Reports from the 5 th IWGT A re-appraisal of the recommendations for photogenotoxicity testing

1. 10th ICEM – Firenze, Italy, August 20-25, 2009 Reports from the 5th IWGTA re-appraisal of the recommendations for photogenotoxicity testing Peter Kasper Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany

2. 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

3. 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)

4. IWGT Report Topics (2000) 5TH IWGT - Basel 2009 Photogenotoxicity Group • 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

5. For which compounds is photogenotoxicity testing indicated? 5TH IWGT - Basel 2009 Photogenotoxicity Group • 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?

6. Can we define a level of molar absorbance? 5TH IWGT - Basel 2009 Photogenotoxicity Group • 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

7. Photoreactivity/ -stability as triggers for testing? 5TH IWGT - Basel 2009 Photogenotoxicity Group • 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

8. Can we define a threshold of skin exposure? 5TH IWGT - Basel 2009 Photogenotoxicity Group • 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

9. Need established non-phototoxic compounds photo-gentox testing? 5TH IWGT - Basel 2009 Photogenotoxicity Group • 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

10. Appropriate testing approach 5TH IWGT - Basel 2009 Photogenotoxicity Group • 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

11. Appropriate testing approach (2) 5TH IWGT - Basel 2009 Photogenotoxicity Group • 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

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

13. 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

14. Positioning of photogenotoxicity within a photosafety testing strategy 5TH IWGT - Basel 2009 Photogenotoxicity Group 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

15. 5TH IWGT - Basel 2009 Photogenotoxicity Group Thank you!