Table 1.
Comparison of study types required for ‘small molecule’ or biological products
| Small chemical product | Biological product | |
|---|---|---|
| Primary pharmacodynamics | In vitro/in vivo studies establishing reason for belief in therapeutic potential | In vitro/in vivo studies establishing reason for belief in therapeutic potential |
| Secondary pharmacodynamics | In vitro screens to identify potential off-target binding with follow-up studies assessing functional effects | Typically, no studies done. Studies may be done to determine Fc-effects of an antibody acting by blocking a cell-bound target |
| Safety pharmacology | In vitro screens of interactions with proteins (e.g. ion channels) and of cellular effects; in vivo studies with focus on endpoints relevant to behaviour, heart electrical activity and blood pressure and lung function tests | No in vitro studies as there is little expectation of an effect on ion channels; in vivo testing is often included in general toxicity tests and only supplemented with dedicated studies if there is a concern |
| Absorption | Studies done to describe basic pharmacokinetic profile of bioavailability, elimination half-life and Cmax/tmax | Studies done to describe basic pharmacokinetic profile of bioavailability, elimination half-life and Cmax/tmax |
| Distribution | Describes the exposure of different organs over time, including regions of particular interest for therapeutic activity (e.g. brain) and for elimination routes (liver, kidney) | Not done, except for cellular and gene therapy products; to prevent vertical transmission, biodistribution to the gonads is of special interest for gene therapy products. |
| Metabolism | Describes the breakdown route – role of CYP P450s or other enzymes | Not done; breakdown is to smaller constituents such as amino acids |
| Excretion | Characterizes roles for e.g. renal, hepatic and biliary routes of elimination | Not done, except for virus-based products. |
| General toxicity | Two species dosed for up to 6 to 9 months | Typically, two species for short term testing and one species for 6 months*; single species where a second species is not pharmacodynamically responsive. |
| Toxicokinetics | Needed to support exposure in toxicity studies | Needed to support exposure in toxicity studies |
| Local tolerance | Usually included in general toxicity studies using clinical route of administration | Usually included in general toxicity studies using clinical route of administration |
| Genotoxicity | In vitro and in vivo effects to determine effects on the genome | Not done, as the product is not expected to interact with the genome.† |
| Carcinogenicity | Lifetime study in rats and/or mice using maximal tolerated doses evaluating incidence of tumours | Such studies are not done as most biological products do not have their primary pharmacodynamic action in rats or mice. Risk judgement is based on biological plausibility and in vitro data.‡ |
| Reproductive toxicity | Fertility testing in males and females in one species; developmental testing in pregnant females in two species during organogenesis; developmental testing of offspring in one species | Dedicated fertility studies are rarely done. Developmental toxicity testing may comprise a single study in primates with dosing from early pregnancy until post-weaning. |
| Environmental risk | Assess risk of impact on the environment and describe actions needed to limit this if potential harm is identified | Not done (except for release of genetically modified organisms), given the nature of the expected breakdown of the product |
*
While ICH S6(R1) 6 states that for chronic use biological products, repeat dose toxicity studies of 6 months duration in rodents or non-rodents are considered sufficient and recognizes that studies of longer duration have not generally provided useful information that changed the clinical course of development, it is not clear whether global regulatory acceptance of a maximum of 6 months testing for ATMPs will be adopted. †An exception is integration testing where viruses are used to delivery gene therapy. ‡An exception is where the product may have long term persistence, e.g. cell based product or gene therapy.