Nonclinical precedent Request an invite
Precedia/Antibody-drug conjugates/Flexibility

What flexibility did FDA and EMA accept for approved ADCs?

From the FDA and EMA reviews of all 14 approved ADCs. Each answer links to the regulator's own sentence.

Check my plan against these
Short answer
8 of 14 approved ADCs had at least one departure from the guideline that regulators accepted.
Safety margin2/14
Impurity or metabolite2/14
DART2/14
Other1/14
Safety pharmacology1/14
Species1/14
GLP1/14

Precedent by precedent

14 approved ADCs, with the reviewers' own words.

Adcetris

brentuximab vedotin · CD30
Safety marginAcceptedBeyond the letter
Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Why: Similar single- and multiple-dose kinetics and the life-threatening indication · Pharmacology or kinetics · Serious disease
“Basis for calculation of exposure ratios were non-clinical studies with a different dosing scheme than the clinical one (for Cmax data from rat study) or single dose studies instead of repeat-dose studies (for AUC data from rat and monkey studies).”
✓ VerifiedEMA assessment report, p. 39Source ↗
Safety marginCriticised but acceptedBeyond the letter
Patient MMAE plasma levels about two orders of magnitude above those in monkeys; animal hepatotoxicity data do not cover human exposure
Why: Hepatobiliary enzyme elevations were reversible and easily monitored in patients · Human data
“However, it should be considered that MMAE plasma levels in patients are two orders of magnitude higher than those observed in monkeys. Therefore, hepatotoxicity might still be of concern.”
✓ VerifiedEMA assessment report, p. 38Source ↗
OtherAcceptedBeyond the letter
No studies of interaction with Fc-gamma receptors submitted
Why: Brentuximab vedotin lacks immunological effector functions · Pharmacology or kinetics
“No studies addressing the potential interaction of brentuximab vedotin with FC-gamma receptors were submitted. However, this is acceptable given the lack of immunological effector functions induced by brentuximab vedotin.”
✓ VerifiedEMA assessment report, p. 34Source ↗
OtherVerdict not stated
No dedicated local tolerance studies; injection sites examined within repeat-dose studies in rats and monkeys
Why: No injection-site effects in rat and monkey repeat-dose studies
“Dedicated studies evaluating local tolerance of brentuximab vedotin were not submitted. Microscopic examination of the injections sites as part of the repeat-dose toxicology studies in both rats and monkeys identified no test article-related effects at the injection sites.”
✓ VerifiedEMA assessment report, p. 32Source ↗

Zynlonta

loncastuximab tesirine · CD19
SpeciesAcceptedBeyond the letter
No pharmacologically relevant species; CD19-mediated toxicity could not be evaluated in any nonclinical species
Why: Considerable nonclinical and clinical safety data exist for CD19- and CD20-specific B-cell-depleting agents · No relevant species · Class precedent · Human data
“Importantly, on‐target (ie, CD19‐mediated) toxicity cannot be evaluated in this or any other nonclinical species; however, a considerable body of data on the nonclinical and clinical safety of CD19‐ and CD20‐specific B‐cell‐depleting agents exists.”
✓ VerifiedFDA multi-discipline review, p. 49Source ↗
DARTVerdict not stated
No reproductive and developmental toxicity studies
Why: Genotoxic cytotoxic drug expected to be embryo-fetal toxic and teratogenic · Pharmacology or kinetics
“Reproductive and developmental toxicology studies were not conducted since cytotoxic (i.e. genotoxic) drugs that affect actively dividing cells, such as loncastuximab tesirine, are expected to be embryo/feto toxic and teratogenic.”
✓ VerifiedFDA multi-discipline review, p. 39Source ↗
GLPCriticised but acceptedBeyond the letter
GLP deviation in a monkey study: formulation analyses out of range with an unvalidated analytical method
Why: Dose-related toxicities indicate correct dosing · Weight of evidence
“Study No. 8374716: Some of the analysed concentrations for formulations were out of range (below LOD), therefore not valid and the analytical method used for those analysis was not validated. The applicant was requested to justify why those deviations to GLP do not jeopardise the validity of the study.”
✓ VerifiedEMA assessment report, p. 35Source ↗

