Gemtesa: what flexibility did regulators accept, and why?

No carcinogenicity studies with ferric maltol; rodent carcinogenicity data on maltol relied on

39-week dermal minipig NOAEL at the maximum feasible dose gave only 0.38x (males) and 0.30x (females) MRHD by AUC

No carcinogenicity studies before approval; mouse and rat studies deferred to postmarketing requirements

Vanzacaftor 2-year rat carcinogenicity study not completed before approval; deferred to postmarketing

No toxicokinetics in safety pharmacology studies; margins derived from repeat-dose study exposures

No carcinogenicity studies before approval; 26-week rasH2 mouse and 2-year rat required postmarketing

No adequate in vivo genotoxicity characterisation of IV artesunate at approval; GLP in vivo micronucleus test deferred

No exposure margin at the NOEL for learning deficits in rat offspring of the pre- and postnatal development study

Only a non-GLP dose-range-finding rat EFD study; no definitive EFD study

No embryo-fetal development study for avutometinib or defactinib; weight-of-evidence assessment instead

No dedicated fertility or pre- and postnatal development studies

Abbreviated program for an NME: 28-day repeat-dose studies in rat and dog only; no chronic adult toxicity studies

No exposure margin: animal-to-human exposure ratios below one at the highest doses in 3-month rat and dog studies

Repeat-dose toxicity limited to a single 28-day IV study in one species (rat)

Rat and transgenic mouse carcinogenicity studies likely did not achieve aldosterone synthase inhibition; treated as off-target assessment only

Positive in vitro micronucleus and mouse lymphoma assays; negative in vivo rat micronucleus and comet assays

No carcinogenicity studies

No juvenile animal studies; adolescent rat and dog repeat-dose studies used to support patients aged 12 years and older

No carcinogenicity studies; absence justified by weight of evidence

Rat fertility, EFD and PPND studies used short boluses giving exposures below human; DART battery incomplete

Rabbit fetal cardiovascular malformations at all doses; low exposure multiple (about 2.1 times human AUC), no developmental NOAEL

Pivotal cabotegravir toxicity studies used the oral route; IM/SC route covered only by a 3-month rat bridging study

2-year rat carcinogenicity study still ongoing at approval; to be completed post-approval (rasH2 mouse study completed)

Rat and dog used although neither matches human metabolism; dog and rat form aniline metabolites not quantifiable in humans

No rodent carcinogenicity studies for a chronically used intranasal drug

Cynomolgus monkey used as non-rodent species without initial cross-reactivity data; CHMP questioned its pharmacological relevance

No new nonclinical program for trospium; relies on prior FDA finding of safety for the approved trospium product

No fertility, embryo-fetal or pre/postnatal development studies despite ovary and estrus-cycle findings in rats

Exposure multiples at the NOAELs in pivotal studies limited to one- to fourfold the MRHD because of exposure saturation

Juvenile rat toxicity and neonatal neurotoxicity studies deferred to postmarketing requirements

No carcinogenicity studies before approval; two-species carcinogenicity deferred to a postmarketing requirement

No adequate general toxicology study: rat study with diluted product did not reach doses that explore taurolidine toxicity

No nonclinical toxicology studies submitted to the IND; only published pharmacology studies

Mouse and two-year rat carcinogenicity studies deferred to after approval as postmarketing requirements

Nonclinical package consists of older studies conducted to support the veterinary product

2-year rat carcinogenicity study still ongoing at approval; completion issued as a postmarketing requirement

No exposure margin for dog skin toxicity: severe skin lesions at exposures approximately equal to clinical AUC at 225 mg/day

Only a rasH2 mouse study before approval; 2-year rat carcinogenicity study deferred to a post-approval commitment

No exposure margin for enmetazobactam liver effects; combination-study NOAELs below MRHD exposure in dogs and rats

Embryo-fetal development assessed only in a preliminary rat study; no definitive study and no second species

In vitro chromosome aberration assay inadequate: 5-hour treatment only, no ~24-hour continuous treatment without activation

Male dog NOAEL in the 9-month study at 0.5 times human AUC at the MRHD

Cynomolgus monkey used as non-rodent species for general toxicology without species justification

Positive Ames assay, including nitroreductase-deficient strains; applicant argued no human relevance

