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1 DEPARTMENT OF HEALTH &, HUMAN SERVICES NOV Food and Drug Administration Rockville M D Mark S. Aikman, Pharm.D. Vice President, Regulatory Affairs and Quality Assurance Osmotica Pharmaceutical Corp Culbreth Drive, Suite 200 Wilmington, NC Dear Dr. Aikman: Re: Docket No. FDA-201O-P-0255 This letter responds to your citizen petition dated May 20, 2010 (Fourth Venlafaxine Petition or petition), I requesting that the Food and Drug Administration (FDA or the Agency) refrain from approving any abbreviated new drug application (ANDA) for a generic 2 version of Osmotica's Venlafaxine Hydrochloride (HC 1) Extended-Release Tablets unless such application contains results from bioequivalence studies conducted under both fed and fasting conditions demonstrating bioequivalence to the reference listed drug (RLD). We have carefully considered your Fourth Venlafaxine Petition. J For the reasons described below, we deny your petition. I. BACKGROUND A. Venlafaxine Products On October 20, 1997, Wyeth Pharmaceuticals, Inc. (Wyeth) obtained approval for Effexor XR (venlafaxine HCl) Extended-Release Capsules (Effexor XR capsules), 37.5 milligrams (mg), 75 mg, loo mg,4 and 150 mg, for the treatment of major depressive disorder. Effexor XR capsules subsequently were approved for the treatment of generalized anxiety disorder in 1999, treatment of social anxiety disorder in 2003, and treatment of panic disorder in On April 16,2003, Lachman Consultant Services, Inc. (Lachman) submitted a suitability petition requesting permission to file an ANDA for a drug product, venlafaxine Hel extended-release tablets, 37.5 mg, 75 mg, and 150 mg, that differed from Effexor XR capsule, the RLD, in dosage I Osmotica's First, Second, and Third Venlafaxine Petitions are described in section LA of this response. 2 The term generic refers to a drug product for which approval is sought in an t\nda submitted under section 5050) of the Federal Food, Drug, and Cosmetic Act (the Act). ) We also considered two comments submitted to Docket No. FDA-2010-P-0255 pertaining to your petition, one from Winston & Strawn LLP submitted on behalf of Sun Pharmaceutical Industries Ltd. (Sun) and its affiliates, and the other from you. 4 The 100 mg strength of Effexor XR capsules has been discontinued from marketing.

2 form (see section 505U)(2)(C) ofthe Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(j)(2)(c)) and 21 CFR ).5 FDA determined that Lachman's request for a change in dosage form (from extended-release capsules to extended-release tablets) was a type of change authorized by section 505(j)(2)(C) ofthe Act, and granted Lachman's suitability petition on March 30, The approval of the suitability petition would permit an ANDA to be submitted for venlafaxine HCl extended-release tablets, 37.5 mg, 75 mg, and 150 mg, that referred to the corresponding strengths of Effexor XR capsules as the basis for ANDA submission (see 21 CFR (a)(3)). Prior to the approval of any ANDA submitted based upon the approved suitability petition, a new drug application (NDA) submitted through the approval pathway described by section 505(b )(2) ofthe Act (505(b)(2) application) was approved for ven1afaxine HC1 extended-release tablets. On May 20,2008, your 505(b)(2) application for 37.5 mg, 75 mg, 150 mg, and 225 mg venlafaxine HC1 extended-release tablets (NDA ) was approved for treatment of major depressive disorder and social anxiety disorder. FDA's approval was based on the Agency's previous findings of safety and effectiveness for Effexor XR capsules and Osmotica's bioequivalence data. Equal doses ofvenlafaxine HCl extended-release tablets are bioequivalent to Effexor XR capsules when administered under fed conditions.? Venlafaxine HCI extendedrelease tablets should be administered in a single dose with food either in the morning or in the evening at approximately the same time of each day. On May 30, 2008, you submitted a citizen petition requesting that FDA refrain from approving any pending ANDA for venlafaxine HC1 extended-release tablets that cites Effexor XR capsules as the RLD and that was submitted based on the March 30, 2005, approved suitability petition (First Ven1afaxine Petition). You also requested that any applicant with such a pending ANDA reference instead your approved venlafaxine HCI extended-release tablets as the RLD and, as required by section 505(j)(2)(D)(i) of the Act, submit a new ANDA to make that change. In addition, you requested that FDA require any such applicant to conduct new bioequivalence studies comparing its proposed product to your approved drug product. FDA granted your First Venlafaxine Petition on November 25, In a citizen petition dated July 24,2009, you requested that FDA clarify the patent certification requirements for an ANDA that relies upon an RLD approved through the pathway described by section 505(b)(2) ofthe Act (21 U.S.C. 355(b)(2)) (Second Ven1afaxine Petition). Specifically, you requested that when an ANDA relies upon an RLD approved through the 505(b )(2) pathway safety and (505(b)(2) application) and the 505(b)(2) application relied upon FDA's finding of effectiveness for a listed drug, FDA require the ANDA applicant to provide an appropriate patent certification or statement to patents listed for the RLD (e.g., Osmotica's venlafaxine HCI 5 See Docket No. FDA-2003-P The original docket number for this suitability petition, 2003P-0159, was changed to FDA-2003-P-0351 as a result of FDA's transition to its new docketing system (Regulations.gov) in January See FDA-2003-P (March 2005). 7 Product Labeling for Venlafaxine Extended-Release Tablets (venlafaxine hydrochloride), NDA ; Revised January Ibid. 9 See FDA-2008-P-0329 (November 2008). 2

