What flexibility did FDA and EMA accept for approved small molecules?

“Carcinogenicity studies with levacetylleucine have not been conducted.”

“A juvenile toxicity study with levacetylleucine has not been conducted.”

“Information was described in the impairment of fertility subsection of labeling (Table 89; Section 13.1) to indicate that studies of fertility and early embryonic development and pre-and postnatal toxicology were not conducted with the drug.”

“However, final study reports for EFD toxicity studies in rats and rabbits have not been submitted.”

“Although there is a deviation from OECD guideline 474 and ICH guideline S2 on genotoxicity study due to the absence of specific toxicokinetic in vivo data in the micronucleus assay, it is known that the rats were exposed to the maximum ethically acceptable dose toxicology studies (2000 mg/kg/day).”

“The Applicant submitted a weight-of-evidence assessment in lieu of a 2-year rat carcinogenicity study. The Agency agreed with the Applicant’s weight-of-evidence assessment that a 2-year rat carcinogenicity study would not add value”

“The Applicant did not conduct a 9-month dog toxicity study, carcinogenicity studies, and a rat PPND study with doxecitine and doxribtimine.”

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

“No dedicated in vitro and in vivo safety pharmacology studies were conducted due to the endogenous nature of doxecitine and doxribtimine.”

“This exposure level represents approximately -fold exceedance of the 1.5 μg TTC for genotoxic impurities established in ICH M7(R2) guidance.”

“A rat 2-year carcinogenicity study was not conducted given that non-melanoma skin cancers have been reported in humans treated with nirogacestat and the fact that human systemic exposures exceed those that can be achieved in animal toxicology studies due to low tolerance in the rat and excess of toxicological findings.”

“Based on the severity of the embryo‐fetal toxicities, and the known requirement for the Notch pathway for normal embryo implantation and development, the weight of evidence provides justification for not conducting the definitive embryo‐fetal toxicity studies in rats and in rabbits, as well as not conducting the rat peri‐ and post‐natal development study.”

“Conduct of additional general toxicology studies were not required based on FDA feedback received at the end‐of‐Phase 1 meeting; therefore, the 6‐month rat and 9‐month dog studies with nirogacestat were not conducted.”

“The exposure margins based on NOAEL/LOAEL observed in all repeat-dose studies performed in the rat, dog and mouse, reproductive toxicity studies performed in the rat, as well as the carcinogenicity study performed in the TgRasH2 mouse are considerable below 1, indicating a lack of safety margins to the adverse effects observed in the non-clinical studies.”

“Considering the clinical context (unmet medical need for a severe condition with a beneficial clinical profile), the clinical judgement that long term treatment is unlikely, that both impurities are considered to have relatively low mutagenic potential, a product specific acceptable intake limit of 20 μg/day (corresponding to 66,667 ppb/day based on a maximum daily dose of 300 mg) for the sum of ASYM-136911 and ASYM-136912 was proposed.”

“In pregnant rabbits maternal toxicity was evident already at exposure levels far below the human exposure at the recommended daily dose of 50 mg (AUC), while embryo-fetal development was not negatively influenced up to an AUC in the range of the human exposure, resulting in no safety margin either for the does (<1 time) or for the offspring (<1 to 1 time).”

“In the PPND study, effects on neurobehavioral development were not assessed using a complex learning and memory task, such as the Biel or Cincinnati water maze, and were, therefore, marginally acceptable.”

“Adverse development effects of opicapone given in combination with levodopa/carbidopa (LD/CD) were not assessed; however, LD/CD is known to cause visceral and skeletal malformations in rabbits. This information should be included in labeling because opicapone is to be indicated as an adjunct to LD/CD.”

“No juvenile, local tolerance, immunotoxicology or dependence studies have been conducted with Opicapone. The absence of these studies has been adequately justified.”

“Although no sampling of BIA 9-1103 was undertaken, the applicant has sought to address this by extrapolating the expected level of BIA 9-1103 in mice and rats using metabolite exposures observed in other completed TK studies.”

“GLP compliant chronic toxicity studies with lactitol were not required because of the Generally Recognized as Safe food additive status of lactitol and extensive ex-US experience with the drug.”

“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 Applicant did not conduct any fertility and early embryonic development study. The Applicant relied on published literature, which indicated that lactitol did not cause any adverse effect on fertility and early embryonic development in rats at doses up to 10000 mg/kg/day (about 4.6 times the recommended daily human dose based on body surface area).”

“The 104-week oral carcinogenicity study in rats was initiated in February 2017, and the study report will be submitted post approval, as per agreement with the Agency.”

“An oral (gavage) toxicity study with lactitol in juvenile rats from postnatal day (PND) 14 through PND 91 to support clinical trials in patients 6 months to less than 6 years of age.”

“A 2-year carcinogenicity study in rats will be conducted as a postmarketing requirement (see Section 24).”

“There were no toxicologically significant differences in findings between the same doses of D-IVA and IVA. Therefore, a bridge to the ivacaftor nonclinical program was justified and no further toxicology studies with D-IVA alone were recommended.”

“No reproductive toxicity studies have been conducted with D-IVA. A bridge between the toxicity profiles of D-IVA and IVA has been adequately established in the 13-week rat toxicity study.”

“TEZ was only assessed in combination studies with an exposure multiple of 1.2 for males and 2.7 for females at a dose where no toxicity was observed (only 1 dose tested). Since TEZ has been well studied and approved in a previous MAA, this limited amount of data is deemed acceptable.”

“The submitted nonclinical safety information on IV artesunate lacks adequate characterization of the in vivo genotoxic potential and the potential risks on female fertility. However, given the severity of the disease and the unmet need for drugs intended to treat severe malaria the current nonclinical package supports approval for marketing in the U.S.”

“Given the conflicting findings in animals and lack of any formal fertility study(ies), the risk that IV artesunate administration poses to human fertility is uncertain.”

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

“Artesunate has not been evaluated in GLP studies for effects on human ether-a-go-go-related gene (hERG) tail currents. The Applicant was not requested to conduct a hERG study using artesunate as no significant QTc prolongation of artesunate was detected in the QT assessment (see Section 10.4.9).”

“The Division agreed to review 28-day repeat-dose toxicology data in two species, an embryo-fetal development study in the rabbit, and 6- month juvenile rabbit study to support this position.”

“Typically, an NME for a chronic indication would require carcinogenicity studies in two species. However, SDX is a prodrug for an approved product (d-MPH) that predominantly releases MPH and other products that are either found endogenously and/or obtained in diet at levels greater than what will be released at the MRHD.”

“Fertility and early embryonic development studies were not conducted with SDX. The Applicant is relying upon the developmental toxicity data in the referenced product labeling.”

“Although rabbit is not a conventional species for a juvenile animal study, we agree that it is the most appropriate species for the two pivotal studies (rabbit is typically used for embryo-fetal development).”

“While this is true, the use of Cynomolgus monkey should be reserved to situations where this species is the only relevant species.”

“The Applicant decided to use an additional rodent model (CD-1 mouse) and subcutaneous administration instead of intravenously administered rabbits, because repeated-dosing with intravenous administration in mice is not feasible.”

“Even though the Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009) states that all the bioassays should be conducted with GLP validated methods, CHMP agreed that the high-quality standards of the bioanalytical methods used here can be considered adequate for the non-clinical analyses.”

“However, this statement was not fully supported by CHMP, considering the low concentration tested and the applicant was asked to justify the concentration of cefiderocol used for the secondary pharmacology screen, also in the context of the convulsions seen in the repeat dose toxicity studies in rats.”

