FDA has carefully considered the information submitted in your petition and other

Transcription

1 t\suwices. (' ~ DEPARTMENT OF HEALTH &. HUMAN SERVICES ~~~~"7:~ Food and Drug Administration Rockvile M D FEB Izumi Hara Senior Vice President and General Counsel Warner Chilcott (US), LLC 100 Enterprise Drive Rockaway, New Jersey Docket No. FDA-20ll-P-0702 Dear Ms. Hara: This letter responds to your citizen petition received by the Food and Drug Administration (FDA or the Agency) on September 23,2011 (Petition), requesting that FDA take certain actions with respect to any abbreviated new drug applications (ANDAs) that reference Mayne Pharmaceuticals International Pty. Ltd.'s Doryx (doxycycline hyclate) delayed-release tablets, 150 miligrams (mg) (NDA ) (Doryx). i Specifically, you request that FDA take the following actions: (l) Refrain from granting final approval for any ANDA for a 150 miligram (mg) doxycycline hyclate delayed-release product referencing Doryx unless and until the ANDA applicant adopts a dual-scored 150 mg tablet configuration; and (2) Require an ANDA for also mg doxycycline hyclate delayed-release product referencing Doryx to have the same labeling as Doryx and not apply section 505G)(l0) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) to permit final approval of the ANDA. FDA has carefully considered the information submitted in your petition and other relevant data available to the Agency. Based on our review of these materials and for the reasons described below, your petition is denied. Today we are approving a generic2 single-scored 150 mg doxycycline hyclate delayed-release product, with a postapproval requirement to comply with the new dual scoring configuration of the reference listed drug product (RLD) when it conducts its next manufacturingiun. J Warner Chilcott (Warner) is the U.S. agent for Mayne Pharmaceuticals International Pty. Ltd. (Mayne), the sponsor of Dory. 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 5050) of the FD&C Act (21 U.S.C. 3550)).

2 I. BACKGROUND A.Doryx Doryx is a tetracycline-class antimicrobial indicated for the treatment ofthe following:. Rickettsial infections. Sexually transmitted infections. Respiratory tract infections. Specific bacterial infections. Ophthalmic infections. Anthrax, including inhalational anthrax (post-exposure). Alternative treatment for selected infections when penicilin is contraindicated. Adjunctive therapy in acute intestinal amebiasis and severe acne. Prophylaxis of malaria Doryx 150 mg delayed-release tablets were originally approved in a supplemental new drug application (NDA) on June 20, On September 13,2011, FDA approved a supplemental NDA for Doryx (S-014) to change the scoring of Doryx 150 mg delayedrelease tablets. The single-scored configuration was replaced by a dual-scored configuration, designed to be broken into doses of 100 mg or 50 mg. The single-scored tablets were designed to be broken into 75 mg doses. B. Legal and Regulatory Background for ANDAs The Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch- Waxman Amendments) created section 505G) ofthefd&c Act (21 U.S.C. 355G)),. which established the current ANDA approval process. To obtain approval, an ANDA applicant is not required to submit evidence to establish the clinical safety and effectiveness ofthe drug product; instead, an ANDA relies on FDA's previous finding that the RLD is safe and effective. To rely on a previous finding of safety and effectiveness, an ANDA applicant must demonstrate, among other things, that its drug product is bioequivalent to the RLD (section 505G)(2)(A)(iv) of the FD&C Act). In addition, ananda must contain, with certain exceptions not relevant here, information to show that the proposed drug has the same active ingredient(s),indications for use, route of administration, dosage form, strength, and labeling as the RLD (section 505G)(2)(A) of the FD&C Act). FDA must approve an ANDA unless the information submitted in the ANDA is insufficient to meet the requirements delineated in section 505(j) of the FD&C Act, including a demonstration ofbioequivalence (section505(j)(4)). The basic assumption underlying the Hatch-Waxman Amendments is that bioequivalent drug products that meet the following criteria are therapeutically equivalent and may be substituted for each other: (1) they contain identical amounts of the same active ingredient(s) in the same route of administration and dosage form; (2) they meet 2

