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Reports from the 5 th IWGT A re-appraisal of the recommendations for photogenotoxicity testing Peter Kasper Federal Institute for Drugs and Medical Devices.

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Presentation on theme: "Reports from the 5 th IWGT A re-appraisal of the recommendations for photogenotoxicity testing Peter Kasper Federal Institute for Drugs and Medical Devices."— Presentation transcript:

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

2 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 TH IWGT - Basel 2009 Photogenotoxicity Group

3 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) 5 TH IWGT - Basel 2009 Photogenotoxicity Group

4 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 5 TH IWGT - Basel 2009 Photogenotoxicity Group

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

6 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 / D. Bauer SOT 2009 (Novartis) Groups 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 5 TH IWGT - Basel 2009 Photogenotoxicity Group

7 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 Groups conclusion: –Potentially useful trigger –Further data from other labs needed –Red Blood Cell test also may define photochemical/ photoreactivity mechanisms 5 TH IWGT - Basel 2009 Photogenotoxicity Group

8 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 Groups conclusion: –Agreed with concept of empirically defined threshold –Data from proposed project required to define a generally applied threshold 5 TH IWGT - Basel 2009 Photogenotoxicity Group

9 N eed 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) Groups conclusion: –Underlying mechanisms for phototoxicity/-genotoxicity are identical –Established non-phototoxic compounds dont need photogenotoxic testing 5 TH IWGT - Basel 2009 Photogenotoxicity Group

10 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) Groups conclusion: –Photoclastogenicity no longer justified for regulatory purposes 5 TH IWGT - Basel 2009 Photogenotoxicity Group

11 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 Groups 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 5 TH IWGT - Basel 2009 Photogenotoxicity Group

12 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 5 TH IWGT - Basel 2009 Photogenotoxicity Group

13 When are data from photogenotoxicity (pgt) studies essentially needed for compounds 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 Groups 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 5 TH IWGT - Basel 2009 Photogenotoxicity Group Positioning of photogenotoxicity within a photosafety testing strategy

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


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