No exposure margin at the 9-month monkey NOAEL: 0.2 (males) and 0.1 (females) times human AUC at 800 mg

Exposure at the 9-month monkey NOAEL about 0.5-fold that of RCC patients (no margin)

Lifetime rat and rasH2 mouse studies in pharmacologically inactive species; on-target thyroid C-cell tumor risk not assessable

Most single- and repeat-dose studies non-GLP; only two 13-week GLP bridging studies (rat, dog) considered pivotal

Embryo-fetal toxicity in rat only; no second-species EFD, pre/postnatal, juvenile or immunotoxicity studies

2-year rat carcinogenicity study ongoing at approval; final report required postmarketing (rasH2 mouse study completed)

No dedicated reproductive and developmental toxicity studies

No dedicated fertility and early embryonic development studies; fertility assessed from repeat-dose reproductive organ histopathology

Embryo-fetal development assessed in rat only; rabbit not usable as no relevant exposure achieved

Juvenile rat NOAEL gives no safety margin for patients under 12; additional juvenile study (from postnatal day 21) deferred to postmarketing

No pre- and postnatal development study despite concern for neurodevelopmental effects of Trk inhibition

Islatravir positive for chromosomal aberrations in vitro (CHO cells); accepted on mechanism and negative Ames and in vivo micronucleus

No fertility/early embryonic, pre- and postnatal development or juvenile toxicity studies

Major human metabolite sotagliflozin-3-O-glucuronide not qualified in animal studies (formed at much lower levels in rodents, absent in dog)

Combination toxicology limited to one non-GLP 4-week (one-cycle) monkey study using separate capsules, not the fixed-dose tablet

No long-term rodent carcinogenicity study; sponsor ICH S9 rationale rejected, waiver granted on low rodent exposure

Most repeat-dose exposure margins for elafibranor below one (CHMP recalculation); findings considered likely clinically relevant

No toxicokinetics of major human metabolite M34.5 in pivotal rat studies; exposure only extrapolated from single-dose ADME data

No exposure margins: NOAEL AUC margins in 4- and 13-week rat and dog studies and rat embryo-fetal study generally below 1

In vitro hERG assay not conducted under GLP and had several deficiencies

Aneugenic in in vitro human lymphocyte micronucleus assays; in vivo rat micronucleus negative

Major human metabolites M2, M3 and M13 not formed in rodents; given SC as a metabolite cocktail in mouse carcinogenicity and rat pre/postnatal studies

No fertility or pre- and postnatal development studies, so neurodevelopmental effects of TRK inhibition were not assessed

Carcinogenicity studies (6-month Tg-rasH2 mouse, 2-year rat) ongoing at approval; final reports deferred to postmarketing

No in vitro chromosomal aberration test with the major human metabolite M6-SUZ; clastogenicity covered by parent in vivo micronucleus assay

No finerenone MR binding data in mouse or rabbit (carcinogenicity and EFD species); relevance argued by receptor homology

Positive genotoxicity (clastogenic in vitro and in vivo, weakly mutagenic in mouse lymphoma) accepted for a topical product

Mouse embryo-fetal skeletal malformations at all doses; lowest dose about 0.3 times human AUC

Mouse instead of rat as the rodent for long-term toxicology and developmental studies

Low exposure margins (0.3 to 2.4) in 28-day and 13-week rat and dog studies; NOAEL exposures similar to or below human exposure

No 2-year rat carcinogenicity study; weight-of-evidence assessment instead, with 26-week Tg-rasH2 mouse study postapproval

Most nonclinical studies, including all repeat-dose toxicity studies, decades old, non-GLP and reported in literature publications

Low exposure margins: NOAEL or LOAEL exposures at or below clinical exposure at the recommended dose

Juvenile rat toxicity study deferred to a postmarketing requirement

Predominant human metabolite CORT125295 absent in rodents; qualified by weight-of-evidence assessment instead of dedicated toxicity studies

Dog axonal dystrophy margin only 6.0-fold (Cmax) and 7.4-fold (AUC); lowest affected dog dose 10 mg/kg/day

Cardiovascular/respiratory safety pharmacology in dogs without data showing dog relevance; female dog and guinea pig studies non-GLP

