Which nonclinical studies did approved monoclonal antibodies skip?

“Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.”

“No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab.”

“Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg.”

“Genotoxicity studies are not considered relevant for a biological product in accordance with ICH S6.”

“Instead, a comprehensive risk assessment including feasibility assessment of available animal models for carcinogenicity testing was performed. Based on the weight of evidence the risk of carcinogenicity can be considered low.”

“In an animal reproduction study, intravenous administration of crizanlizumab-tmca to pregnant cynomolgus monkeys from the onset of organogenesis through delivery resulted in a non-dose related increased fetal loss (abortions/stillbirths) at doses approximately 2.8 times the exposure at the recommended clinical dose at 5 mg/kg/dose once every 4 weeks”

“Genotoxicity No studies have been performed in accordance with ICH S6(R1).”

“In line with ICH S6 (R1), a weight of evidence approach has been provided which suggests that there are no identified concerns for increased carcinogenic risk with the use of tralokinumab.”

“No treatment-related adverse effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development were observed in the infants from birth to 6 months of age.”

“No genotoxicity studies of aducanumab were conducted because antibodies are generally unable to interact with genetic material.”

“Carcinogenicity studies of aducanumab were not conducted because its target, aggregated Aβ, is not present in wild-type rodents. No increases in the incidence or severity of proliferative lesions were observed in the 4-week study in monkey or the 13- or 26-week studies in aged Tg2576 mouse.”

“There were no adverse effects on fertility and early embryonic development, embryofetal development, or pre- and postnatal development in studies of aducanumab (0, 100, 300, and 1000 mg/kg/week IV) conducted in rat.”

“no genotoxicity studies have been conducted, in accordance with ICH S6(R1).”

“Carcinogenicity studies were waived, based on the lack of erenumab activity in rodents, histopathological data from the submitted toxicology studies showing no carcinogenic risk factors (i.e. hyperplasia or neoplasia)”

“The results from the enhanced PPND study were unremarkable; therefore, the NOAEL was 50 mg/kg.”

“Genotoxicity studies have not been conducted, in accordance with ICH S6(R1).”

“Based on published studies in CGRP knockout animals and on the biological activity of CGRP (e.g., promotion of angiogenesis) and on the results from the sponsor’s studies of fremanezumab, it was concluded that standard carcinogenicity studies of fremanezumab were not needed.”

“Reproductive and developmental toxicity was assessed in a fertility + EFD study in rats, a EFD study in rabbits and a PPND study in rats. These studies have not revealed any adverse effects on fertility and pregnancy outcome.”

“According to ICH S6(R1), genotoxicity studies were not performed.”

“A thorough weight of evidence evaluation, in combination with data from the repeat dose toxicity studies, which included exposure to concizumab up to 52 weeks, does not suggest that concizumab has carcinogenic potential.”

“In a 26-week toxicity study in sexually mature male and female cynomolgus monkeys with subcutaneous doses up to 9 mg/kg/day (corresponding to 3400-fold the human exposure, based on AUC 0 to 24h ), concizumab-mtci did not affect fertility”

“Genotoxicity studies with biologics such as garadacimab are not required.”

“Based on the weight of evidence, the Division agreed with the Applicant that a rodent carcinogenicity study was not technically feasible. Further, there appears to be a low or negligible carcinogenic potential based on the results of the 26-week monkey study and review of the published literature regarding chronic inhibition of FXIIa.”

“For the F1 generation, no garadacimab-related effects were observed on mortality, clinical signs, body weight, developmental signs, functional observation battery, eye-blink response, presence of motile sperm, reproductive performance, cesarean section parameters, or preweaning or postweaning macroscopic observations.”

“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”

“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with obiltoxaximab.”

“The No-Observed-Effect Level (NOEL) of ETI-204 for maternal and developmental toxicity was determined to be 32 mg/kg/dose, the highest dose tested”

“The lack of genotoxicity studies is considered justified according to ICH S6”

“2) ofatumumab is not pharmacologically active in rodents and so the standard carcinogenicity bioassays are unsuitable, 3) there is no scientific evidence to suggest that depletion of B cells by any other anti-CD20 therapeutics leads to cancer”

“While the high dose was a no-effect dose for adverse developmental effects, a no-effect dose for mortality and immune effects in offspring was not established because of the limited number of evaluable offspring at the low dose.”

“No genotoxicity studies were performed.”

“No studies have been conducted to assess potential of bevacizumab for carcinogenicity or mutagenicity.”

“The maternal NOAEL was 10 mg/kg. The foetal NOAEL was less than 10 mg/kg, since all treatment doses reduced foetal weights and number of ossification sites, whereas the two higher treatment doses produced a statistically significant increase in multiple malformations.”

“Not conducted per ICH S6.”

“Not conducted per ICH S6, ICH S1, and ICH S9.”

“Reproductive and developmental toxicology studies were not conducted with avelumab. Instead, the Applicant submitted a non-product specific literature based assessment of the potential for avelumab to affect reproduction.”

“No genotoxicity studies were conducted. Belimumab is a monoclonal antibody and is not expected to interact directly with DNA or other chromosomal material.”

“CHMP concurred with the Applicant’s argumentation that the potential risk for malignancy with belimumab can only be evaluated in a clinical setting; the proposal for a clinical post-marketing safety study was supported.”

“There was no evidence of maternal toxicity, effects on embryofetal and infant survival, or structural abnormalities at exposure approximately 9 times the MRHD of 10 mg/kg intravenously or 20 times the MRHD of 200 mg subcutaneously”

“No genotoxicity studies have been conducted. Since brolucizumab is an antibody fragment, the lack of genotoxicity studies is in accordance with the available guideline ICH S6 (R1) and this point is accepted.”

“Similarly, no carcinogenicity studies have been conducted with brolucizumab, as noted in ICH S6 (R1), standard carcinogenicity bioassays are generally not performed for biotechnology-derived pharmaceuticals.”

“There was no impact of IVT administration of brolucizumab on embryo-fetal development, pregnancy or parturition; or on the survival, growth, or postnatal development of offspring at 6 mg/eye (10-fold the MRHD on a mg/kg basis).”

“Genotoxicity studies have not been conducted with nirsevimab. In accordance with ICH S6(R1), genotoxicity studies are not required for biologics as they are not anticipated to interact with DNA or other genetic material.”

“Carcinogenicity studies have not been conducted with nirsevimab. A weight of evidence approach was conducted in accordance with the FDA’s recommendations and applicable ICH guidelines for establishing the carcinogenic potential of nirsevimab and did not reveal any specific carcinogenic risk.”