3 extended-release tablets (NDA )) and for the listed drug upon which the RLD relied (e.g., Effexor XR (venlafaxine HC1) extended-release capsules (NDA )). You asserted that if Sun Pharmaceutical Industries Ltd.'s ANDA for venlafaxine HCI extended-release tablets did not contain such patent certification(s) or statement(s), the ANDA should not have been received by FDA because it was deficient on its face. Accordingly, you requested that FDA require Sun to submit a new ANDA with appropriate patent certifications. On January 21,2010, FDA denied your Second Venlafaxine Petition.IO - In a citizen petition dated August 20, 2009, you requested that FDA require that any company with a pending ANDA for a venlafaxine HCl extended-release drug product, or that submits an ANDA for a ven1afaxine HCl extended-release drug product in the future, conduct appropriate in vitro testing to assess the effect of alcohol on the extended-release dosage form to ensure that there is no "dose dumping" if the drug is consumed with alcohol (Third Venlafaxine Petition). You also requested that if any ANDAs for ven1afaxine HCI extended-release drug products are approved absent data that demonstrate a lack of dose dumping in alcohol, those products should not be designated as therapeutically equivalent to the RLD, but instead should be assigned a "BX" rating (Third Venlafaxine Petition). On February 16, 2010, FDA granted your Third Venlafaxine Petition in part and denied it in part. ii As you requested, FDA is requiring applicants for ven1afaxine HCI extended-release products to conduct in vitro alcohol-induced dose-dumping studies. Therefore, your request that we assign a BX rating to any approved venlafaxine HCI extended-release product absent such data was moot, and your request was denied. On August 18,2010, FDA approved Sun Pharaceutical Industries Ltd.'s ANDA for venlafaxine HCI extended-release tablets (ANDA ). B. Statutory and Regulatory Standards The Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch-Waxman Amendments) created section 505U) ofthe Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(j)), 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 of the 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 505(j)(2)(A)(iv) of the Act). In addition, an ANDA 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 505(j)(2)(A) and (j)(4) of the Act). FDA must approve an ANDA unless the information submitted in the ANDA is insuffcient to meet the requirements delineated in section 505(j)(2)(A) of the Act, including a demonstration ofbioequivalence (section 505(j)(4) ofthe Act). 10 See FDA-2009-P-0356 (January 2010). ii See FDA-2009-P-0403 (February 2010). 3

4 FDA's regulations in 21 CFR part 320 list acceptable methodologies for determining the bioequivalence of drug products. These methodologies include pharmacokinetic studies, pharmacodynamic studies, comparative clinical trials, and in vitro studies. The choice of which study design to use is based on the ability of the design to compare the drug delivered by the two products at the particular site of action of the drug. The courts have expressly upheld FDA's regulatory implementation of the Act's bioequivalence requirements (see, e.g., Schering Corp. v. FDA, 51 F.3d 390 at (3rd Cir. 1995); Fisons Corp. v. Shaiala, 860 F. Supp. 859 (D.D.C. 1994)). Drug products that meet the approval requirements under section 505U) of the Act generally wil be considered by FDA to be "therapeutically equivalent" to the RLD.12 Drug products are considered to be therapeutic equivalents only ifthey are "pharmaceutical equivalents" and if they can be expected to have the same clinical effect and safety profie when administered to patients under the conditions specified in the labeling (which would include the demonstration of bioequivalence). (See Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book), 29th ed., at vii.) Pharmaceutical equivalents have the same dosage form, strength, and route of administration. They contain the same amounts of the same active drug ingredient and meet the same compendia1 or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates. Pharmaceutical equivalents do not necessarily contain the same inactive ingredients and may also differ in characteristics such as shape, scoring, release mechanism, and, within certain narrow limits, labeling (see 21 CFR and the Orange Book at