 0.7 times and 26 times the AUC at the MRHD, respectively.”

“In pregnant rats treated with sparsentan at doses of 80, 160, and 240 mg/kg/day, dose-dependent toxicity and teratogenicity marked by craniofacial malformations, skeletal abnormalities, embryo-fetal lethality, and reduced fetal weight were observed at all doses.”

“Tivozanib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro cytogenetic assay in Chinese hamster ovary cells or in an in vivo mouse bone marrow micronucleus assay.”

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

“In animal studies assessing mating and fertility parameters, oral doses ≥ 0.03 mg/kg/day (0.2 times the maximum recommended clinical dose on a mg/m 2 basis) in rats were associated with increased epididymis and testis weights, and doses ≥ 0.3 mg/kg/day (2 times the maximum recommended clinical dose on a mg/m 2 basis) reduced mating and produced infertility.”

“Orforglipron was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro micronucleus test in human lymphoblastoid cells, or in an in vivo bone marrow micronucleus study in rats.”

“FDA concurs with the Applicant that orforglipron was not carcinogenic in a lifetime study in rats and a 6-month study in rasH2 transgenic mice.”

“In a rabbit embryofetal development study, orforglipron caused off-target embryofetal effects which included decreased fetal and placental weights and malformations at exposures 14x the MRHD.”

“Fruquintinib was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster ovary (CHO) cells. The in vivo bone marrow micronucleus assay in rats was negative.”

“Carcinogenicity studies were not performed and are not required for pharmaceuticals intended for the treatment of advanced cancer (ICH S9).”

“In an embryo-fetal developmental study in pregnant rats, oral administration of fruquintinib during the period of organogenesis resulted in teratogenicity and embryo lethality at exposures below the clinical exposure (see Data ) .”

“Pralsetinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro micronucleus assay in TK6 cells or the in vivo bone marrow micronucleus assay in rats.”

“The Applicant did not conduct carcinogenicity or fertility 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.”

“In the EFD study, multiple visceral and skeletal malformations were observed, as well as developmental variation, even from the lowest dose level of 5 mg/kg/day. 100% post implantation loss was seen at 20 mg/kg/day and above.”

“Vibegron was not mutagenic in in vitro microbial reverse mutation (Ames) assays, showed no genotoxic activity in an in vitro human peripheral blood lymphocyte chromosomal aberration assay, and did not increase the frequency of micronucleated polychromatic erythrocytes in an in vivo rat bone marrow micronucleus assay.”

“Two year carcinogenicity studies were also conducted in mice and rats, with no treatment-related malignancies observed in either species at adequate exposure margins”

“No embryo-fetal developmental toxicity was observed in rats at doses up to 300 mg/kg/day (1867-fold the AUC at the clinical dose) or in rabbits at doses up to 100 mg/kg/day (285-fold the AUC at the clinical dose).”

“Mirdametinib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow chromosomal aberration assay. Mirdametinib was positive in the in vivo micronucleus assay in rats.”

“Mirdametinib was not carcinogenic in a 6-month study in transgenic rasH2 mice that received oral doses up to 5 mg/kg/day”

“In the dose-range finding embryo-foetal development studies, embryofoetal lethality was observed from the non-maternotoxic dose levels of 0.64 and 0.3 mg/kg/day in rats and rabbits, respectively.”

“Treosulfan was mutagenic in the in vitro bacterial mutagenicity assay (Ames test) and clastogenic in the in vitro micronucleus assay in human lymphocytes.”

“Dedicated carcinogenicity or fertility studies were not conducted with treosulfan, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”

“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).”

“Zongertinib was negative for genotoxicity in the following studies: an in vitro bacterial reverse mutation (Ames) assay in the presence or absence of microsomal (S9) mix, and an in vivo peripheral blood micronucleus test coupled with comet assays conducted in hepatic and duodenal tissue isolated from male rats”

“Consistent with the principles discussed in the ICH S9 guidance, carcinogenicity studies are not expected for development of a drug intended for the treatment of patients with advanced cancer.”

“Zongertinib caused delayed development of the urinary system and kidney hydronephrosis at 60 mg/kg/day (approximately 19 times the human exposure based on AUC at the recommended dose).”

“Sevabertinib was not genotoxic in a bacterial reverse mutation (Ames) and an in vitro micronucleus assay, or an in vivo micronucleus assay in rats.”

“Carcinogenicity studies were not conducted for sevabertinib and are not warranted for the proposed indication.”

“Sevabertinib treatment resulted in maternal toxicity (reduced body weight and body weight gain) and a reduction in fetal weights at ≥6 mg/kg/day (≥0.18 times the human exposure based on AUC at the clinical dose).”

“Tenapanor was negative in the Ames test, the in vitro mammalian chromosome aberration assay in human peripheral blood lymphocytes, and the in vivo micronucleus assay in mice following oral and IV administration in rats.”

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

“There were no tenapanor-related effects on female or male fertility at doses up to 50 mg/kg/day in female mice and up to 10 mg/kg/day in male rats. In an embryofetal developmental study in rats, tenapanor was administered orally at dose levels of 1, 10 and 30 mg/kg/day from Gestation Days 6 through 17. Dose levels of 10 and 30 mg/kg/day were not tolerated”

“Taletrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and additional mutagenicity tests. Taletrectinib was not clastogenic or aneugenic in the in vivo micronucleus study in rats in bone marrow and liver.”

“Carcinogenicity studies have not been conducted with taletrectinib and are not warranted for the proposed indication.”

“In animal reproduction studies, oral administration of taletrectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal mortalities and structural abnormalities at exposures that were below or equal to the human exposure based on AUC at the recommended dose”

“While ISL induced chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, this effect was mitigated by the addition of inosine, suggesting it may be related to a perturbation of nucleoside/nucleotide pools rather than direct DNA interaction. Negative results in both a bacterial reverse mutation (Ames) test and an in vivo rat micronucleus assay support this interpretation.”

“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.”

“ISL had no effect on the fertility of male or female rats at exposures ~1000 times the human exposure at the RHD. In rats, skeletal malformations were noted only at very high exposures (~5100 times the exposure at the RHD), with a developmental no-observed-effect level (NOEL) established at exposures ~500 times the human exposure at the RHD.”

“Imlunestrant was not mutagenic in the Ames bacterial reverse mutation assay. Imlunestrant produced chromosomal damage in the in vitro micronucleus assay but did not cause chromosomal damage or DNA strand breaks in vivo when tested up to 2000 mg/kg in the rat comet and bone marrow micronucleus assays.”

“Carcinogenicity studies have not been conducted to support the advanced cancer indication for imlunestrant but are ongoing to support other indications.”

“resulted in embryo-fetal mortality at ≥ 0.3 mg/kg and structural abnormalities at ≥ 3 mg/kg at maternal exposures that were below the human AUC0-24 at the recommended dose.”

“A standard battery of GLP genetic toxicology studies including an in vitro bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration test in CHO cells, and an in vivo rat bone marrow micronucleus assay were completed with sotagliflozin. Sotagliflozin was neither mutagenic nor clastogenic in the three valid assays.”

“Sotagliflozin did not cause any treatment-related, statistically significant neoplasms in transgenic RasH2 (Tg.RasH2) mice or the rat in either sex.”

“Sotagliflozin was not teratogenic in the rat at 100 mg/kg (40X MHRD) or in the rabbit at 200 mg/kg (9X MHRD). In rats, a higher dose (350 mg/kg; 161X MHRD) caused both maternal and fetal toxicity including significant reduction in maternal weight gain, embryo-lethality, reduced fetal weights, altered sex ratio, and cardiovascular and skeletal malformations.”

“Cedazuridine was mutagenic in the Ames assay and genotoxic in the in vitro chromosome aberration assay, but not genotoxic in the in vivo micronucleus assay.”

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

“per ICH S9, reproductive and developmental toxicity studies are not needed for this class of drugs. These drugs are expected to cause malformation or embryofetal lethality.”

“Fedratinib was not mutagenic in a bacterial reverse mutation (Ames) assay, or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or in vivo in a micronucleus test in rats.”

“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.”

“There were no remarkable fedratinib‐related effects in the FEED study. In the EFD study in rats, fedratinib was maternally toxic at the middle and high dose levels with lower gestational body weight gain and decreased gravid uterine weights.”

“Elafibranor was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vivo rat micronucleus assay, and the in vivo comet assay in rats. Elafibranor was positive for mutagenicity in L5178Y tk+/- mouse lymphoma cells.”

“The liver tumors in mice and rats may be attributed to the expected rodent-specific PPARα-related liver toxicity and its related consequences. Therefore, the relevance to humans is uncertain.”

“Treatment of pregnant rats with elafibranor during organogenesis through lactation resulted in stillbirths, reduced survival, decrease in pup body weight, and/or blue/black discoloration of the caudal section of body, which occurred at maternal plasma drug exposures lower than or approximately equal to human exposure at the recommended dose”

“Although the Ames and micronucleus assays were negative for the induction of genetic toxicity, there was an increase in structural abnormalities in the chromosome aberration assay.”

“Although the Sponsor did not definitively identify the MOA for tumor development in rodents, the overall weight of evidence indicates that the rodent liver neoplasms were most likely mediated by rodent-specific CAR activation which is not relevant in humans.”

“Embryofetal development studies revealed increased fetal resorptions and altered morphological development in rats and rabbits at exposures greater than 100-fold and 7-fold, respectively, the exposure at the MRHD.”

“Inavolisib was not mutagenic in the bacterial reverse mutation (Ames) assay. Inavolisib was clastogenic in an in vitro human lymphocyte micronucleus assay. Inavolisib was not genotoxic in an in vivo rat bone marrow micronucleus test and did not induce DNA break in a liver comet assay.”

“Carcinogenicity studies were not conducted, nor warranted, with inavolisib to support the proposed indication in patients with advanced cancer in accordance with ICH S9 guidance.”

“Administration of inavolisib resulted in dose dependent effects on embryo-fetal development at ≥2 mg/kg ( ≥ 0.9 times the human exposure at the recommended dose of 9 mg/day based on AUC) that included decreases in fetal body weight and placental weight, post-implantation loss, lower fetal viability, fetal malformations”

“Nerandomilast was negative for mutagenic and clastogenic potential in a complete battery of genotoxicity assays (e.g., in vitro Ames assay, in vitro chromosome aberration assay, and an in vivo mammalian micronucleus assay).”

“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.”

“Embryofoetal lethality in the form of prenatal embryo-foetal loss (post-implantation loss due to early resorptions) was observed in rats at 6 mg/kg/day (5-fold human AUC exposure at the MRHD) but was not observed in rats at 3 mg/kg/day (3-fold human AUC exposure at the MRHD) or in rabbits at 15 mg/kg/day (4-fold human AUC, unbound exposure at the MRHD).”

“Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay. Pirtobrutinib was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes. Pirtobrutinib was not genotoxic in an in vivo rat bone marrow micronucleus assay at doses up to 2000 mg/kg.”

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

“Doses ≥ 375 mg/kg twice daily caused decreased fetal body weights and increased incidence of malformations and variations in the urinary tract (including absent or abnormal ureters and kidneys), reproductive tract (malpositioned ovaries and misshapen uterus), and bone (misshapen sternebrae).”

