Table 1.
ICH recommended preclinical studies enabling FIH trials
| Study type | Small molecules | Large moleculesa | GLP compliance Requirement |
|---|---|---|---|
| Pharmacodynamics | No | ||
| In vitro (MOA) | X | X | |
| In vivo (MOA and therapeutic effect) | X | X | |
| Safety pharmacology (ICH S7A62 and S7B63) | Yes | ||
| In vitro (concentration‐effect relationship) | X | X | |
| In vivo (dose‐response for CNS, CV, respiratory effects) | X | X | |
| Pharmacokinetics (ICH M3(R2)6) | |||
| In vitro metabolism (across species microsomal metabolism) | X | NA | No |
| In vitro plasma protein binding | X | NA | No |
| Toxicokinetics from repeat dose GLP toxicity studies (ICH S3A64) | X | X | Yes |
| Genotoxicity battery (ICH S2(R1)7) | Yes | ||
| In vitro Ames test | X | *a | |
| In vitro and/or in vivo mammalian cell chromosomal damage evaluation | X | *a | |
| Single‐dose / dose range finding | No and Yesb | ||
| Rodent single‐dose (could be MTD study) | X | NA | |
| Nonrodent single‐dose (could be MTD study) | Xd | Xe | |
| Repeat dose toxicityc (ICH M3(R2)6) | Yes | ||
| Rodent multidose | X | Optionale | |
| Nonrodent multidose | Xd | Xe | |
| Other studies | No | ||
| Immunotoxicity (ICH S865) | X | X | |
| Photosafety (ICH S1010) | X | X | |
| Abuse liabilityf | X | X | |
CNS, central nervous system; CV, cardiovascular; FIH, first‐in‐human; GLP, good laboratory practice; ICH, International Conference on Harmonization; MOA, mechanism of action; MTD, maximum tolerated dose; NA, not applicable.
Refer to ICH S6 (R1).7
Not typically required.
If single‐dose study is pivotal (i.e., used to support a single‐dose FIH trial), it should be GLP compliant, which is more typical for large molecules.
Duration and dosing route dependent on clinical trial design (Table 1 in ref. 6).
Species selection dependent on similarity in metabolism to humans.
Often nonhuman primate or minipig; dependent on presence of target and relative potency of the drug candidate against the target.
Tissue cross‐reactivity dictates which species should be studied. If the biologic is cross‐reactive in both rodents/nonrodents, then both species should be studied. If the biologic is cross‐reactive in only one species (most often nonhuman primate), then only that species is studied. If the biologic is not cross‐reactive to any species, then consider a transgenic or surrogate biologic.
For drugs with abuse potential based on MOA/similarity to known drugs of abuse.