vi, et seq.). Products classified as therapeutically equivalent can be substituted with the expectation that the substituted product wil produce the same clinical effect and safety profile as the prescribed product. (See the Orange Book at vii.) C. Overview of FDA Guidance on Food Effect and Fed Studies In December of 2002, FDA published a guidance document for industry entitled Food-Effect Bioavailabilty and Fed Bioequivalence Studies (the Food Effect Guidance). The Food Effect Guidance provides information on how to meet the bioavailability and bioequivalence requirements set forth in 21 CFR 320, as well as sections (d)(3) and (a)(7) as they apply to oral dosage forms (immediate-release and modified-release), when food effect bioavailability and fed bioequivalence studies should be conducted, and how the studies should be designed and the resulting data analyzed. The Food Effect Guidance gives a brief overview on the effects of food on bioavailability and bioequivalence. Pharmaceutical companies usually conduct food effect bioavailability studies for new drugs and drug products in early drug development to assess the effects of food on the rate and extent of absorption of a drug product administered shortly after a meal (fed conditions), as compared to administration under fasting conditions. ANDA applicants conduct fed studies to demonstrate bioequiva1ence of their proposed product to the RLD under fed conditions. 12 Drug products approved in ANDAs submitted under the suitability petition provisions of section 505G)(2)(C) of the Act wii not be therapeutically equivalent to the RLD that serves as the basis for the petition. 4

5 Food administered with a drug product may change bioavailability by various means (e.g., delay gastric emptying, change gastrointestinal ph, interact with a dosage form or a drug substance). In practice, it is difficult to determine the exact mechanism by which food changes the bioavailability of a drug product without conducting specific mechanistic studies. The food effect on bioavailability is least likely to occur with rapidly dissolving, immediate-release drug products containing highly soluble and highly permeable drug substances (BCS Class 1).13 In some cases, excipients or interactions between excipients and the food-induced changes in gut physiology can contribute to these food effects and influence the demonstration of bioequivalence. For immediate-release drug products in BCS Classes II, III, and IV, and for all modified-release drug products, food effects are most likely to result from a more complex combination of factors that influence the in vivo dissolution of the drug product and/or the absorption ofthe drug substance. In these cases, the relative direction and magnitude of food effects on formulation bioavailabi1ity and the effects on the demonstration ofbioequiva1ence are difficult, if not impossible, to predict without conducting a fed bioequivalence study. Accordingly, as articulated in the Food Effect Guidance, the Agency recommends that a fed bioequivalence study be conducted in addition to a fasting bioequivalence study for ANDAs for orally administered immediate-release dosage forms, unless one ofthe exceptions listed in the Food Effect Guidance applies (e.g., when the Dosage and Administration section of the RLD label states that the product should be taken only on an empty stomach). The Food Effect Guidance also recommends both fed and fasting bioequiva1ence studies for ANDAs for all orally administered modified-release drug products. As with all FDA guidances, the Food Effect Guidance states that it represents the Agency's current thinking on the topic, and that an alternative approach may be used if it satisfies the requirements of the applicable statutes and regulations. II. DISCUSSION You request in the Petition that FDA refrain from approving any ANDA for a generic version of Osmotica's venlafaxine HCI extended-release tablets unless the application contains results from fed and fasting studies that demonstrate bioequivalence to the RLD (Petition at i, 2, and 9). You assert that this is necessary because: (1) FDA's Food Effect Guidance recommends that bioequivalence studies of orally administered modified dosage forms be conducted under both fasting and fed conditions, (2) important information may be overlooked if fasted bioequivalence studies are not performed, and (3) there are no serious safety concerns for bioequivalence studies conducted under the fasted state (Petition at 3-6). You also assert that even though the labeling ofvenlafaxine HC1 extended-release tablets recommends that the product be taken with food, 13The Biopharmaceutics Classification System (BCS) is a scientific framework used by FDA for classifying drug substances based on their aqueous solubilty and intestinal permeability. When combined with dissolution of the drug product, the BCS takes into account two major factors that govern the rate and extent of drug absorption from immediate-release solid oral dosage forms: solubility and permeability. See also the guidance for industr on Waiver of in Vivo Bioavailabilty and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classifcation System. 5