3 applicable standards of strength, quality, purity, and identity; (3) they are manufactured in compliance with current good manufacturing practices regulations; and (4) they are adequately labeled.3 The FD&C Act requires that an ANDA contain "information to show that the labeling proposed for the new (generic) drug is the same as the labeling approved for the listed drug... except for changes required because of differences approved under a petition fied under (section 505(j)(2)(C) of the FD&C Act) or because the new drug and the listed drug are produced or distributed by different manufacturers" (section 505(j)(2)(A)(v) of the FD&C Act). A parallel provision appears in section 505G)(4)(G) of the FD&C Act. 4. Similarly, the regulations at 21 CFR 3l4.94(a)(8)(iv) require the following: Labeling (including the container label, package insert, and, if applicable, Medication Guide) proposed for the (generic) drug product must be the same as the labeling approved for the reference listed drug, except for changes required because of differences approved under a petition fied under (21 CFR ) or because the drug product and the reference listed drug are produced or distributed by different manufacturers. Section 3l4.94(a)(8)(iv) sets forth examples of permissible differences in labeling that may result because the generic drug product and reference listed drug are produced or distributed by different manufacturers. These differences include the following:... differences in expiration date, formulation, bioavailability, or pharmacokinetics, labeling revisions made to comply with current FDA labeling guidelines orother guidance, or omission of an indication or other aspect oflabeling protected by patent or accorded exclusivity under section 505(j)(4)(D) of the (A)ct.5 We have interpreted the difference-due-to-differences-in-manufacturer exception to apply when the ANDA differs in an aspect that is not required by the statute or regulation to be 3 See section 505G) of the FD&C Act. 4 Section 505G)(4)(G) provides that FDA must approve an ANDA unless, among other things, the "information submitted in the application is insufficient to show that the labeling proposed for the drg is the same as the labeling approved for (the reference listed drg) except for changes required because of differences approved under (an ANDA suitability petition) or because the drug and the listed drug are rroduced or distributed by different manufacturers." We note that, due to a series of amendments to the FD&C Act, the reference in 3 l4.94(a)(8)(iv) to section 505G)(4)(D) ofthe FD&C Act corresponds to curent section 505G)(5)(F) of the FD&C Act. 3

4 the same as the RLD (e.g. a difference in inactive ingredients).6 II. DISCUSSION As a result ofthe change in the scoring ofdoryx 150 mg delayed-release tablets from a single-scored to a dual-scored configuration, your petition requests that FDA take certain actions with respect to any ANDAs citing Doryx as the RLD. You make several arguments in support of your requests, and we address each of your arguments below. A. Scoring Configuration for ANDAs Referencing Doryx (doxycycline hyclate) Delayed-Release Tablets, 150 mg On September 13,2011, FDA approved a supplemental NDA for Doryx (S-014) to change the scoring of Doryx 150 mg delayed-release tablets. The single-scored configuration was replaced by a dual-scored configuration that is designed to be broken into doses of 100 mg or 50 mg. The single-scored tablets were designed to be broken into 75mg doses (Petition at 1-2). With the supplement came changes to the Doryx 150 mg labeling. Specifically, Section 16 (HOW SUPPLIED/STORAGE AND HANDLING) includes the statement that the Doryx 150 mg tablets are dual-scored; Section 17 (PATIENT COUNSELING INFORMATION) includes a supplemental Section 17.1 "Instructions for Breaking the 150 mg DORYX Dual-Scored Tablet." In addition, the carton and container labeling for the dual-scored tablet was modified to reduce the risk of pharmacist product substitution (i.e., the dual-scored packaging includes a red triangle on 3 sides of the box with text, "NEW NDC NUMBER, NEW TABLET SHAPE AND SCORING"). You claim that to mitigate the risk of confusion between the dual- and single-scored tablets, you committed to FDA to limit the amount of time the two products would be on the market simultaneously (Petition at 2). In addition, you state that you took steps to educate health care providers on the dual-scored product. You maintain that FDA should not approve an ANDA for a generic single-scored 150 mg doxycycline hyclate delayedrelease product because it would raise public health concerns (Petition at 3). You also 6 See generally, Zeneca Inc. v. Shalala, 213 F.3d 161, 169 (4th Cir. 2000). In Zeneca the Fourth Circuit agreed with FDA's interpretation of section (a)(8)(iv) allowing the generic drug product label for propofol with the preservative sodium metabisulfite to differ from the RLD by containing a waring against possible allergic reaction to the preservative. Specifically, the court concluded that "(b)ecause a difference in preservative is a permitted variation in formulation, it is reasonable for the FDA to interpret its own regulation to allow corresponding differences in labeling to identify the preservative and provide any appropriate warings." Id. See also September 15,2009, letter from Janet Woodcock, Director, Center for Drug Evaluation and Research, to Beth Brannon et ai., Docket Nos. FDA-2005-P-0003, FDA-2006-P-0019, FDA-2006-P-0331, and FDA-2006-P-0391 (FDA permitted the generic product to contain a previously approved formulation of the drug product and carry labeling different from the reformulated RLD product). 4