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

“In addition, it is agreed with the applicant that definitive embryofoetal development and pre/postnatal development studies are not needed in view of this pharmacology-related developmental toxicity as mentioned in section 4.6 of the SmPC containing warnings related to the use of mirdametinib during pregnancy and breastfeeding.”

“The non-clinical programme conducted according to ICH M3 recommendations could be considered sufficient as clinical experience with mirdametinib and its metabolite PD 0315209 is demonstrated to be sufficient to waive the need for long-term animal studies.”

“A marketing authorisation is currently sought for patients aged 2 years and older. No juvenile animal study (JAS) was conducted with mirdametinib. This is in line with the agreed PIP.”

“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.”

“The lack of data from the intended route of administration is considered acceptable based on the limited volume feasible for IV administration to mice.”

“In vivo studies to address metabolism have not been conducted. This is considered acceptable since no metabolites are detected in vitro, and since fosdenopterin is a synthetic replacement for the endogenous molecule (cPMP) expected to be eliminated and excreted in an identical manner to that of the endogenous molecule.”

“Based on the totality of Sponsor’s arguments, this reviewer judged the waiver request for carcinogenicity studies receivable since the weight of evidence indicated no cause for concerns in the animals or humans, nor significant systemic exposure for a long period of time that would justify evaluating the cancer risk with Lotilaner Ophthalmic Solution, 0.25%, for the indication sought.”

“Nasal turbinate and nasopharynx were not examined under the microscope in any of the ocular studies which was a drawback to the complete evaluation of the potential ocular toxicity of Lotilaner Ophthalmic Solution, 0.25%, but does not influence the decision on approvability of this product.”

“There was no designated fertility study conducted, however the results of the 2- generation study suggested that the NOAEL for male fertility was 20 mg/kg/day, which provides a safety margin of X with the MRHD of mg/kg for a 60 kg human.”

“Considering the exposure to Lotilaner was relatively constant in the dog study by oral exposure, this reviewer found the design of monthly administration in the dog acceptable for assessing systemic toxicity in the context of a daily ocular exposure in humans for 6 weeks.”

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

“No juvenile toxicity studies were conducted, although lonafarnib is in this application intended for children. The lack of juvenile toxicity studies has previously been agreed upon. In addition, the age of the animals in the toxicological studies corresponded to human ages from approximately 12 years and older and did not cover the ages of the intended paediatric patients (from 12 months and older).”

“In the rat toxicity studies, mainly the M33 is lower than 50% of the human exposure. Since monkeys were not used in the pivotal EFD studies, the low exposure of M33 in rats is uncertain which may impact the results and conclusion of the reproductive toxicity studies.”

“To better investigate the genotoxic potential of Compound W, the substance itself should have been tested and preferably in a bacterial reverse mutation assay.”

“A rat study conducted with a diluted solution of Defencath did not use high enough levels of the active ingredients to adequately explore the toxicity of taurolidine and identify possible target organs of toxicity (if any).”

“Defencath is not intended for systemic administration, so the Division agreed to waive reproduction toxicity studies for taurolidine and deemed that these data were not needed for labeling.”

“Carcinogenicity 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.”

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

“Concentrations of metabolites M3 and M17 were not directly assessed in pivotal repeat-dose toxicity studies. Instead, levels in these studies were inferred based on the ratio of metabolite to parent observed in non-GLP PK and exploratory studies in relevant species, and no method validation has been submitted for the methods of analysis used to determine metabolite concentrations in these studies.”

“Hence, no safety margin could be determined at the NOAEL for embryo-foetal development with respect to clinical exposure at the 2 mg daily dose (0.2 fold the exposure level), whereas the NOAEL for maternal toxicity of 1 mg/kg/day corresponds to a margin of exposure of 1.7 fold.”

“On a body surface area basis, NOAELs were <0.24 and 720 mg/m2 for guinea pig and monkey, respectively. The human dose is 0.3 mg/m2, resulting in no safety margin.”

“A post-marketing requirement for a juvenile animal toxicology study is recommended to support clinical development of siponimod in the pediatric population under PREA.”

“The Applicant refers to the Agency’s previous findings of safety for the nonclinical pharmacology, pharmacokinetics, and toxicology of the DRSP component of the approved product YAZ® (NDA 021676, approved March 16, 2006) to support the nonclinical safety of drospirenone in Nextstellis.”

“The genotoxicity testing of E4 was not straight-forward. In the first Ames test, E4 was positive, as increased revertants were seen in the TA102 strain.”

“Margins of toxicity are considered to be low, but they are acceptable, considering that the toxicities identified in the programme are clinically well-known from other COC products.”

“In vivo metabolic pathways have not been studied in monkeys. No data on the levels of the two major human metabolites in plasma, the E4-3- and E4-16-glucuronide, is thus available.”

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

“No studies in juvenile animals have been conducted. The lack of such studies is accepted, as the present Marketing Application Authorization refers to the use of Rezzayo in adult patients only.”

“Based on human exposure data and animal toxicokinetics data extrapolated from the 4-week repeated dose toxicity study, there is a low safety margin (2-fold, based on AUC) for the effects observed in male reproductive organs.”

“Considering that the available information suggests that rezafungin may induce dose-dependent intention tremors with relatively low safety margins (2.53 to 6.15- fold, based on systemic exposure [AUC0-168] from the 13-week [NOAEL of 10 mg/kg/dose, since intention tremors were observed at ≥30 mg/kg/dose] and 6 months study [NOAEL of 30 mg/kg/dose, the maximum tested dose])”

“The applicant has submitted a non-clinical package according to the recommendations mentioned in the ICH guideline S9; however, given the long-life expectancy of the patients the claimed indication does not fall under the scope of the ICH S9 guideline.”

“Carcinogenicity studies in mice and rats are warranted to determine the risk of carcinogenicity from vorasidenib for chronic use given the life expectancy of the proposed patient population. Two nonclinical Post Marketing Requirements (PMRs) for rodent carcinogenicity studies were communicated to the Applicant.”

“The claimed indication being out of the scope of the ICH S9 guideline, therefore waiving the conduct of other developmental and reproduction toxicity studies is not considered justified on this sole basis.”

“The lack of longer term toxicity data for metabolite AGI-69460 is not considered acceptable considering that the claimed indication does not fall under the ICH S9 guideline. Formation and accumulation of AGI-69460 is slow in humans, and therefore significant long-term exposure is limited.”

“Potential adverse effects of zuranolone on embryofetal development in pregnant rabbits were not adequately assessed because TK data in satellite animals demonstrated that plasma exposures in some dams were below the limit of detection.”

“In both species the exposure was limited (around 4-fold human exposure in mouse and 4 to 5-fold in rats) but higher doses were not achievable due to pharmacological effects of sedation.”

“Sedation was seen at exposures below the clinical exposure, and tremors were seen at about 5.5-fold the clinical exposure. Higher doses were not achievable due to the sedative effect, but is considered sufficient.”

“In a juvenile rat study with a single dose at PND 7, which corresponds to brain development at the end of the third trimester in humans, apoptotic neurodegeneration in one area of the brain (subiculum) in both males and females was seen. The safety margin is low (1.4-fold at NOEAL).”

“Indeed, the pharmacological relevance of the monkey was therefore questionable, as no cross-reactivity studies with abrocitinib had been presented.”

“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.”

“However, thymomas were evident in females already from the lowest dose, with low margins of exposure to human exposure.”

“No developmental or reproductive toxicity (DART) studies were conducted, consistent with the short duration of clinical use and therapeutic needs of the patient population, but there was no additional data to inform potential endocrine/reproductive toxicity.”

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

“Genetic toxicity was not assessed in any in vivo assay (e.g., rat liver micronucleus formation in vivo to assess clastogenic potential).”

