the May 2010 Draft Guidance on Azelaic Acid, and you request that the FDA take the following actions relating to those comments:

Transcription

1 (.t ~stltvic's. ~"~Iy"~ DEPARTMENT OF HEALTH &. HUMAN SERVICES JUN Food and Drug Administration Rockvile MD David L. Rosen Foley & Lardner LLP 3000 K Street, N.W., Suite 500 Washington, DC Re: Dear Mr. Rosen: This letter responds to your citizen petition submitted on behalf of Intendis, Inc. (Intendis), and received by the Food and Drug Administration (FDA or the Agency) on March 30, 2011 (Petition). With the Petition, you enclosed comments that were previously sent to FDA in response to the posting of the May 2010 Draft Guidance on Azelaic Acid, and you request that the FDA take the following actions relating to those comments: 1. Issue a timely response to Intendis' August 13,2010, comments on the May 2010 Draft Guidance on Azelaic Acid or issue a revised draft guidance in consideration of Intend is' comments; 2. Stay the review and approval of any pending abbreviated new drug applications (ANDAs) or 505(b)(2) new drug applications (NDAs), if any, where studies were conducted based upon the FDA Draft Guidance on Azelaic Acid; and 3. Suspend the Draft Guidance on Azelaic Acid and refrain from providing fuiiher guidance to industry based upon it until FDA considers and addresses Intendis' comments. FDA has carefully considered the Petition and the comments attached thereto, and for the reasons stated below, the Petition is granted in part and denied in paii. i. BACKGROUND A. Bioequivalence Recommendations Process Under a process set foiih in the guidance for industry on Bioequivalence Recommendationsfor Specifc Products (BE Recommendation Process Guidance), FDA issues product-specific draft guidances that set forth the Agency's recommendations for

2 demonstrating bioequivalence of specific products. i These draft guidances are posted on FDA's drug guidance Web page2 and announced periodically by publication of a Notice of Availability (NOA) in the Federal Register. At any time following the posting of a draft recommendation on the FDA's Web site, a member ofthe public may submit comments on that draft recommendation by following the instructions listed on the Web site.3 Following the close of the comment period that is announced inthe NOA, FDA considers all comments received and issues either final recommendations, or revised draft recommendations for further comment. B. Finacea Intendis is the holder ofnda for Finacea (azelaic acid) Gel, 15%, which was approved by FDA on December 24,2002, and is listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known as the Orange Book)4 as a reference listed drug (RLD). Finacea is indicated for the topical treatment of inflammatory papules and pustules of mild to moderate rosacea. C. Statutory and Regulatory Basis for Bioequivalence Determinations and ANDA Approval The Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch- Waxman Amendments) created section 5050) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 3550)) (FD&C Act), which established the ANDAapproval process. To obtain approval, an ANDA applicant is not required to submit clinical studies to demonstrate the safety and effectiveness of a drug product. Instead, an ANDA applicant relies on FDA's previous finding that the RLD is safe and effective. To rely on FDA's previous finding of safety and effectiveness, an ANDA applicant must demonstrate, among other things, that the generic drug product is bioequivalent to the RLD (section 5050)(2)(A)(iv) of the FD&C Act). 1 These basic procedures were first set forth in the draft guidance on BE recommendations issued on May 31,2007 (72 FR 30388). This process guidance was finalized on June 11,2010 (75 FR 33311). 2 Available at htt:// 3 The Web site states "Please submit comments for any of the guidances posted in the Bioequivalence Recommendations for Specific Products website to the Division ofdöckets Management (DDM) under Docket FDA-2007-D For electronic comments refer to the website htt:// OR you can mail your written comments to DDM (HFA-305), FDA, 5630 Fishers Lane, Rm. 1061, Rockvile, MD Please corttact the Regulations.gov HelpDesk at (toll free) for assistance regarding submissions." 4 The Orange Book is available at (last accessed January 23,2012). 2

