Department of Health and Human Services. Re: Docket Nos. FDA-2011-P-0565 and FDA-2011-P-0593

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1 ~, SERVICe. ",+.;+t-.. ~.J''' ~ -Ø. ~"'+"-:~E Department of Health and Human Services Food and Drug Administration New Hampshire Ave Building 51 Silver Spring, MD John Koconis President and Chief Executive Officer LEO Pharma, Inc. 1 Sylvan Way Parsippany, NJ JAN Re: Docket Nos. FDA-2011-P-0565 and FDA-2011-P-0593 Dear Mr. Koconis: This letter responds to two citizen petitions received by the Food and Drug Administration (FDA or the Agency) from LEO Pharma, Inc. (LEO) regarding Dovonex Cream, Taclonex Ointment, and Taclonex Scalp Topical Suspension. 1 2 The petition submitted on August 15, 2011, (the Dovonex Petition) requests that FDA refrain from approving any abbreviated new drug applications (ANDAs) for generic versions of Dovonex Cream (calcipotriene 0.005%) until the following conditions are met: 1. the ANDA applicant has conducted an in vivo bioequivalence study under maximal use conditions; 2. the ANDA applicant has measured 24-hour urinary calcium excretion;3 and 3. the ANDA applicant has conducted provocative testing of irritation, sensitization, phototoxic, and photosensitization potentials when the product's inactive ingredients differ from Dovonex Cream. The petition submitted on July 22,2011, (the Taclonex Petition) requests that FDA refrain from approving any ANDAs for generic versions of Taclonex Ointment (calcipotriene 0.005% and 1 As required by FDA regulations and consistent with long-standing policy, unless the existence of an ANDA has been previously publicly disclosed or acknowledged, FDA wil not publicly disclose the existence of an ANDA before an approval letter is sent to the ANDA applicant pursuant to 21 CFR or a tentative approval letter is sent to the ANDA applicant pursuant to 21 CFR (21 CFR (b)). Thus, any reference to an ANDA for a generic version of Dovonex Cream, Taclonex Ointment, or Taclonex Scalp Topical Suspension is intended to be hypothetical in natue and should not be constred as confirmation that an ANDA is, in fact, pending. 2 Generic is not defined in the Food, Drug & Cosmetic Act (FD&C Act) or in FDA regulations. As used in this response, the term generic drug refers to a new drug product for which approval is sought in an ANDA submitted under section 505G) of the FD&C Act (21 U.S.C. 355(j)). Drug product means "a finished dosage form, e.g., tablet, capsule, or solution, that contains the active drug ingredient, generally, but not necessarily, in association with inactive ingredients" (21 CFR 320.1(b), see also 21 CFR 314.3(b)). 3 As an alternative to urinary calcium testing, you would endorse direct measurement of calcipotriene in the blood (Dovonex Petition at 8).

2 betamethasone dipropionate 0.064%) or Taclonex Scalp Topical Suspension (calcipotriene 0.005% and betamethasone. dipropionate %) until the following conditions are met: 1. the ANDA applicant has conducted an in vivo bioequivalence study under maximal use conditions; 2. the ANDA applicant has measured 24-hour urinary calcium excretion; 3. the ANDA applicant has conducted provocative testing of irritation, sensitization, phototoxic, and photosensitization potentials when the pròduct's inactive ingredients differ from Taclonex Ointment or Taclonex Scalp Topical Suspension; and 4. the ANDA applicant has conducted dynamic hypothalamic-pituitary-adrenal axis (HP A axis) testing through the standard-dose cosyntropin test. We have carefully considered the issues raised in your petitions. For the reasons stated below, your petitions are denied. 1. BACKGROUND A. Calcipotriene and Betamethasone Both calcipotriene and betamethasone are used to treat psoriasis, a chronic disease characterized by thick patches of inflamed, scaly skin created by abnormal, rapid, and excessive proliferation of skin cells. The exact cause of psoriasis is unkown, but it is believed to be of autoimmune origin. It affects an estimated 2 to 2.6 percent of the U.S. population, with a higher incidence among Caucasians. Approximately 15 percent of psoriasis patients develop psoriatic arthritis, a 5 joint condition. Calcipotriene is a synthetic analog of vitamin D3. Although the mechanism of calcipotriene' s antipsoriatic action is not fully understood, evidence from in vitro studies suggests that calcipotriene is roughly equipotent to vitamin D3 in its effects on proliferation and differentiation of a variety of cell types. LEO's Dovonex Cream (calcipotriene 0.005%) (new drug application (NDA) ) is a topically applied product approved on July 22, 1996, for the treatment of 6 plaque psoriasis. Calcipotriene has also been marketed as an ointment, solution, and foam aerosol for topical dermatological use. Betamethasone is a synthetic corticosteroid with anti-inflammatory, antipruritic, and vasoconstrictive properties. Ithas been marketed as a cream, gel, ointment, and lotion for topical dermatological use. With the antifungal agent clotrimazole, betamethasone is also approved as a combination product for topical treatment of certain symptomatic, inflammatory fugal infections oftheskin. LEO's Taclonex Ointment (calcipotriene 0.005% and betamethasone dipropionate 0.064%) (NDA ) was approved on Januar 9, 2006, for topical treatment of 4 As an alternative to urinary calcium testing, you would endorse direct measurement of calcipotriene in the blood. Taclonex Petition at 10. S Psoriasis Fact Sheet, National Institutes of Health, National Institute on Arhritis and Musculoskeletal Skin Diseases (Updated October 2010). Available on the Internet at: htt://report.nih.gov /nihfactsheetslpdfslpsoriasis(nams). pdf. 6 Plaque psoriasis, the most common form of psoriasis, is characterized by raised, inflamed, red lesions covered by silvery white scales. It is also known as psoriasis vulgaris. About Psoriasis. National Psoriasis Foundation website, htt://ww. psoriasis. org/page. aspx?pid=