6 Docket No. 201O-P-0255 this is not suffcient justification for exclusion of a bioequivalence study in the fasted state (Petition at 4 and 7). Finally, you claim that FDA has failed to treat similarly situated applicants ofvenlafaxine HCI extended-release tablets the same (Petition at 8-9). We address each of these points in greater detail below. A. BioequivaIence Studies for VenIafaxIne HCI Extended-Release Tablets 1. FDA's Food-Effect Guidance You reference FDA's Food-Effect Gutdance to support your request that FDA require both fed and fasting bioequivalence studies for approval of generic versions ofvenlafaxine HCI extendedrelease tablets (Petition at 3-4). You state that in this guidance FDA recommends for orally administered modified-release dosage forms, such as venlafaxine HCI extended-release tablets, that bioequivalence be demonstrated through in vivo human studies conducted under both fed and fasting conditions (Petition at 3-4). You assert that you followed this standard practice and conducted four open-label, randomized, crossover trials in both the fed and fasted states to test the bioequivalence of single and multiple doses of venlafaxine HCI extended-release tablets (Petition at 4, 6, and 7). You state that two of these studies were conducted in the fasted and fed state (37.5 mg and 75 mg doses ofvenlafaxine HCI extended-release tablet (test) and Effexor XR capsule (reference)), while the other two were only conducted in the fed state (225 mg dose of test and reference) (Petition at 5-7). You claim that because the 75 mg, 150 mg, and 225 mg strengths ofthe product were proportionally similar and exhibited linear pharmacokinetics, Osmotica was not required to test the 150 mg strength of the product either in the fed or the fasted state (Petition at 6). In general, as previously noted, for modified-release products, we recommend that 14 However, there are bioequivalence studies be conducted in both fasting and fed states. instances where studies under both fed and fasting conditions are not recommended, such as when there are safety concerns, for example, when there is an increased likelihood of nausea and vomiting associated with fasted conditions. Prior to publishing the draft Individual Product Bioequivalence Recommendations Guidance on venlafaxine HCI extended-release capsules in February 2006 (wherein FDA recommended against the conduct ofbioequivalence studies under fasting conditions due to safety concerns), FDA's Office of Generic Drugs (OGD) provided bioequiva1ence recommendations for venlafaxine HCI tablets to sponsors by letter. In a letter in 2002, OGD recommended a single-dose fasting study and a single-dose fed study with the 75 mg strength extended-release capsule. In March 2003, after issues of nausea and vomiting during the fasted bioequivalence studies were brought to OGD's attention, the recommendations for ven1afaxine extended-release capsules and immediate-release tablets were changed. For venlafaxine extended-release capsules, OGD recommended two studies with the 150 mg strength, a single-dose fed study and another single-dose fed 14 See section I.C of this response. 6

7 study with the contents of the capsule sprinkled over a teaspoonful of applesauce. recommendations also noted that the 15 The significant occurrence of nausea and vomiting with both the 37.5 mg16 and 75 mg dose under fasting conditions makes it difficult to perform bioequiva1ence studies under fasting conditions. Today, for the capsule dosage form, OGD continues to recommend bioequiva1ence testing with a single-dose, two-treatment, two-period crossover in vivo fed study with the 150 mg strength and a single-dose, two-treatment, two-period crossover in vivo fed sprinkle study with the 150 mg strength (Draft Guidance on Venlafaxine HCI (extended-release capsules), December 2008). These bioequivalence recommendations state that "( djue to safety concerns, biòequivalence studies under fasting conditions are not recommended." The current recommendations for the tablet dosage form are the same as the capsule, except that a sprinkle bioequivalence study is recommended for the capsule and not for the tablet, because, as per the RLD label, the capsule can be administered by sprinkling its contents on applesauce (Draft Guidance on Venlafaxine HCI (extended-release tablets), March ). The bioequivalence recommendations for the tablet dosage form contain the same warning against performing studies under fasting conditions Osmotica's Venlafaxine HCI Extended-Release Bioequivalence Study (i.e., whether, as petitioner suggests, important information may be overlooked if fasted bioequivalence studies are not performed) You provide data from bioequiva1ence studies, described previously, 19 that you conducted with venlafaxine HCI extended-release tablets to support your request that FDA require both fed and fasting bioequivalence studies for approval of generic versions ofthis product (Petition