1. Skin Stripping vs. Acne Bioequivalent Studies for Tretinoin Generics. Comments at FDA-Advisory Meeting Nov 17, 2000 K.L. Spear M.D. / Dermatologist Spear Pharmaceuticals: Generic R&D

2. Skin Stripping vs. Acne Studies u Some in the Generic Industry claim that the Draft Guidance must be accepted because Generics can not be approved in any other way. u I am here to report that clinical studies can show Bioequivalence and we have performed Acne studies to prove Bioequivalence to our Tretinoin products. u For anti-acne drugs, which act in the pilosebaceous unit, one can never be certain that stripping the stratum corneum layers ever is better than a clinical study.

3. Acne Bioequivalence Studies u The gold standard: Double-blind placebo controlled Acne Bioequivalence studies can be done with reasonable cost: $400,000 per study u Our Generics are Qual.(Q1)identical and Quant.(Q2) same Additionally: Manufactured to have the same viscosity. u We have filed 3 Acne clinical trials showing Bioequivalence to the originator. u ANDA approvals for Tretinoin Cream 0.025%, 0.05%, 0.1% and 0.025% Tretinoin Gel currently sold as: Geneva Pharmaceuticals Tretinoin (Generic company)

4. Acne Results:.1% Retin-A  vs..1%Generic Total Lesion Counts 398 Patients Enrolled/330 Completed No statistical differences

5. Summary Topical Tretinoin Gel and Creams % Improvement Total Lesions at 12 wks Product %Improvement size of study u Retin-A® Brand.1% Cream71.1% 398 Tretinoin Generic.1% Cream 71.0% u Retin-A® Brand.025% Cream52.8% 412 Tretinoin Generic.025% Cream 52.2% u Retin-A ®Brand.025% Gel 56.4% 402 Tretinoin Generic.025% Gel 56.6%

6. We received approval of middle 0.05% Cream by Clinical bracketing and IVR We received approval of middle 0.05% Cream by Clinical bracketing and IVR

7. Attempt of Spear to get waiver of lower strength for 0.01% gel u Since we showed Bioequivalence in the 0.025% Gel strength, we asked for a waiver of another Acne study with supporting data. The 0.01% Gel only differed to the 0.025% by the concentration of active ingredient. u In Vitro release studies can not easily be done on Gels u Meeting at Office of Generic Drugs on July 19, 1999 u For both the.025% and the.01% strengths we provided: In vivo: TEWL our data showing equivalence of our products and originator In vivo: TEWL in same lab showed differences between two different formulations with same active ingredient (Stieva-A.1% differs from Retin-A.1%).

8. Attempt of Spear to get waiver of lower strength for 0.01% gel u For both the.025% and the.01% strengths we provided: u In Vitro: Cadaver Skin Studies showing equivalence of our products and originator with same active and same inactives.  In vitro Cadaver Skin Studies can show differences of products with same active/different inactives. See US Patent 5,650,171 for Avita Gel  Cadaver skin studies.  Clinical correlation: Avita  Gel in clinical studies was not Bioequivalent to Retin-A  Gel and did not get an AB rating.

9. Achieving approval for 0.01% Tretinoin gel Requires Clinical Study u Even though the data was convincing, the Agency felt regulatory speaking that they could not accept. u Therefore another 400 patient acne study on the 0.01% has been performed, results are being tabulated. u In total Spear has done 4 Acne Bioequivalence studies: 0.1% and 0.025% Cream; 0.025% and 0.01% Gel u We have set the standard for approval of tretinoins. u Spear’s experience with the Office of Generic Drugs has been very positive. OGD staff have been willing to help, accessible and genuinely motivated to help bring high quality Generics to the public.

10. Controversies with Skin Stripping u One can show equivalence between a proposed generic and the originator by squeezing it out of the tube and comparing the concentration of active ingredient. u Similarly, if you place it on the skin and strip it off and measure the cream on the tape, one can show that it is the same concentration, no doubt. u However, can you show with tape stripping, differences between two tretinoin products with same active and different inactives as you can with the Cadaver skin study or in Clinical trials.

11. Controversies with Skin Stripping u No mention of 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 it behaves on the inner arm of normal skin is how it behaves in the diseases we are treating.

12. Does Stratum Corneum Stripping Predict Activity in Sebaceous Glands? u Draft Guidance admits that: “For antiacne drug products, target sites are the hair follicles and sebaceous glands.” u Draft Guidance tries to make the case that stratum corneum predicts the amount of drug absorbed, therefore it predicts the amount in sebaceous gland. u No proof of this. This is a Leap of Faith Assumption. Effect is Drug specific as well.

13. Summary of Position u Acne Bioequivalence studies and other clinical trials can be done without excessive expense to the Generic Industry u SS may make sense for Anti-virals/Anti-fungals u Embracing SS as a surrogate for Anti-Acne and Corticosteroid products will always be suspect since they do not act in the stratum corneum u Cadaver skin may be a better DPK marker than skin stripping for tretinoin and corticosteroids. u Draft guidance should only include drugs that act in the stratum corneum like Anti-virals and Anti- fungals.

14. Potential negative Effect on the Generic Topical Products. u The Intent of this Guidance is to bring more Generics to the public. u This guidance could backfire and hurt the reputation of generics which have been only gradually earned. u Brand companies will tell Dermatologists that skin stripping is not good Science and products approved in this way are suspect. u At the end of the day we do not want Generic Drugs reputation tarnished. u We want the public and Physicians to trust them.

15. Skin Stripping vs. Acne Bioequivalent Studies for Tretinoin Generics. Comments at FDA-Advisory Meeting Nov 17, 2000 K.L. Spear M.D. / Dermatologist Spear Pharmaceuticals: Generic R&D