“In accordance with ICH guideline S6(R1), no dedicated studies have been conducted to evaluate the effects of nirsevimab on fertility, embryo-foetal, and prenatal and postnatal development.”

“No genotoxicity studies have been conducted with bimekizumab in line with ICH S6 (R1) guideline.”

“In conclusion, the literature does not suggest a clear concern that inhibition of IL-17A and IL-17F would lead to carcinogenicity or tumor development.”

“The no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was identified as 50 mg/kg/week which is 38 times (based on mg/kg comparison) the maximum recommended human dose”

“Genotoxicity assays are not recommended for biological therapeutics. An Ames assay was conducted, and results were negative.”

“Carcinogenicity studies were not required because ublituximab is not active in rodent; therefore, standard carcinogenicity studies are not feasible.”

“Weekly intravenous administration of ublituximab-xiiy (0 or 30 mg/kg) to pregnant monkeys during the first, second, or third trimester of pregnancy produced a severe immunogenic response in dams, resulting in maternal morbidity and death and embryofetal loss.”

“In line with ICH S6(R1), genotoxicity studies are not considered relevant for proteins and were not performed with caplacizumab.”

“In line with ICH S6(R1), no carcinogenicity studies have been performed. No carcinogenic risk was identified based on the pharmacological mode of action, results from chronic dosing toxicity studies in Cynomolgus monkey (up to 26 weeks)”

“The placental transfer study with caplacizumab in pregnant guinea pigs qualitatively demonstrated foetal exposure to caplacizumab but exact concentrations could not be measured in the foetuses. Exposure of the dams had no effects on foetal development.”

“The lack of genotoxicity testing was considered acceptable, as in accordance with the ICH S6 guideline, the range and type of genotoxicity studies routinely conducted for pharmaceuticals are not applicable to biotechnology-derived pharmaceuticals and therefore are not needed.”

“The CHMP also considered acceptable that no carcinogenicity testing was performed, taking into account the lack of an appropriate animal model, the well-established risk of indirect tumorigenicity caused by prolonged immunosuppression”

“When alemtuzumab was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6–10 or GD 11–15) at intravenous doses of 3 or 10 mg/kg, no teratogenic effects were observed. However, there was an increase in embryolethality”

“Certolizumab pegol was not genotoxic in the Ames test, the human peripheral blood lymphocytes chromosomal aberration assay, or the mouse bone marrow micronucleus assay.”

“No conventional carcinogenicity testing was performed with certolizumab pegol, which was acceptable considering the nature of the compound and the lack of pharmacological activity and immunogenicity of certolizumab pegol in species normally used for such testing.”

“In female rat studies covering dosing throughout the complete reproductive cycle, there were no effects on fertility, reproductive function or developmental effects on offspring.”

“Genetic toxicity studies were not applicable for this therapeutic biologic protein though reslizumab was negative in two in vitro assays.”

“A transgenic mouse (Tg.rasH2) carcinogenicity study was conducted with dose concurrence by the Executive Carcinogenicity Assessment Committee (ECAC). No drug-related neoplasms were found after dosing up to 500 mg/kg IV once every two weeks.”

“No effects on fertility or development parameters were identified at doses up to 50 mg/kg IV; exposure margins of approximately 6-fold were available in the mouse studies.”

“Based on the ICH Guideline for the Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (ICH S6(R1) 2011), genotoxicity studies have not been conducted for secukinumab which is acceptable to CHMP.”

“Since secukinumab cannot be tested in a traditional 2-year rodent study to evaluate carcinogenic potential due to its species specific binding, the sponsor will monitor malignancy in psoriasis patients administered secukinumab as a part of a comprehensive Risk Management Plan.”

“Therefore, the NOAEL for maternal toxicity was determined to be 150 mg/kg/week but for fetal toxicity the NOAEL was 50 mg/kg/week.”

“Genotoxicity and carcinogenicity studies are generally not appropriate for biotechnology-derived monoclonal antibodies such as burosumab. No genotoxicity or carcinogenicity studies have been conducted by the Applicant; this is endorsed.”

“Overall, it is agreed that the carcinogenicity risk of burosumab appears to be low.”

“The Applicant’s proposed NOAEL at 3 mg/kg for pre- and postnatal development in fetuses and offspring is agreed with. It is also agreed that burosumab did not induce teratogenicity in monkeys up to a dose of 30 mg/kg.”

“In accordance with ICH S6, the Applicant did not submit genotoxicity studies; routine tests for genotoxicity are not applicable to biotherapeutics”

“In accordance with ICH S9 the Applicant did not conduct carcinogenicity studies with ramucirumab because these studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”

“Dedicated reproductive toxicology studies examining the effects of ramucirumab administration to animals during pregnancy have not been conducted. Instead the Applicant submitted a literature based assessment of the potential effects of inhibition of VEGFR2 signaling during pregnancy.”

“Y-mAbs has not conducted genetic toxicology studies with naxitamab. In accordance with ICH S6 and ICH S9, these studies are not considered necessary to support a marketing application for a biotechnology-derived pharmaceutical intended to treat advanced cancer.”

“Y-mAbs has not conducted carcinogenicity studies with naxitamab. In accordance with ICH S6 and ICH S9, these studies are not considered necessary to support a marketing application for a biotechnology-derived pharmaceutical intended to treat advanced cancer.”

“Y-mAbs did not conduct dedicated studies to assess fertility or carcinogenicity and these studies are not warranted to support the development of a drug intended to treat patients with advanced cancer. In addition, because the age of the proposed patient population is primarily ≤5 years old, FDA did not request an embryo-fetal development study to support the use of naxitamab.”

“No genotoxicity studies were conducted with daratumumab (as per ICH S6) and no carcinogenicity were conducted with daratumumab (as per ICH S6 and S9).”

“ICH S9 also outlines that carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer, and as such no carcinogenicity studies were needed.”

“No developmental and reproductive toxicity studies were performed. Developmental and reproductive toxicity testing is not feasible in chimpanzees.”

“Genetic toxicology studies are not applicable to monoclonal antibodies and were not conducted with dupilumab based on ICH S6 guidance”

“No carcinogenicity studies were conducted. However, an assessment of the carcinogenic potential of dupilumab was made based on literature data on the role of the IL-4/IL-13 pathway in tumour development and on non-clinical data for both REGN646 and REGN1103.”

“The effect of IL-4Rα blockade on reproductive and developmental toxicity was evaluated in a fertility study in mice which and in an ePPND study in cynomolgus monkeys. No adverse effects were noted.”

