Toxicity Testing for Ocular Drug Products

Abstract

As part of the safety assessment, the Food and Drug Administration evaluates dermal and ocular drug products for their potential ocular toxicity. Several factors (pH, structure-activity relationshipsin vitroalternatives, primary dermal irritation index, and acute dermal toxicity) should be considered for the drug product prior to conducting an ocular irritation assay. The drug product should not be tested further if the drug product has a pH of 2.5 or below or 11.5 or above. The assay should also not be conducted if the active ingredient(s) have analogous chemically active moieties that are known irritants or if the reformulation contains known irritants. Additionally, the assay should not be conducted if the drug product has an acute dermal toxicity lethality at or below 200 mg/kg or a primary dermal irritation index score of 5 or above. The findings fromin vitrosystems like CorrositexTM with ocular and dermal drug products should also be considered prior to performing an irritation assay. Strongly positive findings in these assays could preclude the need for a modified Draize assay. Other alternatives could be used to complement thein vivostudies, assist in defining a mechanism of action, or identify possible biotransformation metabolites of the drug products. When animal testing is to be conducted, a low volume dosing (0.01 ml or g) in one animal may be performed for suspected severe irritants. If the product is not classified as an irritant or moderate irritant, then 0.1 ml or 0.1 g of material should be instilled in two or three more rabbits. The responses are scored according to the modified Draize scoring system at 24, 48, and 72 hours, and, if necessary, at 7 days to assess the potential recovery from the insult. In summary, the Agency encourages the use of alternative tests prior to conducting a modified Draize assay for ocular irritation. Additionally, the Agency encourages the Sponsor to contact the Agency as early as possible for guidance in the development of the drug product. Such interaction could conserve valuable resources and potentially reduce the time to market for the drug product.