Hogan Lovells. December 11, 2013 BY HAND DELIVERY

Transcription

1 Hogan Lovells BY HAND DELIVERY Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, Maryland Re: CITIZEN PETITION SUPPLEMENT On behalf of AbbVie Inc. ("AbbVie") 1, the undersigned respectfully submits this second supplement to the above-referenced citizen petition (the "Petition"). This supplement pertains to the 1% testosterone gel products that are the subject of approved new drug application ("NDA") , for which Perrigo Israel Pharmaceuticals Ltd. ("Perrigo") is the sponsor (the "Perrigo Products"). The Perrigo NDA was submitted under section 505(b)(2) of the Food, Drug, and Cosmetic Act ("FDCA"). It relies on AbbVie's AndroGel (testosterone gel) 1% (NDA ) ("AndroGel 1%") as the reference listed drug, and contains data from the following clinical studies comparing the Perrigo Products to AndroGel 1%: a comparative bioavailability study, a skin transfer study, and a combined hand washing and showering study. Each of these studies was conducted with the product applied only to an upper arm/shoulder. Although the Perrigo Products are (like AndroGel 1%) approved for application to the upper arms/shoulders and on the abdomen, the Perrigo NDA (unlike the AndroGel 1% NDA) contains no data regarding the safety or efficacy of the subject products when applied to the abdomen. 2 The Petition was submitted on behalf of Abbott Laboratories, Inc., AbbVie's predecessor in interest with respect to the matters discussed therein. AbbVie is now identified as the sponsor of NDA , which covers the AndroGel (testosterone gel) 1% products relevant to the Petition. In the present supplement, we refer to AbbVie as the sponsor of NDA , the manufacturer and distributor of AndroGel, and the entity that submitted the Petition. 2 The Perrigo NDA also contains data from a skin irritation and sensitization study that was conducted on the back, which is not an approved application site for the Perrigo Products (or for AndroGel 1%).

2 Page 2 In the absence of abdomen-specific data, there is no basis for the Food and Drug Administration ("FDA" or "the Agency") to conclude that the Perrigo Products which are formulated with different penetration enhancers than used in AndroGel 1% will have the same clinical effect and safety profile as AndroGel 1%. As a result, the Perrigo Products are not therapeutically equivalent to, and cannot be safely substituted for, AndroGel 1%. For this reason, if FDA concludes that it can assign a therapeutic equivalence rating to the Perrigo Products, the Agency must assign them a "BX" rating. 3 Moreover, without abdomen-specific data, FDA has no basis to conclude that the Perrigo Products are safe and effective for use at the abdomen. Accordingly, the Agency should remove from the approved Perrigo labeling all references to this application site. Additionally, to protect against medication errors and inappropriate substitution, FDA should require the Perrigo Products' labeling to contain a clear statement, as do other topical testosterone products, that "The application site and dose of [Product] are not interchangeable with other topical testosterone products." I. ACTIONS REQUESTED AbbVie asks that the Commissioner of Food and Drugs take the following actions: Assign a "BX" rating to the Perrigo Products' listing in Approved Drug Products with Therapeutic Equivalence Evaluations ("the Orange Book"), if the Commissioner determines that the Agency will assign a therapeutic equivalence rating in the Orange Book to these products. This rating would accurately reflect that the Perrigo Products are not therapeutically equivalent to, and cannot safely be substituted for, AndroGel 1%. Revise the prescribing information and other relevant labeling for the Perrigo Products to remove the abdomen as an approved application site, because Perrigo has not demonstrated that its products are safe and effective for administration to the abdomen. Require the approved labeling of the Perrigo Products to carry the following statement: "The application site and dose of [Product] are not interchangeable with other topical testosterone products." This statement 3 As articulated in the Petition, AbbVie believes FDA lacks the legal authority to assign therapeutic equivalence ratings to products approved via NDAs submitted under FDCA section 505(b)(2). It remains AbbVie's position that, before assigning therapeutic equivalence ratings to such products, FDA must conduct a notice-and-comment rulemaking in accordance with the Administrative Procedure Act ("APA") that would, inter alia, establish standards for therapeutic equivalence ratings. The BX rating requested in this supplement is sought in the alternative, i.e., if the Agency assigns therapeutic equivalence codes to the Perrigo Products, either after conducting notice-and-comment rulemaking, or after having rejected AbbVie's position.