“Genotoxicity studies have not been conducted with ansuvimab-zykl. In accordance with International Council for Harmonisation (ICH) S6(R1), genotoxicity studies are not required for biologics.”

“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not required as ansuvimab-zykl will be administered as a single intravenous (IV) infusion.”

“Dedicated reproductive toxicology studies have not been conducted with ansuvimab-zykl. In accordance with ICH S6(R1), reproductive toxicology studies are generally not required for biologics to exogenous targets.”

“Genetic toxicology studies are not applicable to monoclonal antibodies and were not conducted with lebrikizumab based on ICH S6 guidance.”

“There was no evidence of tissue proliferation (i.e., hyperplasia, pre-neoplastic lesions) or immunosuppression in the 9-month intravenous toxicology study in cynomolgus monkeys that received lebrikizumab doses up to 25 mg/kg/week. The overall data suggest that lebrikizumab has low carcinogenic potential.”

“No embryofetal toxicity or malformations, or test article related effects on morphological, functional, or immunological development were observed in the infants from birth through 6 months of age. The NOAEL for maternal and developmental toxicity was 150/50 mg/kg/week (loading/maintenance doses).”

“Consistently with ICH S6(R1) guidance, genotoxicity studies were not conducted because galcanezumab is a monoclonal antibody.”

“Carcinogenicity studies were not required, based on the potential for galcanezumab to counter CGRP associated angiogenesis and immunosuppression, specificity of galcanezumab for CGRP, lack of structural alerts on galcanezumab”

“No drug-related effects were observed in the fetuses/offspring of either species. The only maternal finding of note was a death (Lactation Day 15) at the high dose in the pre- and postnatal study; the cause of death was not identified.”

“No genetic toxicology studies were conducted. Genetic toxicology studies are generally not necessary to support marketing of biotechnology-derived pharmaceuticals such as elotuzumab as discussed in the ICH S6 guidance document.”

“No carcinogenicity studies were conducted. Carcinogenicity studies are not necessary to support the marketing of therapeutics intended to treat patients with advanced cancer as discussed in the ICH S9 guidance document”

“No reproductive and developmental toxicology studies were conducted due to the lack of a pharmacologically-relevant animal species.”

“Genotoxicity studies have not been conducted with MK-1654. In accordance with ICH S6(R1), genotoxicity studies are not needed for biologics as they are not anticipated to interact with deoxyribonucleic acid (DNA) or other genetic material.”

“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”

“In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets. In addition, no male or female reproductive toxicities were observed in the 2-week repeat-dose toxicology study in rats (Study TT #16-1029)”

“No genotoxicity studies were performed with sutimlimab, as monoclonal antibodies are generally considered devoid of mutagenic or clastogenic risk.”

“Given the absence of proliferative lesions observed at either dose tested in the chronic monkey study and the lack of any identified tumorigenic risk based on the mechanism of action and a search of the relevant scientific literature, it is unlikely that sutimlimab possesses significant tumorigenic potential.”

“There were no adverse effects on reproductive or developmental outcomes at 180 mg/kg/week, which represents 4 times the human exposure at the 7.5 g clinical dose.”

“No genotoxicity studies of satralizumab were conducted because antibodies are generally unable to interact with genetic material.”

“Carcinogenicity studies of satralizumab were not conducted because satralizumab does not bind to rat or mouse IL-6R, and the use of a mouse homolog antibody was determined not to be feasible because of immunogenicity.”

“In the ePPND study, administration of satralizumab (0, 2, and 50 mg/kg/week SC) to pregnant females resulted in a dose-dependent reduction in the antibody responses to antigenic challenge in infants.”

“Genotoxicity studies were not conducted as vedolizumab is a humanized monoclonal antibody and so are not required in-line with ICH Guideline S6(R1).”

“In accordance with ICH Guideline S6(R1), conventional carcinogenicity studies (i.e., rodent bioassays) have not been conducted with MLN0002 to assess its carcinogenic potential as it lacks pharmacological activity in mice and rats.”

“MLN0002 did not cause any adverse effect on embryofetal development in rabbits or on pre- and postnatal development in monkeys.”

“the applicant decided to perform a partial genotoxicity study using in vitro and in vivo assays in terms of an AMES test and a rat micronucleus test. No genotoxic potential of Cetuximab was observed.”

“Based on the life-expectancy in the intended therapeutic indication, no long-term carcinogenisity studies are required80.”

“While no fetal malformations occurred in offspring, there was an increased incidence of embryolethality and abortions at doses approximately 1 to 4 times the recommended dose of ERBITUX based on BSA.”

“Genotoxicity testing was not performed. The product is a recombinant IgG2 protein of naturally occurring amino acids and is not expected to react with DNA or other chromosomal material.”

“A low incidence of osteosarcoma (2/54) was observed in high dose males at 19x human exposure. However, the lack of statistical significance of this finding and the large exposure multiple suggests that romosozumab is unlikely to increase the human risk of osteosarcoma.”

“Findings in the definitive FEED and EFD studies included reduced ventral processes of the 6th cervical vertebrae at doses of 100 and 300 mg/kg (17-56x human exposure).”

“no genotoxicity studies were performed with evinacumab, per ICH S6.”

“The Applicant submitted a weight of evidence carcinogenicity assessment for evinacumab based on available evidence from relevant literature and completed animal toxicology studies, which suggested that there is no identified risk of carcinogenicity for evinacumab.”

“The reproductive toxicity of evinacumab was assessed using male and female fertility endpoints collected from the chronic 26-week monkey toxicity study, and by conducting combined female fertility/early embryonic/pre and postnatal development study in rats, embryofetal development studies in rats and rabbits”

“No genotoxicity studies were conducted as monoclonal antibodies do not directly interact with DNA or other chromosomal material, which is in line with ICH S6(R1) guideline.”

“No carcinogenicity studies were conducted. The applicant conducted a weight-of-evidence (WoE) assessment to evaluate the potential of depemokimab to cause carcinogenicity.”

“No developmental and reproductive toxicity (DART) studies were conducted. The DART risk with depemokimab was assessed using a weight-of-evidence (WoE) approach.”

“Genetic toxicity studies were not applicable for this therapeutic biologic protein.”

“Carcinogenicity studies were not conducted since rodents are not pharmacologically relevant species. AstraZeneca submitted a carcinogenicity risk assessment that was evaluated by the CDER Executive Carcinogenicity Assessment Committee.”

