Simulect: what flexibility did regulators accept, and why?

Safety pharmacology studies, including monkey cardiovascular studies, not conducted under formal GLP

No carcinogenicity studies for a chronic non-oncology indication; comprehensive carcinogenic risk assessment instead

No 2-year carcinogenicity study for a chronic dermatology indication; literature weight-of-evidence assessment instead

No fully relevant standard species; chronic toxicity assessed in Tg2576 transgenic disease-model mouse instead

No carcinogenicity studies for a chronic migraine therapy; waiver granted

No carcinogenicity studies for a chronic migraine therapy; weight-of-evidence assessment (CGRP knockout data, CGRP biology, tox findings) instead

No dedicated reproductive and developmental toxicity studies (no embryo-fetal or pre/postnatal studies)

No carcinogenicity study for a chronic prophylaxis indication; rodent study judged not technically feasible, weight-of-evidence assessment instead

Rabbit embryo-fetal NOEL (highest dose) gave AUC 0.62 times human exposure at the maximum recommended dose

No fertility or pre-/postnatal development studies; embryo-fetal study in monkey only

No pre- and postnatal development study; rabbit embryo-fetal study only

No reproductive or developmental toxicity studies; non-product-specific literature assessment of PD-1/PD-L1 role in pregnancy instead

No carcinogenicity study for a chronic autoimmune indication; malignancy risk deferred to a clinical post-marketing safety study

No reproductive and developmental toxicity studies

No juvenile animal toxicity study despite an infant indication

No carcinogenicity studies for a chronic psoriasis therapy; rodent studies waived and a literature weight-of-evidence assessment submitted instead

26-week monkey study tested a single dose level with no recovery period

No pre- and postnatal development study; only guinea pig embryo-fetal development and placental transfer studies

No long-term repeat-dose toxicity study in cynomolgus monkey

Toxicology in cynomolgus monkey, a species in which certolizumab pegol is far less potent against TNFα than in human

Mouse and rabbit embryo-fetal studies without toxicokinetic data or demonstrated pharmacological effect

No carcinogenicity study for chronic psoriasis use; literature-based weight-of-evidence assessment plus clinical malignancy monitoring

Monkey NOAELs at 0.3-0.9x human AUC; no exposure margin at the NOAEL

No embryo-fetal, fertility or pre/postnatal studies; reproductive risk assessed from non-product-specific literature on VEGFR2 inhibition

Repeat-dose toxicity only in immunodeficient nude rats, judged an inadequate toxicology model; juvenile study in a relevant species required postmarketing

Chimpanzee the only relevant species; exploratory studies in cynomolgus monkey used surrogate antibody HuMab-CD38

All toxicology conducted with homologous surrogate antibodies (REGN646 in cynomolgus monkey, REGN1103 in mouse), not with dupilumab

No dedicated reproductive toxicology studies; tissue cross-reactivity study in human fetal/neonatal tissues requested postmarketing

No carcinogenicity studies for a chronic atopic dermatitis indication; weight-of-evidence risk assessment instead

No carcinogenicity studies for a chronic migraine indication; weight-of-evidence assessment instead

No pharmacologically relevant species or valid transgenic mouse; no repeat-dose toxicity studies; safety program mainly in vitro with human cells and tissues

No relevant toxicology species; short-term toxicity study in rat rather than NHP

No carcinogenicity studies for chronic therapy; weight-of-evidence assessment instead

No carcinogenicity studies for a chronic NMOSD indication; no rodent IL-6R binding and mouse homolog not feasible

No rodent carcinogenicity bioassay for a chronic IBD therapy; in vitro tumour-cell study with murine homologue Act-1 instead

No reproductive and developmental toxicity studies; menstrual cyclicity evaluated within the 39-week monkey study

Bioanalytical method validations for pivotal toxicity studies not formally GLP

No in vivo carcinogenicity studies; weight-of-evidence assessment from literature and toxicology studies

No carcinogenicity study for a chronic non-oncology indication; weight-of-evidence assessment using mepolizumab and literature data