3 Page 3 is appropriate because the Perrigo Products have not been shown to be interchangeable with, or safely substitutable for, any other topical testosterone product, including AndroGel 1%, and also because the statement could reduce the risk of medication errors and inappropriate substitution. II. FACTUAL AND LEGAL BACKGROUND A. Product Background 1. AndroGel 1% FDA approved AndroGel 1% on February 28, 2000, for testosterone replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone, including primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired). AndroGel 1% is approved in three presentations: a 2.5 gram unit-dose packet containing 25 mg of testosterone; a 5 gram unit-dose packet containing 50 mg of testosterone; and a 75 gram pump that dispenses gram metered doses. On the basis of clinical data on both sites, AndroGel 1% is approved for application to the upper arms/shoulders and/or to the abdomen The AbbVie Petition Submitted in August 2011, the Petition asks that the Agency not assign therapeutic equivalence ratings to any drug product approved in an NDA referencing AndroGel 1% and submitted under section 505(b)(2) of the FDCA unless and until the Agency has conducted a notice-and-comment rulemaking that would, inter alia, establish standards for such therapeutic equivalence ratings. FDA issued an interim response to the Petition on February 16, 2012, explaining that the Agency had not yet reached a decision on the Petition "because it raises complex issues requiring extensive review and analysis by Agency officials."' 3. December 2012 Supplement Regarding Teva's 505(b)(2) NDA Referencing AndroGel 1% In December 2012, after FDA approved a 505(b)(2) NDA submitted by Teva Pharmaceuticals USA ("Teva") referencing AndroGel 1%, AbbVie submitted a supplement to the Petition.' That supplement asks the Agency to take the following actions with regard to 4 Approved Labeling for NDA ("AndroGel 1% PI") at 2.1; see NDA , Clinical Pharmacology and Biopharmaceutics Review ("AndroGel 1% Clinical Pharmacology Review") at 7 (Feb. 15, 2000). 5 FDA-2011-P FDA-2011-P ("December 2012 Supplement").

4 Docket No. FDA-2011-P Page 4 Teva's NDA for testosterone gel 1% products (25 mg / 2.5 gm packet; 50 mg / 5 gm packet) ("the Teva Products"), and other topical testosterone products: Assign a "BX" rating to the Teva Products, reflecting the fact that they are not therapeutically equivalent to AndroGel 1%, if the Agency concludes that it can assign therapeutic equivalence ratings in this situation; 7 Remove the abdomen application site from the Teva Products' approved labeling, because Teva has provided no data demonstrating that its products are safe or effective at the abdomen; 8 and Require all topical testosterone gel and solution products approved under section 505(b) of the FDCA to carry a "non-interchangeability" labeling statement: "The application site and dose of [product name] are not interchangeable with other topical testosterone products." 9 At present, FDA has not substantively responded to the Petition or to the December 2012 Supplement. The Agency has listed the Teva Products in the active section of the Orange Book, but has not assigned a therapeutic equivalence code to these products. 4. Approval of Perrigo's 505(b)(2) NDA Referencing AndroGel 1% Perrigo initially sought approval of generic testosterone 1% gel products by means of abbreviated new drug applications ("ANDAs") for which AndroGel 1% was the reference product.' FDA refused to approve the Perrigo ANDAs, however, because the subject products were formulated with different penetration enhancers than AndroGel 1%." FDA had previously determined that certain differences in inactive ingredients (particularly penetration enhancers) between a proposed topical testosterone product and its approved reference product trigger the need for clinical skin transfer studies, skin irritation and sensitization studies, hand washing studies, and possibly showering studies. 12 Because the Agency may not require such data in an 7 In this regard, the supplement explains that the Teva Products are not therapeutically equivalent to AndroGel 1%, because, as Agency reviewers recognized, Teva's testing showed its products not to be bioequivalent to AndroGel 1%, and because there is no basis for expecting the Teva Products to have the same clinical effect and safety profile as AndroGel 1% when applied at the abdomen application site. Id. at Id. at Id. at NDA , Cross Discipline Team Leader Review ("Perrigo CDTL Review") at 3 (May 2, 2012). 11 Id. 12 See Citizen Petition Response, Docket No. FDA-2009-P (Aug. 26, 2009) ("2009 Auxilium Petition Response"). Auxilium Pharmaceuticals ("Auxilium") markets Testim (testosterone transdermal gel)