“Benralizumab was not teratogenic in cynomolgus monkeys. The NOAEL for maternal toxicity and teratogenicity was identified at 30 mg/kg.”

“No genotoxicity studies were conducted with emapalumab as per International Conference on Harmonisation S6.”

“No carcinogenicity studies were conducted with emapalumab as per International Conference on Harmonisation S6.”

“The surrogate antibody was detected in the plasma of all treated pregnant mice and their corresponding fetuses. No maternal toxicity occurred and there was no evidence of teratogenicity or effects on embryo-fetal survival or growth.”

“Evaluation of the genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”

“The lack of carcinogenicity studies is considered acceptable based ICH S6 guidance.”

“With regard to the offspring, a complete depletion of B-lymphocytes was observed at both tested dose-levels. B-lymphocyte counts and immunologic function (TDAR) in the infants returned to almost normal levels within 6 months following birth.”

“The in-vivo test was a mouse micronucleus assay involving single iv injection of trastuzumab at 29.5, 59 and 118 mg/kg. All tests gave clearly negative results.”

“Herceptin has not been tested for carcinogenic potential.”

“Reproductive function: No effects on menstrual cycles or sex hormone profiles Embryotoxicity: No maternal toxicity, embryotoxicity or teratogenicity Peri-/Post-natal toxicity: No maternal, foetal or neonatal toxicity”

“No genotoxic effects were seen. This is not a complete genotoxicity test battery (see CPMP/ICH/174/95, S2B). However, for a monoclonal antibody, genotoxicity tests are considered to be of limited value and are therefore not needed (CPMP/ICH/302/95, S6).”

“No carcinogenicity study was performed with adalimumab. The lack of such studies is justified because there is no conventional or alternative model available, (i.e adalimumab has low/no affinity for mouse/rat TNFα, and MAHA developed after single doses).”

“There were no treatment related effects on the maternal animals, gestation, parturition, on fetuses or on the infants.”

“As a monoclonal antibody, genotoxicity assessment of marstacimab was not scientifically appropriate and therefore was not conducted.”

“Based on the WoE provided by the Applicant, the Division agreed that marstacimab is unlikely to pose a significant carcinogenicity safety concern for humans and therefore considered a 2-year study in rats unlikely to provide additional useful information.”

“The study identified no adverse effects at 1000 mg/kg/week (i.e., the no observed adverse effect level (NOAEL), which represented exposure >200-times the clinical exposure at the MRHD).”

“No genotoxicity studies were performed with canakinumab, as it is a protein. This is acceptable according to guideline ICH S6.”

“No carcinogenicity studies were performed with canakinumab. According to guideline ICH S6 carcinogenicity studies are generally not required for monoclonal antibodies.”

“Taken together the reproductive toxicity studies in marmosets and in mice did not identify a signal for reproductive toxicity by neutralization of IL-1b.”

“No genotoxicity studies were performed, in line with ICH S6(R1).”

“Taken together the weight of evidence supports the position that tildrakizumab is unlikely to be associated with increased carcinogenic risk.”

“An embryofetal developmental study conducted with tildrakizumab in pregnant monkeys revealed no treatment-related effects to the developing fetus when tildrakizumab was administered subcutaneously during organogenesis to near parturition at doses up to 159 times the maximum recommended human dose (MRHD). When dosing was continued until parturition, an increase in neonatal death was observed at 59 times the MRHD (see Data).”

“No genetic toxicology studies were conducted.”

“Nipocalimab is a mAb which does not cross-react with rodent FcRn, precluding the conduct of traditional carcinogenicity studies. In line with ICH guideline S6(R1) and based on a WoE approach it was concluded that nipocalimab does not pose an increased carcinogenic risk.”

“These infarcts were associated with fetal loss (one stillborn fetus) at 100 mg/kg and 300 mg/kg (two aborted fetuses).”

“No genotoxicity studies were carried out.”

“No carcinogenitity studies were carried out.”

“Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth), and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab.”

“No studies were conducted in accordance with ICH S6(R1).”

“The Applicant did not conduct carcinogenicity or genetic toxicology studies as they are generally not appropriate for antibody therapies.”

“Under the conditions tested, there were no effects on maternal toxicity or embryo‐fetal mortality or malformations at doses up to 30 mg/kg administered once weekly during the period of organogenesis from GD20 to GD48 in an embryo‐fetal toxicity study in cynomolgus monkeys.”

“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”

“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”

“Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss.”

“Genetic toxicity studies were not applicable for this therapeutic biologic monoclonal antibody.”

“Based on species specificity, a rodent carcinogenicity study with sarilumab was not considered feasible. The Executive Carcinogenicity Assessment Committee (ECAC) concurred that a carcinogenicity study was not feasible.”

“There were no observed effects on fertility in mice. In an expanded prenatal and postnatal development study in monkeys, no effects on evaluated parameters in neonates were observed. The NOAEL was the high dose of 50 mg/kg/week.”

“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for pembrolizumab.”

“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”

“Dedicated nonclinical studies investigating the effects of pembrolizumab on embryofetal development are not warranted at this time to support its use in the intended patient population.”

“No genotoxicity studies of donanemab were conducted because antibodies are generally unable to interact with genetic material.”

“Carcinogenicity studies of donanemab were not conducted because its target, human AβN3pE-x peptide, is not present in wild-type rodents, and carcinogenicity studies in transgenic rodents are not feasible.”

“Developmental and reproductive toxicity studies were not conducted based on the age of the indicated population.”

“Not conducted per ICH S6.”

“Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer (ICHS9). In addition, there were no findings observed in the 39-week repeat-dose study in monkeys that would indicate a carcinogenicity risk”

“IMC-1E10 was teratogenic at maternal IMC-1E10 exposures below the human exposure to olaratumab at the recommended dose of 15 mg/kg.”

“Studies evaluating genotoxicity of biotechnology products, are not mandatory in accordance with ICH S6 guideline”

“On March 19, 2014, the applicant was informed that a carcinogenicity assessment of lecanemab would not be necessary based on the development of neutralizing anti-drug antibodies in rodents treated with lecanemab or the mouse surrogate, mAb158.”

“No reproductive and developmental toxicology studies were conducted with lecanemab. The sponsor was informed on November 6, 2012, that reproductive and development toxicology studies are not required”

“Not conducted per ICH S6.”

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

“Embryo-fetal developmental toxicology studies were not conducted with cemiplimab. Rather, consistent with the alternative approach to providing information on the potential for reproductive toxicity described in ICH S6(R1) and ICH S9, the Applicant provided a literature”

“No genotoxicity testing was conducted. Toripalimab is a large protein molecule and per ICH S6(R1), the range and type of genotoxicity studies “are not applicable to biotechnology-derived pharmaceuticals and therefore are not needed.””

