The US Food and Drug Administration (FDA) has released a draft guidance pertaining to a document currently under development by the International Conference on Harmonisation (ICH) that would harmonize photosafety testing standards between the regulatory authorities of the US, EU and Japan.
That document, S10 Photosafety Evaluation of Pharmaceuticals (PDF), relates to the light-induced reactions caused by some drugs, also referred to as photosensitization, that can affect a patient's tissue (phototoxicity/photoirritation) and immune system (photoallergies).
The guidance is meant to be read in conjunction with section XIV(14) of M3(R2): Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (PDF), which also outlines photosafety testing considerations. FDA is accepting comments on the guidance for 45 days, or until 21 March 2013.
The guidance recently cleared Step 2 of the ICH harmonization process, in which a consensus on the need and format for the guidance is reached. The guidance is now in Step 3 of the ICH process, in which regulators consult and discuss the draft guidance with stakeholders.
"For a chemical to demonstrate phototoxicity and/or photoallergy, the following characteristics are critical," ICH writes. It must absorb natural sunlight or other light in the 290-700 nm range, and then generate a "reactive species," which must then be sufficiently distributed to tissues exposed by the light.
Unless all three conditions are met-absorption, generation and distribution-"a compound will not present a photosafety concern," ICH noted.
Should those three concerns be noted after an initial assessment, it should be studied in either Phase I or Phase II clinical safety testing-i.e. before Phase III efficacy testing.
S10 goes on to outline a number of testing considerations sponsors need to consider in the course of their photosafety testing. For example, products must be assessed for their photoreactive potential and wavelength absorption properties. The pharmacokinetic properties of a chemical must also be assessed to determine if a high enough concentration exists in surface tissue to cause a reaction.
For nonclinical testing, ICH explains that it is "most important that nonclinical photosafety assays show high sensitivity (i.e. produce a low frequency of false negatives)."
False negatives in an assay test could lead to unexpected adverse events in clinical testing later on, ICH writes. "It is not essential that positive assay results always predict a clinically relevant phototoxic response … but the false positive rate for an assay should still be considered when deciding whether or not to use an assay."
Other aspects also present difficulties during nonclinical testing. Seemingly simple factors-sunlight, for example-can be complicated by definition qualities such as the effects of latitude, altitude, season, time, skin type/color and weather on the properties of sunlight. Companies should conform to standards set by organizations, such as CIE-85-1989, for testing their products for potential phototoxicities, ICH wrote.
Chemical assays and in vitro assays should also be validated, the standard explains. To date, no in vivo phototoxicity assays have been validated for use, ICH noted, though it readily conceded that such tests are possible and, if successful, could be considered as a best practice.
ICH goes on to explain that clinical phototoxicity testing is highly variable and should be determined on a case-by-case basis.