FDA Comments on Skin Stripping Results

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

• 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  accepting the Draft Guidance for all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.
• Realizing the importance to Dermatology, Spear
  Pharma commissioned Dr. Franz and Lehman to
  perform a similar skin stripping study at another
  site.
• No financial connection between DermTech
  International and Spear Pharma. Product sent
  blinded to Franz.
• The big issue was Is this test rugged? Will the
  two top places in the country, that perform skin
  stripping, report the same results.
• If SS showed consistency we were prepared to
  start using this test for other drugs in
  development.

3
Controversies with Skin StrippingLocation of
Test.

• Derm products have various sites of action in the
  skin.
• Skin Stripping is really Stratum Corneum
  stripping.
• Antivirals and Antifungals act very
  superficially. SS theoretically may be the right
  test.
• 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 StrippingDiseased Skin

• No data on the effect of diseased skin.
• In Dermatology, we are dealing with diseased skin
  states like Acne, Psoriasis, or Eczema where the
  normal stratum corneum is disturbed.
• 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

• For a test to be rugged slight differences in
  materials or technique should not affect
  comparative results.
• Franz/Lehman followed the draft guidance.
• An FDA letter advised that good reproducibility
  with 4.42 ul/cm2 amount of drug.
• Franz/Lehman adjusted their technique to 5 ul/cm2
  for comparison. Therefore, both sites used a
  similar amount of drug.

6
Results of Skin Stripping

• Comparing Avita Gel 0.025 to Retin-A 0.025 Gel.
• Pershing Avita 0.025 Gel has a lower AUC and
  Cmax indicating that it absorbs less into the
  stratum corneum.
• 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

• If the two top DPK research sites in the country
  get contradictory results, the SS methodology is
  not adequately developed.
• The Draft guidance seeks to apply this skin
  stripping test to all Dermatological drugs.
• 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

• Draft guidance says Comparative clinical trials
  are difficult to perform, highly variable, and
  insensitive.
• Spear Pharma has performed four 400 patient
  clinical trials on tretinoin products, showing
  Bioequivalence to brand.
• Skin stripping study discussed today is certainly
  as difficult to perform, and it seems as highly
  variable and insensitive.
• 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

• 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.
• We suggest the SS Draft Guidance be amended to
  include only Stratum Corneum drugs.
• Other DPK tests should be investigated for the
  deeper action Derm drugs like the Cadaver skin
  test.

10
Avita Clinical correlation to SS

• How does Avita penetrate into Stratum Corneum?
• Avita promoted as less irritating.
• J.Pharm. Sci. 1997 Oct86(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.
• Therefore, skin stripping of stratum corneum
  should have more Avita gel with a higher AUC,
  (Area under the curve) consistent with Franzs
  results.
• 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.