3 psoriasis vulgaris. LEO's Taclonex Scalp Topical Suspension (calcipotriene 0.005% and betamethasone dipropionate 0.064%) (NDA ) was approved on May 9, 2008, for the topical treatment of psoriasis vulgaris of the scalp. B. Statutory and Regulatory Standards for Bioequivalence. 7 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 (FD&C Act), which established the current ANDA approval process. For an ANDA to be approved, the ANDA applicant generally must show that the proposed generic product is bioequivalent to the reference listed drug (RLD) 8 and has the same active ingredient, conditions of use, route of administration, dosage form, strength, and (with certain permissible differences) labeling as the RLD.9 In addition, generic drug products may have inactive ingredients different from the RLD, 10 provided that the differences do not affect the safety or efficacy of the proposed drug product. To obtain approval, an ANDA applicant is not required to submit evidence to establish the clinical safety and effectiveness of the drug product; instead, an ANDA relies on FDA's previous finding that the RLD is safe and effective. 11. i The scientific premise underlying the Hatch-Waxman Amendments is that drug products that are both "pharaceutically equivalent" and "bioequivalent" are "therapeutically equivalent," meaning that the drug products generally may be substituted for each other. "Pharmaceutica ly equivalent" drug products are those "in identical dosage forms that contain identical amounts of the identical active drug ingredient,... that deliver identical amounts of the active drug ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates.,,12 A generic drug product is "bioequivalent" to the RLD if "the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the RLD when administered at the same molar dose of the therapeutic 7 2ID.S.C. 355(j). 8 Reference listed drug or RLD is "the listed drg (i.e., approved drg as further defined in 21 CFR 314.3(b)) identified by FDA as the drug product upon which an applicant relies in seeking approval of its abbreviated application" (21 CFR 314.3(b)). Reference listed drugs are identified in FDA's Approved Drug Products with Therapeutic Equivalents Evaluations (29th edition, 2009)(the Orange Book). 9 Section 505G)(2)(A) of the FD&C Act; 21 CFR (a), (a). An applicant may submit an ANDA for a drug that has a different active ingredient, route of administration, dosage form, or strength from the RLD if the applicant has submitted a petition to the Agency (known as a suitabilty petition) requesting permission to fie such an application and has received the Agency's approval (see sections 505(j)(2)(C), 505(j)(4) of the FD&C Act (21 U.S.C. 355(j)(2)(C), 355G)(4)); see also 21 CFR ,21 CFR (a)) CFR (a)(9)(ii). 11 The Orange Book codes a generic drg product as "A" rated to its RLD if it is therapeutically equivalent to the RLD. It codes a generic drug product as "B" rated to its RLD if the Agency does not consider the product to be therapeutically equivalent to other pharmaceutically equivalent products because actual or potential bioequivalence problems have not yet been resolved (Orange Book, Introduction at xiii; see also 21 CFR 314.3, ) CFR 320.1(c). See also the Orange Book, Introduction at vi-viii. FDA regulations definestrength for 21 CFR part 210 (current good drug manufacturing practice) to include potency (defined as "the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard)." (21 CFR (b)(l6)(ii)). 3

4 ingredient under similar experimental conditions in either a single dose or multiple doses.,,13 Because a generic product has the same active ingredients in the same strengths as the RLD, the purpose of demonstrating bioequivalence to the RLD is to determine whether other changes in the formulation or manufacturing affect the rate at or extent to which the active ingredient 14 reaches the primar site of action. It is presumed that a drug product containing the identical active ingredient wil behave in the same way as the RLD if it reaches the primary site of action at the same rate and to the same extent as the RLD. In addition, a generic drug product must be manufactured in compliance with current good manufacturing practice requirements to assure the drug's identity, strength, quality, and purity. 