“No carcinogenicity studies were conducted. In accordance with ICH S6(R1) “Standard carcinogenicity bioassays are generally inappropriate for biotechnology-derived pharmaceuticals””

“In the pivotal 4-week and 26-week GLP-compliant toxicity studies, evaluation of sexually mature male and female cynomolgus monkey reproductive tissues (organ weights, macroscopic and microscopic examination) did not reveal any adverse effects of toripalimab on reproductive organs.”

“There were no studies on genotoxicity or carcinogenicity. This is acceptable due to the nature of the compound.”

“Animal studies have not been conducted to determine the carcinogenic potential of ranibizumab.”

“Administration of ranibizumab to pregnant monkeys throughout the period of organogenesis resulted in a low incidence of skeletal abnormalities at intravitreal doses 13-times the predicted human exposure”

“Not performed per ICH S6(R1).”

“Not performed per ICH S6(R1), ICH S1A, and ICH S9.”

“Treatment with 50 and 100 mg/kg margetuximab-cmkb resulted in oligohydramnios beginning on GD 75. An infant mortality occurred on post-natal day 63 following maternal exposure to 100 mg/kg margetuximab-cmkb.”

“Genotoxicity studies are generally not necessary to support marketing of biotechnology-derived pharmaceuticals such as tafasitamab as discussed in the ICH S6 guidance document.”

“Carcinogenicity studies are not necessary to support the marketing of therapeutics intended to treat patients with advanced cancer as discussed in the ICH S9 guidance document.”

“Based on a prior agreement with the FDA, the Applicant did not conduct reproductive and developmental toxicity studies with tafasitamab since tafasitamab is administered in combination with lenalidomide, a known teratogen and embryo-fetal toxicant.”

“Genetic toxicology studies are not needed to support the development of nemolizumab, per the International Council for Harmonisation (ICH) S6(R1) guidance”

“There was no evidence of tissue proliferation (i.e., hyperplasia, preneoplastic lesions) or immunosuppression in the 6-month repeat-dose subcutaneous toxicity study in monkeys.”

“Early postnatal death occurred in the offspring of one control monkey and 3 monkeys at 25 mg/kg (36 times the MRHD for PN and 50 times for AD, based on AUC comparison).”

“No formal genotoxicity studies for axatilimab have been conducted. Since monoclonal antibodies are not expected to interact directly with DNA”

“Because axatilimab is not active pharmacologically in rodents, conventional carcinogenicity studies in mice or rats are not relevant for axatilimab.”

“The mechanism of action of axatilimab, the embryo-lethal and phenotypic effects of CSF-1 and CSF-1R deficiency and the role of CSF-1 and CSF-1R in the reproductive system collectively indicate the potential risk for axatilimab on reproductive and embryo-fetal development.”

“Genetic toxicity studies were not applicable for this therapeutic biologic protein.”

“The need for a carcinogenicity study was discussed with the Executive Carcinogenicity Assessment Committee and it was concluded that a carcinogenicity study was not required given the lack of related findings in the 6-month toxicology study in monkeys and since conduct of a study in rodents did not appear to be technically feasible.”

“No effects on fertility or development parameters were identified in monkeys at doses up to 100 mg/kg IV; exposure margins of approximately 70-fold and 30-fold were available for fertility and developmental parameters, respectively. Similarly, no effects on fertility or embryofetal development parameters were identified in mice treated with the surrogate antibody.”

“Genetic toxicology studies were not conduct for ocrelizumab, consistent with ICH S6 guidance.”

“The sponsor submitted a carcinogenicity assessment waiver request under IND 100593 (Serial No. 0675, February 4, 2016). The waiver was granted”

“The results of this study demonstrate an effect on gestation length in dams and adverse effects of ocrelizumab on the neonate, including an increase in stillbirths and neonatal death, B-cell depletion, and microscopic changes in kidney and bone marrow.”

“Not conducted, in line with ICH S6(R1).”

“In general, an overview of the published literature supports that neutralization of IL-23 would not be expected to increase cancer risk, but rather IL-23 increases tumor incidence and promotes tumor growth and progression.”

“However, incidences of embryo/fetal loss were higher in the treated groups compared to control (6.7% [1 of 15] in controls vs 26.7% [4 of 15] at 300 mg/kg) but were within the range of historical control data.”

“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for nivolumab.”

“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”

“maternal nivolumab administration at both doses was associated with fetal/neonatal mortality characterized by: 1) dose-dependent increases in third trimester fetal losses (12.5% and 33.3% at 10 and 50 mg/kg, respectively, relative to 7.1% in controls)”

“The mutagenic potential of garetosmab-grts has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.”

“a weight of evidence carcinogenicity assessment, and tissue cross-reactivity studies.”

“Severe developmental toxicity occurred at 50 mg/kg (approximately nine-times the maximum clinical exposure based on AUC), with 100% mortality of all spontaneously delivered offspring by postnatal Day 6.”

“FDA agrees that genetic toxicology studies are not needed to support the use of penpulimab per ICH S6.”

“Carcinogenicity studies were not conducted with penpulimab, which is consistent with its use in patients with advanced malignancies (see the ICH Guidance S9).”

“No reproductive or embryo-fetal developmental toxicology studies were conducted with penpulimab. Rather, the Applicant provided a literature-based assessment of the potential reproductive toxicity of penpulimab”

“There were no nonclinical genotoxicity or carcinogenicity studies performed with pertuzumab, as per the guidance provided in the International Conference on Harmonisation (ICH) guidance S6”

“According to ICH S6 (R1) guideline standard carcinogenicity bioassays are generally not appropriate for biotechnology derived pharmaceuticals and according to ICH S9 carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with late stage or advanced cancer.”

“Pertuzumab caused fetal lethality in pregnant monkeys treated with loading doses of ≥ 30 mg/kg followed by bi-weekly doses ≥ 10 mg/kg (approximately 0.2 to 2-fold greater than the exposure at the recommended human dose, by AUC).”

“No genotoxicity studies were conducted as crovalimab is a biotechnology-derived pharmaceutical.”

“Based on the mechanism of action, review of the literature, drug class, and the lack of drug-related preneoplastic lesions in monkeys administered crovalimab for up to 26 weeks, the risk of carcinogenicity of crovalimab is low. Crovalimab is not active in rodents; therefore, carcinogenicity studies are not feasible.”