“The preclinical investigations with TCBZ were conducted to support the veterinary product for treatment of fluke diseases. However, the data from these studies are considered valid to support the safety of clinical formulation of TCBZ for the treatment of fascioliasis.”

“As part of the Safety Pharmacology assessments, a stand-alone hERG channel inhibition assay was not conducted with TCBZ. However, in a series of other non-GLP Safety Pharmacology studies, no adverse effects were observed”

“While, overall the repeat-dose study in rats seems adequate, the study design is, to some extent, flawed, as 5 animals per treatment group were housed together in a cage.”

“A second species was not used for investigating the potential effects on embryo-foetal development, which is acceptable in view of the toxicological findings reported in mice (embryolethality, teratogenicity).”

“No specific juvenile toxicity studies have been conducted but studies performed in sexually immature primates and younger mice cover the age of children from 12 years onwards.”

“Aneugenic effects of selumetinb are known as pharmacological action of MEK inhibitors. However, no neoplastic changes were observed in carcinogenicity studies supporting the long-term treatment of children with selumetinib.”

“Since asciminib showed teratogenicity in rats and rabbits at human therapeutic exposures, a pre- /postnatal development study was not performed”

“Although asciminib was tolerated up to the highest dose tested (60 mg/kg), a NOAEL could not be established due to the pancreatic toxicity which was observed at ≥3 mg/kg/day (corresponding to exposure multiples below the intended human dose of 40 mg BID or 80 mg QD).”

“In silico positive impurities were tested with follow up Ames tests. Theses assays were not performed under GLP conditions however according to the study protocols, general rules of OECD and UK MHRA were followed and lack of full GLP compliance is acceptable.”

“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.”

“It was agreed that a definitive juvenile toxicity study in rats is not feasible due to poor tolerance of mavorixafor at low exposures in juvenile rats.”

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

“However, the documentation of the hERG measurements is rather of exploratory nature and the applicant did not adequately justify the lack of GLP compliance, although the study was conducted in 2010, i.e., after implementation of the pertinent ICH S7A and B guidelines in 2001 and 2005.”

“Safety margins based on the Cmax- and AUC0-last-related exposure at the respective NOAELs determined in repeat-dose toxicity studies were negligible in adult or juvenile mice or not existent in dogs when compared to corresponding levels in human DMD patients at the MRHD.”

“We informed the Applicant that based on animal deaths in their 14-day combination study with low and high doses there was now an unknown no observed adverse effect level (NOAEL) and safety margins could not be established to inform dosing.”

“The Applicant did not submit the study protocol for ECAC concurrence on dose selection. The high dose exceeded the MTD and caused excessive decreases in body weight (↓up to 45%), weight gain (↓up to 70%), and food consumption (↓up to 19%), precluding an adequate assessment for carcinogenic effect at this dose.”

“Therefore, the TK data are unreliable to use quantitatively, and they are evaluated only from a qualitative perspective. The safety margin calculations listed in the drug label are based on body surface area and not on exposure data.”

“Conduct a juvenile animal study in rats to support the initiation of clinical studies in pediatric patients from birth to less than 3 years of age.”

“The Division acknowledged the Applicant’s justification for dosing animals every other day in the repeat-dose general toxicology studies.”

“Note that the assessment of histopathology was conducted on Day 3 or Day 4 after the final dose; therefore, the acute assessment of the local effects was not adequate, although clinical observation on the dosing site was conducted at several more acute time points after dosing.”

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

“Most of the study results are derived from the published literature whilst other studies are presented as brief summaries of studies conducted in the 1970s and 1980s.”

“During the review of the NDA, it was determined that the nonclinical data for treosulfan submitted to the NDA in studies or literature for which the Applicant has the right to reference did not provide convincing evidence of DNA alkylation and breaks as the mechanism of action (MOA) of treosulfan or to address genotoxicity potential of the drug.”

“According to the applicant, the margins between the clinical exposure and the exposures in the lowest dose group at which ritlecitinib-related axonal dystrophies were observed (rostral cerebellar vermis at 10 mg/kg/day, study 20099163) are only 6.0-fold in terms of Cmax and 7.4-fold in terms of AUC24.”

“While ritlecitinib was unequivocally an in vitro aneugen, the in vivo relevance of this finding is considered to be low, especially as aneugenicity is generally considered to be a threshold effect and as in vitro aneugenicity was only observed at exceedingly high supra-therapeutic exposures.”

“However, the very small sample size of 4 beagle dogs, actually 3 in the GLP-compliant study, since the data of one dog could not be evaluated, poses an issue with the informative value of the results.”

“Considering that the in vivo safety pharmacology studies have been performed prior to introduction of the ICH S7A guideline and in view of the available GLP-compliant single-and repeated dose toxicity studies and the clinical studies, the lack of GLP compliance is acceptable.”

“Nevertheless, for both rodents, exposure margins obtained at the NOAEL for carcinogenicity are not existing (< 1 x) or rather low (1 – 2 x) with regard to the total concentrations or free concentrations of maribavir based on AUC.”

“These Cmax and AUC exposures have not generally been reached in the non-clinical safety studies, and thus, the non-clinical study package provides no support for this wide therapeutic window.”

“In both species, chronic RDT studies generally may not have explored the full range of aficamten mediated effects in naïve animals due to lack of exposure due to dose limiting aficamten-related (exaggerated) pharmacology. As a result, exposure margins in the chronic RDT studies in rat and dog are below what is expected in ICH M3(R2).”

“The high mortality in the 104-week carcinogenicity necessitated early termination of dose groups.”

“The 2-year rat study, which reached 0.5-fold exposure, similarly demonstrated no concerning signals. Furthermore, M1a was determined to be non-genotoxic based on a comprehensive battery of assays and weight-of-evidence evaluation. Collectively, these data indicate minimal carcinogenic risk for this metabolite, therefore, we conclude that a dedicated carcinogenicity study is not warranted.”

“However, exposure multiples compared to the NOAEL of the clinical exposure demonstrated no margins of exposure within the pivotal long-term repeat-dose toxicology studies (rats: 0.39 (M) for adults and 0.22 (M) for paediatric patients; monkeys: 0.41 (M) for adults and 0.23 (M) for paediatric patients).”

“In monkeys, the studies indicated that gastrointestinal and haematological adverse effects occurred at exposures below those expected clinically. These effects led to early termination of several high-dose groups and shortening of the planned dosing duration, which limits the interpretation of long-term toxicity at clinically relevant exposures.”

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

“Based on the negative results in the in vitro mutagenicity assays and the in vivo micronucleus assays, the weight of evidence supports a negative potential for genotoxicity for sulopenem etzadroxil.”

“However, measurable quantities of formaldehyde were not observed in any of the rat or monkey toxicology studies, although the lower limit of quantitation for formaldehyde in these studies was high, µg/ml.”

“Due to deficiencies in the murine thigh infection model study design and limited interpretability of the findings, the resulting targets (i.e., 16.6 and 20.3% fT>MIC for stasis and 1-log kill, respectively) were deemed unreliable.”

“For relebactam it was noted only males were used in the CV and CNS GLP-studies. However, since no substantial gender differences were observed in the repeat dose toxicology studies, this is considered acceptable.”

“It is noted that no studies on in vivo metabolism of REL have been carried out in rabbit or monkey that were used in reproductive toxicity or CV and repeat dose toxicity studies, respectively. However, since no major REL metabolites have been identified in humans, this is considered acceptable by CHMP.”

“With respect to the 3Rs principles the selection of the monkey should have been further justified. However, the animal models are considered relevant.”

