2005D-0340 Guidance for Industry on Acne Vulgaris: Developing Drugs for Treatment
FDA Comment Number : EC2
Submitter : Dr. Todd Plott Date & Time: 12/21/2005 11:12:52
Organization : Medicis Pharmaceutical
Category : Private Industry
Issue Areas/Comments
The following comments are being submitted electronically in 4 parts. The section below is part 1 of 4.

I am writing to provide comments on Docket No. 2005D-0340 ?Draft Guidance for Industry on Acne Vulgaris: Developing Drugs for Treatment; Availability?.

Medicis Pharmaceutical Company opposes the use of the Investigator Global Assessment (IGA), dichotomized or not, as a measure of efficacy in acne vulgaris. Rather Medicis believes that the use of lesion counts as proposed in the Draft Guidance should be the sole and primary clinical endpoint for determining efficacy.

The Division is aware of the numerous clinical trials in acne vulgaris that have used the IGA conducted by this Sponsor and others. We have the following issues with the Draft Guidance and the proposed use of the IGA that make implementation of the Draft Guidance impossible.

1. The Draft Guidance suggests that each company should validate its IGA before implementation.

This proposal creates a Catch-22. In the Draft Guidance the IGA is required, but it must be validated first. If the IGA cannot be validated, then a clinical study cannot proceed. Thus, there should really be at least one prior successful validation either by the agency or by academia before any requirement for an IGA is instituted. We are not aware of any products approved under the criteria outlined in the Draft Guidance. Generally, a company or academic organization will develop and validate an efficacy grading scale prior to its use in a pivotal study. This scale is then placed either in the public domain through validation by academia or through approval of a drug product by the company concerned. The agency THEN proposes that this scale should be adopted uniformly for any subsequent products looking at this indication. The draft guidance is thus backwards and creates a circumstance where it is theoretically possible that NO scale can be validated necessitating the withdrawal of the guidance after multiple attempts or fruitless research.

2. The sensitivity of the IGA to changes in non-inflammatory lesions is inappropriately low.

Validation generally involves two substantially different tests that must be performed. The first is a correlation between the results of the efficacy scale and some other well-accepted scale. [The second is inter- and intra-observer validation; see no. 9.] This would be an assessment of sensitivity and specificity of the proposed scale against some well-accepted methodology. Previously submitted analysis of randomized controlled clinical trial data from several NDAs establish that the scale is reasonably effective in the tested populations in duplicating the sensitivity and specificity of changes in inflammatory lesion count but is NOT sensitive to improvements in non-inflammatory lesion count. At the November 4-5, 2003 Advisory Panel Meeting the Division indicated that inflammatory lesions had four times the impact on the IGA as did non- inflammatory lesions. Clinicians testified at the Advisory Panel that the IGA is NOT a good measure of efficacy. Thus raising doubts that the proposed scale could be validated.