at 4-5). You claim that important information on the bioequivalence ofven1afaxine HCI extended-release products may be overlooked if fasting bioequivalence studies are not conducted (Petition at 4). In addition, you also allege that in your study Effexor XR capsules and ven1afaxine HCI extended-release tablets behaved somewhat differently relative to the presence of food (Petition at 4-5). You also claim that all doses ofvenlafaxine HC1 extended-release tablets were bioequivalent to equivalent doses of Effexor XR capsules in the fed state, but not in the fasted state (Petition at 4-5). You assert that in the fasted study bioequivalence was met for the 37.5 mg 15 "... The approved labeling of the RLD recommends administration with food. Administration of a single dose of 150 mg under fed conditions is well tolerated..." 16 Some sponsors conducted bioequivalence studies with the 37.5 mg strength. 17 These draft guidances, when finalized, wil represent FDA's current thinkng on the topic. 18 In your comment of September 7, 2010, submitted to this docket, you state that on March 2, 2006, FDA requested that Osmotica conduct 4-way crossover studies with test and reference products being dosed under fasted and fed conditions. You state that accordingly, you conducted bioequivalence studies in the fasted state with venlafaxine HCI extended-release tablets. Although we recognize that there were discussions between Osmotica and FDA during this time frame regarding the conduct of studies in the fasted state, we ultimately advised Osmotica in January 2007 that studies with the 225 mg dose should be conducted only under fed conditions. As explained in this response, we continue to believe that venlafaxine studies under fasting conditions are not appropriate due to safety concerns, which is consistent with the basic principle that no unnecessary human research be performed (21 CFR (a)(1)). 19 See section ILA,l of this response for details of the study design. 7

8 strength tablet, but not for the 75 mg strength tablet (Petition at 5). You allege that the ven1afaxine HCI extended-release tablet demonstrated higher blood levels in the fasted study consistent with those seen in the fed state (Petition at 5). You claim that this represents a lack of food effect for the venlafaxine HCI extended-release tablet, which you allege is consistent with what is normally seen with an osmotic tablet product (Petition at 5). You assert that if bioequivalence studies for venlafaxine HCI extended-release tablets are not conducted under both fed and fasting conditions, then generic versions of this product may be mistakenly determined by FDA to be bioequivalent to Osmotica's venlafaxine HCI extended-release tablet (Petition at 5). We disagree with your assertions that Effexor XR capsules and venlafaxine HCI extendedrelease tablets behave somewhat differently relative to the presence of food and that generic versions ofven1afaxine HCI extended-release tablets may be mistakenly determined to be bioequivalent to the RLD ifbioequivalence studies are not conducted in the fasted state. Food has been shown to not affect the pharmacokinetics ofven1afaxine HCL. Indeed, the labeling of Effexor XR capsules states that "Food did not affect the bioavailability ofvenlafaxine or its active metabolite, ODV. Time of administration (AM vs PM) did not affect the pharmacokinetics ofvenlafaxine and (O-desmethylven1afaxineJ ODV from the 75 mg Effexor XR capsule." Further, the labeling for venlafaxine HCI extended-release tablets states that "Food did not affect the pharmacokinetic parameters AUC, Cmax, and Tmax ofvenlafaxine or its active metabolite, ODV, after administration ofven1afaxine Extended Release Tablets." Therefore, Osmotica's venlafaxine HCI extended-release tablets do not perform differently from Effexor XR capsules in the presence of food. With regard to the conduct of fasted bioequivalence studies, your application for venlafaxine HCI extended-release tablets (NDA ) included the following studies: a single-dose fed study of the 225 mg strength, a fed and fasting study of the 37.5 mg strength, and a fed and fasting study of the 75 mg strength,zo A waiver ofbioequivalence for the 150 mg strength was proportional. granted because the 75 mg, 150 mg, and 225 mg strengths are compositionally In these studies, the 37.5 mg, 75 mg, and 225 mg strengths were determined to be bioequiva1ent to the RLD, Effexor XR, under fed conditions. The 37.5 mg strength was also bioequivalent under fasting conditions. However, while the fasting bioequivalence study of the 75 mg strength was bioequivalent for AUC (90% CI: , ), it just missed the bioequivalence limits of % for Cmax (90% CI: ,126.10).21 We, nonetheless, believe that, in the fasted state, the 75 mg strength ofvenlafaxine HCI extended-release tablets and Effexor XR capsules do not have clinically significant differences because the study met the bioequivalence limits of % for AUC, and it is likely that the study was not sufficiently powered for Cmax. The 90% confidence interval for Cmax in the fasted study was %. Ifmore subjects had been used in this study, the confidence interval would have become narrower and would likely 20 See Clinical Pharmacology and Biopharmaceutics Review ofvenlafaxine HCI extended-release tablets (NA ),9/25/07 available on the Internet at htt://ww.accessdata.fda. gov/ drugsatfda docs/nda/2008/022104s000 Clinhar.pdf 21 As a consequence of failing to meet the bioequivalence limits in the fasted state, the labeling for venlafaxine HCI extended-release tablets states "Equal doses ofvenlafaxine hydrochloride extended-release tablets are bioequivalent to Effexor XR capsules when administered under fed conditions." 8