3 FDA regulations at 21 CFR part 320 list acceptable methodologies for determining the bioequivalence of drug products. For a drug that is not intended to be absorbed into the bloodstream, such as azelaic acid gel, FDA may establish scientifically valid methods to show bioequivalence.5 For example, when a drug product is a locally acting topical formulation, FDA may, as described in 21 CFR part 320, rely on appropriate in vivo and in vitro methods to assess bioequivalence. The choice of which study design to use is based on the abilty of the design to compare the drug delivered by the two products at the particular site of action of the drug. The courts have expressly upheld FDA's regulatory implementation of the FD&C Act's bioequivalence requirements (see, e.g., Schering Corp. v. FDA, 51F.3d 390, (3rd Cir. 1995); Fisons Corp. v. Shalala, 860 F. Supp. 859 (D.D.C. 1994)). D. Intendis' Comments on Draft Guidance on Azelaic Acid In May 2010, in accordance with the BE Recommendation Process guidance, FDA posted a draft bioequivalence guidance for azelaic acid on the FDA Drugs guidance Web page. The draft guidance recommends a randomized, double blind, parallel, three-arm placebo-controlled in vivo study with the primary endpoint of mean percent change from baseline to week 12 in the inflammatory lesion counts, and a secondary endpoint of the Investigator's Global Evaluation (IGE). According to your petition, on August 13, 2010, Intendis sent comments on the Draft Guidance on Azelaic Acid to FDA's Offce of Generic Drugs and Office of Biostatistics. II. DISCUSSION You request that FDA issue a timely response to your comments or a revised draft guidance on azelaic acid. You contend that such a response would be in keeping with the FDA policy on guidance development that encourages scientific discussion of bioequivalence issues through input from the pharmaceutical industry and other members of the public. You also note that in establishing these guidance development procedures, we have encouraged use of good guidance practices with respect to bioequivalence guidance documents, and you acknowledge that these procedures promote interaction and collaboration at early stages in the development of such guidances, and can be a valuable tool in this development (Petition at 3). You request that the Agency stay the approval of any ANDAs or 505(b )(2) applications for azelaic acid drugs where the studies submitted to support approval are based upon the May 2010 draft guidance until the FDA responds to your comments. You also ask that FDA suspend the Draft Guidance on Azelaic Acid until it is finalized. A. Request for Response to Intendis' Comments on Draft Guidance Generally, FDA does not respond to comments sent to the Agency outside of the procedures established in the BE Recommendation Process Guidance. As your Petition notes, submitting comments to the appropriate public docket ensures that any interested 5 Section 505G)(8)(C) of the FD&C Act and 21 CFR

4 FDA stakeholders may provide additional comments or views on the issues raised by Intendis' comments. However, in this circumstance, because the NOA announcing the availability of the Draft Guidance on Azelaic Acid had not yet been issued at the time your Petition was fied,6 we are granting your request for a response to your comments, and address each of your comments as follows. 1. You request that we change the design description from "Randomized, double blind, parallel, placebo-controlled in vivo" to "Randomized, double blind, parallel, threearm, active and placebo-controlled in vivo." (Comments at 1). You state that the Draft Guidance on Azelaic Acid describes a three arm study which is not reflected in the design description. In FDA's guidances for industry describing product-specific BE recommendations, the design subsection generally provides an overview of the study design with key descriptions while the Comments section provides the full details of the study design. We have structured the design subsection to be simple and brief and believe this is a benefit to users. Because the Comments section of this guidance explicitly recommends three treatment arms and describes active-controlled studies, we do not believe it necessary to add these terms to the design description and prefer to keep the design description consistent with that in our other product-specific guidances. 2. You state that the placebo treatment should be clarified to be the generic vehicle alone (i.e., the generic drug product gel base without the active ingredient) (Comments at 1-2). FDA does not require that the placebo treatment of a topical drug product be the generic vehicle. Although use of the generic vehicle is the most COinon form of placebo treatment, we are open to possible rationales supporting the use of a different inert substance. Because it is not necessary for the placebo treatment to be the generic vehicle, we do not agree that the term should be changed. 3. The draft guidance designates the study's primary endpoint as the "mean percent change from baseline to week 12 in the inflammatory (papules and pustules) lesion counts" and provides that the Investigator's Global Evaluation (IGE) should be evaluated as a secondary endpoint. (Draft Guidance on Azelaic Acid at sections 7 and 8). You state that (a) the change from baseline and the IGE should be co-primary endpoints, (b) the change from baseline should be the absolute change, rather than the mean percent change, and (c) "success" in the IGE should be defined as a score consistent with either "clear" or "almost clear/minimal" at the end of treatment and at least a two-grade drop in ige severity from baseline (Comments at 2). a. Co-primary Endpoints: You maintain that the change from baseline and the IGE should be co-primary endpoints because the pivotal studies used in development of the RLD used them as co-primary endpoints and clinical endpoint BE studies should have the same primary variables as the pivotal studies. 6 Due to administrative oversight, the NOA announcing the Draft Guidance on Azelaic Acid was not published until January 25,