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

“Therefore, M22 was not adequately tested in the general toxicology studies in rat and monkey or in any reproductive and developmental toxicology studies in rat. M22 showed minimal pharmacological activity and was negative in in silico analysis and in a non-GLP Ames assay.”

“No justification for omission of juvenile animal studies was provided by the applicant. However, considering the target organs of toxicity (gastrointestinal tract, liver and kidney) identified in the young and adult animals in pivotal repeat-dose toxicity studies, no higher sensitivity to toxicity in comparison to adults is expected as these organs are already fully developed in the proposed paediatric population (16-18 years”

“As lenacapavir became a suspension at concentrations ≥ 0.1 µM in the DMSO/buffer vehicle used for the patch clamp technique no GLP hERG assay was performed.”

“It should be noted that the toxicological programme has in most cases not been conducted with the exact clinical formulations - especially the SC formulation (lenacapavir sodium 26.46% [w/w], PEG300 50.13% [w/w] and water) where several variations have been used in the toxicological studies (containing variations of combinations of PEG200, PEG300, P188, ethanol and/or NaOH).”

“With regard to the DART studies, the choice of conducting repeated oral exposure in rat (which has low bioavailability) and IV exposure in rabbit means that, in practice, a setup where only one animal model has achieved a higher systemic exposure (i.e., rabbit).”

“A 2-year carcinogenicity study in rats (Study VX-445-TX-015) is ongoing and the division agreed that this study could be completed as a Post-Marketing Requirement based on the unmet medical need in the proposed indication (communication dated Jun 28, 2018).”

“However, potential synergistic effects on fertility were not investigated with the triple combination which is acceptable by CHMP since the observation in rat occurs at exposures above those reached in clinic.”

“As there is no validated animal model for CF that fully mimics the human multi organ affected disease and all three components bind specifically to CFTR, the use of in vitro systems to study the pharmacology of elexacaftor only or in combination with tezacaftor and ivacaftor can be accepted.”

“The animal data supports safety of ceftobiprole medocaril sodium for up to 1 month duration, however, based on clinical data treatments for up to six weeks were permitted. We deferred to the clinical review team on the safety of ceftobiprole medocaril sodium administered for this extended duration.”

“The genotoxicity profile of ceftobiprole medocaril sodium was mixed including a negative Ames assay, a positive mouse lymphoma assay, a negative forward mutation assay, and positive chromosomal assays for both the pro-drug and active metabolite suggesting clastogenic potential.”

“The impurity qualification review indicates that the select individual impurities in the DS and DP are not adequately qualified based on the toxicology studies considered.”

“Of specific concern, data from the rat studies did not provide acceptable safety margins as the DART studies were conducted with short boluses that resulted in systemic exposures below that in humans.”

“In addition, a PMR for juvenile animal studies will be issued to further characterize the potential impact of the drug on the developing brain.”

“In lieu of studies in a second species (rat), the Applicant provided a justification based on experimental evidence to demonstrate that Dextran 40 exposure to the embryo or fetus is negligible to support the safety of dextran.”

“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.”

“Based on a review of these data by the PTCC Genetic Toxicology Subcommittee, it was determined that the risk of in vivo mutation was negligible for givinostat.”

“However, no relevant Cmax- and AUC-based safety margins could be established for givinostat at the respective NOAELs in subchronic and chronic toxicity studies in mice, rats and monkeys compared to the envisaged therapeutic human doses of 25 to 70 mg bid in DMD patients.”

“The toxicologic profiling of cedazuridine in combination with decitabine was limited to a non-GLP 4-week/1-cycle study in cynomolgus monkeys. This study did not evaluate the ASTX727 FDC drug product; instead, monkeys were orally administered separate gelatin capsules containing cedazuridine (1, 3, or 6 mg/kg/day) and decitabine (2 mg/kg/day).”

“CNS safety pharmacology studies were therefore not conducted.”

“The nonclinical pharmacology, ADME/TK, and toxicology data submitted to this NOA, in combination with the nonclinical data submitted to support the approval of decitabine for injection (NOA 21790), are adequate to support the approval of ASTX727 for the proposed indication.”

“Pirtobrutinib is an aneugenic genotoxicant; however, human exposure at 200 mg QD is 12-fold lower than the no effect level for this genotoxicity in rats. Thus, this is not a significant risk for cancer patients.”

“Corneal lesions were only observed in 2 dogs treated for 3 months. To date, this has not been identified as a drug class toxicity and has not been identified as a significant safety finding in the human population but is nevertheless described in the product information as it was observed at 0.42-fold human exposure (at the recommended dose of 200 mg based on AUC).”

“Thus, the effect was considered adverse in male rats and is described in the product information as it was observed at 0.69-fold human exposure (at the recommended dose of 200 mg based on AUC).”

“A 2-year rat carcinogenicity study is currently in progress. The incomplete status of the carcinogenicity testing program is in accordance with the FDA’s prior agreement with the Applicant.”

“As the bioavailability of maralixibat is very low (in general below 1%) the use of doses instead of systemic exposure for calculation of safety margins is acceptable as well.”

“Unfortunately, no measure was taken to prevent access of offspring to the maternal diet in the PPND study, where adverse effects on pups’ body weights were considered due to consuming the maternal diet at the time when the offspring start to eat on their own.”

“In conclusion, safety margins established from the 26-week rat and 52-week monkey studies support the proposed 180 mg/day dose of bempedoic acid and correspond to at least <1 and 13 times the clinical exposure at the human dose of 180 mg, respectively, based on AUC exposures at the nonclinical no observed adverse effect levels (NOAELs).”

“The NOAEL is established as 10 mg/kg/day (at doses resulting in exposures below the clinical exposure, based on AUC) considering the absence of effect on growth and neurobehavior in juvenile rats treated at the high dose (10 mg/kg/day) tested.”

“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.”

“Carcinogenicity bioassays were not considered necessary prior to submission and review of a marketing application because of the unmet medical need for the severely debilitating nature of heterotopic ossification in patients with FOP.”

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

“Because of the exaggerated pharmacology in healthy animal models, no safety margins were established at the palovarotene NOAEL doses of <0.03 mg/kg/day and <12 mg/kg/day in the 26-week rat and 39-week dog toxicity studies, respectively (Table 42).”

“The T cell dependent antibody response (TDAR) assay, respiratory, renal, and CNS safety pharmacology studies were conducted in rats, a pharmacologically non-relevant species for CCX168.”

“No dose-limiting effects or target organ of toxicity were noted in the chronic studies and therefore, the toxicology of avacopan is not considered fully explored. However, the maximum dose levels employed were the maximum feasible dose levels based on dose volume and formulation concentration constraints, and/or formulation tolerability.”

“The selection of the main toxicology species, hamster and Cynomolgus monkeys is justified based on pharmacology and pharmacokinetic data.”

“Although the safety margin of vericiguat on hERG current is high (546-fold), the hERG assay deviates significantly from the new ICH S7B Q&A best practices. Specifically, the study used a different voltage protocol, lacked concentration verification and positive controls”

“This is an N-glucuronide that accounts for 70% of human plasma exposure and in rat and mouse accounts for less than 10% of total exposure, reaching <0.24X the human AUC.”

“A non-clinical PMR will be issued to evaluate developmental toxicity in juvenile rats in order to support dosing for potential studies in a pediatric population.”

“Carcinogenicity studies with leniolisib have not been conducted. The 6-month transgenic (Tg-RasH2) mouse carcinogenicity study and 2-year carcinogenicity study with rats are ongoing under Special Protocol Assessments with ECAC concurrence.”

“A pre- and postnatal development study with leniolisib has not been conducted. A pre- and postnatal development study with rats will be submitted as a post-marketing requirement.”