No carcinogenicity studies or mouse surrogate for chronic asthma therapy; carcinogenicity risk assessment instead

Embryo-fetal development tested in mice with the rodent surrogate antibody XMG1.2 instead of emapalumab

Hypersensitivity reactions in the 26-week monkey study at all doses, at 0.7-6 times clinical exposure

No animal model of trastuzumab-anthracycline cardiotoxicity; only a rat surrogate antibody study in a doxorubicin model

No carcinogenicity studies for chronic immune-mediated indications; no conventional or alternative model available

No 6-month repeat-dose toxicity study in the non-rodent (cynomolgus monkey)

Marmoset is the only cross-reactive species (no binding to mouse, rat, rabbit or cynomolgus IL-1β), so canakinumab toxicology was run in marmoset

No carcinogenicity studies for chronic psoriasis use; weight-of-evidence assessment instead

No binding-affinity screen in non-rodent species other than monkey to select the toxicology species

No fertility and early embryonic development study; fertility assessed by reproductive organ weights and histopathology in the 13-week monkey study

No NOAEL in the chronic monkey study; lowest dose gave an exposure margin of only 1-2

No reproductive and developmental toxicity studies; literature-based assessment of PD-1/PD-L1 blockade risk instead

No carcinogenicity studies for chronic rheumatoid arthritis use; carcinogenicity risk assessment accepted by ECAC, with risk managed in labeling

No embryo-fetal study in monkey; literature assessment of pregnancy outcomes in PD-1 knockout mice instead

No pharmacologically active species; off-target toxicity in monkeys (6-week only) and on-target effects with a murine surrogate in transgenic PDAPP mice

No reproductive toxicity studies with olaratumab; literature assessment plus mouse embryo-fetal study with surrogate antibody IMC-1E10

No rodent carcinogenicity studies for long-term use; weight-of-evidence carcinogenicity risk assessment instead

No embryo-fetal development studies; literature review of PD-1/PD-L1 pathway reproductive risk instead

No reproductive or embryo-fetal toxicity studies; weight-of-evidence assessment from published PD-1 pathway data instead

No reproductive toxicology studies

No dedicated fertility studies; embryo-fetal and postnatal effects assessed in a monkey ePPND study only

No reproductive and developmental toxicity studies, including none in the pharmacologically relevant monkey; weight-of-evidence assessment instead

No carcinogenicity studies for chronic prurigo nodularis and atopic dermatitis use; literature weight-of-evidence instead

No reproductive or developmental toxicity studies; weight-of-evidence literature risk assessment (CSF-1/CSF-1R deficiency models) instead

Carcinogenicity study waived for a chronic asthma indication

Pivotal chronic toxicity and embryo-fetal studies used early drug substance not shown comparable to the marketed product

No rodent carcinogenicity study; weight-of-evidence assessment instead

No fertility and early embryonic development study

No NOAEL in the repeat-dose rat study; adverse male reproductive tract toxicity at exposures below clinical exposure

No embryo-fetal development study; weight-of-evidence literature assessment of reproductive toxicity instead

No NOAEL in the 26-week monkey study: severe diarrhoea and increased urea nitrogen at all doses

No carcinogenicity studies for chronic PNH use; weight-of-evidence assessment as crovalimab is not active in rodents

No reproductive toxicity studies; EGFR knockout literature and cetuximab embryo-fetal data used instead

No fertility/early embryonic or pre/postnatal development studies; monkey embryo-fetal study only

No carcinogenicity study for a chronic lipid-lowering antibody; waiver granted on weight of evidence

No reproductive and developmental toxicity studies

No carcinogenicity studies; ovariectomized monkeys treated up to 16 months without preneoplastic lesions

Efficacy established in rabbit and monkey inhalational anthrax models under the Animal Rule instead of human efficacy trials

Chimpanzee the only relevant species; only a small, limited single/short repeat-dose chimpanzee study, rat studies not relevant

Combination toxicity study used a rosuvastatin dose without pharmacological activity in monkeys