1. General Bioequivalence Principles As explained above, to rely on a previous finding of safety and effectiveness of an RLD, an ANDA applicant must demonstrate, among other things, that its generic drug product is "bioequivalent" to the RLD. In 21 CFR (e), FDA defines bioequivalence (in part) as follows:... the absence of a significant difference in the rate and extent to which the active ingredient or active moiety... becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. The statute, regulations, and case law give FDA and ANDA applicants considerable flexibility in determining how this requirement for establishing bioequivalence can be met. Section )(8)(C) ofthe FD&C Act recognizes that different approaches may apply to locally acting drug products that are not intended to be systemically absorbed than would apply to drug products intended to be systemically absorbed. It states the following: For a drug that is not intended to be absorbed into the bloodstream, the Secretary (of Health and Human Services) may establish alternative, scientifically valid methods to show bioequivalence if the alternative methods are expected to detect a significant difference between the drug and the listed drug in safety and therapeutic effect. FDA's regulations also reflect the flexibility that FDA has in choosing the appropriate methods to establish bioequivalence for paricular drug products. Although an ANDA applicant is 13 Section 505G)(8)(B)(i) ofthe FD&C Act (21 US.C. 355(j)(8)(B)(i)). See also sections 505G)(2)(A)(iv), 505(j)(4)(F) of the FD&C Act (21 US.C. 355(j)(2)(A)(iv), 355(j)(4)(F)); 21 CFR (defining reference listed drug), (a)(7) (requiring, as part of ANDA content and format, information to show that the drug product is bioequivalent to the reference listed drug upon which the applicant relies), (a)(6)(i)(providing that FDA wil refuse to approve an ANDA if information submitted is insuffcient to show that the drg product is bioequivalent to the listed drug referred to in the ANDA), 320.1(e). 14 Site of action in the context of this response refers to the skin, not the exact location on the skin CFR 320.1( e) (two products are considered bioequivalent "if there is an absence of a significant difference in the rate and extent to which the active ingredient... becomes available at the site of drug action"). 16 Section 505(j)(4)(A) of U.S.C. 355G)(8)(C). the FD&C Act (21 US.C. 355(j)(4)(A)); see also 21 CFR (b)(l), (b)(13).

5 required to submit "( e Jvidence demonstrating that the drug product that is the subject ofthe 18 (ANDAJ is bioequivalent to the reference listed drug(,j" the regulations similarly make clear that "bioequivalence may be demonstrated by several in vivo and in vitro methods." The regulations provide the following: FDA may require in vivo or in vitro testing, or both, to measure the bioavailability ofa drug product or establish the bioequivalence of specific drug products.... The selection of the method used to meet an in vivo or in vitro testing requirement depends upon the purose ofthe study, the analytical methods available, and the nature of the drug product. Applicants shall conduct bioavailability and bioequivalence testing using the most accurate, sensitive, and reproducible approach available among those set forth in paragraph (b) ofthis section (21 CFR ). The method used must be capable of measuring bioavailability or establishing bioequivalence, as appropriate, for the product being tested. FDA regulations at 21 CFR describe these methods in descending order of accuracy, sensitivity, and reproducibility. They include: (1) in vivo studies in humans that measure concentration of active ingredient or metabolite in appropriate biological fluid as a function of time, (2) in vivo studies in which acute pharmacological effects are measured as a function of time, (3) well-controlled clinical trials (including appropriately designed comparative clinical 20 trials), and (4) in vitro studies. In addition, FDA has the flexibility to use "(ajny other approach 21 deemed adequate by FDA to... establish bioequivalence." 19 Ultimately, under the statute and regulations, the choice ofbioequivalence study design is based on the abilty of the design to compare the drug delivered by the two products at the particular site of action ofthe drug. The courts that have considered FDA's bioequivalence methodologies 22 have also consistently upheld FDA's scientific discretion in this regard. As the Bristol-Myers Squibb cour noted, FDA has been given "the discretion to determine whether in vitro, or in vivo bioequivalence studies, or both, are required for the approval of generic drugs under the 23 abbreviated application process." Thus, bioequivalence for different types of drug products can be shown in different ways. The selection of the method used to meet the bioequivalence testing 1821 CFR320.21(b)(1) CFR (a) CFR CFR (b)(6). 22 See, e.g., Biovail Corp v. FDA, 519 F. Supp. 2d 39, 47 (D.D.C. 2007); Schering Corp. v. FDA, 51 F.3d 390, (3d Cir.), cert. denied, 516 US. 907 (1995); Somerset Ph arms. Inc. v. Shalala, 973 F. Supp. 443, 453 (D. DeL. 1997)("determination of which method is 'the most accurate, sensitive, and reproducible' for measuring bioequivalence is a matter of scientific judgment, falling squarely within the FDA's discretion"); Bristol-Myers Squibb Co. v. Shalala, 923 F. Supp. 212, (D.D.C. 1996) (quoting Schering with approval); Fisons Corp. v. Shalala, 860 F. Supp. 859, (D.D.C. 1994); Glaxo, Inc. v. Shalala, Civ. Act , slip op. at (D.D.C. July 22, 1994) (Green 1., memorandum and order discussing vasoconstrictor assay as method for determining bioequivalence in topical corticosteroids). 23 Bristol-Myers Squibb, 923 F. Supp. at

