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).”

“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.”

“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.”

“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”

“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 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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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).”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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).”

“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.”

“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).”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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”

“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).”

“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.”

“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).”

“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.”

“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.”

“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.”

“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.”

“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).”

“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.”

“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”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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).”

“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”

“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.”

“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.”

“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.”

“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.”

“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.”

“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 .”

“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.”

“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”

“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.”

“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.”

“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.”

“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.”

“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).”

“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.”

“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”

“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.”

“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”

“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.”

“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.”

“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.”

“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.”

“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.”

“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).”

“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”

“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.”

“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”

“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).”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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).”

“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.”

“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]).”

“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.”

“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.”

“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.”

“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.”

“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).”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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”

“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”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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”

“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.”

“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).”

“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.”

“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.”

“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).”

“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.”

“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.”

“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).”

“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”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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).”

“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.”

“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).”

“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.”

“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.”

“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).”

“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.”

“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.”

“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.”

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

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”