Mylotarg

gemtuzumab ozogamicin · CD33
SpeciesVerdict not stated
No pharmacologically relevant species: antibody does not bind monkey CD33 or rat and monkey tissues; toxicity studies address off-target effects only
“hP67.6 bound strongly to human CD33-transfected CHO cells but did not bind to the monkey CD33-transfected CHO cells (study 084032).”
✓ VerifiedEMA assessment report, p. 21Source ↗
DARTAcceptedBeyond the letter
Embryo-fetal development studied in one species (rat) only
Why: Unequivocally positive pilot study results; leukemia indication · Weight of evidence · Serious disease
“Based on the unequivocally positive results obtained from a pilot study, the Agency previously agreed with the Applicant that one species would be sufficient to support an NDA application for CMA-676 in a leukemia indication.”
✓ VerifiedFDA pharmacology/toxicology review, p. 6Source ↗
GLPVerdict not stated
Safety pharmacology studies not GLP compliant
“Safety pharmacology studies were not GLP compliant.”
✓ VerifiedEMA assessment report, p. 21Source ↗
Impurity or metaboliteVerdict not stated
In vivo metabolism not studied with gemtuzumab ozogamicin; inotuzumab ozogamicin data in rats used instead
Why: Inotuzumab ozogamicin shares the same linker-payload and IgG subclass · Class precedent
“In vivo metabolism of gemtuzumab ozogamicin was not evaluated in nonclinical species; however, in vivo metabolism was evaluated in rats after IV administration of [3H]inotuzumab ozogamicin, which shares the same linker-payload and mAb IgG subclass as gemtuzumab ozogamicin”
✓ VerifiedEMA assessment report, p. 28Source ↗

Padcev

enfortumab vedotin · Nectin-4
SpeciesAccepted
Chronic (13-week) toxicity in rat only; monkey limited to 4 weeks
Why: Comparable rat and monkey toxicity profiles; equivalent binding affinity to human Nectin-4 in both species · Within the guideline · Weight of evidence
“In general, similar toxicity profiles were observed across species and therefore only the rat was studied in the chronic (13-week) repeat dose toxicity study (please refer to ICH S6, S9, S9 Q&A).”
✓ VerifiedEMA assessment report, p. 49Source ↗
DARTAccepted
No fertility/early embryonic or pre- and postnatal development studies; male fertility risk from repeat-dose testicular findings
Why: ICH S9: advanced cancer population · Within the guideline · Serious disease
“Dedicated fertility and early embryonic development studies were not conducted in accordance with ICH S9.”
✓ VerifiedEMA assessment report, p. 55Source ↗
DARTAcceptedBeyond the letter
ADC tested only in a preliminary rat EFD study; definitive EFD run with MMAE and another MMAE ADC (SGN-35)
Why: Embryo-fetal toxicity judged appropriately evaluated; findings reported in the SmPC · Class precedent
“Embryo-fetal development toxicity of SGN-35 and SGD-1010 was evaluated in a GLP-compliant repeat-dose IV embryo-fetal development study in pregnant rats.”
✓ VerifiedEMA assessment report, p. 67Source ↗
OtherAccepted
No separate local tolerance studies
Why: ICH S6 · Within the guideline
“Separate studies evaluating local tolerance of enfortumab vedotin were not performed. In accordance with ICH S6, the omission of dedicated local tolerance studies is acceptable.”
✓ VerifiedEMA assessment report, p. 67Source ↗