5 suggest that having two products with different scoring could lead to patient confusion and suboptimal dosing. You assert that FDA practice and documents such as the draft guidance for industry on Tablet Scoring: Nomenclature, Labeling, and Date for Evaluation (Aug. 2011) (Draft Scoring Guidance) and the Manual of Policies and Procedures (MAPP) "Scoring Configuration of Generic Drug Products" (Scoring MAPP) support your argument that the generic product must have the same scoring as the reference product (Petition at 3). We do not agree that approving an ANDA for a generic single-scored 150 mg doxycycline hyclate delayed-release product would raise any new public health concerns, especially if the single-scored ANDA product, like your single scored tablet, wil be marketed concurrently with the double-scored product only for a finite period of time. First, even when both the single-scored and dual-scored tablets are in distribution at the same time, either under your NDA alone or under your NDA and an ANDA for a singlescored tablet, there is very little chance that this marketing of two doxycycline products with different scoring patterns would lead to a safety issue. Doxycycline is approved for treatment of infections, malaria prophylaxis, and as. an adjunctive treatment for severe acne. Unlike medications for certain other chronic diseases where patients may need to use a scored tablet to titrate their dose of medication based on changing disease state or changing response to therapy over time, doxycycline dosage would rarely be adjusted in this manner. Upon receiving a prescription for a particular strength of doxycycline that did not specify the formulation, a pharmacist would determine whether the single-scored or dual-scored 150 mg tablet, or a lower strength tablet of doxycycline, could be used to deliver the prescribed dosage, and therefore could dispense either the single-scored or dual-scored tablet based on the written prescription. It is unlikely that the patient wil have to determine how to use the score for a subsequent unanticipated dosage adjustment (i.e., a change in dosage recommended by the physician after the prescription has been filled) because for these products, doses are not typically adjusted based on a patient's response after the initial prescription. Thus, the risk of medication error because of different scoring configurations wil be limited. Second, all the doses obtained from the two scoring configurations (50/50/50 or 100/50 for the dual-scored 150 mg product, and 75/75 for the single-scored 150 mg product) are available from the approved 75 mg and single-scored 100 mg products sold by the RLD manufacturer and one or more generic manufacturers. We do agree that there is a potential for confusion and dosing errors, as there was when you introduced your dual-scored tablet while stil marketing your single-scored tablet for a finite period but, as discussed above, we expect that dosing errors would be unlikely, as pharmacists would determine whether the single-scored or dual-scored tablets would be dispensed based on the dose prescribed (e.g., a single-scored 150 mg tablet would not be dispensed if the dose prescribed were 100 mg). In seeking approval for your dual-scored tablet without initiating a recall of your single scored tablets, you indicated that you would take steps to limit the amount of time your 5

6 two products wil be on the market. However, you were not specific as to the period of time the single-scored product would remain in the market (e.g., hospitals, retail stores, distributor warehouses), nor is information available describing the typical usage rate for this product that would have allowed the Agency to determine when all remaining stock of your single-scored tablet wil be eliminated from the market. Nonetheless, FDA approved your double-scored product with the knowledge that both your double-scored and your single-scored products would be marketed concurrently for some undefined period of time. Furthermore, you did not add any warnings to the Doryx labeling describing the non-interchangeability between the two different scoring configurations. We note that you did create a new National Drug Code (NDC) number for the dualscored tablet, which may serve as an additional reminder to health care providers that the product is different in some way from your single-scored tablet, but this addition likely would have little impact on product substitution at the pharmacy level because the active ingredient and strength (the information specified on and used to fill the prescription) remain unchanged. Thus, product substitution between the single-scored and dual-scored Doryx 150 mg delayed-release tablets could and likely has occurred with both versions of your product and we are aware of no adverse events in the Adverse Event Reporting, System (AERS) attributable to such substitution. In addition, with respect to the Scoring MAPP and Draft Scoring Guidance, we disagree with your assertion that they require FDA to refuse to approve a generic product with a scoring different from the RLD. First, by definition, MAPPs contain statements of general policies and guidances contain recommendations, not requirements. There is no statutory or regulatory requirement that generic drugs have the same scoring configurations as their RLDs. Moreover, it is important to note that the Draft Scoring Guidance and Scoring MAPP generally address the question of how a generic product should be configured when the configuration of the RLD is krown at the time the ANDA is submitted to the Agency. These general recommendations about sameness advise that in a stable situation where the RLD has not suddenly changed the scoring of its product, identity between RLD and ANDA scoring is optimal. However, they do not recommend (let alone require) that identical scoring between a generic and an RLD must be shown pre-approval in all situations. Of particular relevance here, the Scoring MAPP notes that where the RLD has changed its scoring pattern while an ANDA is pending, FDA wil evaluate the need for and timing of a change in ANDA scoring on a case-by-case basis.? Specifically, the Scoring MAPP has a section titled "Special Considerations" which describes circumstances in which the general recommendations regarding scoring may not apply. The first consideration where general recommendations regarding scoring 7 Although the Draft Scoring Guidance does not separately address expectations when an RLD has changed its scoring pattern while an ANDA is pending, it refers readers to the Scoring MAPP for more information on what recommendations apply in this circumstance (see Draft Scoring Guidance, fn.l 0). 6