Only the Tg.RasH2 mouse study completed before approval; 2-year rat carcinogenicity study in progress and made a postmarketing requirement

In vivo safety pharmacology studies not GLP-compliant (conducted before ICH S7A)

Exposure to major human metabolite M10 not measured in any GLP toxicology study; extrapolated from rat mass balance data

Most toxicology studies used a cis/trans isomer mixture (mix-ISA247) rather than the clinical product, with a limited bridging programme

No new olanzapine nonclinical studies; olanzapine pharmacology, genotoxicity, carcinogenicity and DART data taken from the approved Zyprexa label

No PBC or cholestatic pruritus model; bile acid excretion in healthy mice and dogs and a rat NEC model instead

No margin at 39-week monkey NOAEL: females below 1x and males 1x MRHD AUC

No exposure margin: rat severely toxic dose (cardiac mineralisation) exposure approximately equals clinical exposure

Human metabolites M3 and M17 not measured in pivotal repeat-dose studies; exposure inferred from non-GLP metabolite-to-parent ratios with unvalidated assays

Safety pharmacology limited to a CNS Irwin test within a short oral rat study; no other endpoints assessed

Nonclinical efficacy and mechanism data for arimoclomol alone in patient-derived cells and NPC animal models judged unconvincing

Embryo-fetal development assessed only in non-GLP dose-range-finding studies in rats and rabbits; no definitive GLP studies

Chronic rat and dog exposure margins below ICH M3(R2) expectations because exaggerated pharmacology limited dosing

No ≥6-month nonrodent toxicity study for unrestricted, repeated intermittent lifetime use; dog studies subchronic only

26-week rat NOAEL below clinical exposure (<1x AUC); 52-week monkey NOAEL 13x

No new nonclinical program for drospirenone; relies on FDA's previous findings of safety for the listed drug YAZ

Brain not adequately evaluated in pivotal dog toxicity studies despite rat brain mineralization; nonclinical deficiency in first-cycle Not Approvable letter

No carcinogenicity studies before approval (advanced cancer); EMA required a 6-month Tg-rasH2 mouse study post-approval

No carcinogenicity study before approval; single-species study deferred to a postmarketing requirement

Rat pre- and postnatal development study deficient (too few offspring, weak neurobehavioral assessment); repeat required postmarketing

No sperm count or viability analyses in animals despite testicular toxicity and incomplete reversibility of epididymal findings

No 2-year rat carcinogenicity study; only 26-week Tg rasH2 mouse study plus weight-of-evidence assessment

No juvenile toxicity studies for a paediatric indication; youngest animals corresponded to 12 to 16 years of human age

Major active metabolite M21 not covered by animal exposure; no safety margins for M21

Major human metabolite TRV0109662 not shown qualified in EFD studies (failed ISR); no dedicated metabolite study, original EFD samples reanalysed instead

No rodent carcinogenicity bioassays; applicant cited the ICH S1A ocular-route provision

Rabbit embryofetal study: no exposure margin for maternal or developmental toxicity (<1 to 1 times human AUC)

Rat reproductive and developmental data discounted because of low relugolix affinity for rat GnRH receptors; rabbit EFD used for labeling

Narrow NOAEL exposure margins in chronic studies: 3.8 in rat and 1.5 in monkey

Positive in vitro clastogenicity for sulopenem etzadroxil and sulopenem; judged non-genotoxic on negative in vivo micronucleus and Ames results

No exposure margin for rat embryo-fetal toxicity: maternal toxicity and embryo-fetal mortality at about 0.1 times human AUC

Positive in vitro micronucleus assay after continuous treatment; overall judged non-genotoxic on negative Ames and in vivo micronucleus

Adverse effects in animals at exposures comparable to or below anticipated clinical exposure

Rat carcinogenicity study terminated early (Week 91 males, Week 89 females) due to low control survival

No combination toxicity studies of nirmatrelvir with ritonavir

Embryo-fetal development assessed only in a non-GLP dose range-finding rat study

In vitro genotoxicity concentrations below ICH S2 requirements; in vivo micronucleus exposure only 2-fold or 1.4-fold human exposure

No GLP chronic toxicity studies by the applicant; chronic toxicity supported by published literature