Datroway

datopotamab deruxtecan · Trop-2
DARTAccepted
No fertility, embryo-fetal or pre- and postnatal development studies; fertility assessed from repeat-dose studies
Why: Payload DXd is genotoxic and toxic to actively dividing cells · Within the guideline · Pharmacology or kinetics
“The Applicant did not conduct fertility or embryo-fetal development toxicology studies with datopotamab deruxtecan as DXd is genotoxic and affects actively dividing cells, and therefore, these studies are not warranted to support the proposed indication.”
✓ VerifiedFDA multi-discipline review, p. 47Source ↗
Safety marginAccepted
Monkey NOAEL for lung, cornea, skin, liver and thymus toxicity gave a margin of exposure of 0.25; no margin for intestinal toxicity
Why: Sought indication is within the scope of ICH S9 · Within the guideline · Serious disease
“In monkeys, slight intestinal toxicity was observed at ≥10 mg/kg, and no exposure margin was determined (margin of exposure <0.25). The NOAEL for pulmonary, corneal, dermal, hepatic and lymphoid (thymic) toxicity was concluded to be 10 mg/kg corresponding to a margin of exposure of 0.25.”
✓ VerifiedEMA assessment report, p. 52Source ↗
Safety pharmacologyAcceptedBeyond the letter
Safety pharmacology study in male monkeys only
Why: No significant gender differences in exposure or target organs of toxicity · Pharmacology or kinetics
“Only male monkeys were used in the safety pharmacology study; however, this was sufficiently justified and supported by a lack of significant gender differences in exposure or target organs of toxicity.”
✓ VerifiedEMA assessment report, p. 55Source ↗

Elahere

mirvetuximab soravtansine · FRα
DARTAccepted
No reproductive or developmental toxicity studies at all, including embryo-fetal development
Why: Cytotoxic payload targets rapidly dividing cells; maytansinoid class has described developmental toxicity · Within the guideline · Class precedent · Pharmacology or kinetics
“The absence of any reproductive or developmental studies was justified by referring to ICH S9.”
✓ VerifiedEMA assessment report, p. 63Source ↗
Safety marginVerdict not stated
No exposure margin at the monkey NOAEL: AUC multiple 0.09 (AUC0-24 vs AUCtau) to 0.57 (AUC0-∞)
“When monkey AUC0-24 was compared to human AUCtau (area under the concentration vs. time curve over the dosing interval 21 days) exposure margin was 0.09; however, when monkey AUC0-∞ was used for comparison the exposure multiple was 0.57.”
✓ VerifiedEMA assessment report, p. 56Source ↗
Impurity or metaboliteAcceptedBeyond the letter
Maytansinoid impurities qualified with single-dose mouse studies only
Why: Patients are dosed once every 3 weeks · Pharmacology or kinetics
“The impurities were dosed only once in mouse qualification studies; however this can be accepted since posology in patients is once every 3 weeks (21-day cycle).”
✓ VerifiedEMA assessment report, p. 63Source ↗

Trodelvy

sacituzumab govitecan · Trop-2
DARTAccepted
No embryo-fetal development or fertility studies; genotoxic SN-38 payload assumed teratogenic
Why: SN-38 is genotoxic and targets rapidly dividing cells; advanced cancer indication · Within the guideline
“No embryo-fetal developmental toxicology studies were conducted or warranted to support this BLA submission, based on ICH S9.”
✓ VerifiedFDA multi-discipline review, p. 175Source ↗
OtherAccepted
No general toxicity studies with the SN-38 payload alone; published irinotecan and SN-38 toxicity data relied on
Why: ICH S9 and published literature on irinotecan and SN-38 toxicity · Within the guideline · Class precedent
“General toxicity studies with the toxin moiety SN-38 were not conducted. This is acceptable, in line with ICH S9 and taking into account published literature on the toxicity of irinotecan and its active metabolite SN-38.”
✓ VerifiedEMA assessment report, p. 34Source ↗
Impurity or metaboliteAcceptedBeyond the letter
No nonclinical metabolism or excretion studies; literature on irinotecan metabolism in humans used instead
Why: Known human metabolism of irinotecan · Class precedent · Human data
“Studies on metabolism and excretion were not performed for sacituzumab govitecan. , instead the applicant refers to literature on the metabolism of irinotecan in humans which is accepted.”
✓ VerifiedEMA assessment report, p. 34Source ↗