7 may not apply is, in fact, where the RLD changes its scoring pattern after an ANDA has been received. It states, among other things, that when the RLD makes such a change while an ANDA is pending, a reasonable time is necessary to accomplish the manufacturing revisions needed to implement a scoring change. Generally the Agency considers a reasonable time for an applicant to make the change to be the length of time until the applicant manufactures the first or next production batch. However, the Scoring MAPP acknowledges that sometimes the generic manufacturer may need to obtain new tablet dies that define the size and shape of the tablet before it can change its scoring pattern and that this might take a little longer. In addition, the Scoring MAPP recognizes that the generic manufacturer may also wish to deplete existing stock in much the same way that you were permitted to deplete existing stock of your single-scored tablet rather than being required to conduct a recall after the new scoring pattern for your NDA was approved. Thus, when the change in the scoring of the RLD occurs close to the time that the generic drug expects approval, as was the case here, the generic company may have already manufactured several batches that use the previous configuration. In such a case, FDA normally would not require ANDA applicants to comply with the new scoring configuration until the manufacture of the next batch. Concurrent marketing of products with different scoring configurations by the ANDA applicant and the RLD under these circumstances would be expected to cause no more confusion than the RLD concurrently marketing the old configuration and the new configuration, as it did here. The marketing of the single-scored generic product would be for a finite and limited period to allow for a transition to the dual-scored tablet. The Draft Scoring Guidance and Scoring MAPP do not reference any regulatory requirements regarding sameness of scoring between a generic and RLD product. In fact, as noted above, no such requirements exist. Although the Agency recognizes that consistent scoring between a generic drug and the RLD is generally desirable, this is not a. requirement in every case. We have made several fact-specific exceptions to this general recommendation and we have, on multiple occasions, approved generic products that had scoring different from the RLD. In some of these cases we have approved an ANDA with a postapproval commitment to change the scoring configuration with the next production batch. In other cases, a generic product was not scored or had a different scoring configuration because, for example, the RLD had exclusivity or patent protection for their score (or for a dose obtainable using the score) and FDA determined that identical scoring configuration was not essential to the safe and effective use of the product. Below is a list of some examples where FDA has made exceptions to the general recommendations that RLD and ANDA scoring should be the same.. FDA approved generic losartan potassium tablets with an unscored 50 mg tablet where the RLD was scored. FDA requested a postapproval commitment to change the scoring configuration with the next production batch so that it would be the same as the RLD (Cozaar 50 mg). 7

