1. 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

2. 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

3. 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)

4. 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

5. 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?

6. 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 / 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
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

8. 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

9. 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

10. 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

11. 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

12. 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

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
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

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