“While the carcinogenicity study generated adequate clinical exposure margins for the parent drug and its primary metabolite (M30/34) in rats, it provided very low exposure margins to the other two main metabolites (M27 and M18/21).”

“No dedicated male fertility study was conducted. Instead, male reproductive organs were assessed in a repeated dose toxicity study, which is acceptable.”

“The Applicant conducted a non-GLP dose range-finding embryo-fetal development study in Sprague-Dawley rats. Because this study demonstrated clear findings at exposure levels below the clinical exposure at the 13.5 mg human dose, this study was sufficient to characterize the potential developmental risk.”

“Since the currently intended indication of Pemazyre is for treatment of adults, the lack of juvenile toxicity studies in animals is acceptable; pemigatinib was granted a full paediatric waiver for development for the treatment of either cholangiocarcinoma or urothelial carcinoma (EMA decision P/0386/2018).”

“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.”

“It is, however, of note that the data available from the general toxicology studies indicate that the plasma exposures for PB and TUDCA achieved in animals at the highest doses tested in the nonclinical studies were lower than those in humans at the maximum recommended human doses (6 gm NaPB and 3 mg TUDCA).”

“A long–term rat 2-year carcinogenicity study in rats is ongoing and will be submitted post-marketing. During a Pre-submission meeting held on 17 April 2024, the rapporteur agreed that it is acceptable to submit the report of the 2-year rat carcinogenicity study as a post-marketing commitment.”

“The lack of juvenile animal studies is acceptable. The medicinal product has been granted a product-specific waiver for all subsets of the paediatric population.”

“Repeat-dose chronic toxicity studies in rodents and nonrodents have not been conducted with CuHis. PMRs for conducting additional nonclinical studies have not been issued as nonclinical studies to evaluate safety of CuHis are unlikely to provide information beyond what is already known and can be monitored clinically.”

“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. Further, the limited life expectancy of patients with MD negates the need for DART studies in animals to support its use in the clinic.”

“Carcinogenicity studies have not been conducted with ferric maltol.”

“No standalone safety pharmacology studies were conducted for ferric maltol, which is scientifically justified as the active moiety is iron.”

“The Applicant provided a Weight of Evidence (WoE) assessment for avutometinib in lieu of an embryo fetal development study.”

“In the repeat-dose toxicology studies up to 13-weeks duration in rats, myocardial degeneration and necrosis were observed at doses ≥ 0.01 mg/kg/day (below the human exposure at the recommended dose based on AUC).”

“Concerning the association CAB/RPV, it should be acknowledged the lack of combination toxicity studies due to the clinical experience with CAB and RPV, the lack of similar target organ indicating a potential additive/synergic interaction.”

“No study was conducted with the CAB-RPV combination which is acceptable. RPV is already marketed in Europe, and studies conducted in animals have shown no effect on reproductive function.”

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

“Considering the technical challenge of long-term administration via intranasal route in rodents, the rapid biotransformation of etripamil, and the intended intermittent clinical treatment (potentially 36 dosing occasions per year over a lifetime), a chronic toxicity study in one species (cynomolgus monkeys) was considered acceptable.”

“For the NOAELs in the combination studies of enmetazobactam given together with cefepime, the margin to the exposure at the MRHD was 0.71 in dogs and 0.86 or lower in rats.”

“Note: The study design for this study deviated from recommendations in the ICH S5(R3) Guideline. Males in the study were administered vehicle or test article for 1-month during the premating period, but dosing was not continued during the mating period at least until verification of conception as recommended in the Guideline.”

“The Applicant argues that the positive finding in the Ames assay does not indicate a risk to humans because bacterial nitroreductase enzymes contribute to the mutagenicity of fexinidazole and equivalent enzymes in mammalian cells cannot nitroreduce compounds with low redox potential and generate mutagenic by-products.”

“Based on these findings, the NOAEL for maternal toxicity and embryofetal development in the rabbit was 10 mg/kg/day, equivalent to a dose of less than 0.01 times the maintenance dose based on Cmax comparisons).”

“Several deficiencies were evident in the hERG assay, which was not conducted under GLP conditions as per ICH S7B.”

“A definitive juvenile toxicity rat study is agreed in the PIP, with the completion of this study deferred to September 2025.”

“Note that the doses used in these studies assessed approximately 55% of the ICH recommended doses for the trans-isomer (for example if the Ames assay maximal dose is 5000 µg, only about 2500 µg, rather than 4500 µg of the trans-isomer (if voclosporin was assayed) would be assayed for this dose.”

“Therefore, the safety margins are lower than the optimal 10x. However, the toxicological profile of voclosporin was similar to that of cyclosporine and the findings observed were either expected due to the pharmacological action of the drug (e.g., thymic medullary atrophy, absence of germinal centers, lymphomas) and/or to the known class specific adverse effects”

“However, the Applicant did not submit a ≥6-month toxicity study in a nonrodent species and did not provide sufficient scientific justification for why such a study was not warranted to support the safety of unrestricted use of tradipitant over a lifetime for this indication.”

“Metabolite M3 is the only metabolite qualified by the levels present in the nonclinical studies, while M2, M4, and M8 were not measured, not present, or present at low levels in animals and therefore not considered qualified for safety using typical approaches.”

“Although the major active metabolite M21 is not considered qualified based on free exposure in animal species in line with the ICH M3(R2), it can be considered qualified based on pharmacodynamic activities similar to MMB.”

“No in vitro genotoxicity studies were performed with the major active metabolite M21.”

“It is noted, the in vitro hERG assay, in the safety pharmacology package and reported in study 1087275, was carried out under non-GLP conditions. It should have been conducted according to GLP, as stated in ICH-S7B.”

“The main metabolite M11, a direct N-glucuronide conjugate only detected in man and considered inactive was not further studied. This is considered acceptable.”

“The assay was negative, indicating no mutagenic potential of quizartinib in this model, which overrules the positive in vitro findings in the Ames test.”

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

“Carcinogenicity studies in two species (26-week study in TgRasH2 mouse and 2-year study in rat) are to be conducted as post-marketing requirements (PMR), as agreed to by the Division (IND 44020 Type C Meeting Minutes, January 11, 2018)”

“There is currently no information on plasma levels of M47 in animal species. Although M47 is a sulfate conjugate, there are concerns that it may have pharmacological activity, depending on the extent of its distribution into the CNS (Hartneck C. Molecules 18:12012-12028, 2013). The nonclinical safety of these metabolites is to be addressed in studies conducted as PMRs.”

“As the TK analysis was not included in the safety pharmacology studies, the safety margins have been calculated based on the exposure measured in the repeat-dose toxicity studies.”

“The formulation of topical delgocitinib used in the in vivo PD studies (ointment) differs from the suggested commercial formulation (cream). However, this is not considered to impact the assessment of in vivo PD of delgocitinib and the studies were considered acceptable.”

“The plasma AUC values associated with the No-Observed-Adverse-Effect Level (NOAEL) and Lowest-Observed-Adverse-Effect Level (LOAEL) doses in rabbits are approximately 2- and 5-times respectively the plasma AUC exposures expected for fed patients.”

“Results from an in vitro hERG assay indicated that the ibrexafungerp IC50 for hERG inhibition was 1.4-fold higher than the plasma Cmax value associated with the recommended clinical dose of 600 mg/day ibrexafungerp in fed patients.”

“The Applicant was unable to identify an alternative nonclinical species with a similar metabolic profile to humans and, therefore, the rat and dog were used.”

“Oral administration of lumateperone caused systemic intracytoplasmic accumulation of pigmented material in dogs, rats, and mice, with little to no exposure margin relative to the 42- mg MRHD on both a mg/m2 and AUC plasma exposure basis.”