“The NOAEL for pre- and postnatal development was 100 mg/kg/dose in this study, corresponding to exposure levels (AUC) 5- to 14-fold higher than in humans at the maximum recommended dose.”

“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for necitumumab.”

“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”

“Cetuximab was detected in amniotic fluid and the serum of embryos from treated dams and caused embryolethality and abortions at doses of 1.6 to 4 times the recommended human dose.”

“Not conducted per ICH S6(R1).”

“Not conducted per ICH S6(R1), S1, and S9.”

“administration of mogamulizumab to pregnant cynomolgus monkeys from the start of organogenesis through delivery did not show a potential for embryo-foetal lethality, teratogenicity, or foetal growth retardation.”

“Alirocumab is not expected to interact directly with DNA and mutagenicity studies were not conducted, in accordance with ICH-S6.”

“Weight of evidence supported the waiver of carcinogenicity studies with alirocumab; no formal carcinogenicity assessment was conducted, per ICH-S6.”

“Reproductive and developmental toxicity studies were conducted in rats and monkeys; no teratogenic effects were observed at exposure margins of 12-fold and 81-fold, respectively. Alirocumab did not produce any effect on fertility parameters evaluated as part of the 6-month toxicity study in monkeys.”

“No carcinogenicity or genotoxicity studies have been conducted with idarucizumab.”

“Studies to evaluate the mutagenic and carcinogenic potential of idarucizumab have not been performed as based on its mechanism of action and the characteristics of proteins no carcinogenic or genotoxic effects were anticipated.”

“No treatment-related effects have been identified in reproductive tissues of either sex during repeat dose intravenous toxicity studies of up to four weeks in the rat and two weeks in monkeys.”

“No studies were conducted. Denosumab is a recombinant protein and contains no inorganic or synthetic organic linkages or other non-protein portions.”

“No carcinogenicity studies were conducted in accordance with available regulatory guidance. Ovariectomized monkey treated for up to 16 months with denosumab showed no evidence of pre neoplastic lesions.”

“In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes, abnormal bone growth, and decreased neonatal growth”

“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.”

“Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.”

“A single embryonic-fetal development study was conducted in pregnant, healthy New Zealand White rabbits administered two intravenous doses of raxibacumab up to 120 mg/kg (three times the human dose on a mg/kg basis) on gestation days 7 and 14. No evidence of harm to the pregnant dam or the fetuses due to raxibacumab was observed.”

“Genotoxicity tests are considered to be of limited value for this type of product. Still, a complete test battery has been performed. Infliximab did not show any genotoxic activity in these studies.”

“These data gave no support for the hypothesis that inhibition of TNFα is associated with an enhanced risk for tumour development.”

“In these experiments, it was demonstrated that cV1q crossed the placenta but there was no indication of impairment of reproductive function, embryotoxicity or teratogenicity.”

“Evolocumab is not expected to interact directly with DNA and mutagenicity studies were not conducted, per ICH-S6.”

“Evolocumab did not cause any drug-related tumors when administered to hamsters for up to 2 years in a lifetime carcinogenicity assay at doses administered once every other week that provide a 38-, 15- and 6.6-fold safety margin”

“In an expanded developmental study in monkeys in which offspring were followed into infancy for 6 months, no significant drug-related effects were observed.”

“The lack of reproductive, mutagenic, genotoxic and carcinogenic studies is justified, and SPC has been amended appropriately.”

“No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of RITUXAN or to determine potential effects on fertility in males or females.”

“Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum.”

“No genetic toxicology studies were conducted.”

“Based on a weight of evidence assessment, conduct of carcinogenicity studies were deemed not necessary for UCB7665.”

“Subcutaneous administration of 0, 50, or 150 mg/kg UCB7665 every 3 days to pregnant female cynomolgus monkeys from gestational day (GD) 20 through parturition caused embryonic losses in 3 of 19 females at both doses.”

“Genetic toxicity studies have not been conducted with anifrolumab. Genetic toxicity studies are generally not applicable for biotechnology-derived pharmaceuticals such as anifrolumab, as discussed in the ICH S6(R1) guidance document.”

“Carcinogenicity studies with anifrolumab were not conducted. Anifrolumab does not bind to murine IFNAR1 and does not inhibit the biological activity of murine IFN-α.”

“There was no evidence of anifrolumab-fnia related maternal toxicity, embryo-fetal toxicity, or post-natal developmental effects.”

“The FDA concurs with the Applicant that genotoxicity studies are not warranted per ICH guidance S6.”

“No fertility and early embryonic development, or carcinogenicity studies have been conducted or are warranted based on the proposed indication.”

“Effects observed in target antigen CD38 knockout animal models include the depletion of fetal CD38 positive immune cells and a decrease in bone density.”

“Based on ICH S6 (Guideline for the Safety Evaluation of Biotechnology-Derived Pharmaceuticals) guidelines, no genetic toxicology studies were conducted with brodalumab.”

“Therefore, it is impossible to know the carcinogenicity risk of brodalumab.”

“Under the experimental conditions, a NOAEL for embryofetal development and for prenatal and postnatal development was identified as 90 mg/kg/week.”

“Genotoxicity studies as outlined in ICH S2B (1997) have not been conducted for golimumab.”

“No carcinogenicity study was performed with golimumab as standard rodent studies are not meaningful due to lack of pharmacologic activity in this species. However, with the current knowledge, a possible risk for the development of lymphomas or other malignancies in patients treated with a TNF-antagonist cannot be excluded.”

“In cynomolgus monkeys, no adverse effects were seen related to golimumab treatment, including effects on the immunological development in the F1 infants followed for 6 months post delivery.”

“Negative results have been obtained in the Ames test and in chromosomal aberration tests with V79 Chinese Hamster Cells as expected for a proteinous substances like Simulect.”

“No long-term or fertility studies in laboratory animals have been performed to evaluate the potential of Simulect to produce carcinogenicity or fertility impairment, respectively.”

“No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgus monkeys 100 days post coitum following dosing with basiliximab during the organogenesis period; blood levels in pregnant monkeys were 13-fold higher than those seen in human patients.”

“Genetic toxicology studies were not needed to support the development and approval of risankizumab, per the ICH S6(R1) guidance.”

“Overall the risk for malignancy associated with long-term inhibition of IL-23 following administration of risankizumab to humans is considered to be low.”

“However, as compared to the control group, a dose-dependent increase in fetal/infant loss was noted in the risankizumab-treated groups. The percent fetal/infant loss was 19%, 32%, and 43% in the vehicle control, 5 mg/kg, and 50 mg/kg groups, respectively.”