6 .. 24 study, the analytical methods available, and the nature of the drug product. requirement is specific to the particular product at issue, and depends upon the purpose of the For drug products intended to be absorbed and to act systemically, the rate and extent of systemic absorption is usually the most sensitive, accurate, and reliable indicator of the rate and extent to which. the active ingredient 25 becomes available at the site of drug action. Therefore, the determination of bioequivalence of drug products whose primary mechanism of action depends on systemic absorption usually rests on a pharmacokinetic comparison of drug and/or metabolite concentrations in an accessible biologic fluid, such as blood, after administration of a single or multiple doses of each drug product to healthy volunteers. For some drugs, particularly those that are intended to act locally (i.e., drug products that are not intended to produce measurable concentrations of drug or metabolite in an accessible biological fluid), other designs are often used to determine whether a generic version is bioequivalent to the listed drug it references. For drugs not intended to act systemically, a showing that the active ingredient or therapeutic ingredient in the proposed generic drug reaches the site of action at a rate and extent that is not significantly different from that of the RLD, along with satisfaction of the other requirements for ANDA approval, may permit FDA to conclude that the proposed generic drug can be expected to behave the same way in the body as the RLD FDA's Draft Guidance on Bioequivalence Recommendations for Calcipotriene Cream 27 FDA's Draft Guidance on Calcípotriene provides recommendations regarding how to design bioequivalence studies to support calcipotriene topical cream, 0.005% ANDAs. The guidance recommends conducting one randomized, double blind, 8-week, parallel, placebo controlled, in vivo bioequivalence studywith clinical endpoints in healthy males and nonpregnant females with a clinical diagnosis of plaque psoriasis. The recommended co-primary endpoints are the proportion of subjects in each treatment group with treatment success (defined as absent or very mild disease, a score of 0 or 1, within the treatment area when using the provided Physician's Global Assessment of Disease Severity at the week 8 visit), and the proportion of subjects in each treatment group with clinical success (defined as absent or mild, a score of 0 or 1, at the target lesion site when using the provided Psoriasis Area Severity Index at the week 8 visit). The recommendations also direct the ANDA applicants to monitor the subjects' serum calcium, seru albumin and albumin-corrected serum calcium levels at the baseline and week 8 visits due to the potential risk of hypercalcemia CFR (a) CFR at (b)(1)(i); FDA guidance for industr, Topical Dermatologic Corticosteroids: In Vivo Bioequivalence (1995) (Topical BE Guidance), p. 2, available at htt://ww.fda.gov/ downloadsldrugs/guidancecomplianceregu1atoryinformation/guidances/ucm pdf U.S.C. 355(j(8)(C); 21 CFR at (b)(1)(i); Topical BE Guidance at This draft guidance was posted on FDA's Web site in August

7 3. FDA's Draft Guidance on Bioequivalence Recommendations for Betamethasone Dipropionate; Calcipotriene Hydrate Ointment and Topical Suspension FDA has issued two formulation-specific draft guidances that provide recommendations on how to design bioequivalence studies to support ca1cipotriene and betamethasone dipropionate topical ointment ANDAs and calcipotriene and betamethasone dipropionate topical suspension ANDAs.28 The draft guidances recommend two vasoconstrictor studies to evaluate the betamethasone dipropionate component: a pilot dose duration-response study followed by a pivotal in vivo vasoconstrictor assay in healthy males and females. The draft guidances recommend conducting a third study to assess the calcipotriene component: a randomized, double blind, 4-week, parallel, placebo controlled, in vivo bioequivalence study with clinical endpoints in healthy males and nonpregnant females with a clinical diagnosis of plaque psoriasis. The recommended co-primary endpoints are the proportion of subjects in each treatment group with treatment success (defined as absent or very mild disease, a score of 0 or 1, within the treatment area(s) when using the provided Physician's Global Assessment of Disease Severity at the week 4 visit), and the proportion of subjects in each treatment group with clinical success (defined as absent or mild, a score of 0 or 1, at the target lesion site when using the provided Psoriasis Area Severity Index at the week 4 visit). The recommendations also direct the ANDA applicants to monitor the subjects' serum calcium, serum albumin and albumin-corrected serum calcium levels at the baseline and week 4 visits due to the potential risk of hypercalcemia. The draft guidances also recommend that ANDA applicants refer to the Topical Dermatologic Corticosteroids: In Vivo Bioequivalence (Topical BE Guidance), discussed below. 