5 Page 5 ANDA, FDA requires all proposed products referencing an approved topical testosterone product but containing different penetration enhancers to be submitted in NDAs under FDCA 505(b)(2)." Consistent with this, FDA required Perrigo to conduct a number of clinical studies and resubmit its application as a 505(b)(2) NDA." FDA approved Perrigo's NDA on January 31, 2013, although FDA's review documents discussing the scientific basis for the approval were not made public until five months later. Like AndroGel 1%, the Perrigo Products are approved as a testosterone replacement therapy for the treatment of conditions associated with deficiency or absence of endogenous testosterone, including congenital or acquired primary hypogonadism and hypogonadotropic hypogonadism.' And like AndroGel 1%, the Perrigo Products are approved for topical application to the upper arms/shoulders and/or abdomen. 16 The publicly available review documents indicate that the Perrigo NDA contains data from four clinical studies.' 7 The pivotal efficacy study ( ) compared the single-dose bioavailability of Perrigo's product to AndroGel 1%." The other three were supportive safety studies: a skin transfer study (M1IU09001), a combined hand washing and showering study (PRG-806), and a combined skin irritation (DS310208) and sensitization study (DS102308).' 9 None of the Perrigo studies, which are summarized below, contain any data regarding the use of the Perrigo Products when applied to the abdomen: Bioequivalence (BE) Study ( : 20 The pivotal study compared the pharmacokinetics of Perrigo's testosterone gel formulation to AndroGel 1%. This was a randomized, open label, 3-way crossover, bioequivalence study in 24 hypogonadal male volunteers, comparing two formulations of Perrigo's testosterone gel and AndroGel 1% following a 100 mg dose (10 g of gel) to a single side of the upper arms/shoulders, e.g., the left upper arm/shoulder. 1%, under NDA , which was approved by FDA on October 31, For further discussion of the 2009 Auxilium Petition Response, see December 2012 Supplement at Auxilium Petition Response at NDA , Medical Review ("Perrigo Medical Review") at 7-8 (Jan. 29, 2013). 15 See Approved Labeling for NDA ("Perrigo PI") at Id. at Perrigo Medical Review at Id. at Id. at Id. at

6 Page 6 Skin Transfer Study (MlIU09001):' This was a safety study in which serum testosterone levels were measured in the female partners of men, following skinto-skin contact. This open-label, single-dose, randomized, 4-period, 4-treatment crossover study assessed the relative transfer of testosterone from a subject who had received a single dose of the Perrigo product. Potential for transfer from males to females was assessed, with males wearing t-shirts and males not wearing t-shirts. Here, too, subjects applied a 100 mg dose (10 g of gel) to a single side of the upper arms/shoulders application site. Hand Washing and Showering Study (PRG-806): 22 This was an open-label, 3- period safety study in which Perrigo measured the amount of residual testosterone present on a subject's hand, arm and shoulder in healthy adult male subjects following washing. Patients applied a single topical dose of 100 mg of testosterone (10 g of gel), using the palm of one hand to apply to the opposite upper arm/shoulder. The study measured the amount of testosterone on the hand and upper arm/shoulder application site before and after washing. Hand washing occurred immediately after application; application site washing occurred two hours after application. Skin Irritation (DS310208) and Sensitization Study (DS102308): 23 In this combined within-subject comparison study, five substances (Perrigo's investigational product, AndroGel 1%, a vehicle, and two controls (positive control: sodium laurel sulfate 0.2%; negative control: saline)) were applied to healthy volunteers. The objectives of this study were to determine the irritation potential of Perrigo's product on normal skin and to determine the potential of Perrigo's product to cause sensitization by repeated topical application. Five patches were applied in a randomized pattern to the subjects' backs over the course of three consecutive weeks, and the patch sites were assessed multiple times throughout the study for signs of both irritation and sensitization. FDA has listed the Perrigo products in the "active section" of the Orange Book, and indicated that NDA received three-year "new product" ("NP") exclusivity, on the basis of the clinical studies submitted in the NDA. Although the Orange Book listing of the Perrigo testosterone products suggests that they are pharmaceutically equivalent to AndroGel 1%, they are not listed with a therapeutic equivalence code Id. at Id. at Id. at See section II.B. infra (describing FDA standards for pharmaceutical equivalence).