Lung toxicity NOAEL in rats below human exposure (0.7-fold based on plasma exposure)

2-year rat carcinogenicity study ongoing at approval and deferred post-marketing, despite mutagenic circulating metabolite M50

No in vivo pyruvate kinase deficiency model; efficacy shown in a β-thalassemia mouse model, normal mice and patient RBCs ex vivo

General and reproductive toxicity largely from 1970s legacy studies not in full GLP compliance, many without toxicokinetics

No in vivo phototoxicity follow-up after a positive in vitro 3T3 NRU assay, contrary to ICH S10 and CHMP advice

Female mouse carcinogenicity study inadequate: high dose not an MTD or MFD and below 25-fold human exposure

Tg.rasH2 mouse high dose gave only 4.37- to 8.5-fold AUC multiples, below the 50-fold ICH S1 criterion

Core nonclinical package taken from published literature on the Japanese landiolol product ONO-1101 (Onoact) rather than new studies

Embryo-fetal assessment limited to a dose-range-finding study in mice; no definitive or second-species study

No carcinogenicity studies with relebactam or imipenem/cilastatin

No carcinogenicity studies before approval; mouse and rat studies deferred to post-marketing requirements

No carcinogenicity studies before approval although MTC patients can live long; rat and mouse studies required postmarketing

No embryo-fetal development studies; drug is given with palbociclib and fulvestrant, both known embryo-fetal toxicants

Single preliminary rat embryo-fetal study only; no definitive or second-species embryo-fetal study

In vivo mouse micronucleus assay judged inadequate by the primary reviewer: exposure to major human metabolites not demonstrated

Rat pre/postnatal study lacked behavior, motor activity, sensory function and reflex development testing

No carcinogenicity studies at US approval; waiver for chronic GVHD refused and rodent studies deferred to postmarketing requirements

No carcinogenicity studies

No NOAEL in 26-week rat study: endocrine pancreas fibrosis, haemorrhage and pigment at all doses

No exposure margin for teratogenicity: rat and rabbit embryo-fetal NOAELs at exposures similar to or below the clinical dose

2-year rat carcinogenicity study ongoing at approval; report deferred to post-marketing

No exposure margins: CNS toxicity at 0.2 times human Cmax and skin, red-cell effects at 0.1 times human AUC

No stand-alone CNS or respiratory safety pharmacology studies; assessed within toxicity studies

No carcinogenicity studies submitted for chronic-phase CML in patients pretreated with two or more TKIs

No 2-year rat carcinogenicity study before approval; weight-of-evidence waiver refused and study deferred to a postmarketing requirement

26-week rat NOAEL exposure below human AUC at the MRHD (~0.1x males, ~0.8x females)

Carcinogenicity studies (26-week Tg.rasH2 mouse, 2-year rat) deferred to post-marketing requirements

No rodent carcinogenicity studies before approval for chronic use; weight-of-evidence assessment submitted; two-species studies required postmarketing

Low margin in GLP monkey cardiovascular telemetry study: NOEL at 3x clinical Cmax

No completed carcinogenicity studies at submission; rasH2 mouse and 2-year rat studies ongoing, submitted post-approval

No exposure margin at general toxicology NOAELs: about 1 in dog and below 1 in mouse and rat (AUC)

NOAEL exposures in rat and dog within the range of human exposure; below 1 in female monkeys

Respiratory, renal, CNS safety pharmacology and TDAR studies done only in rats, a pharmacologically non-relevant species

No NOAEL in the juvenile rat study: deaths, mostly from malignant lymphoma, even at 50 mg/kg, approximately equal to adult human exposure at 800 mg BID

No exposure margin: NOAEL AUC in chronic rat and dog studies about 4% of human exposure at 500 mg

2-year rat carcinogenicity study of elexacaftor ongoing at approval; completed as a postmarketing requirement

Only preliminary rat embryo-fetal studies; no definitive or second-species embryo-fetal study

Safety margins below 1 at all dose levels in rat and dog toxicity studies versus human exposure at 125 mg QD

Rodent carcinogenicity studies waived for a chronic topical ocular drug; reviewer noted unexplored literature on TRPM8 in cancer

No dedicated carcinogenicity studies with aprocitentan; mouse and rat studies of parent drug macitentan used instead