5 In the development of a new drug, phase 3 clinical studies are designed to demonstrate the efficacy and safety of the new drug product for its intended use. ANDA applicants, however, are not required to demonstrate the effcacy or safety of the proposed generic product; the product wil be considered safe and effective if it is found to be bioequivalent to the approved RLD. To demonstrate bioequivalence, FDA recommends BE study designs with clinical endpoints that will best detect differences in performance between the test product and the RLD. Detecting such differences generally does not require more than one primary clinical endpoint.w e believe that for azelaic acid, the change from baseline wil best detect differences in performance between the proposed product and the RLD and should therefore be the sole primary endpoint for BE studies, with IGE as a secondary endpoint to support borderline applications. This is consistent with the BE recommendations FDA has made for other drug products approved for the topical treatment of inflammatory lesions of rosacea, including topical metronidazole drugs. b. Change from Baseline: You suggest that the change from baseline should be the absolute change, rather than the mean percent change. FDA has evaluated both the use of absolute change from baseline and percent change from baseline in acne vulgaris studies and has not found any cases in which a study met BE criteria on percent change from baseline and not on absolute change from baseline. Because sponsors have reported that they need to enroll larger study populations to meet the 90% confidence interval criteria using the absolute change, FDA has decided to recommend the percent change from baseline. This decreases the burden on industry without compromising the adequacy of the measure. c. Definition of Success: You request that "success" in the IGE be defined as a score consistent with either "clear" or "almost clear/minimal" at the end of treatment and at least a two-grade drop in IGE severity from baseline. We do not agree that a two-grade drop in IGE severity should be added to the definition of "success," and believe that the more stringent standard you propose places an unnecessary burden on ANDA applicants who choose to utilize the secondary endpoint. In the comparable case of new acne drugs, FDA generally accepts either definition of success in studies, as long as the definition is determined prior to conducting the study. We see no reason to raise the standard higher for azelaic acid ANDA applicants by adding an additional requirement to meet this endpoint. 4. To establish bioequivalence for the primary endpoint, the Draft Guidance requires that a 90% confidence interval for the test/reference ratio of mean percent change from baseline to week 12 in the inflammatory lesion counts be contained within (0.80, 1.25) for a continuous variable. For the secondary endpoint (IGE), comment #23 of the Draft Guidance on Azelaic Acid recommends that a 90% confidence interval of the difference in clinical success rate or success proportion between the test and reference product on the IGE should be contained within (-0.20, +0.20) for a dichotomous variable. 5

6 a. Percentage for Confidence Interval: You assert that the guidance should require use of 95% confidence intervals for both endpoints, instead of 90%, because this product is not systemically active and local dermal bioavailabilty is a direct consequence of the clinical endpoints.(comments at 3-4). The inherent variability in the clinical performance of any product makes unlikely that even a comparison of the RLD to itself would reliably meet a 95% confidence interval. Therefore, we do not believe it would be appropriate to apply such an interval to the BE studies for generic azelaic acid. b. Exclusion of Placebo Effect: You also assert that for continuous variables the guidance should use the ratio of differences in means instead of the ratio of mean change, and for dichotomous variables the guidance should use a fraction of the difference of observed rates. You state that these changes are necessary to assure exclusion of the placebo effect. The FDA has adequately addressed the need to exclude the placebo effect in the azelaic acid draft BE guidance in comment #21, which states the following: "As a parameter for determining adequate study sensitivity, the test product and RLD should both be statistically superior to placebo (p~0.05, two-sided) for the primary endpoint (mean percent change from baseline), using the mitt study population and LOCF." (Draft Guidance on Azelaic Acid p.4). We do not believe that further changes are necessary to ensure exclusion of the placebo effect. 5. Study Sensitivity: Your comments state that the test product and RLD should both be statistically superior to placebo (p~0.05, two sided) for both co-primary endpoints, rather than just the current primary endpoint as stated in the draft guidance (Comments at 5). For reasons discussed above, we do not agree that these should be co-primary endpoints, and, therefore, we do not agree that both should have to be statistically superior to placebo.? 6. Your comments propose changes to the appropriate statistical analysis method for the BE criteria set forth in the draft guidance (Comments at 5-7). For reasons discussed above, we do not agree that the bioequivalence criteria should be changed to be based on the ratio of differences in means (for continuous variables) and on a fraction of the difference of rates (for dichotomous variables). Because your proposed changes to the statistical analysis method are intended to implement these changes to the bioequivalence criteria, we do not agree that the statistical analysis method should be changed in the ways you propose. For the foregoing reasons, we decline to make any ofthe changes you propose in your Comments to the Draft Guidance on Azelaic Acid. 7 We note that in reality, studies that meet BE limits for the lesion counts generally also meet BE limits for the IGE, which appears to be a less sensitive endpoint. 6