7 Page 7 B. Regulatory Framework for Therapeutic Equivalence Determinations and Therapeutic Equivalence Codes FDA evaluates the therapeutic equivalence of all multisource drug products, i.e., all pharmaceutically equivalent drug products available from more than one manufacturer!' As a general matter, products are pharmaceutical equivalents if they contain the same active ingredient(s) in the same strength or concentration, and are of the same dosage form and route of administration.' A finding of therapeutic equivalence means FDA has concluded that two products may be safely and effectively substituted for each other!' and ordinarily permits substitution of one product for the other under state pharmacy laws. FDA deems two products therapeutically equivalent only if they are pharmaceutical equivalents and "can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling."' This requires them, among other things, to be bioequivalent, adequately labeled, and manufactured in compliance with Current Good Manufacturing Practice regulations. 29 Multisource prescription drug products determined to be therapeutic equivalents are assigned an "A" rating in the Orange Book, along with one of six possible sub-codes." In this context, products that share an "A" rating can be substituted one for the other, with no expected difference in safety or effectiveness in the patient?' Products not shown to be therapeutically equivalent are assigned a "B" rating, along with one of ten sub-codes." If the data are "insufficient to determine therapeutic equivalence," FDA assigns the products a "BX" code, which means "the drug products are presumed to be therapeutically inequivalent."" III. ARGUMENT In the underlying Petition, AbbVie has requested that FDA not assign therapeutic equivalence codes to products referencing AndroGel 1% and submitted under a 505(b)(2) NDA unless and until the Agency conducts a notice-and-comment rulemaking to, inter alia, establish 25 Orange Book Preface at iv, See id. at vi; see also 21 CFR 320.1(c). 27 See Orange Book Preface at vii. 28 Id 29 Id 30 See id. at xiii-xvii. 31 Id. at vii. 32 Id at Xvii-XX. 33 Id. at xx.

8 Docket No. FDA P-0610 Page 8 clear standards for assigning therapeutic equivalence ratings to 505(b)(2) products. 34 Absent such a rulemaking, assigning therapeutic equivalence codes to such products would be arbitrary and capricious and violate the APA." And if FDA determines that it may assign therapeutic equivalence ratings to products submitted under FDCA 505(b)(2), the Agency must assign a BX rating to the Perrigo Products. The BX rating is the only appropriate rating because, as discussed below, there is no basis to expect them to have the same clinical effect and safety profile as AndroGel 1%, when applied to either the abdomen or to the upper arms/shoulders. Moreover, the complete lack of any abdomen-application data means Perrigo has not demonstrated that its products are safe and effective when applied at that site, and the products' labeling therefore must be revised to remove any reference (including but not limited to application instructions) to such use. The Perrigo Products' labeling should also be revised to include a clear statement that the products are not interchangeable with any other approved topical testosterone product. A. The Perrigo Products May Not be Deemed Therapeutically Equivalent to AndroGel 1%, Because There is No Basis to Expect Them to Have the Same Clinical Effect and Safety Profile as AndroGel 1%. There is no basis for FDA to conclude that the Perrigo Products are therapeutically equivalent to AndroGel 1%, because Perrigo has not demonstrated that its products will have the same clinical effect and safety profile as AndroGel 1% under the approved conditions of use.' The Agency therefore must assign Perrigo's testosterone gel products a "BX" rating in the Orange Book, indicating that the Perrigo Products are not therapeutically equivalent to, and cannot safely be substituted for, AndroGel 1%. 1. The Perrigo Products have not been shown to have the same safety and effectiveness profile as AndroGel 1% when applied to the abdomen. AndroGel 1% is approved for application to the upper arms/shoulders and the abdomen, based on clinical data in the NDA from studies of the product used at both application sites.' The Perrigo NDA, in contrast, contains data only on the use of the subject products on a single upper arm/shoulder. Although the Perrigo studies compared the Perrigo Products to AndroGel 34 Petition at Id. 36 See Orange Book Preface at vii. 37 AndroGel 1% PI at 2.1 and 14.1; AndroGel 1% Clinical Pharmacology Review at 7.