Enhertu

fam-trastuzumab deruxtecan · HER2
DARTAccepted
No embryo-fetal development or other reproductive toxicity studies with the ADC
Why: ICH S9; genotoxic payload targeting dividing cells; HER2-directed antibody use in pregnancy caused oligohydramnios · Within the guideline · Class precedent · Human data
“As recommended by ICH S9 guidance, embryo-fetal toxicity studies were not conducted based on the justification that these studies are not warranted to support the proposed indication because MAAA-1181a is genotoxic and targets rapidly dividing cells, and the use of a HER2 directed antibody during pregnancy resulted in cases of oligohydramnios.”
✓ VerifiedFDA multi-discipline review, p. 43Source ↗
Safety marginAccepted with a conditionBeyond the letter
Clinical deruxtecan (payload) plasma exposures exceed animal exposures at the NOAEL
Why: Observed animal toxicities treated as potential safety concerns and addressed in the risk management plan
“Considering that toxicity is likely related to continuous exposure to deruxtecan after treatment with trastuzumab deruxtecan, and clinical deruxtecan plasma exposures exceed plasma exposures in animals at the NOAEL, the observed toxicities in cynomolgus monkeys are potential safety concerns (see also Clinical Safety section).”
✓ VerifiedEMA assessment report, p. 58Source ↗

Decnupaz

pivekimab sunirine · CD123
SpeciesVerdict not stated
No pharmacologically relevant toxicology species: no CD123 cross-reactivity in mouse, rat or cynomolgus monkey; monkey studies assess off-target and payload toxicity only
“pivekimab sunirine does not cross-react with CD123 in standard animal species used for toxicology studies (mouse, rat, or cynomolgus monkey).”
✓ VerifiedFDA multi-discipline review, p. 42Source ↗
DARTAccepted
No reproductive and developmental toxicity studies, including embryo-fetal development, for the ADC
Why: In accordance with ICH S9 and prior FDA feedback · Within the guideline
“No reproductive and developmental studies have been conducted with PVEK, in accordance with ICH S9 and FDA feedback (Reference ID: 4704103). The FDA's Assessment: The FDA concurs.”
✓ VerifiedFDA multi-discipline review, p. 62Source ↗
Safety marginVerdict not stated
No NOAEL in the 13-week monkey study: thymic atrophy at the lowest dose tested
“Adverse toxicity was observed at all doses since even the lowest tested dose of 0.01 Ab mg/kg produced thymic atrophy in males.”
✓ VerifiedFDA multi-discipline review, p. 61Source ↗

Kadcyla

ado-trastuzumab emtansine · HER2
DARTAccepted
No embryo-fetal development studies with the ADC
Why: DM1 is genotoxic; consistent with ICH S9 for the indicated patient population · Within the guideline · Pharmacology or kinetics
“In addition, DM1 was demonstrated to be genotoxic. Based on these findings and consistent with ICH S9, embryo-fetal developmental toxicity studies were not required for the indicated patient population.”
✓ VerifiedFDA pharmacology/toxicology review, p. 6Source ↗
DARTVerdict not stated
No dedicated fertility studies; fertility risk inferred from general toxicity studies
Why: General toxicity studies indicate adverse effects on fertility can be expected · Weight of evidence
“Dedicated fertility studies have not been conducted with trastuzumab emtansine. However, based on results from general animal toxicity studies, adverse effects on fertility can be expected (see SmPC section 5.3).”
✓ VerifiedEMA assessment report, p. 36Source ↗
Safety marginVerdict not stated
Highest well-tolerated doses in rats and monkeys approximately equivalent to the clinical dose (no margin)
“Administration of trastuzumab emtansine was well tolerated in rats and monkeys at doses up to 20 and 10 mg/kg, respectively, corresponding to 2040 µg DM1/m2 in both species, which is approximately equivalent to the clinical dose of trastuzumab emtansine in patients.”
✓ VerifiedEMA assessment report, p. 36Source ↗