“Daprodustat was negative for mutagenic or clastogenic potential in the in vitro bacterial reverse mutation assay, the in vitro human lymphocyte chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.”

“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 (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”

“Daprodustat administered orally to pregnant rats and rabbits during the period of organogenesis was associated with adverse fetal outcomes, including embryonic and fetal loss and reduced fetal weight, at doses that caused maternal toxicity and polycythemia ( see Data ).”

“Zidesamtinib was genotoxic in the in vivo rat micronucleus assays. Zidesamtinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro assay in human lymphoblastoid TK6 cells.”

“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.”

“There was 100% post-implantation loss at ≥8 mg/kg/day (approximately 3.5 times the human exposure based on AUC at the recommended dose).”

“Leniolisib was not genotoxic in the in vitro Ames assay, in vitro chromosomal aberration assay in human lymphocytes, or micronucleus assays in TK6 cells ( in vitro ) and rats ( in vivo ).”

“Leniolisib was not carcinogenic in the 6-month carcinogenicity study in Tg.rasH2 transgenic mice at doses up to 80 mg/kg/day.”

“In animal reproduction studies, oral administration of leniolisib to pregnant rats and rabbits during the period of organogenesis at exposures approximately 2-6 times the MRHD on an AUC basis, produced embryofetal toxicity including malformations ( see Data ).”

“Suzetrigine was not mutagenic in the bacterial reverse mutation assay (Ames test), or clastogenic in the in vitro micronucleus assay with a human TK6 lymphoblastoid cell line, or in the in vivo rat bone marrow micronucleus assay.”

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

“SUZ doses up to 1000 mg/kg did not affect male reproductive performance when administered at least 28 days before mating and throughout mating. In a female fertility study in rats, increased preimplantation loss was observed at oral SUZ doses of 15 mg/kg when administered prior to mating and through gestation day (GD) 7.”

“Finerenone was also negative in the in vitro chromosomal aberration assay in mammalian cells and in the in vivo mouse micronucleus test.”

“Two-year carcinogenicity studies conducted in mice and rats showed no significant increase in neoplasms in males or females in either study; the CDER Exec CAC concurred with this conclusion.”

“In the embryo-fetal toxicity study in rats, finerenone resulted in reduced placental weights and signs of fetal toxicity, including reduced fetal weights and retarded ossification at the maternal toxic dose of 10 mg/kg/day, corresponding to an AUC unbound of 19 times that in humans.”

“Tirbanibulin was negative in an in vitro bacterial reverse mutation (Ames) assay. Tirbanibulin was positive in an in vitro chromosomal aberration assay with Chinese hamster ovary (CHO) cells, an in vitro mouse lymphoma assay with L5178/TK +/- cells, and an in vivo micronucleus assay in rats.”

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

“Tirbanibulin induced fetal deaths and external, visceral, and skeletal malformations when administered orally to pregnant rats during the period of organogenesis at doses greater than or equal to 1.25 mg/kg/day,”

“Ziftomenib was not mutagenic in an in vitro bacterial reverse mutation assay and was not genotoxic in an in vitro micronucleus assay or in an in vivo mouse bone marrow micronucleus assay.”

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

“External malformations were elevated in the high-dose group fetuses and composed of cleft palates. Skeletal malformations were observed in all test article dose groups, notably in the ribs, skull, and vertebra.”

“Selumetinib was not mutagenic or clastogenic in vitro . Selumetinib did result in an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action, but at doses > 160 mg/kg (~38-times the human C max at the clinical dose of 25 mg/m 2 ).”

“Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m 2 .”

“In embryo-fetal development studies in mice at doses > 2.5 mg/kg twice daily (~5-times the human exposure based on area under the curve [AUC] at the clinical dose of 25 mg/m 2 twice daily), selumetinib caused increases in post-implantation loss, a reduction in mean fetal and litter weights, and an increased occurrence of open eye and cleft palate”

“Adagrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not genotoxic in an in vitro chromosomal aberration assay or an in vivo micronucleus assay in rats.”

“Dedicated carcinogenicity studies were not conducted with adagrasib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”

“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.”

“Doxecitine and doxribtimine were not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vivo rat micronucleus assay. However, doxecitine and doxribtimine induced a statistically significant, dose-dependent increase in chromosomal aberrations in human peripheral blood lymphocytes in the absence of metabolic activation.”

“To address the remaining nonclinical data gaps, the Applicant will conduct the following postapproval studies: a 9-month dog study and a 26-week carcinogenicity study in Tg-rasH2 mice with doxecitine and doxribtimine”

“In embryofetal development studies, oral administration of doxecitine and doxribtimine to pregnant rats and rabbits during organogenesis resulted in maternal toxicity (decreased body weight gain and food consumption) and fetal malformations (dilated aorta with narrow pulmonary trunk) in the rabbit at 2000 mg/kg/day.”

“Based on the weight of evidence from these studies, nifurtimox is considered to be genotoxic and the product label for Lampit will include a Warning for genotoxicity.”

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

“In preliminary embryo-fetal studies in rats and mice and a comprehensive study in rabbits, nifurtimox produced dose-related maternal and/or fetal toxicity in all test species as well as a fetal malformation in rabbits.”

“Lazertinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro chromosome aberration assay in Chinese hamster lung cells or the in vivo bone marrow micronucleus assay in rats.”

“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.”

“There was an increase in the incidence of skeletal malformations in the vertebra and skull (fused maxillary process/zygomatic arch), and unossified hyoid skull (skeletal variation) at 45 mg/kg compared to controls.”

“In genotoxicity studies, deuruxolitinib was negative in the Ames test, an in vitro chromosome aberration assay, and an in vivo rat bone marrow micronucleus assay. It was positive in an in vitro micronucleus assay.”

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

“In an embryo-fetal toxicity study in rats, lower fetal weight and increased skeletal malformations were noted at 60 mg/kg/day, with no significant maternal toxicity observed.”

“Relacorilant was not genotoxic in the bacterial reverse mutation (Ames) assay, an in vitro human lymphocyte micronucleus assay, or an in vivo micronucleus assay in rats.”

“Per the review by Dr. Feleke Eshete in DPT-CHEN and discussion by the Executive Carcinogenicity Assessment Committee, there was no evidence of drug-related neoplasms in rats in the 2-year study or in mice in the 26-week study.”

“In animal embryo-fetal development studies, oral administration of relacorilant to pregnant rabbits during the period of organogenesis resulted in embryo-fetal mortality and structural abnormalities at maternal doses of ≥ 10 mg/kg/day (0.6 times the human exposure based on area under the curve (AUC) at the recommended dose).”

“Ritlecitinib was aneugenic in vitro, as determined by an in vitro micronucleus assay in TK6 cells and follow-up in vitro mechanism experiments. However, ritlecitinib was not mutagenic in a reverse mutation assay in bacterial cells.”

“In a 2-year rat carcinogenicity study, ritlecitinib increased the incidence of combined benign and malignant thymomas in female rats, and thyroid follicular adenomas and combined follicular adenomas and carcinomas in male rats at 100 mg/kg/day (29 times the MRHD based on AUC comparison). No ritlecitinib-related tumors were noted at doses up to 30 mg/kg/day (6.3 times the MRHD based on AUC comparison).”

“In an embryo-fetal development study in pregnant rats, oral administration of ritlecitinib from gestation days 6 to 17 decreased fetal body weights and caused fetal skeletal malformations (malformed vertebrae and ribs) and variations (delayed ossification) at doses ≥175 mg/kg/day (49 times the MRHD based on AUC comparison).”

“Genetic toxicology studies showed that seladelpar was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma assay, and the in vivo mouse micronucleus test.”

“In a 2-year study in mice, oral administration of seladelpar produced hepatocellular adenoma or carcinoma at 6 times the human exposure (AUC at the recommended dose) in males and at 140 times the human exposure in females.”

“Seladelpar had no effects on fertility or reproductive function in male rats at up to 271 times the human exposure (AUC) at the recommended dose or in female rats at up to 115 times the human exposure.”

“Maralixibat was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using Chinese hamster ovary cells, or the in vivo rat micronucleus assay.”

“Maralixibat chloride was not tumorigenic in a 2-year oral carcinogenicity study in rats with administration of up to 100 mg/kg/day (approximately 233 to 870 times the maximum recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice with doses of up to 25 (males) or 75 (females) mg/kg/day, no drug-related tumors were observed”

“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. Two juvenile animal toxicity studies were performed in rats. No adverse findings were observed in the reproductive and developmental toxicology studies.”

“Although maribavir demonstrated mutagenic potential in the absence of metabolic activation in the mouse lymphoma assay, given the negative results of the in vivo rat micronucleus assay and the negative bacterial mutation assay, the weight of evidence indicates that maribavir does not exhibit genotoxic potential.”

“Maribavir was not carcinogenic in rats at any dose tested, corresponding to maribavir exposures less than human exposure at the RHD. At 150 mg/kg/day in male mice only, an increased incidence of hemangiosarcoma and combined hemangioma/ hemangiosarcoma was observed across multiple tissues at exposures less than the human exposure at the RHD.”

“A decrease in the number of viable fetuses, and increase in early resorptions and post-implantation losses were observed at ≥100 mg/kg/day (at exposures approximately half the human exposure at the RHD).”

“Though both sotorasib and the M24 metabolite showed some potential for induction of micronuclei in vitro, neither was mutagenic in in vitro bacterial reverse mutation (Ames) assays and sotorasib was not genotoxic in the in vivo erythrocyte micronucleus test and alkaline comet assay in rats.”

“The Applicant did not conduct carcinogenicity or fertility 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.”

“In rat and rabbit embryo-fetal development studies, oral sotorasib did not cause adverse developmental effects or embryo-lethality at exposures up to 4.6 times the human exposure at the 960 mg clinical dose”

“Mix-ISA247 (approximately 50: 50 cis-trans mixture) was negative for genetic toxicity in the in vitro bacteria reverse mutation assay (Ames) test, a chromosomal aberration test with CHO cells, and an in vivo micronucleus assay in rats after single oral doses up to 2000 mg/kg.”

“Two-year studies were conducted in rats and mice. In the rat study, there were no voclosporin-related neoplasms in either males or females. In the mouse study, females had a significant increase in voclosporin-related malignant lymphomas at the high dose of 30 mg/kg/day”

“Mix-ISA247 caused a decrease in litter size and numbers of viable pups and an increase in resorptions (both early and late) at 25 mg/kg/day in the embryofetal development study in rats.”

“SAM was negative in a complete and adequate battery of genetic toxicology assays.”

“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.”

“SAM administration to pregnant rats during the period of organogenesis resulted in decreased fetal weights, increased skeletal variations, and a slight increase in total malformations at doses that were maternally toxic and greater than 248 times the MRHD based on AUC.”

“Linerixibat did not cause gene mutation or chromosomal damage in a bacterial mutagenicity assay (Ames test), a chromosomal aberration assay using Chinese hamster ovary cells, or an in vivo rat bone marrow micronucleus assay”

“Linerixibat was not tumorigenic in a 2-year oral carcinogenicity study in rats with oral administration of up to 1,000 mg/kg/day (approximately 3,900 times the recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice, no drug-related tumors were observed following administration of linerixibat up to 160 mg/kg/day.”