9 Page 9 1%, none of the studies reported in the Perrigo NDA were conducted with the proposed product being applied to the abdomen. In the absence of any abdomen-specific data, there is no basis for making any conclusions regarding the safety and effectiveness of the Perrigo Products when applied to the abdomen, let alone determining that the Perrigo Products are comparable to AndroGel 1% when applied at that site. a. No data on transfer risk. The Perrigo Products' labeling explicitly warns, "[t]he potential for dermal testosterone transfer following testosterone gel application on the abdomen has not been evaluated." 38 That this statement was required in the labeling indicates FDA's recognition that nothing is known about skin transfer risk from the abdomen with the Perrigo Products, as well as the Agency's determination that the absence of such data is important for healthcare providers to know. This distinguishes the Perrigo Products from AndroGel 1% in a way that precludes a finding of therapeutic equivalence. The lack of data regarding transfer risk when the Perrigo Products are applied to the abdomen is particularly significant, given that data show the abdomen to present a greater risk of transfer than the upper arms/shoulders. Studies conducted on other topical testosterone products have shown that testosterone is generally absorbed less on the abdomen than on the upper arms/shoulders." And as the Agency knows, the difference can be clinically significant. AndroGel 1.62% (NDA ), for example, was studied at both application sites, but approved for administration on the upper arms/shoulders only, because the risk of skin transfer was unacceptably higher when the product was applied to the abdomen. Testim also was approved only for application at the upper arms/shoulders, apparently because of transfer risk at the abdomen. 4' Accordingly, one cannot extrapolate from transfer data on use of the Perrigo Products and AndroGel 1% on the upper arms/shoulder to reach a conclusion regarding comparative safety when applied to the abdomen. 38 Perrigo PI at See, e.g., A. Guay, T. Smith, and L. Offutt, Absorption of Testosterone Gel 1% (Testim) from Three Different Application Sites, Journal of Sexual Medicine 2601, (June 22, 2009) (attached); see also NDA , Medical Review ("AndroGel 1.62% Medical Review") at 20 (April 20, 2011) ("Testosterone exposure is 30-40% lower when applied to the abdomen compared to the shoulders/upper arms."). 40 See AndroGel 1.62% Medical Review at 20, Data from two skin transfer studies submitted with the AndroGel 1.62% NDA showed that use of a t-shirt effectively prevented transfer of a 2.5 mg dose, but not a 5 mg dose applied to the abdomen. Id. at 155. A subsequent study demonstrated that a t-shirt prevented transfer of a 5 mg dose applied to the upper arms/shoulders. Id. 41 See NDA , Medical Review ("Testim Medical Review") at 7, (Oct. 30, 2002).

10 Page 10 b. No data on bioavailability. Additionally, FDA may not reach into the AndroGel 1% NDA to analyze AndroGel data in order to reach a conclusion regarding efficacy of the Perrigo products when applied to the abdomen. As with the Perrigo 505(b)(2) NDA, the Teva NDA contained no data assessing use of Teva's products on the abdomen. 42 In that instance, FDA apparently concluded that similarity of the Teva Products to AndroGel 1% when applied to the upper arms/shoulders allowed the Agency to assume that the Teva Products would have the same efficacy as AndroGel 1% when applied to the abdomen. This assumption was based, however, on a manipulation of data from Study UMD , a phase 1 study presented in the AndroGel 1% NDA." As the December 2012 Supplement explains, FDA's reliance on this study was legally impermissible, as well as scientifically suspect." That FDA sought to rely on the AbbVie data indicates the Agency's recognition that Teva's bioequivalence study, conducted exclusively on the upper arms/shoulders, was insufficient to demonstrate the efficacy of the Teva Products on the abdomen. Perrigo's pivotal clinical trial, conducted only on one upper arm/shoulder, is similarly inadequate to demonstrate the efficacy of the Perrigo Products when applied to the abdomen. As with the Teva products, and for the same reasons, the AndroGel 1% study cannot form any part of the basis for a conclusion regarding the safety or efficacy of the Perrigo Products when applied to the abdomen.' Until Perrigo provides data comparing the efficacy of its products and AndroGel 1% when applied at the abdomen, the Agency has no basis to conclude that the Perrigo Products can be expected to have the same clinical effect as AndroGel 1% applied at that site. 42 See December 2012 Supplement at (citing NDA , Medical Officer's NDA Filing Memorandum at 4 (Feb. 25, 2011); NDA , Clinical Pharmacology Review at 20-21). 43 See December 2012 Supplement at (citing NDA , Clinical Pharmacology Review at 20-21). " See December 2012 Supplement at As explained in the December 2012 Supplement, Study UMD was a phase 1 study to evaluate the safety and pharmacokinetics of different ways of applying a 10 mg dose of AndroGel 1%. It was not designed to evaluate the relative bioavailability of the product when applied at different sites, yet FDA manipulated the data to serve that purpose with regard to the Teva products. Id. 45 Id. Unlike with regard to the Teva products, the publicly available review documents for the Perrigo NDA contain no direct reference to reliance on the AndroGel 1% study. FDA nonetheless may have improperly relied on the study, particularly because, as discussed, data from the Perrigo studies on a single upper arm/shoulder cannot be extrapolated into a conclusion as to safety and efficacy when the products are applied to the abdomen.