4. FDA's Guidance for Industry on Establishing Bioequivalence for Topical Corticosteroids FDA issued guidance specifically addressing the method for ANDA applicants to establish bioequivalence for topical corticosteroids: Topical Dermatologic Corticosteroids: In Vivo Bioequivalence (issued June 2, 1995).29 Consistent with the Topical BE Guidance, FDA has determined that the vasoconstrictor assay (also referred to as the skin blanching, Stoughton- McKenzie, or vasoconstriction test or bioassay) is the most appropriate method for determining whether a proposed generic topical dermatological corticosteroid (also referred to as topical 30 corticosteroid) is bioequivalent to the listed drug it references. For many years before the Topical BE Guidance was issued in 1995, FDA relied on this pharmacodynamic effect method to 31 evaluate generic topical corticosteroid drug products. Since 1995, FDA has used the vasoconstrictor assay methodology set forth in the Topical BE 32 Guidance to evaluate the bioequivalence of generic topical corticosteroid drug products. The 28 Draft Guidance on Betamethasone Dipropionate; Calcipotriene Hydrate. These draft guidances published on FDA's Web site in March See Topical BE Guidance. 30 Topical BE Guidance, p Topical BE Guidance, pp Some recent examples of ANDA approvals of topical corticosteroids where bioequivalence was established using the vasoconstrictor assay are: 7

8 vasoconstrictor assay approach described in the Topical BE Guidance is based on the fact that corticosteroids produce blanching (skin pallor) or vasoconstriction in the microvasculature of the skin.33 The Topical BE Guidance recommends that applicants conduct two in vivo studies - a pilot study and a pivotal study - using the vasoconstrictor assay. The recommended pilot study is a dose duration-response study (i.e., designed to determine the appropriate dose duration for use in the pivotal study). In the pilot study, researchers topically apply a corticosteroidcontaining formulation (i.e., the RLD)to several sites on the forears of healthy human subjects for several different durations (with other untreated sites serving as controls), then remove the formulation and, after each removal, assess the degree of skin blanching at the site. The Topical BE Guidance recommends that the skin blanching be measured multiple times (e.g., at various intervals over two consecutive 24-hour peno. d s). 34 The Topical BE Guidance recommends that after the pilot study identifies the appropriate dose duràtion to be used for the pivotal in vivo bioequivalence study, the pivotal study be used to document the bioequivalence ofthe generic to the RLD using the same pharmacodynamic 35 vasoconstrictor assay used in the pilot dose-duration study. The Topical BE Guidance sets forth FDA's recommendations regarding, among other things, study design, subject inclusion and exclusion criteria, study restrictions, subject screening for response, assay precision, and data and statistical analysis. 'd As with. all bioanalytical 36 methods, this pharmacodynamic test requires careful vali ation by ANDA applicants. The Topical BE Guidance continues to reflect FDA's scientific view regarding the most appropriate method for determining whether a proposed generic topical corticosteroid drug product is bioequivalent to the listed drug it references.. fluocinonide cream 0.05%, ANDA , approved 2004 betamethasone dipropionategel 0.05%, ANDA , approved 2003 mometasone furoate cream 0.1%, ANDA , approved fluticasone propionate cream 0.05%, ANDA , approved 2006 The vasoconstrictor studies submitted in support of the above ANDAs were bioequivalence studies in which the. vasoconstrictor response of the generic was compared to that of the corresponding reference listed drug in human subjects. Briefly, in these vasoconstrictor studies, the area-under-the-effect curve (AUEC) is compared for the generic (test) and reference product. The "effect" used to calculate the AUEC is the amount of vasoconstriction, usually measured by a chromameter. The 90 percent confidence intervals of the ratios of the test/reference AUECs must fall within the limits of 0.8 to 1.25 for the generic to be deemed bioequivalent to the reference. 33 Topical BE Guidance, p. 2 (citations omitted). 34 Topical BE Guidance, pp. 6, Topical BE Guidance, p Topical BE Guidance, p. 1. 8

9 II. DISCUSSION In your petitions, you request that FDA refrain from approving any ANDAs for which Taclonex Ointment and Taclonex Scalp Tropical Suspension (calcipotriene 0.005% and betamethasone dipropionate 0.064%) or Dovonex Cream (calcipotriene 0.005%) is the RLD until the following conditions are met; 1. The ANDA applicant has conducted its in vivo bioequivalence study under maximal use conditions; 2. The ANDA applicant has measured 24-hour urinary calcium excretion; and 3. The ANDA applicant has conducted provocative testing of irritation, sensitization, phototoxic, and photosensitization potentials when its product's inactive ingredients differ from the RLD. For generic Taclonex products, the petitioner also requests that FDA require ANDA applicants to conduct dynamic HPA-axis testing through the standard-dose cosyntropiri test. You make several arguments in support of your requests. We address your arguments below. A. Maximal Use Conditions In your Petitions, you argue that an ANDA applicant should be required to conduct a bioequivalence study under maximal use conditions and measure 24-hour urinary calcium excretion or blood calcipotriene levels, because serum calcium levels may not adequately capture disruptions in calcium metabolism. You state that evaluation under maximal use conditions, either by stratified inclusion of a subgroup of subjects with extensive body surface area involvement in the clinical endpoint bioequivalence study or by conducting a separate study, is