“Reproductive and developmental toxicology studies using oral administration of linerixibat 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.”

“Elinzanetant showed no genotoxic potential in bacterial mutation assay (Ames test), mouse lymphoma assay, and in vivo bone marrow micronucleus test in rats.”

“In a 2-year carcinogenicity study in female rats, oral doses of elinzanetant ≥60 mg/kg/day (29-fold the total AUC(0-24) at the human therapeutic dose) increased the incidence of endometrial adenocarcinoma, the combination of malignant and benign endometrial tumors and squamous cell carcinoma of the uterus, and lymphomas of the hematolymphoid system.”

“Based on findings from animal reproduction studies, elinzanetant may cause pregnancy loss or stillbirth when administered during pregnancy. Fetal malformations were not observed in these animal studies.”

“Futibatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Futibatinib was clastogenic in an in vitro chromosomal aberration assay after a 6 hour treatment. Futibatinib was not clastogenic in a rat bone marrow micronucleus assay or a rat DNA damaging (comet) assay.”

“Carcinogenicity studies have not been conducted with futibatinib and are not recommended for the proposed indication.”

“Fetal survival was unaffected at 0.5 mg/kg per day; however, once daily oral administration of futibatinib at the 0.5 mg/kg dose level (approximately 0.2 times the recommended clinical dose of 20 mg based on BSA) resulted in reduced mean fetal body weight and an increase in fetal skeletal and visceral malformations, major blood vessel variations, and reduced ossification.”

“In genetic toxicology studies, siponimod was negative in the in vitro reverse mutation assay in bacterial cell (Ames) and mammalian cell assays and in in vivo clastogenicity assays (micronucleus) in mouse and rat.”

“The carcinogenicity study in mouse was adequate and positive for malignant lymphoma in F at all doses and for hemangiosarcoma and combined hemangioma and hemangiosarcoma in M and F at all doses. The carcinogenicity study in rat was adequate and positive for thyroid follicular cell adenoma and combined follicular cell adenoma and carcinoma in HDM.”

“In the reproductive and development studies, oral siponimod was teratogenic in rats and lethal to fetuses in both rats and rabbits, without a clear NOAEL for fetal toxicity in rats (<1 mg/kg/day) and a NOAEL of 0.1 mg/kg/day in rabbit.”

“Perfluorohexyloctane was not mutagenic or clastogenic in a standard battery of genotoxicity tests, including a bacterial mutagenicity assay (Ames assay), an in vitro chromosome aberration assay using human peripheral lymphocytes, and an in vivo bone marrow micronucleus assay in rats.”

“Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of perfluorohexyloctane.”

“no adverse maternal or developmental effects were observed in rats at doses up to 162 times the recommended human ophthalmic dose (RHOD) ( see Data ). Maternal toxicity, miscarriages and reduced fetal weights were observed in rabbits at all doses tested, with the lowest dose as 41 times the RHOD.”

“Arimoclomol was not genotoxic in the Ames assay at up to 5,000 µg/plate, was not mutagenic in the mouse forward mutation assay at up to 1,000 µg/ml, or in the in vivo mouse micronucleus assay at doses up to 2,500 mg/kg/day.”

“In a 2-year carcinogenicity study in Han Wistar rats, and a 26-week carcinogenicity study in Transgenic rasH2 mice, oral administration of arimoclomol did not increase the incidence of tumors at systemic exposures that were approximately 8-fold and 11-fold the human exposure, based on AUC at the MRHD.”

“In fertility and early embryonic development study (FEED) in rats, an arimoclomol dose of 1,000 mg/kg/day reduced fertility and the fecundity index in male and female rats, resulted in reduction in the number of corpora lutea, and increased pre-implantation loss in female rats. The NOAEL for the fertility study in rats is considered to be 750 mg/kg/day, which is equivalent to a 4-fold safety margin for the 600 mg/day clinical dose.”

“Dordaviprone was negative for mutagenicity in the Ames test and negative for clastogenicity in both the in vitro and in vivo micronucleus tests.”

“Carcinogenicity studies have not been conducted with dordaviprone and are not warranted for the proposed indication.”

“In animal embryo-fetal development studies, oral administration of dordaviprone to pregnant rats and rabbits during the period of organogenesis caused embryofetal mortality, alterations to growth, and structural abnormalities at exposures below the human exposure at the highest recommended dose”

“Aficamten was not mutagenic or clastogenic in a standard battery of genotoxicity studies including the Ames assay and a combined in vivo micronucleus assay and comet assay.”

“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 at doses up to 3 mg/kg/day (corresponding to 4-times the exposure at the MRHD based on AUCunbound).”

“A rat embryofetal development (EFD) study demonstrated an increase in external malformations (kinked tail) at aficamten exposures higher than clinical exposures at the MRHD.”

“Tradipitant was negative in a complete battery of genetic toxicity studies, including the Ames assay, an in vitro chromosomal aberration assay in human lymphocytes, and an in vivo micronucleus assay in mice.”

“In transgenic rasH2 mice orally administered tradipitant (15, 50, or 1500 mg/kg/day) for 26 weeks, there was no increase in tumors. In rats orally administered tradipitant (10, 30, or 150 mg/kg/day) for at least 104 weeks, a dose- related increase in the incidence of thyroid follicular cell tumors (adenomas or adenomas combined with carcinomas), correlating with the findings of thyroid masses and cysts, was observed at all tested doses”

“No effects on fertility, maternal health, or embryo-fetal development were observed in rats treated with tradipitant during the periods of mating and organogenesis at doses up to 1000 mg/kg/day (57-fold the maximum clinical dose, based on HED; 2.2-fold based on AUC).”

“Bempedoic acid was not mutagenic in the Ames test. Increases in chromosome aberration were observed in human peripheral blood lymphocytes in vitro, but only in the presence of S9 and at a concentration associated with a level of cytotoxicity that approached or exceeded the maximum permissible.”

“In the 2-year rat carcinogenicity study, the incidences of hepatocellular adenomas, hepatocellular adenomas combined with carcinomas, thyroid follicular cell adenomas, follicular cell adenomas combined with carcinomas, and pancreas islet cell adenomas combined with carcinomas were statistical increased in male rats at 30 mg/kg/day.”

“The low safety margins identified from fertility, embryo-fetal and pre-and postnatal development studies conducted in rat (Table 47) are considered acceptable, because the adverse effects were only observed at maternally toxic doses.”

“Weight of evidence indicates that E4 is not considered genotoxic in a full battery of in vitro and in vivo assays (Ames assay, in vitro mouse lymphoma assay, an in vivo rat micronucleus assay, and in vivo rat Comet assay).”

“E4 doses of up to 0.8 mg/kg/day were administered orally to female rats for 104 weeks. At the high-dose of 0.8 mg/kg/day E4 (0.7x the MRHD on an AUC basis), there was an increased incidence of mammary neoplasms”

“The observed fetal growth retardation and developmental effects were likely consequences of maternal toxicity in the pregnant female rat and rabbit. There are no indications for intrinsic teratogenic properties of E4 or DRSP in either rat or rabbit.”

“Istradefylline was negative in 4 Ames assays for bacterial mutagenicity, the chromosomal aberration assay in Chinese hamster lung cells, the micronucleus assay in mice or the UDS assay in rats.”

“In lifetime oral carcinogenicity studies, there was no evidence of carcinogenicity in mouse (0, 25, 125, or 250 mg/kg) or rat (0, 30, 100, or 320 mg/kg).”

“oral administration of istradefylline during pregnancy resulted in teratogenicity (increased incidences of fetal structural abnormalities, embryofetal and offspring mortality and growth deficits) at clinically relevant exposures and in the absence of maternal toxicity.”

“Darolutamide was clastogenic in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. However, darolutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in an in vivo combined bone marrow micronucleus assay and comet assay in the liver and duodenum of the rat.”

“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”

“No embryo-fetal development toxicology studies were conducted or warranted to support this NDA submission, as the proposed indication does not include females.”

“Fosdenopterin was without genotoxic potential in vitro and in vivo in the standard battery of tests indicated in ICH S2(R1).”

“Carcinogenicity studies with fosdenopterin have not been conducted. A carcinogenicity study in a single species will be conducted as a postmarketing requirement.”

“Nonclinical reproductive and developmental toxicity studies with fosdenopterin have not been conducted. These studies will be conducted as a postmarketing requirement.”

“BHV-3000 was negative in Ames, chromosomal aberration, and rat bone marrow micronucleus assays.”

“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 in TgRasH2 mice (0, 30, 100 300 mg/kg) and SD rats (0, 5, 15, 45 mg/kg), respectively.”

“Two fertility studies in SD rat indicated uterine atrophy at doses greater than 25 mg/kg, and decreased conception and increased pre-implantation loss at 150 mg/kg. There was no embryofetal toxicity in rat or rabbit.”

“Zoliflodacin was not genotoxic in the mouse lymphoma assay (MLA) and rat in vivo micronucleus assay. In the Ames bacterial reverse mutation assay, zoliflodacin was mutagenic in the TA102 strain, consistent with its pharmacologic action as a bacterial topoisomerase II inhibitor.”

“Carcinogenicity studies have not been conducted with zoliflodacin.”

“In the mouse EFD study, exencephaly, a neural tube malformation, was present in litters in the 500 and 1000 mg/kg/day groups at levels above current and historical control rates.”

“Nirogacestat was not considered genotoxic since it was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human chromosome aberration assay or in vivo rat bone marrow micronucleus assay.”

“The results showed an increased incidence of whole body hemangiosarcomas in 100 mg/kg/day males that was above the historical control value for the test facility but did not reach statistical significance for trend and pairwise comparisons. The study was negative for drug‐related neoplasms in female mice.”

“Daily oral administration of nirogacestat to pregnant rats resulted in decreased fetal body weights, post‐ implantation loss, and fetal subcutis edema at doses ≥ 20 mg/kg/day (approximately 0.85 times the exposure in patients with desmoid tumors based on AUC at the 150 mg BID dose).”

“Ensifentrine was negative for genotoxicity in the following assays: in vitro Ames test for bacterial gene mutation, in vivo comet test (lung and liver) with rats, and in vivo micronucleus assay with mice.”

“A two-year inhalation study in Han Wistar rats and a 6-month oral study in Tg.rasH2 transgenic mice were conducted to assess the carcinogenic potential of ensifentrine. No evidence of tumorigenicity was observed in male and female rats at an exposure approximately 40 times the MRHDID.”

“The male reproductive tract toxicity observed in the rat repeat dose toxicity studies resulted in impaired reproductive performance including decreased mating index and decreased fertility index, increased pre- and post-implantation loss, and decreased live embryos per litter in untreated females at 30 times the MRDHID.”

“Despite a transient positive chromosomal aberration result at precipitating concentrations in vitro, the overall evidence strongly indicates that tovorafenib lacks clinically relevant genotoxic potential, a conclusion reinforced by negative in vivo micronucleus testing.”

“Tovorafenib was not carcinogenic in the 6-month study in transgenic rasH2 mice that received oral doses up to 100 mg/kg/day.”

“In an embryo-fetal development study, once daily oral administration of tovorafenib to pregnant rats during the period of organogenesis from gestation days 7 through 17 at doses of 37.5, 75, and 150 mg/kg resulted in early resorptions and total litter loss at all doses.”