11 Page The Perrigo Products have not been shown to have the same safety and effectiveness profile as AndroGel 1% when applied to the upper arms and shoulders. Data regarding application of the Perrigo Products to a single upper arm/shoulder show that the products do not have the same safety profile as AndroGel 1% when applied to both upper arms/shoulders. In fact, the available data suggest that the risk of transfer is greater with the Perrigo Products than with AndroGel 1%. Moreover, flaws in the Perrigo studies suggest that the transfer risk with the Perrigo Products has been understated, and the comparability of effectiveness has been overstated. a. Differences in transfer risk. Perrigo's skin transfer study, M1IU09001, was an open-label, single-dose, randomized, 4-period, 4-treatment crossover study that assessed the relative transfer of testosterone from a subject who had received a single dose of the Perrigo product.'" Two 5 gm packets (100 mg of testosterone) were applied to the upper arm and shoulder on one side of the subject's body." Potential for transfer from males to females was assessed, both with males wearing t-shirts and males not wearing t-shirts, based on the increase versus baseline of serum testosterone levels in the female partners. This study showed that, when the males did not wear a t-shirt, female partners' mean testosterone AUC0.24 and C max were more than twice their mean baseline values." Even when a t-shirt covered the application site, there was a 16% and 48% increase in testosterone AUC0-24 and Cma, respectively, compared to baseline in these females." This compares unfavorably with 46 Perrigo Medical Review at Perrigo PI at As noted below, this is inconsistent with how the Perrigo Products are labeled for application to the upper arms/shoulders. 48 Id. 49 Id.; see also Perrigo CDTL Review at 16 ("However, transfer is not eliminated completely by the [t-shirt] barrier as has been reported with many other testosterone gel products."). These results exceed (in some instances dramatically) the testosterone increase in the female partners reported with the other approved topical testosterone products, when tested with a t-shirt covering the application site. See, e.g., Approved Labeling for NDA ("Axiron PI") at 12.3 ("Study results show a 13% and 17% increase in testosterone exposure (AUC0_24) and maximum testosterone concentration (Cmax), respectively, compared to baseline in these females."); Approved Labeling for NDA ("AndroGel 1.62% PI") at 12.3 ("[M]ean testosterone C an and Cmax in female subjects increased by 6% and 11%, respectively, compared to mean baseline testosterone concentrations"); Approved Labeling for NDA ("Fortesta PI") at 12.3 ("When transfer occurred with FORTESTA while covering a thigh with boxers shorts, mean C an decreased by 3% and mean C max increased by 2%, compared to direct skin-to-skin transfer with placebo."). Nonetheless, the Division of Reproductive and Urologic Products concluded that the increases shown in the study of the Perrigo Products did not preclude

12 Page 12 AndroGel 1%, where "[w]hen a shirt covered the application site(s), the transfer of testosterone from the males to the female partners was completely prevented." 50 Moreover, the Perrigo study is flawed in a way that likely understates the rate of testosterone transfer to female partners. In Study MlIU09001, the entire 10 g dose of testosterone gel was applied to an upper arm and shoulder on just one side of the body.' This does not reflect actual use conditions; the instructions for administration direct patients to apply the Perrigo Products so that they are "evenly distributed between the right and left upper arms/shoulders." 52 As FDA noted, application to just one upper arm/shoulder means the surface area for transfer to the female partner is reduced by half." b. Flawed effectiveness comparison. Similarly, because Perrigo's pivotal effectiveness study was also conducted with the entire dose applied to one upper arm/shoulder, those data may be unreliable for demonstrating that the pharmacokinetics of the Perrigo Products are comparable to AndroGel 1%. As with the transfer study, cutting the surface area in half likely biased the study in favor of Perrigo's desired outcome. The body of data obtained through the years of developing AndroGel 1% and AndroGel 1.62% suggests that the pharmacokinetics of testosterone gels are not dose proportional, and that surface area is an important factor influencing absorption of the active ingredient.' Accordingly, because both the test and reference products were applied to only one approval, apparently because total testosterone levels in the female partners stayed "within the normal range for female[s] of 0-90 ng/dl." Perrigo CDTL Review at AndroGel 1% PI at This labeling statement reflects the results of a skin transfer study with AndroGel 1%, in which the female partners had a maximum mean serum total T concentration of ng/dl at 24 hours on Day 7, compared to a baseline maximum mean serum total T concentration of ng/dl (± SD), when the application site was covered with a t-shirt. See NDA , Medical Officer Review at (Feb. 15, 2000). The Perrigo Products present a greater risk of transfer than the Teva products, as well. See Approved Labeling for NDA at 12.3 (11% and 16% increase in testosterone AUC0_24 and testosterone C max, respectively). 51 NDA , Clinical Pharmacology Review ("Perrigo Clinical Pharmacology Review") (May 1, 2012) at Perrigo PI at Perrigo Clinical Pharmacology Review at 30 (stating that application of entire dose to just one side of the body "leads to a 50% reduction in the surface area for transfer as compared to" application to the upper arms and shoulders on both sides of the body. Perrigo's showering study was similarly flawed, in that the entire dose was applied to one upper arm/shoulder. See id. at 34. This means the data regarding how much testosterone remains on the skin after showering do not reflect the approved conditions of use. 54 See, e.g., AndroGel 1% Clinical Pharmacology Review at (Figures 1.0 and 1.3, describing results from Study UMD ); NDA , Clinical Pharmacology and Biopharmaceutics Review (Oct. 22, 2009) ("AndroGel 1.62% Clinical Pharmacology Review") at 23 (Table 12, describing results from Study ).