9 Docket No. 201O-P-0255 have met the bioequiva1ence limits of %.22 One reason why the study may have been underpowered is that 6 of 36 subjects dropped out of the study before completion. Even though you believe that Osmotica's failure ofthe 75 mg strength to meet the 90% confidence interval for Cmax in the fasted study is significant, you did not provide any information regarding the implications of your specific product's failure for generic manufacturers seeking to use Osmotica's venlafaxine HC1 extended-release tablet as an RLD. As a result of our review of this data, we conclude that the failure of the 75 mg strength to meet the 90% confidence interval for Cmax in the fasted study, while meeting all other bioequivalence criteria for all strengths, does not justify conduct ofbioequivalence studies in the fasted state for approval of generic versions ofvenlafaxine HC1 extended-release tablets. FDA ensures that generic versions ofvenlafaxine HCI extended-release tablets have the same safety and efficacy as the RLD by evaluating in vitro measures together with the fed bioequivalence study. For the in vitro measures, FDA evaluates the generic venlafaxine RCi extended-release tablet formulation design and dissolution data at multiple phs and alcohol contents. This ensures that there are no significantly different in vitro dissolution profiles from the RLD at multiple ph conditions and alcohol contents that could potentially occur if a product were dosed with alcohol, under fasting conditions or with a different type of food. 3. Osmotica's Safety Data for Venlafaxine HCI Extended-Release Products You provide safety data from bioequivalence studies, described previous1y,23 that you conducted with venlafaxine HC1 extended-release tablets to support your request that FDA require both fed and fasting bioequivalence studies for approval of generic versions of this product (Petition at 5-6). You claim that there were no serious safety concerns identified in these bioequivalence studies (Petition at 5-6). You allege that the safety and tolerability was similar across the studies, adverse events were of mild to moderate severity for both the test (tablet) and reference ( capsule) formulations, no deaths or serious adverse events were reported over the course of the studies, and the rates of nausea and vomiting generally were not different between the test and reference formulations. You claim that there was little difference in the rates of nausea and vomiting in the fasted and fed conditions for the 37.5 mg and 75 mg doses of the test formulation. You provide the following data to support your claim?4 For the 37.5 mg strength tablet, 3 subjects out of35 subjects (8.6%) experienced nausea in the fed group, and 3 subjects out of 36 subjects (8.3%) experienced nausea in the fasted group. For the 75 mg strength tablet, 3 subjects out of31 subjects (9.7%) 22 The width of the 90% confidence interval is influenced by the number of subjects in the study and the inherent pharmacokinetic variability of the drug substance. In fact, the pharmacokinetic variability of the drug substance needs to be considered when an investigator calculates how many subjects to enroii in a bioequivalence study. This is called "powering" the study, because a study of two bioequivalent products should contain enough subjects to demonstrate bioequivalence with 80% power. It is possible that a bioequivalence study of two bioequivalent products wii not meet % acceptance criteria, if, due to the pharmacokinetic variability of the drug substance, not enough subjects were enroiied to show bioequivalence. 23 See section II. A. 1 of this response for details of the study design. 24 Data from Wright, C.W. et ai., "Bioequivalence of Single and Multiple Doses ofvenlafaxine Extended-Release Tablets and Capsules in the Fasted and Fed States: Four Open-Label, Randomized Crossover Trials in Healthy Volunteers." Clinical Therapeutics, 31: ,