Polivy

polatuzumab vedotin · CD79b
SpeciesVerdict not stated
Polatuzumab does not bind monkey CD79b; target-mediated toxicity assessed with a surrogate ADC binding monkey CD79b
Why: Three amino-acid difference in the CD79b epitope between humans and cynomolgus monkeys · No relevant species
“Peptide sequence alignment of CD79b between humans and cynomolgus monkeys showed a variation in three amino acids in the N-terminal epitope region. Therefore, a surrogate ADC (DCDS5017A) that binds specifically to cynomolgus monkey CD79b was generated for testing target-mediated effects.”
✓ VerifiedFDA pharmacology/toxicology review, p. 15Source ↗
DARTVerdict not stated
No embryo-fetal study with the ADC; embryo-fetal toxicity assessed with the MMAE payload in rats
“Dedicated embryo-fetal developmental toxicity studies were not conducted with polatuzumab vedotin. However, MMAE (SGD-1010) was evaluated in rats in a GLP embryo-fetal developmental and TK study (Study 8204397) to determine maternal and embryo-fetal toxicity and teratogenic potential.”
✓ VerifiedFDA pharmacology/toxicology review, p. 44Source ↗
DARTAccepted
No fertility study with the ADC or MMAE; male fertility risk inferred from repeat-dose rat studies
Why: Not needed for the proposed indication; repeat-dose rat studies indicate potential male fertility impairment · Within the guideline · Weight of evidence
“A designated fertility study was not conducted with polatuzumab vedotin or MMAE and is not needed for the proposed indication. However, results of repeat-dose toxicity studies in rats indicate the potential for polatuzumab vedotin to impair fertility in males.”
✓ VerifiedFDA pharmacology/toxicology review, p. 11Source ↗

Besponsa

inotuzumab ozogamicin · CD22
SpeciesVerdict not stated
No pharmacologically relevant toxicology species: antibody does not bind rat or monkey CD22, so only target-independent payload toxicity assessed
“The lack of G544 cross-species reactivity indicates the utility of the nonclinical toxicology studies will be limited to the assessment of target-independent toxicities associated with conjugated and unconjugated calicheamicin.”
✓ VerifiedFDA multi-discipline review, p. 36Source ↗
Safety marginVerdict not stated
No NOAEL for male reproductive organ toxicity in rats; effects at approximately 0.3 times human clinical AUC
“The NOAEL was not identified for the effects on male reproductive organs, which were observed at approximately 0.3 times the human clinical exposure based on AUC (SmPC section 5.3).”
✓ VerifiedEMA assessment report, p. 42Source ↗

Emrelis

telisotuzumab vedotin · c-Met
DARTAccepted
No fertility, embryo-fetal or pre/postnatal development studies with the ADC; MMAE payload EFD data relied on
Why: MMAE is genotoxic and affects actively dividing cells; advanced cancer indication per ICH S9 · Within the guideline · Pharmacology or kinetics · Serious disease
“The Applicant did not conduct reproductive or embryofetal development (EFD) toxicology studies with telisotuzumab vedotin as MMAE is genotoxic and affects rapidly dividing cells and the intended indication is for the treatment of patients with advanced cancer, in accordance with the ICH S9 guidance.”
✓ VerifiedFDA multi-discipline review, p. 35Source ↗

Tivdak

tisotumab vedotin · Tissue factor
DARTVerdict not stated
No embryo-fetal development study with the ADC; rat EFD study of the MMAE payload (from brentuximab vedotin) relied on
Why: MMAE payload EFD study in rats, previously reviewed for brentuximab vedotin
“Dedicated embryo-fetal developmental toxicity studies were not conducted with tisotumab vedotin. However, MMAE (SGD-1010) was evaluated in rats as part of a GLP embryo-fetal developmental and TK study that was initially reviewed by the FDA under BLA 125388 for brentuximab vedotin.”
✓ VerifiedFDA multi-discipline review, p. 57Source ↗