This letter does not respond to your requests pertaining to cocaine HCI; the Agency wil address those in a subsequent response to your petition.

Transcription

1 :\SUW1CES. ( -l ~1'~",,7: DEPARTMENT OF HEALTH &. HUMA SERVICES Food and Drug Administration Rockville MD JUL Marc J. Scheineson, Esq. Donald E. Segal, Esq. Alston & Bird LLP 950 F Street, NW Washington, DC Re: Dear Mr. Scheineson and Mr. Segal: This letter provides a partial response to the citizen petition dated February 24,2012, that you submitted on behalf of Lannett Company Inc. and its wholly owned subsidiary, Cody Laboratories, Inc. (collectively, "Lannett"). In your petition, you request that the Food and Drug Administration (FDA) affirm the "grandfather" status of oxycodone hydrochloride (HCI), including Lannetts OxycodoneHCI Oral Concentrate Solution, 20 miligrams (mg)/mililiter (ml) ("Lannetts Oxycodone HCI Product"), and cocaine HCI, including Lannetts Cocaine HCI Topical Solution, 40 mg/ml and 100 mg/ml ("Lannetts Cocaine HCI Product"), under the 1938 grandfather clause of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (Petition at 2). You also request that we acknowledge that Lannetts Oxycodone HCI Product and Lannetts Cocaine HCI Product may be legally marketed based on their "grandfather" status and that the new drug requirements, including premarket approval and user fees, are not applicable (Petition at 2). This letter does not respond to your requests pertaining to cocaine HCI; the Agency wil address those in a subsequent response to your petition. FDA has carefully considered the information submitted in your petition pertaining to oxycodone HCI and other relevant data available to the Agency. For the reasons set forth below, your requests pertaining to oxycodone HCI are denied. 1 i We note that we agree with your statement on page 15 of the Petition, that '''grandfather' status does not mean a product is unregulated." The 1938 grandfather clause applies only to the new drug provisions of the Act and not to the adulteration or misbranding provisions (Sections 501 and 502 of the Act (21 U.S.C )). Thus, the grandfather provision does not prevent the Agency from ensuring that any drug product, even one that might be "grandfathered," is not adulterated or misbranded.

2 Docket No. FDA-2012-P-0189 I. BACKGROUND A. Oxycodone HC) Oxycodone HCI is a potent opioid narcotic agonist, and its principal therapeutic action is analgesia. Because of its high potential tor abuse, oxycodone is a controlled substance in Schedule II of the Controlled Substances Act (CSA), 21 U.S.C. section 801. et seq. B. Statutory Framework In 1938, Congress enacted the FD&C Act, under which manufacturers of "new drugs" were required to obtain premarket approval by submitting reports of safety investigations and proposed drug labeling to FDA for review. In 1962, Congress amended the FD&C Act to require manufacturers of "new drugs" to submit to FDA additional evidence, including adequate and well-controlled clinical investigations, establishing that their drugs are not only safe but also effective under "the conditions of use prescribed, recommended, or suggested in their labeling.,,2 In both the 1938 and the 1962 laws, Congress exempted drugs that met the requirements of narow grandfather clauses from certain provisions of the FD&C Act. The 1938 grandfather clause, which is codified at section 201 (p)(1) of the FD&C Act (21 U.S.C. 321 (p )(1 ), states that a "new drug" is: (1) Any drug... the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof, exceptthat such a drug not so recognized shall not be deemed to be a 'new drug' if at any time prior to the enactment of this Act (on June 25, 1938) it was subject to the Food and Drugs Act of June 30, 1906, as amended, and if at such time its labeling contained the same representations concerning the conditions of its use... The 1962 grandfather clause, which is not codified, provides that: In the case of any drug which, on the day immediately preceding the enactment date (on October 9, 1962), (a) was commercially used or sold in the United States, (B) was not a new drug as defined by (21 U.S.C. 321(p)) of the basic Act as then in force, and (C) was not covered by an effective application under section 505 of that Act, the amendments to (21 U.S.C. 321(p)) made by this Act shall not apply to such drug when intended solely for use under the conditions prescribed, recommended, or suggested in labeling with respect to such drug on that day.3 2 Pub. 1. No , 52 Stat Pub , section 107(c)(4), 76 Stat. 780,

3 Thus, under the 1938 grandfather clause, if a drug was marketed under the Federal Food and Drugs Act of 1906 (the 1906 Act) prior to the enactment of the FD&C Act in 1938, and the drug's labeling contains the same representations concerning the conditions of its use as before the enactment of the FD&C Act in 1938, the drug is not a new drug. If it is not a new drug, it is not subject to the new drug provisions of the FD&C Act, such as the new drug application provisions found in section 505 of the FD&C Act (21 U.S.C. 355). As stated in FDA's final guidance, Marketed Unapproved Drugs - Compliance Policy Guide: FDA believes that there are very few drugs on the market that are actually entitled to grandfather status because the drugs currently on the market likely differ from the previous versions in some respect, such as formulation, dosage or strength, dosage form, route of administration, indications, or intended patient population. (...) However, the Agency recognizes that it is at least theoretically possible.4 II. DISCUSSION We are denying the requests in your petition pertaining to oxycodone HCI on two principal grounds. First, we reject your implicit contention that oxycodone HCI products as a class are" grandfathered" under the grandfather clause. Furthermore, the evidence provided with your petition is inadequate to demonstrate that Lannett s Oxycodone HCI Product meets the requirements of the 1938 grandfather clause. A. A Class Approach Is Not Applicable With Respect to the 1938 Grandfather Clause Exemption You request that FDA affrm the "grandfather" status of oxycodone HCI, including Lannetts Oxycodone HCI Product (Petition at 1). Because you reference oxycodone HCI broadly in this context, we infer that your intent was to request that FDA affrm the "grandfather" status of all oxycodone HCI products, including but not limited to Lannetts Oxycodone HCI Product. We disagree with the underlying premise of your request, namely that a determination as to whether drug products are exempt from the new drug safety and effectiveness requirements of the FD&C Act by virtue of the 1938 grandfather clause can or should be made on a class-wide (i.e., non-product-specific) basis; such a determination for all oxycodone HCI products (or indeed for any class of products) is not appropriate because determinations with respect to "grandfather" status are made on a product-specific basis. 4 Guidance for FDA staff and industr, Marketed Unapproved Drugs - Compliance Policy Guide History of FDA Marketing (Marketed Unapproved Drugs CPG) September 2011, Appendix: Brief Approval Requirements and Categories of Drugs That Lack Required FDA Approval, at 12, available on the Center for Drug Evaluation and Research (CDER) guidance page at 3

