10th ICEM – Firenze, Italy, August 20-25, 2009 Reports from the 5th IWGT A re-appraisal of the recommendations for photogenotoxicity testing Peter Kasper Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany

Photogenotoxicity Group 5TH IWGT - Basel 2009 Photogenotoxicity Group 10 Group members Daniel Bauer, Novartis Pharma, Switzerland Elmar Gocke*, Roche, Switzerland Peggy J. Guzzie-Peck*, J&J Pharma, USA (Co-Chair) Satoru Itoh, Daiichi Sankyo, Japan Abby Jacobs*, FDA CDER, USA Peter Kasper, BfArM, Germany (Chair) Cyrille Krul, TNO, The Netherlands Anthony Lynch, GSK, UK (Rapporteur) Andreas Schepky, Beiersdorf AG, Germany Noriho Tanaka*, Food & Drug Safety Center, Japan * Member of the IWGT Photogenotoxicity Working Group 1999

Photogenotoxicity Group 5TH IWGT - Basel 2009 Photogenotoxicity Group Groups objective: Re-evaluation of recommendations for photogenotoxicity testing of IWGT 1999 in view of the experiences gathered over the last decade in view of reported pseudo-photoclasto-genicity effects in view of changing regulatory guidances (EU pharma)

Photogenotoxicity Group 5TH IWGT - Basel 2009 Photogenotoxicity Group IWGT Report Topics (2000) Discussion on experimental conditions Criteria for defining for which compounds photogenotoxicity testing is needed Recommendations for adequate test models & a test battery New topic for discussion 2009: Positioning of photogenotoxicity within a photosafety testing strategy

For which compounds is photogenotoxicity testing indicated? 5TH IWGT - Basel 2009 Photogenotoxicity Group For which compounds is photogenotoxicity testing indicated? If (1) compound absorbs within the solar spectrum and (2) is present in the cells that are exposed to radiation Can we define “critical“ threshold levels for the molar absorbance? Photoreactivity/ -stability as triggers for testing? Can we define a threshold of skin exposure? Need established non-phototoxic compounds photogenotoxicity testing?

Can we define a level of molar absorbance? 5TH IWGT - Basel 2009 Photogenotoxicity Group Can we define a level of molar absorbance? IWGT 1999: No data to define “critical“ threshold levels for the molar absorbance New data: Correlation of MEC values and phototoxicity potential Henry et al. 2009 / D. Bauer SOT 2009 (Novartis) Group‘s conclusion: No photosafety testing below MEC 1000 L mol-1 cm-1 Further data post-meeting for confirmation Harmonisation of MEC determination in progress Harmonised protocols may support increased MEC threshold >1000 L mol-1 cm-1

Photoreactivity/ -stability as triggers for testing? 5TH IWGT - Basel 2009 Photogenotoxicity Group Photoreactivity/ -stability as triggers for testing? IWGT 1999: Photostability not considered as a sufficient argument to omit testing Data: GSK presentation correlation photoreactivity/stability & 3T3NRU/CHO Cab test Group‘s conclusion: Potentially useful trigger Further data from other labs needed Red Blood Cell test also may define photochemical/ photoreactivity mechanisms

Can we define a threshold of skin exposure? 5TH IWGT - Basel 2009 Photogenotoxicity Group Can we define a threshold of skin exposure? IWGT 1999: No data to define “critical“ threshold levels for the compound concentration in the skin Data: research proposal for defining threshold for photosafety concern with use of well-established, potent human phototoxicants Group‘s conclusion: Agreed with concept of empirically defined threshold Data from proposed project required to define a generally applied threshold

Need established non-phototoxic compounds photo-gentox testing? 5TH IWGT - Basel 2009 Photogenotoxicity Group Need established non-phototoxic compounds photo-gentox testing? IWGT 1999: Absence of phototoxicity in relevant studies is not a “completely sufficient“ criterion to omit testing Data: data indicating photogenotoxic-only compounds not convincing (“pseudo-effects“) Group‘s conclusion: Underlying mechanisms for phototoxicity/-genotoxicity are identical Established non-phototoxic compounds don‘t need photogenotoxic testing

Appropriate testing approach 5TH IWGT - Basel 2009 Photogenotoxicity Group Appropriate testing approach IWGT 1999: photoclastogenicity test preferred initial test Data: Dufour et al 2006, Lynch et al 2008 Clear evidence for pseudo-photoclastogenicity effects In absence of UV/vis absorption Preirradiation followed by treatment with compound Further evidence with other cell lines/endpoints (V79 MN) Group‘s conclusion: Photoclastogenicity no longer justified for regulatory purposes

Appropriate testing approach (2) 5TH IWGT - Basel 2009 Photogenotoxicity Group Appropriate testing approach (2) IWGT 1999: photoclastogenicity test preferred initial test Data: Photo-Ames test In vivo photo MN/comet test 3D human skin models Group‘s conclusion: Ames: Concerns regarding sensitivity (endpoint gene mutation) In vivo / 3D skin models promising; however still limited data No preferred test for routine photogenotoxicity testing at the present time

Positioning of photogenotoxicity within a photosafety testing strategy 5TH IWGT - Basel 2009 Photogenotoxicity Group Positioning of photogenotoxicity within a photosafety testing strategy Current guideline recommendations FDA guidance / ICH M3R2 EMEA guidline (revision) EU Cosmetic Conclusion: Photogenotoxicity as required endpoint in current EMEA guideline only

When are data from photogenotoxicity (pgt) studies essentially needed for compound’s assessment? (Assumption: UV-vis absorption + skin exposure) Data profile: results from other photosafety studies Phototox neg. – no pgt testing Phototox in vitro positive – no pgt testing Phototox in vitro positive, in vivo (animal and/or clinical) negative – no pgt testing Phototox in vitro and in vivo animal positive /clinical negative or positive – no pgt testing Risk (photocarc)-benefit assessment with consideration of clinical aspects / human use Short vs. long-term use Systemic vs topical application

Positioning of photogenotoxicity within a photosafety testing strategy 5TH IWGT - Basel 2009 Photogenotoxicity Group Positioning of photogenotoxicity within a photosafety testing strategy Group‘s consensus statement: No added value of photogenotoxicity data for overall photosafety assessment Therefore no photogenotoxicity testing recommended Proposals for better triggers for testing still important for phototoxicity testing

Photogenotoxicity Group 5TH IWGT - Basel 2009 Photogenotoxicity Group Thank you!