“Non-clinical genotoxicity studies are not generally considered relevant to biotechnology products (ICH S6 guideline).”

“The 26-week repeat dose toxicity study with a murine anti-mouse C5 antibody (BB5.1mAb) showed no cytotoxic or proliferative activities suggestive of carcinogenic risk at dose levels up to 60 mg/kg/week”

“When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death.”

“Genotoxicity and stand-alone safety pharmacology studies were not conducted.”

“there are no concrete reasons to believe that inhibition of IL36R by spesolimab would lead to carcinogenicity. The Executive Carcinogenicity Assessment committee (ECAC) concurred with this conclusion.”

“The maternal and developmental NOAELs were both 50 mg/kg/dose.”

“Genotoxicity tests were not conducted.”

“Direct evaluation of carcinogenic potential of CNTO 1275 (STELARA, ustekinumab) in carcinogenicity studies or rodent tumour immune surveillance models is precluded by the limited species reactivity of CNTO 1275 (STELARA, ustekinumab) which does not bind to or neutralise IL-12 or IL-23 from mice or rats.”

“In studies of embryo-fetal development in cynomolgus monkeys dosed intravenously or subcutaneously and pre-and post-natal development dosed subcutaneously, there were no effects on gestation, parturition, lactation or morphology or development of the offspring.”

“Genetic toxicology studies were not conducted or needed per ICH S6 guidance.”

“Rodent carcinogenicity studies have not been conducted with siltuximab. Evidence from studies conducted with siltuximab and other IL-6 inhibitors suggest that the potential for siltuximab to cause carcinogenicity is low.”

“Siltuximab crossed the placenta and resulted in reduced globulin levels in pregnant animals and in the offspring; this may be secondary to a decreased production of immunoglobulin as expected from the pharmacology of this product.”

“Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.”

“Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.”

“Pregnancy Category C: Synagis® 110 is not indicated for adult usage and animal reproduction studies have not been conducted.”

“No genotoxicity studies have been performed for lanadelumab in accordance with ICHS6. This is considered acceptable.”

“The conduct of carcinogenicity studies in rodents was not feasible based on the development of ADA in SD rats after repeated dosing. Based on the results of the 39-week study in monkeys as well as evidence from the available scientific literature, chronic inhibition of bradykinin production via DX-2930 treatment is unlikely to affect carcinogenic risk in HAE patients.”

“In the ePPND study in pregnant cynomolgus monkeys administered once weekly doses of 10 or 50 mg/kg (highest dose tested), there were no lanadelumab-related effects on pregnancy and parturition, embryo foetal development, survival, growth, and/or postnatal development of offspring.”

“Based on ICH S6 (Guideline for the Safety Evaluation of Biotechnology-Derived Pharmaceuticals) guidelines, no genetic toxicology studies were conducted with ixekizumab.”

“Thirdly, the literature does not suggest an increased risk for tumorigenicity in relation to neutralisation of IL-17. Overall, the carcinogenic potential of ixekizumab was considered to be low.”

“No treatment-related effects were observed during these studies. Neonatal deaths occurred in the infants of two monkeys administered ixekizumab at 5 mg/kg/week and two monkeys administered ixekizumab at 50 mg/kg/week.”

“Genotoxicity studies have not been conducted, which is in accordance with ICH S6(R1).”

“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9. Furthermore, due to its mechanism of action, atezolizumab is not expected to be associated with an increased carcinogenic risk.”

“Reproductive and developmental toxicity studies have not been conducted with atezolizumab. However, in the chronic toxicity study in sexually mature monkeys, atezolizumab treatment at the high-dose resulted in irregular menstrual cycles and a lack of newly formed corpora lutea in the ovaries.”

“Genotoxicity studies have not been conducted, in accordance with ICH S6(R1).”

“Based on the mechanism of action and supporting literature, the risk of carcinogenicity can be expected to be low.”

“Teprotumumab reduced fetal growth (measured by ultrasound in-life; body weight and measurements at C-section) and was clearly teratogenic in all 5/5 fetuses.”

“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”

“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”

“Given the role of the PD-1/PD-L1 pathway in maintaining materno-fetal tolerance, treatment with tislelizumab during pregnancy may lead to abortion or still births.”

“In line with the guideline on the pre-clinical safety evaluation of biotechnology-derived pharmaceuticals (ICH S6 R1), no genotoxicity studies were carried out.”

“The conduct of carcinogenicity studies in rodents was not feasible as tezepelumab does not bind to rodents’ TSLP. Therefore, a carcinogenicity risk assessment was conducted.”

“In the maternal, embryo-fetal, and neonatal toxicity (ePPND) study, pregnant female cynomolgus monkeys were dosed Q7D at 50 or 300 mg/kg IV from early gestation through delivery. There were no tezepelumab-related effects (maternal, fetal, or infant).”

“Genetic toxicology studies are not applicable to mAbs and were not conducted with guselkumab based on ICH S6R1 guidance”

“does not support a causal mechanistic/target-related link between IL-23 inhibition and increased cancer risk”

“no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of guselkumab during organogenesis through parturition at doses up to 30 times the maximum recommended human dose (MRHD). Neonatal deaths were observed at 6- to 30-times the MRHD”

“As ibalizumab is a biotechnology-derived protein product made of natural amino acids, and as per ICH S6(R1), genotoxicity studies are not applicable and therefore have not been conducted.”

“The conclusion of this report made by the applicant was that given the weight of evidence, ibalizumab is not expected to be carcinogenic. Standard 2-year carcinogenicity studies in rodents or 6-month studies in transgenic mice were not possible, because ibalizumab does not bind rodent CD4.”

“In a reproductive study in monkeys, reversible decreases in CD4+ T cells and B cells and increases in CD8+ T cells were observed within the first 4 weeks after birth in infants born to pregnant monkeys receiving ibalizumab-uiyk intravenously ( see Data ).”

“There were no indications for a mutagenic potential as expected for a protein-like monoclonal antibody nor for potential contaminants or product excipients in the drug product.”

“Standard short or long term carcinogenicity studies were not performed due to the proteinous nature of the test article. Two in vitro and three in vivo studies were performed to study the effects the natalizumab on human α 4 expressing tumour cell lines in vitro and in vivo (as transplants into SCID and nude mice).”

“Natalizumab treatment at 30 mg/kg resulted in a significant reduction (approx 50%) in pregnancy rates, an effect that was not seen at 0; 3 or 10 mg/kg.”

“No genetic toxicology studies have been conducted with teplizumab or the surrogate.”