7 B. Request to Stay Approval of ANDAs or SOS(b )(2) NDAs You request that FDA stay the review and approval of any pending ANDAs or 505(b )(2) NDAs where studies were conducted based upon the Draft Guidance on Azelaic Acid. FDA regulations at 21 CFR 1O.35(e) provide for a stay of action in two different circumstances. The Agency shall grant a stay of action if all four ofthe following criteria apply: (1) the petitioner wil otherwise suffer irreparable injury, (2) the case is not frivolous and is being pursued in good faith, (3) the petitioner has demonstrated sound public policy grounds supporting the stay, and (4) the delay resulting from the stay is not outweighed by public health or other public interests. Because your petition does not demonstrate (or even allege) all four criteria, FDA is not obligated to grant a stay. The regulations also state that "The Commissioner may grant a stay in any proceeding if it is in the public interest and in the interest of justice." Your petition fails to set forth any reason why a stay would be in the public interest or is in the interest of justice. As discussed in detail above, we do not agree with your proposed changes to the draft guidance and believe that the draft guidance accurately describes the appropriate approach to BE studies for azelaic acid. Because your petition does not present any basis for the grant of a stay, we decline to grant a stay under 21 CFR 10.35(e).8 C. Request to Suspend Draft Guidance on Azelaic Acid Pending Consideration of Intendis' Comments Y our request that FDA suspend the Draft Guidance on Azelaic Acid pending its consideration of Intendis' Comments is denied as moot, since this response addresses those comments. We further note, however, that under good guidance practice rules at 21 CFR , the submission of public comments on a draft guidance does not operate to suspend the draft guidance pending the analysis and consideration of those comments and issuance of a final document. Guidance documents represent the Agency's current thinking on a particular subj ect. They do not create or confer any rights for or on any person and do not operate to bind FDA or the public. It is therefore unnecessary, inappropriate, and contrary to good guidance practice to suspend a draft guidance pending consideration of public comments. III. CONCLUSION We have reviewed the petition and other relevant information available to us. For the reasons discussed above, your request that FDA issue a response to,intendis' comments 8 We also note that FDA decides whether to approve a new generic drug based on evaluation of the scientific information provided in the ANDA for the drug. In assessing whether an ANDA applicant has provided suffcient evidence in its application to establish that the proposed drug is bioequivalent to the RLD, the Agency applies the requirements of the FD&C Act and FDA's regulations, as discussed above in section I of this document, and relies upon its scientific experience and judgment. FDA need not finalize a draftproduct-specífic bioequivalence guidance before evaluating or approving ANDAs. Indeed, FDA need not publish product-specific bioequivalence guidance at all before evaluating or approving AND As. If FDA fmds that an ANDA includes suffcient evidence to demonstrate bioequivalence and meets the other statutory and regulatory requirements, the Agency must approve the application. 7

8 on the Draft Guidance on Azelaic Acid is granted, and your requests that FDA stay approval of any ANDAs or 505(b )(2) applications relying on the draft guidance and suspend the draft guidance pending response to Intendis' comments are denied. Sincerely, 8