10 experienced nausea in the fed group, and 3 subjects out of 33 subjects (9.1 %) experienced nausea in the fasted group. There were no reports of vomiting for any subject taking the 37.5 mg strength tablet product in either the fasted or fed conditions. Additionally, no subjects administered the 75 mg strength tablet product experienced vomiting in the fed group, while only 1 subject out of 32 subjects (3.1 %) experienced vomiting in the fasted group. Accordingly, you assert that FDA's recommendation in its draft individual product bioequivalence guidance on venlafaxine HCI extended-release tablets against conduct ofbioequiva1ence studies under fasting conditions due to "safety concerns" is not necessary (Petition at 7). You allege that this recommendation is a deviation from FDA guidance and policy that is not necessary from a safety perspective, and is likely to cause important information on the bioequivalence ofvenlafaxine products to be overlooked by ANDA applicants and by FDA (Petition at 7). We disagree with your assertion that there are no safety concerns that would preclude conduct of bioequivalence studies ofvenlafaxine in the fasted state. Based on adverse event data available to the Agency for ven1afaxine drug products,25 nausea and vomiting were observed to occur at a significantly higher rate when venlafaxine was given in the fasted state, and particularly at higher doses.26 The higher rate of vomiting raises a number of concerns. Vomiting causes loss of drug substance available for absorption, and subjects who experience vomiting are excluded from the study. Thus, additional subjects would need to be recruited to account for potential dropouts. In addition, even though nausea and vomiting are of a transient nature, we are careful not to expose healthy subjects to unnecessary health risks or discomfort. This concern is especially important for bioequivalence recommendations for AND As, as large numbers of subjects may be involved in bioequivalence studies for generic drugs submitted in AND As. Further, co-administration of an antiemetic drug is reported to significantly decrease the nausea and vomiting rates in venlafaxine bioequivalence studies. However, co-administration of an antiemetic drug in venlafaxine bioequiva1ence studies is not preferred because it may complicate the study design and could raise its own safety issues. For example, additional studies would be required to exclude the potential pharmacokinetic interaction of the antiemetic drug with venlafaxine. Also, safety issues could emerge as incidences of dizziness and faintness have been reported with use of both venlafaxine and antiemetic drugs. After careful evaluation of potential safety concerns and product risks, and given that food does not affect the pharmacokinetics ofvenlafaxine HCI, FDA has recommended and continues to recommend only fed bioequivalence studies for ven1afaxine products. This is consistent with FDA's practice for products with safety concerns. 4. Labeling You claim that while the labeling of Effexor XR capsules and venlafaxine HCI extended-release tablets recommends that the products be taken with food, this does not provide a sufficient basis 25 For example, see medical offcer's review ofvenlafaxine HCI (NA ),8/24/07, p. 12 available on the Internet at htt://ww.accessdata.fda.gov/dmgsatfda docs/nda/2008/022104s000 MedR.pdf.. 26 We note that compared to immediate-release products, there were somewhat lower incidence rates of vomiting and nausea in extended-release products, including both Effexor XR capsules and venlafaxine HCI extended-release tablets, possibly due to a slower rate of absorption. 10

11 for FDA not to require a bioequivalence study under fasting conditions (Petition at 4 and 7). You allege that patients can and inherently wil take venlafaxine HCI extended-release tablets while fasting (Petition at 4). You also claim that while the labeling of Ambien CR (zolpidem) extended-release tablets states that the product should be taken without food, FDA's August 2009 draft bioequivalence guidance for this product requires that generic applicants perform bioequivalence studies under both fed and fasting conditions (Petition at 7). You assert that this furher supports your request that FDA require conduct of both fed and fasting bioequivalence studies for approval of generic versions ofvenlafaxine HCI extended-release tablets (Petition at 4). FDA does not base its decision on whether or not to omit a fasting or fed bioequivalence study on labeling statements regarding administration with food. As previously noted, in general, for modified-release products, we recommend both fasting and fed bioequivalence studies.27 However, when there is a safety concern and/or other factors28 prevent conduct of bioequivalence studies under both fasting and fed conditions, only the bioequivalence study that is relevant (fed or fasting) is recommended. In the case ofvenlafaxine HCl extended-release tablets, our decision to recommend fed-only bioequivalence studies and to include in the labeling a recommendation that the drug be taken with food is due to the well-documented safety issues of nausea and vomiting associated with drug use in the fasted state. In addition, your claim that the Ambien CR labeling states that the product should be taken without food is incorrect. Ambien CR's labeling states that: The recommended dose of Ambien CR for adults is 12.5 mg once daily immediately before bedtime. Ambien CR extended-release tablets should be swallowed whole, and not be divided, crushed, or