“The genotoxicity of momelotinib was evaluated in a battery of in vitro and in vivo tests (bacterial reverse mutation assay, in vitro mammalian cytogenetic test using human lymphocytes, and in vivo micronucleus assay). Overall, momelotinib was not genotoxic under the test conditions.”

“Oral administration of the top dose of 15 mg/kg/day of momelotinib (17-times the MRHD) for 2 years significantly increased the incidence of testicular Leydig cell tumors in male rats (11/60 versus 2/60 in control males, Table 32).”

“MMB, when administered orally to pregnant rats and rabbits during organogenesis showed evidence of embryo-fetal toxicities, but no teratogenicity.”

“Oliceridine was negative in an in vitro Ames bacterial reverse mutation assay, the in vitro chromosomal aberration assay using human peripheral blood lymphocytes, and the in vivo rat micronucleus assay.”

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

“A battery of reproductive toxicity studies identified effects on female fertility (longer estrous cycle, reduced number of implantation sites, increased preimplantation loss, and reduced viable embryos) and postnatal development (reduced live litter size, postnatal survival, and body weight). No effects on male fertility or EFD were observed.”

“Omidenepag was not mutagenic in the bacterial reverse mutation (Ames) test and the in vivo mouse micronucleus test. Omidenepag isopropyl was positive (mutagenic and clastogenic) without metabolic activation in the in vitro mouse lymphoma forward mutation assay.”

“Lifetime rodent studies have not been performed to evaluate the carcinogenic potential of omidenepag isopropyl or omidenepag. In rats dosed by subcutaneous injection daily for 26 weeks, nephroblastoma and a spermatic cord tumor were found at 0.003 mg/kg/day (33 times the RHOD based on the estimated area under the curve [AUC]).”

“In animal reproduction studies, subcutaneous administration of omidenepag isopropyl to pregnant rabbits throughout the period of organogenesis produced fetal skeletal anomalies at a dose of 24 times the clinical dose, based on estimated plasma C max .”

“Opicapone was negative in a standard battery of genetic toxicology (Ames, in vitro chromosomal aberration in peripheral human lymphocytes, in vivo CD-1 mouse micronucleus) assays.”

“No drug-related tumors were observed in mouse or rat.”

“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.”

“Relugolix was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay nor clastogenic in the in vitro chromosomal aberration assay and in vivo rat bone marrow micronucleus assay.”

“Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day. Relugolix was not carcinogenic in mice or rats at exposures up to approximately 75 or 224 times, respectively, the human exposure at the recommended dose of 120 mg daily based on AUC.”

“In an embryo-fetal development study in rabbits, oral administration of relugolix during the period of organogenesis resulted in embryo-fetal lethality at the highest dose tested, 9 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC).”

“Berotralstat produced negative results in the bacterial reverse gene mutation assay, an in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and an in vivo micronucleus assay in 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.”

“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.”

“Sulopenem etzadroxil was negative for mutations in an in vitro Ames assay with and without metabolic activation but positive for chromosome aberrations with and without metabolic activation in vitro in peripheral human lymphocytes and Chinese hamster ovary cells. In vivo, sulopenem etzadroxil was negative for genetic toxicity in a bone marrow micronucleus assay in rats.”

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

“Sulopenem etzadroxil did not inhibit fertility in male and female rats and was not associated with fetal malformations in embryo-fetal studies in rats and rabbits. However, in mice, a higher litter and fetal incidence of cleft palate in fetuses occurred at a sulopenem etzadroxil dose associated with sulopenem exposures approximately 46-times the mean clinical exposure”

“In genetic toxicology studies, elacestrant was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or, clastogenic in either in vitro chromosome aberration assays or an in vivo rat bone marrow micronucleus assay.”

“Carcinogenicity studies were not conducted with elacestrant in accordance with ICH S9 guidance; however, of note, in the rat 26-week repeat dose toxicology study B-granulosa cell tumor was observed at ≥25 mg/kg/day”

“Elacestrant was embryo lethal and teratogenic when administered to pregnant rats at ≤30 mg/kg via daily oral gavage during the period of organogenesis on gestational days 6 through 17 followed by cesarean section on gestational day 21.”

“Oveporexton was found to be negative in an Ames assay and in an in vivo micronucleus assay; however, it was found to be positive for induction of micronuclei in an in vitro micronucleus assay following 24-hours of continuous treatment. Overall oveporexton was determined to be non-genotoxic.”

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

“There were no drug-related effects on the incidence of congenital malformations or embryo-fetal lethality in either rats or rabbits.”

“Voxelotor was not genotoxic in the reverse mutation bacterial (Ames) test, rat Comet assay, or rat micronucleus assay.”

“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). In rats, increased incidence of hepatocellular adenoma and adrenal pheochromocytoma was seen in high-dose females (100 mg/kg/day).”

“Voxelotor did not have an effect on the embryo-foetal development in either rats or rabbits at dose levels causing maternal toxicity.”

“Paltusotine was negative in the bacterial mutagenicity assay (Ames test) with Salmonella and Escherichia coli, the in vitro micronucleus test in Chinese hamster ovary cells, and the in vivo micronucleus test in rat bone marrow.”

“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.”

“Findings in rats included preimplantation loss and reduced number of live embryos, and findings in rabbits included delayed fetal development and sporadic malformations.”

“Nirmatrelvir was negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli , the in vitro micronucleus assay using human lymphoblastoid TK6 cells, and the in vivo rat micronucleus assays.”

“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 the rabbit EFD study, lower fetal body weights (9% decrease) were observed at 1,000 mg/kg/day in the absence of significant maternal toxicity findings.”

“Pemigatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro chromosomal aberration assay in human peripheral blood lymphocytes or the in vivo bone marrow micronucleus assay in rats.”

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

“Once daily oral administration of pemigatinib to pregnant rats during the period of organogenesis (gestation Days 6 to 17) resulted in reduced maternal body weight and food consumption at dose levels ≥0.3 mg/kg (approximately 0.6 times the exposure based on AUC at the human dose of 13.5 mg) accompanied by 100% post-implantation loss (early resorptions).”

“Alpelisib did not induce mutations in the bacterial reverse mutation (Ames) assays and was not genotoxic in either the in vitro micronucleus and chromosome aberration tests or the in vivo rat micronucleus assay at 20 mg/kg, the top dose tested (1.7x human exposure based on AUC).”

“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”

“In rats, oral administration of alpelisib resulted in maternal toxicity (body weight loss, low food consumption) and no viable fetuses (post-implantation loss) at 30 mg/kg/day (approximately 3 times the exposure in humans at the recommended dose of 300 mg/day based on AUC).”

“The Applicant did not conduct genotoxicity studies with lactitol and relied on the published literature. Lactitol was examined for potential mutagenicity in the Ames test, chromosome aberration test with cultured mammalian cells, and in vivo mouse micronucleus test. The results showed that lactitol has no mutagenicity potential”

“In a 2-year carcinogenicity study in rats, lactitol was not tumorigenic at daily oral doses up to 2 g/kg/day (about 0.93 times the recommended daily human dose based on body surface area). In a 6-month carcinogenicity study in Tg.rasH2 mice at daily oral doses of lactitol up to 2 g/kg/day (about 0.47 times the recommended daily human dose based on body surface area), there were no drug-related neoplasms.”

“In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of lactitol to rats and rabbits during organogenesis at doses much higher than the maximum recommended human dosage.”

“Ponesimod was negative in in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in rat) assays.”

“In the 2-year rat carcinogenicity study, there were no drug-related increases in neoplasms in M or F. The mouse study was positive for hemangiomas and hemangiosarcomas, with an increase in incidences at all doses in M and in HDF.”

“In the reproductive and development studies with oral ponesimod, fertility was not affected in F or M (NOAEL was 100 mg/kg/day), but teratogenicity and fetal lethality was observed in both rats and rabbits.”

“No mutagenic or clastogenic effects were detected in conventional genotoxicity studies with pretomanid. A circulating metabolite of pretomanid, M50, was mutagenic in a bacterial reverse mutation assay.”

“No carcinogenic potential was revealed in a 6-month study in transgenic mice where this metabolite was produced. In a 2-year study in rats, there was no evidence of carcinogenic risk.”

“Reduced fertility was observed in male rats given daily oral pretomanid for 13 weeks at 30 mg/kg. At 100 mg/kg, pretomanid was associated with reduced body weight, and complete infertility, associated with testicular atrophy, lower sperm counts, reduced sperm motility, lower serum inhibin B concentration, and higher serum FSH concentration.”

“Mitapivat was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mitapivat was not clastogenic in an in vitro human lymphocyte micronucleus assay, or in an in vivo rat bone marrow micronucleus assay.”

“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.”

“Enlarged or fused placenta and/or a distended amniotic sac, an increase in post-implantation loss (early and late resorptions), a decrease in the mean number of viable fetuses, lower mean fetal weights, and external, visceral, and skeletal malformations were observed at the high dose (100 mg/kg twice daily, 63 times the MRHD”

“It was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay (human peripheral blood) or the in vivo rat bone marrow micronucleus assay.”

“Viloxazine did not increase the incidence of tumors in rats treated for 2 years at oral doses of 22, 43, and 87 mg/kg/day. The high dose of 87 mg/kg/day is approximately equal to the MRHD of 600 mg in adults, based on mg/m 2 . Viloxazine did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks at oral doses of 4.3, 13, and 43 mg/kg/day.”

“However, at a dose of 82 mg/kg/day, viloxazine increased early and late resorptions, delayed fetal development, and caused low incidences of fetal malformations or anomalies (craniorachischisis, missing cervical vertebrae, and morphological changes associated with hydranencephaly).”

“Ripretinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in isolated human lymphocytes or the in vivo micronucleus and comet assays in rats.”

“The lack of carcinogenicity studies is acceptable and according to the ICH S9 guideline.”

“At the dose of 20 mg/kg daily (approximately 0.4 times the estimated clinical exposure at 150 mg), fetal malformations associated with the cardiovascular and skeletal systems were observed.”

“Atogepant was negative in Organisation for Economic Cooperation and Development-compliant Ames, in vitro chromosomal aberration, and in vivo rat bone marrow micronucleus assays.”

“Based on the FDA statistical analysis of the 2-year mouse and rat carcinogenicity studies, atogepant was not carcinogenic. The study in female mice was not adequate because the HD was not adequately justified”

“In animal studies, oral administration of atogepant during organogenesis resulted in embryolethality, adverse effects on embryofetal development (decreased fetal body weight in rats, increased incidences of fetal variations in rats and rabbits) at maternal exposures greater those used clinically.”

“Daridorexant was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or in the in vitro mammalian chromosome aberration assay in human lymphocytes and was not clastogenic in the in vivo rat micronucleus assay.”

“Daridorexant did not increase the incidence of tumors in rats treated for 2 years at oral doses of 15, 50, and 150 mg/kg/day. The high dose of 150 mg/kg/day is approximately 4 times the MRHD of 50 mg, based on AUC. Daridorexant did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks”

“Embryo-fetal development toxicity studies were conducted in rats and rabbits. Treatment-related effects on embryo-foetal survival or foetal malformations were not reported in any species.”

“Landiolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK +/- , and in vivo micronucleus test in rats).”

“The sponsor has not conducted carcinogenicity studies citing ICH M3 (R2) since the product is intended for short-term use.”

“Viability was low for rat pups in the 50 or 100 mg/kg/day groups, and body weight of male fetuses were decreased in the 100 mg/kg/day group, but there were no malformations.”

“Daraxonrasib was not mutagenic in the GLP in vitro Ames assay, not clastogenic in the GLP in vitro micronucleus assay with human peripheral blood lymphocytes, and not genotoxic in the GLP in vivo micronucleus study in mice.”

“Carcinogenicity studies were not conducted with daraxonrasib, consistent with ICH S9 recommendations for advanced cancer indications.”

“In an embryo-fetal development study in mice (25, 50, and 75 mg/kg/day), daraxonrasib caused embryo-fetal toxicity at ≥50 mg/kg/day (2.5x exposure at the recommended dose based on AUC).”

“Relebactam was shown to be negative for mutagenicity and/or clastogeniceffects in an Ames assay, a chromosomal aberration study, and in vivo in a rat bone marrow micronucleus assay.”

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

“In rats and rabbits, malformations and variations were not increased by relebactam above concurrent or historical control levels. However, in mice, increases in specificexternal and/or skeletal alterations were observed.”

“The genotoxic potential of AMX0035 was tested in a standard battery of in vitro (Ames, chromosomal aberration in human lymphocytes) and in vivo (micronucleus in CD-1 mouse) assays, which were adequate and negative.”

“Carcinogenicity studies have not been conducted. Carcinogenicity studies in mouse and rat may be conducted post-approval, as agreed to by the Division (Meeting Minutes, April 7, 2020, and July 22, 2021) because of the seriousness of the indication.”

“There were no adverse effects on maternal health or offspring health and development in fertility, EFD, or PPND studies.”

“In the standard genotoxicity battery, selpercatinib was negative in both the Ames and the in vitro micronucleus assay regardless of metabolic activation. In the in vivo micronucleus assay in rats, selpercatinib did cause increases in micronuclei at high dose levels”

“not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice”

“Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily.”

“Gedatolisib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and not clastogenic in a human lymphocyte chromosomal aberration assay. Gedatolisib was not genotoxic in the in vivo rat bone marrow micronucleus assay.”

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

“Fertility and early embryonic development studies are not required as gedatolisib is indicated for the treatment of patients with advanced cancer. In addition, embryo-fetal development studies were not conducted as gedatolisib will be administered in combination with palbociclib and fulvestrant, both of which are known to cause embryo-fetal developmental toxicities.”

“Revumenib was tested in GLP in vitro bacterial reverse mutation and mammalian cell micronucleus assays and an in vivo micronucleus assay in Sprague Dawley rats. There were no revumenib-related genotoxic effects in vitro or in vivo.”

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

“There was a dose-dependent increase in the number of resorptions (including total litter resorption at 300 mg/kg/day), post-implantation loss, and malformations at all revumenib doses, suggesting potential fetal toxicity at exposures 0.6 times the human exposure (AUC) at the recommended dose of 270 mg twice daily.”

“Lasmiditan was negative in adequately designed and conducted in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.”

“Lasmiditan was not carcinogenic in 2-year rat or 6-month Tg rasH2 mouse studies.”

“Oral administration of lasmiditan (0, 50, 75, or 115 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in malformations (skeletal and visceral), increases in skeletal variations and embryofetal mortality, and decreased fetal body weight were observed at the highest dose tested, which was associated with maternal toxicity.”

“Resmetirom was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using cultured human peripheral blood lymphocytes, the in vitro micronucleus test using L5178Y tk+/- mouse lymphoma cells, or the in vivo rat micronucleus assay.”

“In a 2-year carcinogenicity study in mice, resmetirom at 100 mg/kg/day (51 times the maximum recommended dose based on AUC) produced a statistically significant increase in combined incidence of leiomyoma (benign) and leiomyosarcoma (malignant) in uterus”

“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. No effects on fertility and early embryonic development were observed at 30 mg/kg/day”

“Olutasidenib was not genotoxic in the in vitro bacterial reverse mutation (Ames), in vitro human lymphocyte micronucleus, and in vivo rat bone marrow micronucleus assays.”

“Carcinogenicity of olutasidenib was not evaluated in accordance with ICH S9.”

“In embryo-fetal development studies, oral olutasidenib resulted in embryo-fetal death and altered fetal growth when administered to pregnant rats and rabbits during the period of organogenesis at exposures up to 10 times and 0.7 times, respectively, the human exposure at the recommended daily dose”

“Belumosudil was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in either the in vitro chromosomal aberrations assay in human peripheral lymphocytes or in the vivo bone marrow micronucleus assay in rats.”

“Belumosudil did not result in any carcinogenic effect in a 6-month CByB6F1-Tg (HRAS)2Jic hemizygous mouse study at oral doses up to 15 mg/kg/day in female and 30 mg/kg/day in male mice.”

“Embryo-fetal findings occurred at doses ≥ 50 mg/kg/day and included spontaneous abortion, increased post-implantation loss, decreased percentage of live fetuses, decreased fetal body weight, and skeletal/external malformations.”

“Rezafungin was negative in a standard battery of assays, including an in vitro bacterial reverse mutation assay, an in vitro mammalian clastogenicity assay, and an in vivo rat bone marrow micronucleus assay.”

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

“Rezafungin did not affect mating or fertility in male and female rats following IV administration once every 3 days at doses up to 45 mg/kg (6 times the clinical exposure, based on AUC determined in a separate rat study). Decreased sperm motility was noted at ≥30 mg/kg and most males at 45 mg/kg showed mild/moderate hypospermia and had no detectable motile sperm.”

“Remibrutinib was considered negative for genotoxicity in an Ames test, an in vitro micronucleus assay in peripheral human lymphocytes, and an in vivo micronucleus assay in rats.”

“A 2-year oral study in Wistar rats and a 6-month oral study in Tg.rasH2 mice were conducted to assess the carcinogenic potential of remibrutinib. No evidence of tumorigenicity was observed in male and female Tg.rasH2 mice at doses up to 1500 mg/kg/day or in rats at exposures approximately 8x and 98x the MRHD in males and female rats, respectively.”

“Remibrutinib did not affect fertility and was nonteratogenic in rats. In rabbits, remibrutinib treatment resulted in maternal toxicity and adverse developmental outcomes at doses ≥300 mg/kg/day. In the rat pre- and postnatal development study, remibrutinib treatment resulted in increased number of stillborn pups, dead pups, and a smaller litter size at 1000 mg/kg/day.”

“The outcome of the bacterial Ames test and the micronucleus test was negative. In the in vitro mammalian chromosome aberration test in human peripheral blood lymphocytes, upadacitinib was found negative for induction of structural chromosome aberrations but positive for induction of numerical chromosome aberration.”

“Upadacitinib, at exposures (based on AUC) approximately 4 and 10 times the clinical dose of 15 mg in male and female Sprague-Dawley rats, respectively, was not carcinogenic in a 2 year carcinogenicity study in Sprague-Dawley rats. Upadacitinib was not carcinogenic in a 26 week carcinogenicity study in CByB6F1-Tg(HRAS)2Jic transgenic mice.”

“Adverse effects attributed to UPA were observed in the rat fertility (increased postimplantation loss and reduced live fetuses per litter), rat EFD (skeletal malformations), and rabbit EFD (skeletal malformations, postimplantation loss, decreased fetal body weights) studies. No adverse findings were noted in the PPND study.”

“In vivo, vimseltinib administered to rats at doses up to 200 mg/kg/day did not increase bone marrow micronucleated polychromatic erythrocytes, nor did vimseltinib increase liver DNA strand breaks. The overall assessment was that vimseltinib was negative for genotoxicity.”

“In a 6-month transgenic mouse carcinogenicity study at doses up to 12.5 mg/kg/day, vimseltinib was negative for carcinogenic findings. The Applicant is currently conducting a 104-week carcinogenicity study in Sprague Dawley rats to be submitted as a PMR.”

“Structural abnormalities (skeletal variations) occurred at ≥2.5 mg/kg/day (approximately 3 times the exposure at the recommended dose based on AUC). Additional structural abnormalities (cardiac malformations) were observed at the highest dose of 15 mg/kg/day”

“Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, but demonstrated a potential for abnormal chromosome segregation (aneugenicity) in cultured human peripheral blood lymphocytes. Entrectinib was not clastogenic or aneugenic in the in vivo micronucleus assay in rats and did not induce DNA damage in a comet assay in rats.”

“Carcinogenicity studies were not conducted with entrectinib.”

“In an embryo-foetal developmental study in rats, maternal toxicity (decreased body weight gain and food consumption) and foetal malformations (including body closure defects and malformations of the vertebrae and ribs), were observed at 200 mg/kg/day of entrectinib”

“Fostemsavir was not genotoxic in the bacterial reverse mutation assay (Ames test in Salmonella and E. coli), a chromosome aberration test in human lymphocytes, and rat bone marrow micronucleus test.”

“In a 2-year carcinogenicity study conducted in rats and a 26-week carcinogenicity study conducted in transgenic mice, fostemsavir produced no statistically significant increases in tumors over controls.”

“Teratogenic effects occurred in rats at the maternally toxic dose of 1,000 mg/kg/day, such as cleft palate, open eyes, shortened snout, microstomia, misaligned mouth/jaw, and protruding tongue (SF =144).”

“Asciminib was not genotoxic in an in vitro bacterial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes (HPBL) or an in vivo rat peripheral blood reticulocyte micronucleus assay.”

“In a 2-year carcinogenicity study, rats were administered oral doses of asciminib at 20, 66, and 200 mg/kg/day in males and 10, 30, and 66 mg/kg/day in females. Asciminib induced a statistically significant increase in the incidence of benign Sertoli cell tumors in the ovaries of high-dose females.”

“Malformations were evident at 150 mg/kg and included cleft palate, anasarca (edema), and cardiac abnormalities.”

“Based on the weight of evidence, SEPHIENCE is not genotoxic. SEPHIENCE was negative in the Ames assay. SEPHIENCE was positive in an in vitro chromosomal aberration assay without metabolic activation but not with metabolic activation. SEPHIENCE was negative in the in vivo (micronucleus and comet) assays in rats.”

“The 2-year carcinogenicity bioassay was not included in this submission. Even though there was a negative finding in the 6-month transgenic mouse carcinogenicity study”

“There were no maternal or embryo-fetal developmental toxicities noted at doses up to 1000 mg/kg/day, which was the NOAEL of the study; the AUC0-24 at this dose is approximately 9-fold the exposure at the MRHD (Table 53).”

“Centanafadine was negative in a valid, full battery of genetic toxicology assays including a reverse bacterial mutagenicity (Ames) assay, a chromosome aberration assay (CHO cells), and a rat in vivo micronucleus assay.”

“Centanafadine was adequately evaluated in a 6-month transgenic mouse carcinogenicity study and a 2-year rat carcinogenicity study. There was no evidence of drug-related neoplasms in either study.”

“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.”

“Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a chromosomal aberration assay in human peripheral blood lymphocytes but negative in in vivo (micronucleus and comet in rat) assays.”

