Safety Assessment For Ophthalmic Products

Preclinical trial design for ocular drugs depends on the drug type, whether a new chemical entity (NCE) or a reformulation of an approved drug. For first-in-human (FIH) studies, two non-rodent species are preferred. Dogs and rabbits are suitable for most delivery routes, including topical, subconjunctival, intracameral, subretinal, and intravitreal (IVT). Pigs are ideal for subretinal and IVT injections, while nonhuman primates (NHPs) work well for subconjunctival, intracameral, subretinal, and IVT routes. For gene therapy, dogs and small species like rats or mice with retinal mutations similar to retinitis pigmentosa (RP) are optimal for subretinal injections. In certain cases, a single species may suffice with adequate scientific justification.

Ocular pharmacokinetic (PK) studies, which assess absorption, distribution, metabolism, and excretion (ADME), typically require only one species without pharmacological relevance. Before pivotal repeat-dose ocular studies, an ocular tolerability study is advised, often using a single-dose study in rabbits. This involves a 20–30 µl dose with hourly observation and slit-lamp biomicroscopy or ophthalmoscopy to evaluate tolerability. Pivotal toxicity studies typically include biomicroscopy, indirect ophthalmoscopy, tonometry, optical coherence tomography (OCT), or electroretinograms (ERG) if retinal exposure is expected, along with histopathology. While systemic toxicokinetics (TK) are standard for evaluating systemic effects, ocular TK is rarely performed due to limited tissue availability, with microscopic examination and ocular PK studies serving as alternatives.

Before FIH trials, systemic toxicity evaluation in at least one species (via intravenous or oral administration) is recommended to maximize systemic exposure, alongside two in vitro genetic toxicity tests. Additional reproductive toxicity or safety pharmacology studies may be required based on ICH guidelines. A full systemic evaluation can include one or both species, with separate studies in rats as needed for comprehensive ocular development.