13 Page 13 upper arm/shoulder and at the highest dose, each formulation was likely absorbed at a rate that markedly exceeds what occurs under the approved conditions of use, thus reducing the potential to detect differences in bioavailability. In essence, the Perrigo study relied on a "best case" scenario, and the data generated at the single upper arm/shoulder application site was not sufficient to form a conclusion about the products' comparative bioavailability." B. The Perrigo Products Have Not Been Shown to be Safe and Effective When Applied to the Abdomen, and Therefore Cannot Be Approved for That Use. As discussed above, the Perrigo NDA contains no data supporting application of the subject products to the abdomen. Perrigo, therefore, has not demonstrated that its products are safe and effective when applied to that site. Consequently, Perrigo has not met the statutory burden for obtaining approval of the Perrigo Products for use on the abdomen, and their labeling should be revised to remove any references to such use. The FDCA explicitly requires all NDAs to include clinical data demonstrating the proposed product's safety and efficacy for all proposed conditions of use." FDCA 505(b)(2) allows an NDA to meet that obligation, at least in part, by relying on studies not conducted by the NDA sponsor, and to which the NDA sponsor does not have a right of reference. 57 Nevertheless, the obligation to demonstrate safety and efficacy, and the standards by which the data are evaluated, are the same." The extent of permissible reliance on a reference listed drug is determined by the nature and extent of the similarities (and differences) between the proposed product and the reference product. A 505(b)(2) applicant must provide its own product-specific data to support any material differences between the proposed product and the reference product. 59 For topical testosterone products, changes in inactive ingredients such as penetration enhancers are material differences.' The Agency has expressly determined that an application for a topical testosterone product that contains a different penetration enhancer than a reference product must include product-specific data regarding the risk of skin transfer and the effect of 55 Further, for the scientific and legal reasons previously discussed, the data from Study UMD presented in the AndroGel 1% NDA cannot be relied on to draw any conclusions regarding the pharmacokinetics of the Perrigo Products when applied to both shoulders/upper arms, as the approved labeling directs. See supra at III.A.1.b.; see also December 2012 Supplement at USC 355(b)(1) USC 355(b)(2) USC 355(b)(1). 59 Citizen Petition Response, Docket Nos. 2001P-0323, 2002P-0447, 2003P-0848 (Oct. 14, 2003) at Auxilium Petition Response at 5.

14 Page 14 hand washing (and perhaps showering). 6' That is, in fact, the reason FDA required Perrigo to submit a 505(b)(2) NDA, instead of an ANDA. 62 Although the Perrigo NDA contains the required data regarding the proposed products when applied to an upper arm/shoulder, Perrigo provided nothing on the safety and efficacy of the products when applied to the abdomen (or to both upper arms/shoulders). Without product-specific data regarding the use of the Perrigo Products on the abdomen, the Agency has no basis for concluding that these products are safe and effective for use at that site, particularly with regard to the risk of skin transfer. Moreover, for the reasons discussed above, FDA cannot extrapolate from Perrigo's data regarding one upper arm/shoulder application site or from the AndroGel 1% data regarding application at the abdomen. FDA has acknowledged the necessity of product-specific information with regard to transfer risk when a proposed product contains different penetration enhancers than the reference product.' Apparently recognizing the significance of the lack of any abdomen-specific data from Perrigo, FDA has required the labeling for the Perrigo Products to state: "The potential for dermal testosterone transfer following testosterone gel application on the abdomen has not been evaluated."64 But this labeling statement is insufficient to ensure that the Perrigo Products can be safely applied to the abdomen. Perrigo has provided no data demonstrating its products' safety and efficacy when applied at the abdomen, and therefore has not met the statutory standard for approval for that use. Accordingly, FDA cannot approve the Perrigo Products for application at the abdomen, and must require revision of the Perrigo Products' labeling to delete any references to application at the abdomen. C. The Labeling for the Perrigo Products Should Clearly State That They Are Not Interchangeable With Other Topical Testosterone Products. In the December 2012 Supplement, AbbVie asked that FDA require the approved labeling for all topical testosterone products approved under section 505(b) of the FDCA, including the Teva Products, to state that "The application site and dose of [Product] are not interchangeable with other topical testosterone products." 65 Although that request, by its terms, 61 Id. 62 Perrigo CDTL Review at Auxilium Petition Response at 5. ("[I]f a testosterone transdermal gel product were to be formulated with different penetration enhancers than the reference listed drug, absent transfer studies, we would not have a basis to determine whether the potential absorption of testosterone from the product in the course of a secondary contact is the same as that of the reference listed drug."). 64 Perrigo PI at To AbbVie's knowledge, Perrigo and Teva are the only sponsors of a topical testosterone product not to have studied the risk of skin transfer at all approved application sites. See December 2012 Supplement at December 2012 Supplement at 18.