“The in vitro chromosomal aberration assay was inadequate because although gepirone was negative for 5-hour treatment, with and without metabolic activation, this negative finding (without activation) should have been followed up with a study using continuous treatment with gepirone (without activation) for ~ 24 hours (1.5 cell doubling times) in accordance with current guidelines.”

“It is also noted that although the current practice is to express exposure multiples in the labeling based on AUC ratios, the pharmacokinetics and drug metabolism data provide a strong rationale for expressing exposure multiples in the toxicity studies on the basis of body surface area (Mg/M2”

“Since orforglipron is not pharmacologically active in wild-type rodents or rasH2 transgenic mice, the absence of thyroid C-cell neoplasia, an on-target effect, was expected.”

“Off-target safety was further characterized in several nonpharmacologically relevant species, including rats (general toxicology and reproductive safety assessment), rasH2 transgenic mice (carcinogenicity assessment), and rabbits (reproductive safety assessment).”

“The main human metabolite sotagliflozin-3-O-glucuronide was formed in rats and mice at much lower levels than in humans and was not found in dog. Whereas this metabolite is not qualified in these animal studies it is not considered a safety concern, based on experience with other glucuronides.”

“While it is generally not acceptable to disregard an adverse effect that is related to primary pharmacology, and glucosuria would normally be considered an adverse effect, in this case such NOAEL determination would not be meaningful. Glucosuria is the desired effect in the clinical situation.”

“No long-term carcinogenicity study has been conducted, and this was justified by the applicant by referring to ICH guideline S9 (treatment of advanced cancer). However, this is not applicable to fedratinib and instead ICH S1 applies.”

“Although no teratogenic effects were observed in rat or rabbit embryo-foetal toxicity studies, the exposure to fedratinib in these studies was well below the clinical exposure. The relevance of these studies for human safety is therefore limited.”

“With regard to genotoxicity, elafibranor was conclusively demonstrated to be clastogenic in vitro; however, it produced negative results in two in vivo micronucleus tests, as well as in vivo Comet assay and UDS test in liver.”

“It should be noted that GFT3351 is not formed as a major metabolite in rats, thus its genotoxicity in vivo is not considered to be covered by in vivo tests conducted with elafibranor in rats.”

“Findings in the uterus, vagina, and estrous cycle observed in the 4-week toxicity study were not observed following a 4-week recovery period. Recovery was not assessed in the 3-month study in rats.”

“For genotoxicity, one impurity RO7304383 was tested in Ames test in a non-GLP study, whereas the other impurity, RO7304403, was investigated in silico analysis of genotoxicity and is considered qualified.”

“It should be taken into consideration that low margins of exposure ranging from 0.3 to 2.4 were observed in the 28-day and 13-week repeat-dose studies in rat and dog. And in general, the observed exposure at NOAEL levels were similar or below the exposure level at the maximum human recommended dose.”

“The Applicant did not conduct definitive GLP genotoxicity assays with M68 and M11.”

“Thus, we were unable to conclude that TRV0109662 had been adequately qualified with respect to an impact on embryo-fetal development.”

“If the drug product is approved in this review cycle, the following additional studies are recommended as post-marketing requirements as outlined in the agreed initial Pediatric Study Plan:”

“As revumenib caused clear evidence of embryo-fetal effects, further embryo-fetal studies were not conducted.”

“A juvenile study was not requested by the FDA, and the Applicant conducted this study at their discretion.”

“The submission did not adequately address the carcinogenicity potential of belumosudil for chronic use. Given that the patient population includes subjects with non-cancerous conditions and long life expectancy, rodent studies should be conducted to determine the risk of carcinogenicity from belumosudil.”

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

“Upadacitinib is a potent teratogen in rats and rabbits, with NOAELs in these studies associated with exposes similar to or less than the proposed clinical dose. While other approved JAK inhibitors are also teratogenic, the review team expressed concern regarding the lack of exposure margins between the embryo-fetal toxicity and the proposed clinical dose level.”

“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.”

“At the NOAEL, male AUC is lower than (~0.1x), and female AUC is approximately equal to (~0.8x), human AUC at the MRHD.”

“The Applicant’s drug specification proposed a limit for the enantiomer impurity (EB-1070) which was above the qualification threshold recommended in the ICH Q3A(R2)1 guidance. Based on the toxicology data submitted by the Applicant, the proposed limit for the EB-1070 impurity is considered qualified.”

“Since the QTc-prolonging potential of solriamfetol has been qualitatively and quantitatively characterized on basis of the aforementioned studies, the position of the Applicant not to repeat in vitro hERG and isolated cardiac tissue studies under formally GLP-compliant conditions appears acceptable.”

“Although TK is not performed, drug-related clinical signs and changes in body weight gain and food consumption were observed and were consistent with previous repeat dose studies in the rabbits, therefore qualitatively confirming drug exposure.”

“In the repeat-dose toxicology studies in rats and dogs, systemic exposure of ZAAD-1006a was not assessed, and therefore its toxicological potential was not evaluated.”

“The suboptimal study design in which both sexes received pexidartinib prior to mating makes clear attribution of the reduced fertility by sex impossible.”

“Exposure in animals at the ‘no observed adverse effect level’ (NOAEL) were all below human exposure at the clinical dose of 600 mg QD (Table 63). Key to interpreting the toxicology data is to understand that the nonclinical toxicology studies were conducted in healthy and non-anemic animals, in which vadadustat produces polycythemia.”

“Vadadustat was negative for mutagenicity (Ames assay) but positive results were obtained in the in vitro CHO assay for chromosomal aberrations and the GreenScreen assay.”

“Although there was no separate male fertility study in this drug development program, it is not considered an approvability issue. Assessment of tapinarof effects on male fertility was conducted in the 4-week subcutaneous rat study.”

“From a pharmacology/toxicology perspective, the applicant’s proposal of setting the acceptable limit of these two impurities at times higher than TTC of 1.5 µg/day appears reasonable, because (1) the clinical route of administration for tapinarof is topical, which provides very limited amount of systemic exposure of these impurities; (2) two carcinogenicity studies have been conducted with tapinarof and no drug-related neoplasms was noted;”

“Overall, the nonclinical studies are adequate to support approval of ozanimod for the proposed indication, although systemic exposures to the two major (and active) human metabolites (CC112273 and CC1084037) were lower in several pivotal studies than in humans at the maximum recommended human dose (0.92 mg/day).”

“Dr. Toscano concluded that the PPND study is inadequate because of the lack of sufficient exposure to CC1084037 and recommended the metabolite be assessed in a PPND study as a post-marketing requirement.”

“No effects were seen in the 50 mg/kg/day group which is the NOEL for this effect. Based on AUC-exposure data at the NOEL of 50 mg/kg/day, no safety margin to human exposure at the MRHD exists for this effect.”

“The study has not included a toxicokinetic analysis. Based on data from the repeated dose toxicity studies in rats, it is estimated that systemic exposure (AUC) in rats at 350 mg/kg/day was 21-fold human exposure.”

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

“In all toxicity studies (except carcinogenicity), plasma exposure (Cmax and AUC) at the no-observed adverse effect level is less than those in humans at the MRHD suggesting potential risk even at the therapeutic dose range.”

“No TK assessments of M34.5 have been performed in any of the pivotal safety studies (including carcinogenicity and reproductive toxicity studies) conducted in the rat.”

“Since no inhibition on PCC (plasma corticosterone concentration) in rats and monkeys not infused with ACTH is seen, toxicity associated with cortisol inhibition cannot be studied.”