No exposure margin: liver and GI toxicity in rats and monkeys at safety margins below 1 (clinically relevant doses)

Major human metabolite ZAAD-1006a not measured in rat and dog toxicity studies; off-target screening deferred to a postmarketing commitment

Mouse 104-week carcinogenicity study inadequate: AUC margin at highest dose below 25-fold the MRHD

Rabbit embryo-fetal study exposures only 0.03 to 0.08 times clinical exposure, with high variability and no dose-dependence

Prodrug tebipenem pivoxil positive in vitro (mammalian gene mutation, CHO chromosomal aberration); in vivo micronucleus negative

No exposure margin: NOAEL exposures in all species below human exposure at 600 mg QD

No exposure margin at NOAELs for severe haematopoietic inhibition in monkeys (MOE 0.07-0.10) and dogs (MOE 0.41-0.54)

No NOAEL established in chronic rat or dog toxicity studies

No recovery phase in the 4-week rat and monkey toxicity studies

Exposure to major human metabolites M3 and M6 not investigated in mice and dogs; coverage shown in rats only

Sub-chronic and chronic toxicity studies conducted in female animals only

Only a preliminary rat embryo-fetal study; no definitive or second-species embryo-fetal study

In vitro hERG assay deviated from ICH S7B Q&A best practices (voltage protocol, no concentration verification or positive controls)

26-week rat NOAEL exposure about 0.2 times the MRHD by AUC

Potential mutagenic drug-substance impurity specified above the default ICH M7 acceptable intake, without impurity-specific safety data

Chronic dog NOAEL exposure only 0.06x (males) and 0.02x (females) the clinical AUC

No chronic toxicity study, although the long-life-expectancy indication falls outside ICH S9

Rat (pharmacologically inactive) used only for off-target toxicity; DART conducted in rabbit, a pharmacologically active species

Male arm of the subcutaneous rat carcinogenicity study of inadequate duration; only female rat data adequate

No in vivo pharmacology studies; efficacy supported by in vitro TTR stabilisation only

No safety margin in the monkey (convulsions) at the NOAEL, whether based on Cmax or AUC

Chronic rat NOAEL exposure only approximated clinical AUC at the maximum recommended dose

No carcinogenicity studies before US approval for chronic use in VHL disease; mouse and rat studies required postmarketing

No developmental NOAEL in the rat embryo-fetal study: malformations at all doses

Repeat-dose juvenile toxicity study (to inform dosing from birth to under one year) still ongoing at approval; completion under a postmarketing commitment

Rat embryo-fetal study inadequate: high embryofetal death left too few fetuses to evaluate teratogenic potential; repeat study required postmarketing

Carcinogenicity studies waived on a weight-of-evidence basis

Cardiovascular telemetry study in minipigs too flawed for regulatory use

Eight drug-substance impurities with carcinogenic concern classified as ICH M7 Class 5 on lack of mutagenicity

No carcinogenicity studies before approval; rat and mouse carcinogenicity studies deferred to postmarketing requirements

No safety margin: toxicity in rats and monkeys at exposures below clinical exposure

Juvenile animal toxicology study deferred to a post-marketing requirement to support pediatric development

Bacterial reverse mutation assay of a (redacted) test article limited to low concentrations because of antibacterial cytotoxicity

No exposure margin: persistent ocular toxicity in rats at about 0.8 times the clinical AUC at 200 mg

No exposure margin at the 9-month monkey NOAEL (0.95-fold human steady-state AUC at 1 mg QD)

Major active human metabolites CC112273 and CC1084037 under-represented in pivotal toxicity, carcinogenicity and DART studies

Margins based on MTDs rather than NOAELs; exposure margins well below one in all studies and species

Animal data support only up to one month of dosing, while clinical treatment up to six weeks was permitted

No carcinogenicity study before approval; deferred to a postapproval study as agreed at the pre-IND meeting

Mouse and rat carcinogenicity studies not conducted before approval; deferred to postmarketing requirements as agreed with the Division

No carcinogenicity studies

Rabbit embryofetal study inadequate (plasma exposure below detection in some dams); second-species study required postapproval

No chronic repeat-dose toxicity studies in rodents or nonrodents, and no safety pharmacology studies