15 Page 15 applies to the Perrigo Products, AbbVie here reiterates that request specifically with regard to the Perrigo Products. As discussed herein, the Perrigo Products are not therapeutically equivalent to, and are therefore not interchangeable with, AndroGel 1%. For this reason, AbbVie has requested that FDA assign the Perrigo Products a "BX" rating in the Orange Book, if the Agency concludes that it has the authority to assign therapeutic equivalence ratings to these products. A "BX" rating will reduce the likelihood that the Perrigo Products are automatically substituted for AndroGel 1%. However, the risk of medication errors and inappropriate substitution remains high for the Perrigo Products, because they share many characteristics with AndroGel 1%, including active ingredient, dosage form, route of administration, package configurations and strengths. In addition, as the Agency previously recognized with regard to the Teva Products, the Perrigo Products carry a particularly high risk of inappropriate substitution because they carry no trade name." At present, FDA continues to permit inconsistent labeling statements throughout the product class. Some, but not all, of the approved topical testosterone products (including the Perrigo Products) have the following statement in their labeling: "Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure."' Similarly, the statement regarding non-interchangeability that AbbVie requests for all topical testosterone products approved via NDAs "The application site and dose of [Product] are not interchangeable with other topical testosterone products" is currently contained in the labeling for AndroGel 1% and several other products, but not all topical testosterone products." Although the "systemic exposure" statement may be literally true as far as it goes, it is misleading in the absence of clear communication that the products are not interchangeable." Like all other topical testosterone products approved via NDAs, the Perrigo Products are not interchangeable with, nor substitutable for, any other approved topical testosterone product approved under FDCA 505(b). For that reason, the labeling for all of these products should be 66 See id. at 18 (citing NDA , Medical Officer's NDA Filing Memorandum at 11 ("The lack of a trade name may engender a potential for medication errors.")). 67 The other products with this "systemic exposure" statement in the labeling are Testim, the Teva Products, AndroGel 1% and AndroGel 1.62%. 68 The other products with this "non-interchangeability" statement in the labeling are Testim, AndroGel 1.62%, Axiron, and Fortesta. 69 See December 2012 Supplement at 18. AndroGel 1%, AndroGel 1.62% and (with recent labeling changes) Testim are the only products in the class that carry both a "systemic exposure" statement and the "noninterchangeability" statement. See id. at 5.

16 Page 16 required to contain the same clear statement regarding non-interchangeability as is currently required of only some products in the class. IV. CONCLUSION If FDA concludes that it can assign therapeutic equivalence codes to the Perrigo Products, the Agency must assign a "BX" rating, reflecting the fact that the products are not therapeutically equivalent to AndroGel 1%. Perrigo has not provided any data regarding the application of its products to the abdomen, which is one of the approved conditions of use of AndroGel 1%. Accordingly, there is no basis for FDA to conclude that the Perrigo Products can be expected to have the same clinical effect and safety profile as AndroGel 1% when administered to patients under the conditions specified in the labeling, which is the essence of a finding of therapeutic equivalence. In addition, because Perrigo has not demonstrated that its products are safe and effective when applied to the abdomen, the Perrigo Products' labeling should be revised to delete any reference to use at that application site. Further, to mitigate the risk of inappropriate substitution and other medication error that exist even with a "BX" rating, the Perrigo Products' labeling should also be revised to include a statement that the products are not interchangeable with other approved topical testosterone products. V. CERTIFICATION The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition. Respectfully submitted, Attachment cc: Dan Himmelfarb, Mayer Brown LLP Neal B. Parker, AbbVie Inc. Perry C. Siatis, AbbVie Inc.