“In a 2-year carcinogenicity study in rats, oral administration of omaveloxolone at levels of 0.1, 0.3, or 1 mg/kg/day in males and 0.3, 1, or 3 mg/kg/day in females resulted in increased incidences of liver cholangioma and combined cholangioma/cholangiocarcinoma in female rats at the highest dose tested (1.9 times the maximum recommended human dose of 150 mg/day based on AUC).”

“In animal studies, administration of omaveloxolone during pregnancy or throughout pregnancy and lactation produced evidence of developmental toxicity (embryofetal mortality and growth impairment, and mortality, growth impairment, and neurobehavioral deficits in offspring) at plasma exposures similar to or less than exposures in humans”

“Sofpironium bromide was not mutagenic or clastogenic in the bacterial reverse mutation assay, in vitro mammalian chromosome aberration assay, and rat in vivo micronucleus assay.”

“The carcinogenic potential of sofpironium bromide was assessed in a 2-year dermal mouse carcinogenicity study and a 2-year subcutaneous rat carcinogenicity study. There were no drug-related neoplasms associated with daily topical administration of sofpironium bromide topical gel to mice at doses of up to 20% sofpironium bromide”

“The maternal and fetal survival, growth and development NOAEL was 10 mg/kg/day in embryo-fetal development studies in rats following sc administration. In rabbits, the NOAEL for embryo-fetal development toxicity was 2 mg/kg/day sc sofpironium bromide and the NOAEL for fetal malformation was 10 mg/kg/day.”

“The in vitro Ames assay and in vivo mouse micronucleus assays were negative. Although an in vitro chromosomal aberration assay was positive, a clastogenic response was only evident at cytotoxic concentrations (mitotic index ≥50%).”

“Carcinogenicity assessment in two rodent species is considered necessary as a post marketing requirement.”

“Administration of daily oral doses of palovarotene to pregnant rats during the period of organogenesis resulted in multiple fetal external, visceral, and skeletal malformations at ≥0.25 mg/kg/day (below clinical exposures), consistent with the pattern of retinoid-mediated embryopathy.”

“Deucravacitinib and its two major metabolites, BMT-158170 and BMT-153261, tested negative in a battery of genotoxicity studies, i.e., Ames tests (deucravacitinib and metabolites), an in vitro mammalian chromosome aberration test (deucravacitinib), in vitro micronucleus tests (metabolites), and an in vivo mammalian (rat) erythrocyte micronucleus test.”

“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.”

“In animal reproduction studies, no effects on embryo-fetal development were observed with oral administration of deucravacitinib to rats and rabbits during organogenesis at doses that were at least 72 times the maximum recommended human dose (MRHD) of 6 mg once daily (see Data ) .”

“Lenacapavir was negative for mutagenesis in the in vitro reverse mutation assay, negative for clastogenicity in the in vitro assay using human peripheral lymphocytes, and negative for genotoxicity in the in vivo micronucleus assay in rats.”

“A treatment-related increase in the incidence of malignant sarcoma at the injection site was observed in males and a treatment-related increase in combined benign fibroma and malignant fibrosarcoma at the injection site was observed in females, at the highest dose (927 mg/kg).”

“In animal reproduction studies, no adverse developmental effects were observed when lenacapavir was administered to rats and rabbits at exposures (AUC) ≥16 times the exposure in humans at the recommended human dose (RHD) of SUNLENCA”

“Solriamfetol was non-genotoxic in an adequate battery of genotoxicity assays.”

“Solriamfetol was not carcinogenic and did not induce tumors in rats or mice when administered orally at doses up to approximately 3.5- and 9- times the MRHD of 300 mg/day to rats and mice, respectively, based on AUC.”

“In embryo-fetal developmental studies, oral administration of solriamfetol during organogenesis caused maternal and fetal toxicities in rats and rabbits at doses ≥ 2- and 2.5- times- and was teratogenic at doses 9.5- and ≥ 2.5- times, respectively, the MRHD”

“Capmatinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. Capmatinib was not clastogenic in an in vivo bone marrow micronucleus test in rats.”

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

“Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures less than the human exposure based on AUC at the 400 mg twice daily clinical dose ( see Data ).”

“Avacopan was negative in all assays including the in vitro bacterial mutagenicity study (Ames test), in vitro mouse lymphoma forward-mutation assay, and in vivo rat bone marrow micronucleus study.”

“Two-year carcinogenicity studies in Sprague-Dawley rats and Syrian hamsters were conducted to assess the carcinogenic potential of avacopan. Avacopan demonstrated no tumorigenic potential in a study with rats that received oral doses up to 100 mg/kg/day (approximately 3 times the MRHD in adults on an AUC basis) and a study in hamsters that received oral doses up to 100 mg/kg/day (approximately 6 times the MRHD in adults on an AUC basis).”

“In embryofetal development studies with hamsters and rabbits, no fetal harm or malformations were observed with oral doses of CCX168 up 1000 and 200 mg/kg/day.”

“Tazemetostat did not cause genetic damage in a standard battery of studies including a screening and pivotal bacterial reverse mutation (Ames) assay, an in vitro micronucleus assessment in human peripheral blood lymphocytes, and an in vivo micronucleus assessment in rats after oral administration.”

“Dedicated carcinogenicity studies were not conducted with tazemetostat and are not required to support the use of a drug intended to treat patients with advanced cancer; however, findings in the rodent studies demonstrate that the drug has clear carcinogenic potential”

“Administration of tazemetostat to pregnant rats and rabbits during organogenesis resulted in dose-dependent increases in skeletal developmental abnormalities in both species beginning at maternal exposures approximately 1.5 times the adult human exposure”

“In a standard genotoxicity battery, neither tepotinib nor the major metabolite M506 were positive in either the Ames or the in vitro micronucleus assay regardless of metabolic activation. Tepotinib was also negative in the in vivo micronucleus assay.”

“Dedicated carcinogenicity studies were not conducted with tepotinib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”

“At dose levels ≥ 5 mg/kg there was an increased frequency of skeletal abnormalities, including misshapen scapula and clavicle, malpositioned calcaneus and talus, malrotated hind paw, and incomplete ossification of sternebra.”

“Elexacaftor was not genotoxic in a bacterial and a mammalian in vitro assay in the presence or absence of S9 metabolizing mix. Elexacaftor was also not genotoxic in a chromosomal aberration assay in vivo.”

“A 6-month study in Tg.rasH2 transgenic mice showed no evidence of tumorigenicity at 50 mg/kg/day dose, the highest dose tested. A two-year study was conducted in rats to assess the carcinogenic potential of elexacaftor. No evidence of tumorigenicity was observed in rats at elexacaftor oral doses up to 10 mg/kg/day”

“In conclusion, the NOAEL for reproductive toxicity was determined to be 55 mg/kg/day in males and 25 mg/kg/day in females based on lower male and female fertility, male copulation, and female conception indices at 75 mg/kg/day (males) and 35 mg/kg/day (females).”

“Capivasertib induced a statistically significant increase in the incidence of micronucleated immature erythrocytes at 150 mg/kg in the in vivo rat bone marrow micronucleus assay through an aneugenic mode of action.”

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

“Administration of capivasertib to rats prior to implantation until Day 16 of gestation resulted in minor fetal visceral variations, an increase in post-implantation loss, and reduced gravid uterine and fetal weights at 150 mg/kg/day.”

“Infigratinib was not mutagenic in the bacterial reverse mutation test. Infigratinib was not clastogenic in an in vitro human peripheral blood lymphocyte chromosome aberration assay or an in vivo bone marrow micronucleus assay in rats.”

“Carcinogenicity studies are not recommended for the proposed indication.”

“Increases in embryo‐fetal death, with corresponding reductions in the numbers of viable fetuses, were observed at 10 mg/kg/day, and reductions in mean fetal body weights were observed at 3 and 10 mg/kg/day. Fetal abnormalities were observed at increased incidences at all doses.”

“All studies were valid and acoltremon was negative in the Ames test, an in vitro chromosomal aberration test in human peripheral blood lymphocytes, and an in vivo micronucleus assay in the rat.”

“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.”

“In embryofetal developmental studies in pregnant rats and rabbits dosed by intravenous injection daily during organogenesis from gestation days 6-17 and gestation days 7-19, respectively, no maternal or fetal toxicity was observed at 806- and 2151-fold the MRHOD of acoltremon on a mg/m 2 basis.”

“There was no evidence of mutagenicity or clastogenicity for aprocitentan in a standard battery of tests that included in vitro bacterial reverse mutation and chromosomal aberration assays, and an in vivo rat micronucleus study.”

“The carcinogenicity assessment of aprocitentan was based on carcinogenicity studies conducted with another ERA, macitentan, for which its major metabolite is aprocitentan. No carcinogenicity studies were conducted with aprocitentan alone.”

“In embryo-fetal developmental (EFD) toxicity studies, treatment with macitentan (for which aprocitentan is a major metabolite) in pregnant rats and rabbits revealed teratogenicity and developmental toxicity at all doses tested, and therefore a no observed adverse effect level (NOAEL) for embryo fetal toxicity in the rat and rabbits could not be established.”

“Tucatinib did not induce mutations in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration test or the in vivo mouse bone marrow micronucleus assay at doses up to the high dose of 2000 mg/kg.”

“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”

“Tucatinib administered to pregnant dams caused teratogenicity in rabbits and embryo-fetal toxicity in rats.”

“Pexidartinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in peripheral human lymphocytes or the in vivo bone marrow micronucleus assay in rats.”

“The Applicant also conducted a two-year (104-week) carcinogenicity study in rats and a 26-week carcinogenicity study in transgenic mice. Pexidartinib was negative for carcinogenicity in these studies.”

“Oral administration of pexidartinib to pregnant animals during the period of organogenesis resulted in malformations, post-implantation loss, and abortion at maternal exposures that were approximately equal to the human exposure at the recommended dose (see Data ) .”

“In genetic toxicology assessments, ubrogepant was negative in OECD-compliant Ames, in vitro chromosomal aberration, and in vivo rat bone marrow micronucleus assays.”

“In adequately designed and conducted 104-week oral carcinogenicity studies in CD-1 mouse (0, 5, 15, and 50 mg/kg/day) and Wistar rat (males: 0, 10, 30, and 100 mg/kg/day; females: 0, 10, 30, and 150 mg/kg/day), ubrogepant was negative for drug-related neoplasms.”

“In animal studies, adverse effects on embryofetal development were observed following administration of ubrogepant during pregnancy (increased embryofetal mortality in rabbits) or during pregnancy and lactation (decreased body weight in offspring in rats) at doses greater than those used clinically and which were associated with maternal toxicity”

“Umbralisib was not mutagenic in a bacterial mutagenicity (Ames) assay. Umbralisib was not clastogenic in an in vitro micronucleus assay using human (TK6) lymphoblast cells or in an in vivo micronucleus assay in mice at doses up to 1000 mg/kg.”

“No carcinogenicity studies have been conducted or are warranted to support the marketing of umbralisib for the current indications.”

“Malformations were observed at doses of 200 mg/kg/day (cleft palate) and 400 mg/kg/day (cleft palate and nasopharyngeal fistula).”