8 . FDA approved generic unscored tramadol hydrochloride 50 mg tablets where the RLD was scored because the 25 mg dose ofthe RLD (which was obtainable by using half a scored tablet) was protected by exclusivity.. FDA permitted a generic alprazolam 2 mg tablet to have a scoring configuration different from the RLD because the scoring pattern of the RLD was protected by patent.. FDA permitted a generic manufacturer to add a score to efavirenz 600 mg tablets when the RLD did not have a score.. FDA permitted a generic manufacturer to double score its 10 mg dextroamphetamine tablets when the RLD had a single score. Looking at the facts and circumstances of this case (including the fact that the RLD made scoring changes on the eve of expected generic approval and marketed the scored and unscored tablets concurently without any added warnings, and the fact that the risk of medication error due to substitution of a single-scored tablet for a dual-scored tablet is low), we deny your request that FDA refrain from granting final approval for any ANDA for also mg doxycycline hyc1ate delayed-release tablet referencing Doryx unless and until the ANDA applicant adopts a dual-scored 150 mg tablet configuration. We wil consider requests for approval of ANDAs for single-scored 150 mg doxycycline delayedrelease tablets on a case-by-case basis. B. Labeling for ANDAs Referencing the Doryx (doxycycline hyclate) Delayed-Release Tablets, 150 mg In your petition, you argue that an ANDA for a 150 mg delayed-release tablet referencing Doryx must have the same labeling as Doryx and FDA should not apply section 505(j)( 1 0) of the FD&C Act to permit approval of a generic product referencing Doryx (Petition at 5). You note that section 505(j)(10) allows an ANDA that relies on a teference product for which a labeling change has been approved within 60 days of expiration of the reference product sponsor's 30-month stay to be eligible for approval despite the labeling change, provided certain conditions are met (Petition at 5-6). You argue that FDA canot rely on this section ofthe FD&C Act to approve a generic product referencing Doryx with a single-scored tablet because the change to the dual-scored tablet was a change to the product itself, not simply a labeling change, and FDA does not have authority to approve an ANDA that does not otherwise meet requirements for approval under 505(j). In addition, according to your petition, it would be nearly impossible for the ANDA applicant to change its manufacturing practices to transition to a dual-scored tablet and revise its labeling within the 60 days permitted under section 505G)(1 0). We conclude that issues regarding applicabilty of 505(j)(l0) are moot. More than 60 days have passed since you obtained approval for the labeling change reflecting the dual scoring of the product. 8

9 You further claim that the difference-due-to-different-manufacturers exceptions to the requirement that a generic drug must have the same labeling as the reference product canot be applied to this situation. You state that a generic product's omission ofthe new information regarding use ofthe dual-scored tablet would affect the safe use ofthat product and should not be permitted. We disagree. We believe that labeling differences of the type you suggest would be acceptable under the relevant statute and regulations as a permissible difference due to difference in manufacturer. As mentioned above, generic products are permitted to have labeling that differs from the labeling ofthe RLD. FDA regulations in (a)(8)(iv) require that the "labeling... proposed for the (generic J drug product must be the same as the labeling approved for the reference listed drug, except for changes required because of differences approved under a petition fied under or because the drug product and the reference listed drug are produced or distributed by diferent manufacturers" the (emphasis added). FDA has interpreted this exception to apply when an aspect of ANDA product that is not required by statute or regulation to be the same as that of the RLD (such as an inactive ingredient) is different, and the difference necessitates a difference in labeling. Here, because the labeling difference for an ANDA would relate to an aspect of the product that is not required by statute or regulation to be the same as that oftherld (i.e., the scoring pattern), the difference in labeling for a generic singlescored 150 mg doxycycline hyclate would fall within the difference-due-to-differentmanufacturers exception set out at 21 CFR (a)(8)(iv). The Doryx 150 mg product is currently marketed as a dual-scored product (with the single-scored product stil on the market until the inventory is returned to the RLD manufacturer or is depleted). For an ANDA applicant that seeks approval of a singlescored product (identical to the RLD prior to its change to the dual-scored product) and seeks to omit the information regarding the dual score, FDA may permit such a difference. The new instructions for splitting the tablet added by the RLD do not have a bearing on the single-scored generic product because these instructions pertain only to the dual-scored configuration and the generic product is not dual-scored. It is therefore possible to simply omit these instructions from labeling for a generic single-scored product without adverse consequence. Thus, in this instance, FDA may allow a 150 mg doxycycline hyclate delayed-release product to have labeling different from Doryx to account for differences in scoring configuration because the product is produced by a different manufacturer. Any ANDA manufacturer who receives approval for a singlescored tablet wil be expected to change to a dual-scored tablet upon the manufacture of its next production batch. We make this type of decision on a case-by-case basis in accordance with relevant statutes and FDA regulations. 8 See 505U)(2)(A) and 505G)(4)(G) of the FD&C Act; 21 CFR 3l4.94(a)(8)(iv). 9

10 III. CONCLUSION We have reviewed your petition and other relevant information available to the Agency. For the reasons discussed above, your petition requesting that FDA take certain actions with respect to all ANDAs seeking approval of the single-scored 150 mg doxycycline hyclate delayed-release product is denied. Woodcock, M.D. Director Center for Drug Evaluation and Research 10