No long-term animal studies; observation limited to 90 days although B-cell recovery was incomplete

No carcinogenicity studies for a chronic non-oncology indication; weight-of-evidence carcinogenicity risk assessment instead

No carcinogenicity studies for chronic SLE therapy; literature weight of evidence suggests increased malignancy risk from IFNAR blockade

No pharmacologically relevant toxicology species (only chimpanzee binds); monkey toxicity study in a non-relevant species

No carcinogenicity studies for a chronic non-oncology indication; literature-based weight-of-evidence assessment of IL-17RA inhibition, judged inconclusive

Nominal monkey margins of 50 and above uncertain: golimumab has 34-fold lower affinity and 72-fold lower potency for cynomolgus TNFα

No carcinogenicity study for chronic inflammatory indications; weight-of-evidence assessment with ECAC concurrence

No relevant species for eculizumab; all toxicology in mice with surrogate anti-mouse C5 antibody BB5.1, cross-reactivity profile not compared

No pharmacologically relevant species; repeat-dose and DART toxicology done only with a mouse-specific surrogate antibody (BI674304)

No carcinogenicity or rodent tumour immune surveillance studies; ustekinumab does not bind mouse or rat IL-12/IL-23

No rodent carcinogenicity study; carcinogenic risk assessed by weight of evidence including murine tumour surveillance studies with surrogate

No repeat-dose toxicity studies (including reproductive toxicity); single-dose studies only

No rodent carcinogenicity study for chronic HAE prophylaxis (neutralising ADA in rats); weight-of-evidence assessment instead

No carcinogenicity studies for chronic psoriasis use; weight-of-evidence review of nonclinical data and IL-17A literature instead

No reproductive and developmental toxicity studies; non-product-specific literature-based assessment of pregnancy risk instead

No definitive GLP embryofetal study; only a preliminary non-GLP monkey EFD study, GLP study waived

Pivotal 13-week monkey toxicology study failed GLP inspection; a new GLP-compliant 13-week study was run during the procedure

No carcinogenicity studies; weight-of-evidence risk assessment from chronic monkey data and TSLP literature

No carcinogenicity studies for chronic psoriasis use; literature and monkey-data weight-of-evidence assessment instead

No carcinogenicity studies for a chronic HIV therapy; risk addressed by clinical monitoring and post-marketing surveillance

No standard carcinogenicity studies; in vitro and SCID/nude mouse xenograft studies with human alpha-4 expressing tumour cells instead

Teplizumab tested only in a single-dose chimpanzee study; repeat-dose and DART studies used a mouse surrogate anti-CD3 antibody

No toxicity studies with ravulizumab (no relevant species); reliance on surrogate BB5.1 mouse studies from the eculizumab application

Only a 28-day rat repeat-dose study; chronic toxicity and peripheral neuropathy to be investigated after approval

No developmental and reproductive toxicity studies; literature-based risk assessment instead

No cross-reactive animal species; all toxicology in human CD19 transgenic mice

No NOAEL in the monkey embryo-fetal study: abortions or fetal death and maternal toxicity at the lowest dose

No carcinogenicity studies for chronic use; weight-of-evidence risk assessment reviewed by ECAC

No rodent carcinogenicity studies for a chronic IgA nephropathy indication; carcinogenicity risk assessment instead

Chronic toxicity in cynomolgus monkey only; no chronic rat study because rat anti-drug antibodies precluded meaningful long-term studies

Embryo-fetal development studied in one species only (mouse)

No carcinogenicity study for chronic asthma use; carcinogenic potential to be judged from clinical safety data

No reproductive toxicity data at approval; monkey combined embryo-fetal/pre-postnatal study still ongoing

Carcinogenic potential not assessed at all (no studies, no weight-of-evidence assessment) for a chronic MS immunomodulator

Foreign bacterial toxin target: no species for target-mediated toxicity; only short-term mouse toxicity studies

No animal reproductive or developmental toxicity studies; weight-of-evidence assessment instead