“The short duration of treatment, the absence of pharmacologic activity in the rodent (for teplizumab itself), and the observations of anaphylaxis and hypersensitivity following various dosing regimens in the rodent limit the utility of carcinogenic assessments”

“In an embryofetal development study there was an increased incidence of post-implantation loss at the HD of 20 mg/kg that included the loss of the entire litter for multiple females leading to identifications of the MD (0.3 mg/kg) as the NOAEL.”

“In line with ICH S6 (R1), genotoxicity studies were not performed with ALXN1210.”

“The carcinogenic potential of ALXN1210 in animals is unknown. However, in the 26‐week repeat dose toxicology study in mice with BB5.1, multiple hematopoietic neoplasms (lymphoma/lung/salivary glands/thymus) occurred in 1 high dose female (60 mg/kg/week)”

“When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, 2 cases of retinal dysplasia and 1 case of umbilical hernia were observed among 230 offspring”

“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for dinutuximab.”

“Carcinogenicity studies were not required to support the licensing application for a product intended to treat advanced human cancer”

“In the repeat-dose toxicity studies, administration of dinutuximab in male and female rats resulted in no adverse effects on reproductive organs at exposures that were at least 60 fold higher than those observed clinically.”

“Consistent with ICH S6(R1) guidance, no genotoxicity studies were conducted with cosibelimab as its large molecular weight prevents it from entering the cytoplasm/nucleus of cells and subsequently interacting with deoxyribonucleic acid (DNA).”

“Per ICH S9, no carcinogenicity study or carcinogenicity risk assessment was performed.”

“A literature-based risk assessment of developmental and reproductive risk was conducted in lieu of performing developmental and reproductive toxicology studies.”

“No genotoxicity studies were conducted, which is acceptable in accordance with ICH S6.”

“In accordance with the weight of evidence approach outlined in ICH S6 (R1), the applicant has presented argumentation for waiving of carcinogenicity studies.”

“Animals that received IV doses (0, 3, or 30 mg/kg) inebilizumab weekly beginning 15 days prior to mating and through GD15 showed reduced fertility index at both dose levels.”

“Panitumumab has not been evaluated in genotoxicity studies.”

“No carcinogenicity or mutagenicity studies of panitumumab have been conducted.”

“There were no fetal malformations or other evidence of teratogenesis noted in the offspring; however, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).”

“Genetic toxicology studies with pozelimab have not been conducted, in accordance with ICH S6(R1).”

“Carcinogenicity studies with pozelimab have not been conducted. The Applicant conducted a carcinogenicity risk assessment for pozelimab and concluded that the carcinogenic potential is low.”

“No adverse effects of pozelimab were observed on male or female fertility parameters in the 26- week repeat-dose toxicity study at doses up to 100 mg/kg/week. Additionally, no adverse effects of pozelimab were observed on maternal or infant health or on juvenile development at doses up to 50 mg/kg/week”

“Genotoxicity studies were not conducted for sibeprenlimab, a monoclonal antibody, which lacks the ability to directly interact with DNA.”

“A carcinogenicity risk assessment was submitted by the applicant, which was reviewed under the IND. Rodent carcinogenicity studies were deemed not to be warranted to establish an adequate assessment of carcinogenicity risk for sibeprenlimab.”

“subcutaneous administration of sibeprenlimab once every 2 weeks to pregnant cynomolgus monkeys from gestation Day 20 through delivery did not result in any adverse effects on embryofetal or postnatal development at one tested dose of 101 mg/kg”

“Genotoxicity studies have not been conducted in accordance with ICH S6(R1).”

“Since blockade of CGRP would prevent these effects, the carcinogenic risk associated with eptinezumab is considered low.”

“The NOAEL was 150 mg/kg/week in the rat fertility, rat and rabbit embryofetal development, and rat pre- and postnatal studies.”

“No genotoxicity studies have been conducted per ICH S6 and ICH S9 guidelines.”

“No carcinogenicity studies have been conducted. Zolbetuximab. is intended for the treatment of patients with advanced cancer in the scope of the ICH S9.”

“In an embryo-fetal development toxicity study, zolbetuximab was intravenously administered to pregnant mice during the period of organogenesis and did not result in embryo-fetal toxicity at doses up to 300 mg/kg (approximately 1.9 times the recommended clinical dose based on AUC).”

“A standard Ames test was negative. A full genotoxicity test battery and carcinogenicity evaluation have not been conducted for omalizumab, due to the absence of a relevant species appropriate for such studies.”

“No carcinogenicity study with omalizumab was performed since omalizumab does not bind rodent IgE.”

“at doses of 0, 3, 15 and 75 mg/kg once daily on Days 20-22, and then once weekly through Day 50 did not elicit maternal toxicity, embryotoxicity or teratogenicity.”

“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”

“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”

“In animal reproduction studies, narsoplimab-wuug was administered subcutaneously and intravenously twice weekly to pregnant mice and rabbits during organogenesis at dose exposures up to 22 and 91-fold, respectively, the human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC).”

“No standard genotoxicity battery of studies was performed with ipilimumab.”

“considering the lack of relevance of the rodent species for ipilimumab, the limited value of short-term carcinogenicity studies with homologous products (as reflected in the draft reviewed version of the guideline), and the advanced condition intended to be treated by ipilimumab, the lack of conventional carcinogenicity studies is acceptable.”

“Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at a dose of 3 mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality.”

“Genetic toxicology studies were not conducted because, as a monoclonal antibody, DAC HYP is not expected to interact directly with DNA.”

“Because DAC HYP is pharmacologically active only in monkey, carcinogenicity studies are not feasible; therefore, the carcinogenic potential of DAC HYP was not assessed.”

“Once-weekly SC dosing with 50 mg/kg DAC-HYP during gestation days (GD) 50-160 did not affect pre- or postnatal development. However, once-weekly SC administration of 200 mg/kg DAC-HYP administered during the first 5 weeks of pregnancy increased the incidence of fetal loss.”

“No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.”

“No studies have been performed to test the potential of bezlotoxumab for carcinogenicity or genotoxicity.”

“There were no notable effects in the male and female reproductive organs in mice based on repeat dose toxicity studies and no binding to reproductive tissues was observed in tissue cross-reactivity studies.”

“Genetic toxicology studies were not warranted.”

“Carcinogenicity studies were not warranted.”

“Reproductive and developmental toxicology studies were not conducted with retifanlimab. Instead, the Applicant submitted a weight-of-evidence reproductive risk assessment for retifanlimab.”