necessary to ensure the safety of the generic topical product containing calcipotriene and betamethasone dipropionate or a generic topical product containing calcipotriene.37 I i The systemic absorption of calcipotriene from these topical products is minimal, and the products do not raise safety concerns under normal clinical use.' Under maximal use conditions, treatment with a combination of calcipotriene plus betamethasone ointment or suspension does not produce a quantifiable serum level of calcipotriene or betamethasone after as long as 8 weeks 40 of treatment. Your Petitions propose a maximal use condition, i.e., applying the calcipotriene topical product over 15 percent of the subject's body surface area, which is approximately 2550 cm2 in an adult with an average body surface area (1.7 m2). Such a study would require a dosage of approximately 10 grams per application, or 20 grams per day, given that the empirical 37 See Taclonex petition at 5-10 and Dovonex petition at Segaert S, Duvold LA. Calcipotriene cream: a review of its use in the management of psoriasis. J Dermatolog Treat 17: (2006). 39 McCormack PL. Calcipotriene/ Betamethasone Dipropionate: a review of its use in the treatment of psoriasis vulgaris ofthe tr, limb and scalp. Drugs 71(6): (2011). 40 Clinical pharmacology and biopharmaceutics review oftaclonex Scalp Topical Suspension, NDA (March 14, 2008) at i 6. htt://ww.accessdata.fda.gov/drgsatfda _ docs/nda/2008/022185s000 _ ClinPharmR.pdf. 9

10 41 application dose in psoriasis treatment is 40 g/m2 for cream. An eight-week treatment of calcipotriene ointment under maximum usage (twice daily, 120 g per week) did not show any incidences of hypercalcemia or hypercalciurea, calcium mobilization from bone, or clinically significant changes in bone density.42 A dose even higher than the maximum usage (30 grams of Dovonex ointment per day for 2 weeks) did not produce a significant alteration in blood or urine 43 calcium concentration and was well tolerated. The blood calcipotriene level stabilizes approximately 5 days after the initial application, even under the maximum use condition proposed in the Petitions. Therefore, we expect the systemic absorption to be low and the treatment to be safe. Currently, for ANDA applications for locally acting products with known minimal systemic exposure, such as Dovonex Cream, Tac10nex Ointment, or Taclonex Scalp Topical Suspension, FDA's Office of Generic Drugs does not require evaluation of systemic exposure. Evaluation by only one clinical endpoint bioequivalence study for each individual product is suffcient to ensure equivalent safety profies unless there is a compelling reason to compare systemic exposure between the test and reference products. You maintain that FDA's guidance on developing new topical acne products, which recommends the maximal use studies, supports requiring such 44 studies of ANDA applicants who are developing anti-psoriatic topical drug products. However, that guidance was prepared by FDA's Offce of New Drugs (OND) and is used to guide new drug applicants in the development of new topical drugs for treatment of acne vulgaris. Maximal use studies may be routinely requested by OND for new topical drug products to fully understand the systemic exposure of the new drugs. However, generic applicants are not required to repeat the testing requested for new drug products, because the generic applicants can rely on the studies the drug product. conducted in the NDA to establish the safety and efficacy of Your Petitions also request that FDA require all generic products containing calcipotriene to measure either 24 hour urinary calcium excretion or blood calcipotriene levels instead of serum calcium levels. In support of this request, you cite several studies to support your claim that urinar calcium excretion is more sensitive than serum calcium. For example, you refer to an open-label, non-randomized, two-arm study that was conducted in 30 nonpregnant adult subjects with chronic plaque psoriasis.45 In the first arm of this study conducted in 20 subjects, 24-hour urine calcium excretion was measured prior to treatment and then monthly for twelve months with the conclusion that there was no significant change in urine calcium over the year. Although the ten subjects in the second arm ofthe study, who were exposed to higher doses of calcipotriol ointment, had slightly higher mean urinar calcium excretion rates, both the pre- and post-treatment mean urinary excretion rates were within normal values and mean seru calcium 41 Osborne JE, Hutchinson PE. The importance of accurate dosage of topical agents: a method of estimating involved area and application to calcipotriol treatment failures. J Eur Dermatol Venereo/16: (2002). 42 Guzzo C, Lazarus G, Goffe BS, et al. Topical calcipotriene has no short-term effect on calcium and bone metabolism of patients with psoriasis. J Am Acad DermatoI34(3): (1996). 43 Blum R, Schwartzel E, Siskin S, et al. Evaluating the safety of calcipotriene30 g per day in patients with psoriasis: a parallel group, vehicle-controlled study. J Clin Pharmacol38( 4): (1998). 44 See Draft Guidance for Industr, Acne Vulgaris: Developing Drugs for Treatment (Sept. 2005) at Berth-ones J, et ai., Urine calcium excretion during treatment of psoriasis with topical calcipotriol, Br. J Dermatol. 129 (4): 411 (Oct. 1993) (Exhibit 6). 10