“The prodrug, tebipenem pivoxil was found to be mutagenic in a mammalian cell gene mutation assay and induced chromosomal aberrations in Chinese hamster ovary (CHO) cells in vitro; however, it was not clastogenic in an in vivo bone marrow micronucleus study in mice.”

“As noted in that review, no adverse developmental effects were noted in embryofetal development (EFD) studies following oral administration of tebipenem pivoxil to pregnant mice, rats and monkeys during periods of organogenesis.”

“Vadadustat was negative for mutagenicity in the Ames assay. Vadadustat yielded clastogenic activity from two in vitro assays but was negative for genotoxic activity when administered to Sprague Dawley rats in an in vivo COMET and chromosomal aberration study.”

“Vadadustat was not carcinogenic in RasH2 transgenic mice and was not carcinogenic in Sprague Dawley rats administered vadadustat up to approximately 0.3-fold the clinical dose of 600 mg, based on AUC.”

“Vadadustat did not affect fertility or cause teratogenicity, although lower fetal weight (-7%), lower pup weight (-5% to -11%), and reduced fetal skeletal ossifications occurred at dose levels associated with maternal toxicity.”

“In genotoxicity studies, quizartinib was mutagenic in a bacterial reverse mutation assay. Quizartinib was not genotoxic in the following assays: mouse lymphoma thymidine kinase mutation assay, chromosome aberration assay in human peripheral blood lymphocytes, and rat bone marrow micronucleus assay (tested to the maximum tolerated dose, MTD).”

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

“In an embryo-fetal development (EFD) study in rats, quizartinib at doses resulting in exposures approximately 3 times the exposure at the maximum recommended human dose (MRHD) was associated with adverse developmental outcomes including structural abnormalities (anasarca and edema) and alterations to growth (lower fetal weights and effects on skeletal ossification).”

“There was no evidence of mutagenicity or clastogenicity for atrasentan in in vitro bacteria reverse mutation and chromosomal aberration assays, or in an in vivo mouse micronucleus study.”

“The carcinogenicity assessment of atrasentan in a 2-year rat study showed uterine stromal polyps in females at exposures 24 times the MRHD.”

“In animal reproduction studies, oral administration of atrasentan to pregnant rats and rabbits throughout organogenesis at doses that were below the maximum recommended human dose (MRHD) based on area under the curve (AUC) caused teratogenic effects in rats and rabbits”

“Remdesivir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.”

“Given the short-term administration of VEKLURY for the treatment of COVID-19, long-term animal studies to evaluate the carcinogenic potential of remdesivir were not conducted.”

“In the reproductive and development toxicity studies, there was a decrease in corpora lutea, a consequent decrease in implantation sites and viable embryos, and lower ovary and uterus/cervix/oviduct weights in the rats at 10 mg/kg; these changes were observed at a systemically toxic dose. There were no remarkable findings in male rats in the fertility study, no adverse findings in embryo-fetal studies in rats and rabbits, and no adverse changes in the pre- and postnatal study in rats.”

“Mutagenesis Etrasimod was negative in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (rat micronucleus) assays.”

“hemangioma/hemangiosarcoma were observed at exposures ≥ 46-fold the exposure at the MRHD (based on AUC comparison). In a two-year carcinogenicity study in rats, no evidence of carcinogenic potential was observed at exposures up to 88- and 198-fold the exposure at the MRHD in males and females, respectively (based on AUC comparison).”

“In animal reproduction studies, administration of etrasimod during organogenesis produced adverse effects on development, including embryolethality and fetal malformations, in both rats and rabbits at maternal exposures 5 and 6 times, respectively, the exposure at the maximum recommended human dose (MRHD).”

“Fezolinetant showed no genotoxic potential by the bacterial reverse mutation test, chromosomal aberration test, or in vivo micronucleus test.”

“In a 2-year female rat carcinogenicity study and a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 186-fold and 47-fold the human AUC 24 at the human therapeutic dose of 45 mg, respectively.”

“In embryo-fetal toxicity animal studies with fezolinetant, embryo-lethality occurred at high doses above the human therapeutic dose in rats and rabbits, but no teratogenicity was observed. In the pre- and post-natal development animal study, delayed parturition and embryo-lethality occurred at high doses above the human therapeutic dose in rats.”

“Vepdegestrant and its major metabolite ARV-473 did not induce mutations in the bacterial reverse mutation (Ames) assay. Vepdegestrant was not clastogenic in the in vitro human lymphocyte micronucleus assay or in the in vivo micronucleus study in rats.”

“Administration of ARV-471 did not result in statistically significant ovarian tumors in transgenic rasH2 mice at daily doses up to 800 mg/kg/day for 6 months.”

“Oral administration of vepdegestrant resulted in embryo-fetal mortality (increased resorptions, post-implantation loss and reduced number of live fetuses) at ≥30 mg/kg/day (0.3 times the human AUC at the recommended dose).”

“Vericiguat was not genotoxic in the in vitro microbial mutagenicity (Ames) assay, the in vitro mouse lymphoma assay and the in vivo rat and mouse micronucleus assay.”

“Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats. Vericiguat did not show a carcinogenic effect in mice dosed up to 150 mg/kg/day (males) or up to 250 mg/kg/day (females).”

“An increased incidence of cardiac ventricular septal defect along with truncus arteriosus communis was observed at ≥2.5 mg/kg/day, which is ≥4 times the human exposure at the MRHD.”

“Oteseconazole was negative in the bacterial reverse mutation assay, in vitro chromosomal aberration assay, and in vivo micronucleus assay in rats.”

“In a 2-year oral carcinogenicity study of oteseconazole, male Sprague Dawley rats showed increased incidence of Leydig cell adenomas of the testes and thyroid follicular cell adenomas/carcinomas combined at ≥1.5 mg/kg/day.”

“In pre- and postnatal studies, oteseconazole administration to pregnant and lactating rats at 7.5 mg/kg/day resulted in lens opacities, swollen eyes, hemorrhage, hyphema, buphthalmos, corneal ulceration, retinal and optic nerve atrophy, as well as lens degeneration.”

“Aceclidine did not show any potential to cause genetic toxicity in a series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in cultured human peripheral blood lymphocytes; and 3) an in vivo chromosome aberration assay (micronucleus test) in mice.”

“Long term studies in animals have not been performed to evaluate carcinogenic potential.”

“In embryofetal development studies, oral administration of aceclidine to pregnant rats and rabbits throughout organogenesis produced no maternal toxicity, skeletal anomalies, nor reduction in fetal body weight at 1.5 mg/kg/day”

“pacritinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration assay (Chinese hamster ovary cells) or in vivo in a micronucleus test in mice”

“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.”

“The NOAEL for embryo-fetal development was also considered the MD based on higher post-implantation loss, lower mean fetal body weights, and altered external fetal morphology (cleft palate) observed in the presence of maternal toxicity at the HD.”

“Vonoprazan was not genotoxic in the bacterial reverse mutation assay, an in vitro chromosomal aberration assay in Chinese Hamster lung cells, and an in vivo rat bone marrow micronucleus test.”

“In a 2-year carcinogenicity study in mice and rats, hepatocellular adenomas and carcinomas and drug-related increases in benign and malignant neuroendocrine cell tumors in the stomachs were noted.”

“In the embryofetal development study in rats, fetal abnormalities were limited to the 300 mg/kg/day dose and included ventricular septal defect and mal-positioned subclavian artery in fetuses, as well as tail abnormalities and small anal opening.”

“Vorasidenib and its major circulating metabolite, AGI-69460, were negative for genotoxicity in a full battery of tests including an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in human lymphocytes, a chromosomal aberration assay, and an in vivo bone marrow micronucleus assay in rats.”

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

“Embryo-fetal toxicity (higher incidence of early resorptions, and visceral malformations of kidney and testes) occurred in rats at the maternally toxic dose of 75 mg/kg/day (approximately 170 times the human exposure based on the AUC at the highest recommended dose).”

“Danicopan was not genotoxic in the Ames bacterial reverse mutation assay, in vitro micronucleus assay in human peripheral blood lymphocytes, or in the in vivo micronucleus assay in rats.”

“Danicopan was not carcinogenic in the 6-month carcinogenicity study in the TgRasH2 mouse model. Danicopan was not carcinogenic in the 2-year rat carcinogenicity study at exposures 15- to 23-times the exposure at the MRHD (based on AUC).”

“There were no effects on early embryonic development and fetal development in NZW rabbits (where danicopan is pharmacodynamically active) up to a mean maternal systemic exposure 18-times the exposure at the MRHD (based on AUC) or during post-natal development up to a mean maternal systemic exposure 9-times the exposure at the MRHD (based on AUC).”

“Tapinarof was not mutagenic or clastogenic in the Ames bacterial reverse mutation assay, the in vitro mammalian chromosome aberration test, and the in vitro mouse lymphoma assay. Tapinarof was not genotoxic in two in vivo micronucleus assays in mice and rats.”

“No drug-related neoplasms were noted in mice after 98 (females) to 102 (males) weeks of daily topical administration at doses up to 3% tapinarof cream (44 times the MRHD based on AUC comparisons). No drug-related neoplasms were noted in female rats after 83 weeks of daily subcutaneous administration at doses up to 1 mg/kg/day tapinarof (9 times the MRHD based on AUC comparisons).”

“There were test article-related decreases in F1 pup survival and viability at ≥6 mg/kg/day that resulted in reduced litter sizes and decreased pup weights. The NOAEL was 1 mg/kg/day for tapinarof effects on prenatal and postnatal development of the offspring in rats.”

“Fx-1006A was negative for genotoxicity in an in vitro bacterial reverse mutation assay, an in vitro chromosomal aberration assay in human lymphocytes, and an in vivo rat micronucleus assay.”

“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.”

“Reduced survival, birth weight, postweaning body weight, delayed male sexual maturity, and impaired learning and memory were observed in the offspring of dams dosed at 15 mg/kg/day.”

“Pitolisant and its metabolites were not mutagenic in the in vitro bacterial reverse mutation assay (Ames), or clastogenic in the in vitro mammalian chromosomal aberration assay. Pitolisant was negative in the in vivo mouse micronucleus assay.”

“A two-year carcinogenicity study of pitolisant was conducted in rats and a 6-month carcinogenicity study was conducted in tgRasH2 mice. The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”

“At the maternally toxic doses, fetal toxicity included stillbirths, postnatal pup mortality (due to lack of milk or failure to nurse) and decreased pup length and weight. Pitolisant was teratogenic at 22 times the MRHD based on mg/m2 , causing major malformations including cleft palate and abnormal limb flexure.”

“Rilzabrutinib was not mutagenic in an in vitro bacterial reverse mutagenicity (Ames) assay, was not clastogenic in an in vitro human peripheral lymphocyte chromosomal aberration assay, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.”

“Rilzabrutinib was not carcinogenic in a 6-month study in Tg.rasH2 mice at doses up to 300 mg/kg/day. In a 2-year rat carcinogenicity study at doses of 10, 30 or 100 and 5, 15 or 50 mg/kg/day in males and females, respectively, there were no rilzabrutinib-related tumors.”

“However, adverse visceral and skeletal findings occurred in rat fetuses at a maternally toxic dose at exposures 22 times the human exposure (based on AUC) at the MRHD (see Animal Data).”

“Belzutifan was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in the in vitro micronucleus assay in human peripheral blood lymphocytes or the in vivo bone marrow erythrocyte micronucleus test in rats.”