chewed. The effect of Ambien CR may be slowed by ingestion with or immediately after a meal. A food-effect study in 45 healthy subjects compared the pharmacokinetics of Ambien CR 12.5 mg when administered while fasting or within 30 minutes after a meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 23% and 30%, respectively, while median T max was increased from 2 hours to 4 hours. The half-life was not changed. These results suggest that, for faster sleep onset, Ambien CR should not be administered with or immediately after a meal., Thus, there are no safety concerns associated with conduct of Ambien CR bioequivalence studies under either fasting or fed conditions. Thus, consistent with our general bioequivalence recommendations for modified-release products, both fasting and fed studies are recommended to demonstrate bioequiva1ence of Ambien CR See section LC of this response. 28 For example, bioequivalence studies with Sular (Nisoldipine ER) should only be conducted under fasted conditions. The labeling for Sular recommends that it be taken on an empty stomach (1 hour before or 2 hours after a meal) because ofa pronounced food-effect on Sular's pharmacokinetics. See Pharmacokinetics and Metabolism subsection of the CLINICAL PHARMACOLOGY section ofsular's labeling, revised Februar See section II.A.3 of response. 11

12 B. Treatment of Similarly Situated Parties You assert that FDA's change to the bioequivalence study requirements is suspect because it fails to treat similarly situated applicants the same (Petition at 8). You provide information from the Administrative Procedure Act and relevant court cases to support your assertion (Petition at 8). You believe that FDA should treat ANDA applicants seeking approval of a generic version of Osmotic a's venlafaxine HCI extended-release tablets similarly to the majority of modifiedrelease dosage forms, and hold them to the same standards with regard to the studies required to demonstrate bioequivalence (Petition at 8-9). You state that other than FDA's draft bioequivalence guidance on venlafaxine HCI extended-release tablets, you are not aware of a single instance in which FDA has issued an individual product bioequiva1ence recommendation for an extended-release tablet drug product that does not require bioequiva1ence studies to be conducted under both fasted and fed conditions. We disagree with your assertion that FDA's change to the bioequiva1ence study requirements suggests that the agency has failed to treat similarly situated applicants the same. We also disagree with your assertion that the venlafaxine HCL extended-release tablet bioequivalence guidance is the only individual product bioequivalence recommendation for an extended-release tablet that does not require bioequivalence studies to be conducted under both fed and fasting conditions. As previously described,3o as of March 2003, OGD has recommended only fed bioequivalence studies for venlafaxine products. This is consistent with OGD's practice for other products with similar safety concerns. Currently, the individual product bioequiva1ence recommendation guidance contains six other modified-release drug products which request either only fasting or only fed bioequiva1ence studies. Table 1 below contains a summary of these modified-release drug products that only request fasting or fed bioequivalence studies. Table 1. Bioequivalence Study Recommendations for Modified-Release Drug Products NDA Drug product Recommended Recommendation Bioeq uivaience Date Study Azithromycin ER suspension* Fasting only July 2008 draft Didanosine DR capsule Fasting only May 2008 finalized Indomethacin ER capsule Fed only Feb 2010 draft Mycophenolic acid DR tablet Fasting only Dec 2008 draft Nisoldipine ER tablet Fasting only May 2009 draft Testosterone ER buccal tablet Fasting only May 2008 finalized * ER = extended-release and DR = delayed-release Thus, we disagree with your assertion that FDA's change to the bioequivalence study requirements suggests that the agency has failed to treat similarly situated applicants the same. When determining our bioequivalence recommendations, we consider a number of drug-specific issues, such as whether there are safety or tolerability issues associated with the fed or fasted studies. With respect to the issue of whether to require fed and/or fasted studies, our bioequivalence recommendations are based on each drug product individually. As explained in 30 See section ILA.1 of response. 12

13 Docket No. 201O-P-0255 the response, our bioequivalence recommendations for ven1afaxine HC1 are based on careful considerations of the characteristics of this specific drug and the safety concerns associated with conducting fasted studies. III. CONCLUSION For the reasons stated above, we do not agree that ANDAs for a generic version of Osmotic a's venlafaxine HC1 extended-release tablets must contain results that demonstrate bioequivalence to the RLD under fasting conditions. Consequently, we deny your Petition. "" Janet oodcock, M.D. Director Center for Drug Evaluation and Research 13