11 concentration remained unchanged. 46 You also cite the maximal use study conducted by LEO using acombination of Taclonex Ointment and Taclonex Scalp Topical Suspension. Although two of 32 patients developed elevated urinary calcium levels during treatment, LEO claimed the results were due to random biological variation and were not clinically relevant. LEO used both serum calcium and 24-hour urinary calcium excretion as markers to evaluate calcium metabolism.47 Despite exposure to higher doses during the maximal use study, patients' serum calcium values were within the normal range and the mean 24-hour urinary calcium excretion was similar to baseline at Week 4 and Week 8. No signs of abnormal calcium metabolism were observed even under maximal use conditions in this study. These studies do not indicate that 24- hour urinary calcium excretion is more sensitive than serum calcium. As discussed earlier, levels of calcipotriene in blood are undetectable, even under maximum use conditions; therefore, measurement of serum calcium is also more sensitive than measurement of blood calcipotriene levels. In conclusion, a bioequivalence study conducted under maximal use conditions is not necessary to establish bioequivalence for topical calcipotriene products. Serum calcium levels measured in the bioequivalence study with clinical endpoints are a suffcient marker of abnormal calcium metabolism in the generic product and the RLD. We do not find that the studies cited in your Petitions support your request to require measurement of 24-hour urinary calcium excretion. Rather, the data in the studies cited indicate that the 24-hour urinary calcium excretion has comparable sensitivity as serum calcium and does not provide additional information when the occurrence of hypocalcaemia is so low. Therefore, your request that all ANDA applicants be required to conduct the bioequivalence study under maximal use conditions, and measure 24- hour urinary calcium excretion or blood calcipotriene levels, is denied. B. Dynamic HPA Axis Testing In the Taclonex Petition, you request that FDA require an ANDA applicant to conduct dynamic HP A axis testing. You argue that the vasoconstrictor bioassay may not reliably predict betamethasone dipropionate's bioavailability in the presence of calcipotriene, and that the vasoconstrictor assay does not qualify as a scientifically valid method for detecting significant differences in safety between a generic calcipotriene and betamethasone dipropionate combination product and Taclonex. You further state that long-term treatment with a potent corticosteroid like betamethasone may result in adrenal atrophy and an inability to respond adequately to hormonal stimulation for a long period after treatment is discontinued. You emphasize that bioavailability of betamethasone dipropionate must be established accurately and reliably to ensure safety of the generic product.48 As stated above, after long-term treatment with betamethasone under maximal use conditions the systemic level of beta met has one remains undetectable. Although FDA's Office of New Drugs 46 Bourke JF, Berth-Jones J; Hutchinson PE, Hypercalcaemia with topicalcalcipotriol, BMJ306:1344 (May 15, 1993) (Exhibit 7). This reference clarifies that the ten patients enrolled in the second arm ofthe study reported by Berth-Jones et al (1993) with extensive disease who used 100 grams of calcipotriol ointment per week for four weeks had mean urinary calcium excretion rates that rose slightly from 4.75 mmol/24 hrs to 5.89 mmol/24 hrs, which were both within normal values (i.e., 2.5 to 7.5 mmol/24 hrs) for the test. 47 Medical review of Taclonex Scalp Topical Suspension, NDA (April 10, 2008), at See Taclonex petition at

12 typically requests an assessment of the effect of any new topical product containing a corticosteroid on the HP A axis as part of its safety evaluation, this assessment is not necessary for generic versions of a topical product containing a corticosteroid. Instead, the vasoconstrictor assay is recommended as a reliable surrogate for determining the equivalence of local availability of steroids, Applicants for ANDA products documented to be bioequivalent by the vasoconstrictor assay are not required to submit HP A axis suppression test data because the local availability wil correlate with potential systemic exposure. ' You maintain that the vasoconstrictor assay does not accurately reflect the local bioavailability of betamethasone because the calcipotriene has vasodilatory effects that counteract and reduce the vasoconstriction and skin blanching induced by the steroid. We acknowledge that calcipòtriene. has the potential to interfere with vasoconstriction and skin blanching, but the available data do not indicate that calcipotriene has a significant vasodilatory effect. For example, LEO's own Taclonex Ointment study showed no interference of calcipotriene with the vasoconstrictor assay. The study was to determine whether the bioavailability of the betamethasone component of Taclonex ointment was equivalent to that of the betamethasone-alone formulation (Diprosone Ointment) using a vasoconstrictor assay. Both ointments contain betamethasone dipropionate in the same concentration 51 (0.5 mg/g). f' The two formulations b were found. to be bioequivalent din terms of the vasoconstrictor assay. The results indicated