“presented the results of the 6-month Tg. rasH2 mouse carcinogenicity study with belzutifan at doses up to 600 mg/kg/day. The results indicate no belzutifan-related neoplastic findings at any dose level and no carcinogenic risk were identified in the study.”

“The Applicant conducted a pilot embryo-fetal development study in rats. Oral administration of belzutifan at doses up to 200 mg/kg/day to pregnant rats during the period of organogenesis caused embryo-fetal lethality (post-implantation loss) at ≥ 60 mg/kg/day”

“Clascoterone did not display clear genotoxic potential in a standard battery of genetic toxicity studies. Clascoterone was not mutagenic in an in vitro reverse bacterial mutation assay or clastogenic in an in vitro chromosome aberration assay.”

“Clascoterone cream (0.1%, 1%, or 5%) was not carcinogenic after daily topical administration in a 2-year carcinogenicity study in rats.”

“a developmental NOAEL could not be determined because clascoterone-related malformations were noted in three fetuses at the low dose (LD) and 1 fetus each at the mid dose (MD) and HD.”

“Durlobactam did not induce statistically significant increases in micronucleated PCEs at any test article dose up to 2000 mg/kg.”

“At doses up to 3 times the maximum recommended dose based on AUC comparisons, there were no toxicologically significant drug-related effects of durlobactam in pups born to rats dosed for 2 weeks prior to pairing, during pairing, and up to gestation Day 17.”

“CBM was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays.”

“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.”

“Oral administration of CBM to pregnant rats throughout organogenesis at doses of up to 60 mg/kg/day resulted in increased embryofetal mortality, reduced fetal body weights, and incomplete fetal skeletal ossification at the highest dose tested, which was associated with maternal toxicity.”

“AHC 2224920 was negative for genotoxic potential in a complete battery of genotoxicity GLP studies (i.e., Ames test, in vitro chromosome aberration test in cultured human lymphocytes and in vivo micronuclei assay in rats).”

“As agreed with the Sponsor during their pre-NDA interaction with the Division, carcinogenicity studies were not conducted to support the approval of Lotilaner Ophthalmic Solution, 0.25%, for the treatment of Demodex blepharitis.”

“There was a marked effect on mean fetal weight at 50 mg/kg/day and there was an indication of a developmental delay characterized by an increased number of fetuses with incomplete ossification of individual bones of the skeleton.”

“Abametapir and abametapir-COOH, the major human metabolite, were not mutagenic in the Ames test. Abametapir caused increases in chromosome aberrations in Human lymphocytes but only at cytotoxic concentrations and was negative in the in vivo rat micronucleus assay”

“Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of XEGLYZE or abametapir.”

“Abametapir has been tested for reproductive and developmental toxicology in rats and rabbits after oral administration with no significant findings independent of maternal toxicity.”

“Lefamulin did not elicit genotoxic potential in an in vivo rat bone marrow micronucleus assay for clastogenicity or in the in vitro Mouse Lymphoma Ly5178Y TK+/- mutation assay.”

“No carcinogenicity studies have been carried out, as the expected clinical use is of short duration.”

“Effects on embryo-foetal development were evaluated in rats and rabbits. Overall, a reduced live pup birth index in rats indicated an effect of lefamulin on embryo-foetal survival at high doses”

“Ensitrelvir was not genotoxic in the reverse mutation bacterial (Ames) test, in vitro micronucleus assay using human lymphoblastoid TK6 cells, or the in vivo rat micronucleus assays.”

“Carcinogenesis studies were not conducted due to the short duration of drug administration.”

“In rabbits, malformations and variations of the axial skeleton, embryofetal lethality, abortion, and post-implantation loss, accompanied by maternal toxicity were observed, with a NOAEL of 30 mg/kg/day and a safety margin of 3X.”

“Mavorixafor (free base) was not mutagenic in the Ames assay (bacterial reverse mutation assay), or clastogenic in vitro (chromosome aberration assay in human peripheral lymphocytes) or in vivo (rat bone marrow micronucleus assay).”

“Carcinogenicity studies with mavorixafor have not been conducted. There was a prior agreement with the Applicant regarding the need for postmarketing requirement (PMR) studies to assess the carcinogenicity potential of mavorixafor.”

“No dedicated fertility and early embryonic development, definitive embryo-fetal development, or pre- and post-natal development toxicity studies were conducted with mavorixafor. The Applicant provided a weight-of-evidence assessment informing potential reproductive risks associated with mavorixafor treatment.”

“Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.”

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

“Adverse developmental outcomes occurred at ≥ 0.75 mg/kg/day and included alterations to growth (e.g., fetal weights in the 0.75 and 2 mg/kg/day groups were 13.5% and 32.4% lower than controls) and structural abnormalities (such as incomplete or delayed ossification of sternebra(e) and/or vertebral arches, and/or unossified and bent ribs).”

“Zavegepant was negative for mutagenicity and clastogenicity in an adequate battery of genetic toxicology (Ames, in vitro chromosomal aberration in Chinese hamster ovary cells, and in vivo rat micronucleus) assays.”

“Intranasal administration of zavegepant (0, 0.3, 0.8, or 2.5 mg/day) to Tg.rasH2 mice for 26 weeks resulted in no evidence of drug-related tumors. Intranasal administration of zavegepant (0, 2, 9, or 18.8 mg/kg/day) to rats for up to 96 weeks resulted in no evidence of drug-related tumors.”

“Reproductive and developmental toxicology studies were conducted in SD rat and New Zealand White rabbit. There were no reproductive or developmental toxicities at doses resulting in drug exposures at least 2,000-fold higher than human exposure (i.e., AUC) at the proposed clinical dose.”

“Zidebactam was negative for genetic toxicity in vitro in a mutagenicity assay in mouse lymphoma cells, and a chromosomal aberration assay in human peripheral blood lymphocytes, and in vivo in a mouse micronucleus assay in bone marrow cells.”

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

“In pregnant rabbits, intravenous administration of zidebactam during organogenesis was associated with increased late fetal resorptions and total fetal loss in two litters at a dose of 600 mg/kg/day (approximately 5 times the RHD) and distended bladder, a fetal anomaly, at zidebactam doses greater than or equal to 300 mg/kg/day (approximately 3 times the RHD).”

“Sunvozertinib was not mutagenic in an in vitro bacterial reverse mutation assay. Additionally, sunvozertinib did not cause chromosomal aberrations in an in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells. Sunvozertinib was not clastogenic in an in vivo bone marrow micronucleus test in rats”

“The Applicant did not conduct a carcinogenicity study with sunvozertinib; consistent with ICH S9, these studies are not warranted for the development of a drug intended for the treatment of patients with advanced cancer.”

“In the embryo-fetal development toxicity studies, sunvozertinib resulted in decreased body weight and abortion in pregnant rats and/or rabbits, dead fetuses, decreased fetal weight, heart malformations, increased supernumerary bone of fontanelle bone, and misaligned sternebra in fetus.”

“Iberdomide showed increased chromosomal aberrations at ≥ 550 μg/mL in the in vitro clastogenicity assay; however, the results of the Ames assay and in vivo assays were negative for genotoxicity. Given the totality of the data, iberdomide is not considered genotoxic.”

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

“Oral administration of iberdomide in pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes including embryo-fetal mortality, alterations to growth, and structural abnormalities.”

“Metabolite CC1084037 was negative in an Ames assay, and positive in an in vitro chromosomal aberration assay in human (TK6) cells but negative in an in vivo rat micronucleus/comet assay.”

“Oral administration of ozanimod (0, 8, 25, or 80 mg/kg/day) to Tg.rasH2 mice for 26-weeks resulted in an increase in hemangioma and hemangiosarcoma (combined) in males and females at the mid and high doses tested. Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to rats for 2 years resulted in no increase in tumors.”

“There were no effects on fertility in male or female animals dosed with ozanimod. Embryolethality and developmental effects (e.g., incomplete skeletal ossification, malpositioned vertebrae, malformed or absent arteries, anasarca, malpositioned testes, and cleft palate) occurred in pregnant rats and/or rabbits exposed to ozanimod and its metabolites during gestation.”

“Lurbinectedin was negative in the in vitro Ames assay but induced mutations in the mouse TK lymphoma assay, confirming that, as expected based on its mechanism of action, lurbinectedin is genotoxic.”

“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”

“Six pregnant rats received a single lurbinectedin dose of 0.1 mg/kg (0.6 mg/m2 ) or vehicle control on Day 10. There were no viable fetuses in lurbinectedin-treated dams.”

“However, in vivo ceftobiprole medocaril sodium was negative in both the micronucleus assay and rat liver unscheduled DNA synthesis reducing concern for potential clastogenic activity.”

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

“Intravenous administration of ceftobiprole medocaril sodium to pregnant rats and monkeys during organogenesis showed no evidence of adverse fetal developmental outcomes at doses approximately 1.4 times and 0.9 times the MRHD, respectively, based on BSA comparison.”

“Lonafarnib was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using human whole blood lymphocytes, or the in vivo mouse micronucleus assay.”

“The Applicant will be required to conduct a carcinogenicity study postapproval.”

“In pregnant rats, post-implantation loss (resorptions) was seen at plasma drug exposures approximately equal to that achieved in humans. In pregnant rabbits, skeletal malformations were seen at plasma drug exposures lower than human exposures.”

“Ganaxolone was negative for genotoxicity in in vitro (Ames and mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays. The major circulating human metabolite, oxy-dehydro-ganaxolone, was negative for mutagenicity in the in vitro Ames assay but positive for clastogenicity in an in vitro mammalian chromosomal aberration test in human peripheral blood lymphocytes.”

“Oral administration of ganaxolone (150, 500, and 1000 mg/kg/day in males and 100, 300, and 1000 mg/kg/day in females) to Tg.rasH2 mice for up to 26 weeks did not result in an increase in tumors. No carcinogenicity studies have been conducted with ganaxolone in rats.”

“In the EFD study in mouse, an increase in fetal malformations (external, visceral) was observed at all doses (0, 50, 175, and 300 mg/kg/day) in the absence of maternal toxicity.”

“Brexanolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay.”

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

“In animal reproduction studies, malformations were not seen in rats or rabbits at plasma levels up to 5 and 6 times the maximum recommended human dose (MRHD), respectively. Developmental toxicities were seen in the fetuses of rats and rabbits at 5 and ≥3 times the plasma levels at the MRHD, respectively.”

“Zuranolone was negative in Ames, in vitro chromosomal aberration, and rat bone marrow micronucleus assays.”

“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.”

“Malformations were observed in 10 HD pups (5 litters): exencephaly (1 fetus), absent tail (2 littermates), short thread-like tail and/or malformation of the sacral and caudal vertebrae (2 littermates), umbilical hernia and depressed eye bulges (1 fetus), absent or small lens of the eye (2 littermates) and vertebral/rib malformations (2 littermates).”

“ZYCUBO was not mutagenic or clastogenic in a standard battery of genotoxicity tests [bacterial mutagenicity (Ames), micronucleus assay in TK6 cells (in vitro) , and rat bone marrow micronucleus assay (in vivo)] .”

“Rodent carcinogenicity studies have not been conducted with CuHis. 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.”

“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.”