Photosafety Testing, Lighting the Way Forward
While photosafety testing has been an important part of preclinical drug development for over 30 years, it’s poorly understood as to the accepted methodologies, when to initiate evaluation, the expectations of the regulatory agencies, and how to interpret results. The lack of clarity in current regulatory guidances, controversy over the interpretation of in vitro assays and the absence of formally validated/accepted in vivo assays has affected the ability to clearly understand how to evaluate photosafety in a drug discovery program.
But serious efforts have been made in the last five years to address this uncertainty. Current methods are being evaluated and refined, new ones are being proposed, and efforts have been taken to clearly state regulatory expectations.
Current EMA and FDA Guidance Documents
Formal efforts to standardize photosafety testing began in the 1990’s. In 2002, the European Agency for the Evaluation of Medicinal Products (EMA) issued the Note for Guidance on Photosafety Testing (2). A year later, the US Food and Drug Administration (FDA) published the Guidance for Industry: Photosafety Testing.
Both guidances indicate that photosafety testing is warranted for test materials when the:
- Spectrophotometric absorption is between 290 and 700 nm (the ultraviolet and visible spectrum that hits the Earth)
- Test material is topically or locally applied to the skin, or reaches the eyes or skin following systemic administration
Differences between the documents include the amount of background information provided in the documents, with much more in the FDA Guidance, the inclusion of preclinical photoallergy assessment and the use of photogenotoxicity evaluations (recommended by the EMA, not by the FDA) and emphasis on in vitro methods by the EMA, notably the 3T3 Neutral Red Uptake phototoxicity test (3T3 NRU).
Areas of Concern
Industry and regulatory groups began assessing the data to determine how well the Guidance-recommended approaches were addressing photosafety concerns. These reviews revealed shortcomings in the approaches that both documents presented and raised concerns about the utility of the recommended approaches to testing and the data generated.
As the result of these shortcomings, the International Conference on Harmonization on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) formally endorsed development of the Final Concept Paper for S10: Photosafety Evaluation of Pharmaceuticals in June of 2010. This document formalized many of the concerns that had arisen in the years since the issuance of the EMA and FDA guidance documents and provided a path forward to address these concerns.
The Path Forward
Release of the Step 2 document of the ICH S10 for public comment is anticipated by the end of the year. This Guidance has the potential to leave unchanged, substantially alter or eliminate current testing strategies, all of which will be addressed during the public comment period and then formal adoption of the guidance, hopefully by the end of 2013.