1. FDA Comments on Skin Stripping Results K.L. Spear MD- Board Certified Dermatologist President Spear Pharmaceuticals- a Generic R/D Company

2. Spear Pharmaceuticals supported the Study of Franz/Lehman u The FDA sponsored skin stripping study of Dr. Pershing was to be a critical step forward in accepting the Draft Guidance for all Dermatological Drugs. u Realizing the importance to Dermatology, Spear Pharma commissioned Dr. Franz and Lehman to perform a similar skin stripping study at another site. u No financial connection between DermTech International and Spear Pharma. Product sent blinded to Franz. u The big issue was: Is this test rugged? Will the two top places in the country, that perform skin stripping, report the same results. u If SS showed consistency we were prepared to start using this test for other drugs in development.

3. Controversies with Skin Stripping: Location of Test. u Derm products have various sites of action in the skin. u Skin Stripping is really Stratum Corneum stripping. u Antivirals and Antifungals act very superficially. SS theoretically may be the right test. u No available data to confirm that skin stripping predictive of action below the stratum corneum, for example anti-acne drugs and corticosteroids.

4. Controversies with Skin Stripping: Diseased Skin u No data on the effect of diseased skin. u In Dermatology, we are dealing with diseased skin states like Acne, Psoriasis, or Eczema where the normal stratum corneum is disturbed. u It is a leap of faith to say that how SS behaves on the inner arm of normal skin, predicts the effects of drugs on diseased skin.

5. Comparing the Two Sites: Technique u For a test to be rugged slight differences in materials or technique should not affect comparative results. u Franz/Lehman followed the draft guidance. u An FDA letter advised that good reproducibility with 4.42 ul/cm 2 amount of drug. u Franz/Lehman adjusted their technique to 5 ul/cm 2 for comparison. Therefore, both sites used a similar amount of drug.

6. Results of Skin Stripping u Comparing Avita Gel 0.025% to Retin-A 0.025% Gel. u Pershing: Avita 0.025% Gel has a lower AUC and Cmax indicating that it absorbs less into the stratum corneum. u Franz: Avita 0.025% Gel has a higher AUC and Cmax indicating that it absorbs more into the stratum corneum.

7. Conclusion on Skin Stripping: For tretinoins u If the two top DPK research sites in the country get contradictory results, the SS methodology is not adequately developed. u The Draft guidance seeks to apply this skin stripping test to all Dermatological drugs. u We can not comment on other classes of Derm drugs, but in this example for Anti-Acne tretinoins, SS is not rugged.

8. Clinical Trials vs. Surrogate Markers u Draft guidance says: Comparative clinical trials are difficult to perform, highly variable, and insensitive. u Spear Pharma has performed four: 400 patient clinical trials on tretinoin products, showing Bioequivalence to brand. u Skin stripping study discussed today is certainly as difficult to perform, and it seems as highly variable and insensitive. u Some claim that the Draft Guidance must be accepted because Generics can not be approved in any other way. Clinical trials can be done, and remain the only confirmatory studies for drugs that act below the stratum corneum.

9. Conclusion on Skin Stripping u The FDA seeks to lump all Dermatologic Drugs into one test. The skin is complex and has multiple sites of action, we believe one test does not fit all. u We suggest the SS Draft Guidance be amended to include only Stratum Corneum drugs. u Other DPK tests should be investigated for the deeper action Derm drugs like the Cadaver skin test.

10. Avita Clinical correlation to SS u How does Avita penetrate into Stratum Corneum? u Avita promoted as less irritating. u J.Pharm. Sci. 1997 Oct;86(10);1138-43.Quigley et al. of Penederm.: Avita with the PP-2 compound reduces tretinoin penetration while enhancing epidermal deposition compared to Retin-A. u Therefore, skin stripping of stratum corneum should have more Avita gel with a higher AUC, (Area under the curve) consistent with Franz’s results. u Clinical results: Lucky et al. J.A.A.D. in 215 patient study no difference clinically in total lesion counts at 12 weeks for Avita 0.025% Gel vs Retin-A 0.025% gel.