that the presence of calcipotriene in Taclonex ointment did not adversely influence the vasoconstrictive effect of the bethamethasone component. FDA's curent approach 0 recommendmg oth a vasoconstnctor assay an. a clinical endpoint study has been used to establish bioequivalence for other topical products with a combination of a corticosteroidal component and a non-corticosteroidal component. For example, a vasoconstrictor assay and a bioequivalence study with clinical endpoints were recommended for the combination topical product Lotlisone (betamethasone dipropionate EQ 0.05% base and clotrimazole 0.1%) cream or lotion, and five generic products have been approved as bioequivalent to the RLD based on this approach. Your Taclonex Petition attempts to distinguish the Lotrisone bioequivalence recommendations from those for Taclonex by arguing that the purpose of Lotrisone's vasoconstrictor assay and its clinical endpoint study is to separately evaluate the local bioavailability of the steroid and the anti-fungal agent, respectively, while both betamethasone and calcipotriene contribute to the clinical endpoint in the Taclonex study. However, the clinical endpoint study for Taclonex is sensitive even if both components contribute to the same clinical effect because a clinical study showed that the combination product was superior to each of the individual products: the reduction in the Psoriasis Area Severity Index at Week 4 was 73.2 percent for patients treated with the combination product compared with 48.8 percent for patients treated with a product 49 See Topical BE Guidance. 50 In the case of Taclonex Scalp Topical Suspension, the vasoconstrictor assay may not demonstrate activity in the scalp because the formulation may interact differently with patients' hair, but it can serve as a measure of the steroid potency of the formulation when tested on patients' arms. The results of study with clinical the bioequivalence endpoints considered with the results of the vasoconstrictor assay (tested on the arm instead of the scalp) are sufficient to establish the bioequivalence of a generic product to Taclonex Scalp Topical Suspension. 51 Traulsen J. Bioavailability of beta met has one dipropionate when combined with calcipotriol. Int J Dermatol43: (2004). 12

13 containing betamethasone alone and 63.1 percent for patients treated with a product containing., 52 calcipotriene alone. Accordingly, for topical combination products containing both a steroidal active ingredient and a non-steroidal active ingredient, a vasoconstrictor study and bioequivalence study with clinical endpoints are adequate to support the equivalent bioavailability of each individual active ingredient, given the known dose-response relationship of each active ingredient that is observed for vasoconstriction and clinical effect. The equivalent results in the vasoconstrictor studies and the bioequivalence study with clinical endpoints are sufficient to ensure the bioequivalence of the generic and reference drug products, and therefore equal effects of the generic and reference combination drug products on the HP A axis. Therefore, your request that all ANDA applicants referring to Tac10nex Ointment and Taclonex Scalp Topical Suspension be required to conduct dynamic HPA-axis testing is denied. C. Provocative Testing ofirritation, Sensitization, Phototoxic, and Photosensitization Potentials Finally, both of your Petitions request that FDA require an ANDA applicant to conduct provocative testing of irritation, sensitization, phototoxic, and photosensitization potentials to ensure the dermal safety of its product relative to the RLD. You argue that the Agency's recommended studies are not designed to identify significant differences in irritation, sensitization, or phototoxic or photosensitization potential that may result in rare, but serious,. 53 reactlons. Although provocative testing of irritation and sensitization may be requested by OND for new topical drug products, generic applicants are not required to repeat this safety testing. If a generic topical drug product uses an inactive ingredient that differs from the inactive ingredient in the the new RLD, FDA may request comparative testing or deny approval ofthe ANDA if any of inactive ingredients are considered likely to significantly increase the potential for irritation, 54 In addition, ANDA applicants must monitor sensitization, phototoxicity, or photosensitization. the irritation and sensitization reactions during the bioequivalence study with clinical endpoints, and FDA wil assess those adverse reactions during its review of the ANDA. Therefore, we deny your request that FDA require all ANDA applicants to conduct provocative testing of irritation, sensitization, phototoxic, and photosensitization potentials to ensure the dermal safety of its product relative to Dovonex Cream, Tac10nex Ointment, or Tac10nex Scalp Topical Suspension. 52 Papp KA, Larsen FG, Faufrann R, et al. Early onset of action and effcacy of a combination of calcipotriene and betamethasone dipropionate in the treatment of psoriasis. J Am Acad Dermatol48 (1): (2003). 53 See Taclonex petition at and Dovonex petition at CFR314.94(a)(9)(v). 13

14 IlL CONCLUSION For the reasons discussed in this response, your Petitions are denied. Sincerely, Janet VV oodcock, 11.D. Director Center for Drug Evaluation and Research 14