“An in vitro chromosomal aberration test was not conducted with M6-SUZ. However, the chromosomal aberration potential of M6-SUZ was assessed through the in vivo micronucleus assay that tested the parent SUZ, which was negative for genotoxicity.”

“Because of the low number of monkeys in the study, the lack of recovery groups, and known variability in male reproductive organ weights in this species, the nonhuman primate data do not provide an ideal model to evaluate the potential risk of SUZ to male reproductive tissues in these longer duration studies.”

“PMR 4655-1 Conduct a juvenile toxicity study to evaluate the potential toxicity of deuruxolitinib, including the potential effects on growth, development, and reproduction, when administered orally to juvenile rats.”

“It was positive in an in vitro micronucleus assay. The positive response could be due to a potential aneugenic effect.”

“No in vitro affinity or potency studies have been presented in the primary pharmacology section to assess the relevance of dog for the cardiovascular and respiratory studies which is a deficiency.”

“Several deficiencies were identified with regards to bioanalysis. Despite these deficiencies, it is concluded that bioanalysis/TK data from the most critical studies can be considered reliable.”

“The battery of nonclinical studies conducted to support clinical development and a marketing application for rimegepant was adequate, except for the completed pre- and postnatal development study in rat, which had several deficiencies.”

“In addition, a juvenile animal toxicology study should be a PMR to support clinical development in pediatric patients <12 years of age, under PREA.”

“The applicant states that a 2-year oral carcinogenicity study in the rat is ongoing. A genotoxic concern based on the positive mutagenicity results of the M50 metabolite cannot at this point be excluded.”

“In a 13-week study, exposures at the NOAEL were similar to or slightly higher than anticipated human exposures at the proposed dose. In a 26-week study, exposures at the NOAEL were lower than predicted human exposures.”

“The Applicant stated that in vivo studies were conducted in normal C57BL/6 mice and in the murine Hbbth3/+ model of β-thalassemia, another hemolytic anemia, because suitable animal models of PKD were not available during the early development of mitapivat.”

“NOAEL is 25 mg/kg/BID (1.2× MRHD, based on AUC) and 50 mg/kg/BID (2.2× MRHD, based on AUC) in males and females, respectively, based on the occurrence of subcapsular inflammation/necrosis at higher doses.”

“Many of the nonclinical legacy general toxicity and reproductive and developmental toxicity studies were completed in the 1970s, before the good laboratory practice (GLP) regulation was implemented; therefore, they are not in full compliance with GLP.”

“The Agency expressed concern over the lack of a safety margin between the no observed adverse effect level (NOAEL) exposures for seizures in animals and the blood levels already attained in clinical trials.”

“Selection of high dose for carcinogenicity study should be 50-fold ratio (AUC) in TgrasH2 mice according to ICHS1, however the multiple of exposure ratio for the 1000 mg/kg high dose are only 8.5-4.37 fold (males-females) for Daridorexant, and comprised between 5.3 and 7.7 fold for metabolites.”

“Based on the maternal death and cataplexy-like clinical signs, 300 mg/kg/day was selected as the high dose for the current study, which is acceptable, although 450 mg/kg/day could have been selected and tested as the high dose.”

“Whereas a NOAEL was established at the highest tested dose level of 300 mg/kg/day in the 39-week dog study, no NOAEL was established in the 26-week rat study due to an increased incidence and severity of endocrine pancreas fibrosis, haemorrhage and pigment at all tested dose levels (i.e., doses of 30, 300, and 1000 mg/kg/day).”

“Given ocular and neurobehavioral findings in the completed juvenile toxicity study in rats, an additional PREA PMR will be issued for a repeat juvenile toxicity study in older rats that approximate children 6 years of age.”

“As the product is intended to be administered for the treatment of hot flushes in menopausal women, sub-chronic and chronic studies were performed in female animals only, which is acceptable.”

“Considering the proposed indication for the treatment of hot flushes associated with menopause, the dosing of only female animals is considered acceptable.”

“No in vivo studies were performed by the applicant. The CHMP considered that at the time of the preclinical development of tafamidis, an animal model of ATTR-PN that would reflect the clinical disease or resemble the pathology was not available, and that none of the transgenic animals described in the literature reproduce the pathology seen in ATTR patients.”

“The carcinogenic potential of tafamidis was not studied in a long term rodent carcinogenicity study. This was considered acceptable given the severity and low incidence of the disease together with the fact that no alert signals were identified in the nonclinical studies conducted including the TgrasH2 mouse model.”

“The NOAEL was 2.5 mg/kg with Cmax of 12.4 ng/ml representing 2.4-fold of the expected clinical exposure which is not considered acceptable as a safety margins. As this effect appears in the clinical exposure range it is included in the RMP part II module SII and the SmPC section 5.3.”

“Despite impurity BLU112316 level (0.55%) is above the qualification thresholds defined in ICH Q3A (0.15%), it is qualified up to 0.78% based on the 3-month rat toxicity study.”

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

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

“No non-clinical PD drug interaction studies were performed and a justification that PD interactions of endothelin antagonists and angiotensin receptor blockers with other drugs have been well characterised in the past was provided. The approach is acceptable to the CHMP.”

“Similarly, the dedicated study to assess respiratory function (0849PH1) was declared as non-GLP compliant; fruquintinib had no effect on respiratory system.”

“Because of the deficiencies in the embryo-fetal studies in rats and mice, a new embryo-fetal study of acceptable design in rats will be conducted as a postmarketing requirement.”

“Analytical methods (C-AT120019 and C-AT120020) used in repeat dose toxicity studies in rats and dogs, however, are not GLP compliant. It was, however, sufficiently demonstrated that the analytical methods supporting GLP repeat dose toxicity studies were adequately validated, as these were in compliance with domestic reliability standards.”

“The in vivo rat micronucleus test (report # 02-226) dose selection was inadequate.”

“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.”

“However, it is notable that the M2 metabolite, a principal metabolite in humans present at ~10% of the parent pacritinib, is not a predominant metabolite in any of the nonclinical species.”

“A programme of juvenile animal studies was initiated in rats aged 10 days to support paediatric development of rilzabrutinib from 1 year of age, but subsequently deleted from the PIP due to extension of the waiver to patients below 10 years of age.”

“As of metabolites, partial information was provided. Therefore, the applicant committed to conduct additional post-authorisation studies to confirm the structure of the metabolites.”

“Based on extensive clinical experience with amisulpride, outside of the Unites States, at higher doses, the Division agreed that a 28-day repeat dose toxicity in a single species would be adequate for the proposed indication in which only a single dose will be administered.”

“As aldosterone synthase inhibition was not likely achieved at the doses tested in these rodent studies, the findings are considered an off-target assessment; notably, low aldosterone has not been identified in the published literature as an independent risk factor for carcinogenicity.”

“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.”

“The omission of conducting ADME study of BGB-3111 in dog was justified in the next round of assessment by the following points: i) In vitro metabolic profiles (liver microsomes) were similar between rat, dog and humans.”

“As per previous agreements, no nonclinical toxicology studies were submitted in the IND (IND 117053). Only published pharmacology studies were submitted in the IND.”

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

“Though the Applicant did not submit a definitive GLP-compliant in vitro study, the available GLP-compliant safety studies have provided sufficient safety data along with this supportive study.”

“The NOAEL was determined to be 0.1 mg/kg/day, which does not provide a margin of safety to support study of pediatric patients <12 years of age. An additional juvenile toxicity study in juvenile rats starting at postnatal day 21 will be required (refer to Postmarketing Requirements and Commitment, Section 14) below.”

“Metabolite RDC-1066 was discovered in human plasma late in clinical development and was not measured in initial nonclinical toxicity studies. Therefore, a series of nonclinical GLP PK bridging studies were conducted in rats, mice, dogs, and rabbits administered oral doses of SAM for 5 to 14 consecutive days”

“A number of adverse effects were observed in the test animals at dose levels comparable or even lower than the anticipated clinical exposure.”

“Only four studies on genotoxic potential of impurities were conducted in compliance with GLP. Three of the impurities were tested positive in the non-GLP AMES tests and three impurities were tested negative.”

“The justification is basically that there is no need for a follow up. This statement is in contrast to the ICH S10 Guidance on photosafety evaluation of pharmaceuticals as well as the advice given by CHMP.”

“The study in female mice was not adequate because the HD was not adequately justified; it was not demonstrated to be a maximum tolerated dose or maximum feasible dose and did not achieve plasma exposures at least 25-fold that at in humans at the MRHD.”

“Lasmiditan was negative in a bone marrow micronucleus assay in ICR mice (IV); however, the study was not adequate because systemic exposure to all major human metabolites was not demonstrated.”

“The applicant explained that further embryo-foetal development studies were not conducted with capivasertib as it has been shown to be embryolethal.”

“Given the indication, the long-life expectancy and prolonged treatment, it is important to address the carcinogenicity potential of belzutifan for chronic use. Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”

“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.”

“Unfortunately, it was not performed with hamster S9 mix, at least at low concentrations as it is known to be cytotoxic for many cell cultures. In addition, no nitrosamine positive controls were included in the study.”

“Nonclinical studies adequately bridged the data from studies conducted with tosylate salt to those conducted with the free base, and both sets of studies contributed to characterizing the toxicity profile of crinecerfont.”

“No secondary pharmacodynamic and pharmacodynamic drug interaction studies were performed by the applicant, which is considered acceptable, considering the high level of selectivity of tivozanib hydrochloride for the VEGF pathway.”

“Genotoxicity studies paused based on the uncertainty about the genotoxic potential of the M13 metabolite of GSK 1278863 following the results of mouse lymphoma assay and the initial mouse liver comet assay”

“The genetic toxicity of the M9 metabolite was not directly tested and is not warranted since the active pharmaceutical ingredient (i.e., zidesamtinib) is genotoxic.”

“Although tirbanibulin is a genetic toxicant, this matter may be appropriately addressed through labeling. The product is intended for short-term use only, which partially assuages concerns about genotoxicity.”

“In general, low exposure margins based on systemic exposure at NOAELs or LOAELs were observed in animal studies, and corresponded to clinical exposures at or below the recommended human dose of 240 mg/kg/day.”

“The FDA agreed that due to the significant findings in the non-GLP dose-range finding embryo-fetal development studies in rats and rabbits that additional GLP-compliant studies do not need to be conducted.”

“The nonclinical deficiency was an inadequate evaluation of brain in the pivotal toxicity studies in dog, a concern raised by the finding of brain mineralization in rat.”

“It was noted that the two in vitro studies were not conducted in compliance with GLP standard. Furthermore, there was no control group and no analysis related to the effect of the metabolite and one of the diastereomers in the non-conscious dog study.”

“Hence, the safety margin based on exposures at the NOAELs in the chronic toxicity studies in rat (20mg/kg/day) and monkey (30mg/kg/day) is 3.8 and 1.5 respectively.”

“Due to low survival of water and vehicle control animals, the study was terminated early during Week 91 for males and Week 89 for females. However, at least 28 animals/sex in each group survived to Week 80, which provided enough animals to adequately evaluate carcinogenicity.”

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

“It is concluded in this review that the reliance on ONO-1101 literature for nonclinical support is justifiable since both products share the same active salt and appear to be pharmaceutically equivalent. Both products are administered intravenously for the same medical condition and comparable PK parameters were obtained for the LAN and Onact in healthy volunteers at the same doses.”

“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.”

“Oxalic acid was not detected in toxicity studies in rats and dogs and was not investigated further in clinical studies. However, resmetirom associated oxalic acid intake and exposure is expected to be in the physiological range, hence it was agreed that further studies were not necessary.”

“The safety margin on the GLP cardiovascular telemetry study in monkeys was low (NOEL = 0.65 mg/kg (Cmax 0.13 µg/mL; 3X RHD Cmax). Clinically, hemodynamic changes occurred in BMS-986165-treated subjects with psoriasis, however the changes were not clinically meaningful.”

“Further, binding of capmatinib to mutated MET were not thoroughly investigated during the nonclinical development. At this point, clinical data could provide a justification for the absence of these studies.”

“The safety margins at all dose levels was <1 based on a comparison of Cmax or AUC values in rat and dog toxicity studies to the human exposure (6284 ng*hr/mL; Cycle 1, Day 15) at the recommended dose of 125 mg QD, reflecting the greater sensitivity of the nonclinical species in the toxicology program to the pharmacologic effects (ie, inhibition of FGFR1‐3) of infigratinib.”

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

“Phototoxicity studies have not been conducted with atrasentan.”

“Furthermore, an effect on QT prolongation of M3 and M6 will be evaluated post authorisation by an automated patch-clamp test on M3 and M6 for their effects on the hERG potassium channel current in vitro (non-GLP).”

“Also, a repeat dose juvenile toxicity study is ongoing to inform dosing in patients from birth to less than1 year of age. A postmarketing commitment for the study completion and final report submission dates will be issued upon approval.”

“There was a small increase in visceral malformations at the HD; however, teratogenic potential could not be fully evaluated because of the high rate of embryofetal deaths, which resulted in an inadequate number of fetuses examined.”

“exhibited antibacterial activity and produced cytotoxicity in bacterial lawns in concentrations of ≥ mcg/plate. As a consequence, only low concentrations of could be tested in this assay, and the mutagenicity potential of higher concentrations were not assessed.”

“Although allopregnanolone is an endogenous neuroactive steroid, it is not clear if there is a threshold effect above which increased apoptotic neurodegeneration would occur.”

“The cardiovascular malformations in rabbit fetuses justify a concern for a clinically significant risk to embryo-fetal development. These finding were observed in one of the two animal species tested. The exposure multiple at which the fetal cardiovascular malformations occurred is low (approximately 2.1 times the human AUC at 120 mcg/kg).”

“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.”

“No data was presented however a thorough justification was presented including affinity to MR with aldosterone in rabbit and mouse preparations and presentations on sequence homologies of the receptors.”

“A predominant metabolite, CORT125295, was identified in human plasma that was not present in rodent species. The Applicant provided a weight of evidence assessment for the safety of CORT125295.”

“While the fertility in the rats recovered after a 4-week recovery period, there was incomplete reversibility of the histopathology in the epididymides in rats and dogs. Analyses of sperm count and viability have not been conducted in animals or humans.”

“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.”

“PTC also requested a carcinogenicity waiver on March 20, 2023. Following a review of PTC’s weight of evidence document which was proposed in lieu of conducting a 2-year rat carcinogenicity study, the Agency informed PTC on June 2, 2023, that the neoplastic and preneoplastic findings observed with sepiapterin in rats necessitated a 2-year rat carcinogenicity study.”

“No dedicated carcinogenicity studies were conducted with aprocitentan. Aprocitentan is a major metabolite of macitentan, and its exposure represented ≥38% of the total exposure to macitentan and aprocitentan in the macitentan carcinogenicity studies. Therefore, the macitentan carcinogenicity studies, conducted in B6C3F1 mice and Wistar rats, were considered acceptable to assess the carcinogenic potential of aprocitentan.”

“The sponsor subsequently conducted a cardiovascular study in minipigs using telemetry (71456) which was too flawed for regulatory use.”