4 The term drug as it is used in the FD&C Act's "new drug" definition, section 201 (p) of the FD&C Act (21 U.S.C. section 321(p)), refers not only to the active ingredients of a drug product but to the entire finished product, including all inactive ingredients. Because the 1938 grandfather clause exemption is part of the definition of a "new drug" in section 201 (p) of the FD&C Act, to be exempt under the 1938 grandfather clause from the "new drug" definition in section 201 (p) of the FD&C Act, a manufacturer must prove that "the identical drug(,)" including all inactive ingredients, was on the market between January 1, 1907, and June 25, 1938, and that its "composition is completely identical to its composition" prior to enactment of the FD&C Act in To support a contention that a drug product is exempt under the 1938 grandfather clause (or, for that matter, the 1962 grandfather clause),? the sponsor must provide documentation, including but not limited to pre labeling, to demonstrate that the product meets all of the criteria for "grandfather" status, including that the product as marketed today has the same formulation, strength, dosage form, route of administration, indication( s), intended patient population( s), and other conditions of use as the pre product. For example, in 21 CFR (e)(2) the Agency stated that to support a claim of "grandfather" status, the sponsor must submit, among other things:. "(a) copy of each pertinent document or record to establish the exact quantitative formulation of the drug (both active and inactive ingredients) on the date of initial marketing of the drug";. "(a) statement whether such formulation has at any subsequent time been changed in any manner... (and, ifnot) a copy of representative documents or records showing the formula at representative points in time"; 5 5 See United States v. Generix Drug Corp., 460 U.S. 453, 454, 460 (1983) (rejecting the contention "that the term 'drug' means only the active ingredient in a product"and holding that "drug" refers "to the entire product"). We address your arguments that Generix is inapplicable to Lannett in section II.B.2 of this response. 6 Laetrile Commissioner's Decision, 42 FR at (August 5, 1977) (emphasis added); see also id. (noting that "(t)he proof required would necessarily involve the production of quantitative formulas, labeling, and evidence of marketing both for the pre use and for the present use."); Rutherford v. United States., 616 F.2d 455,457 (10th Cir. 1980) (holding that "the several requirements\' of the grandfather clause cannot be met where a drug has not exhibited "consistency in (its) formula"). We note that when FDA set forth the requirements to qualify for the 1938 grandfather clause in the Laetrile Commissioner's Decision, the agency mistakenly referred to introduction into interstate commerce "after Jille 30, 1906." The effective date of the 1906 Act was January 1, 1907, and thus the relevant date for introduction into interstate commerce for purposes of qualifying for the 1938 grandfather clause is January 1,1907, not June 30, Accordingly, further references in this response to the Laetrile Commissioner's Decision use this corrected date. 7 We note that in United States v. Allan Drug Corp., 357 F.2d 713,718 (10th Cir. 1966), cert.denied, 385 U.S. 899 (1966), the court stated that "(w)hile the exempting language of the (1938 grandfather clause) and the (1962 grandfather clause) is verbally different, they are undoubtedly intended to mean the same thing." /d. In light of this finding, this response refers without distinction to precedents discussing either or both clauses. 4

5 . "(a) copy of each pertinent document or record to establish the identity of each item of written, printed, or graphic matter used as labeling on the date the drug was initially marketed";. "(a) statement whether such labeling has at any subsequent time been discontinued or changed in any manner... (and, if not) a copy of representative documents or records showing labeling at representative points in time";. "(a) copy of each pertinent document or record to establish the exact date the drug was initially marketed"; and. "(a) statement whether such marketing has at any subsequent time been discontinued... (and, if so) the exact date of each such discontinuance..., together with a copy of each pertinent document or record to establish each such date."g As the foregoing discussion shows, the determination of whether a drug product is or is not anew drug under the 1938 grandfather clause of the FD&C Act is a fact-intensive determination of whether a specifc drug product is the same drug product as was marketed between Januar 1, 1907, and June 25, For this reason, we deny your request that FDA affrm the "grandfather" status of oxycodone HCI under the 1938 grandfather clause of the FD&C Act. B. The Evidence Provided with the Petition Is Inadequate to Support a Conclusion That Lannett's Oxycodone HCI Meets the Requirements of the 1938 Grandfather Clause Under well-recognized principles of statutory interpretation, exemptions from a general statutory requirement (such as the grandfather clauses) are to be construed narrowly, and the burden of establishing entitlement to such an exemption is on the person who claims the exemption.10 Therefore, to support your contention that Lanett's Oxycodone HCI 8 You argue in your petition that it is incorrect for FDA to rely on the requirements set forth in 21 CFR ( e )(2) to establish the burden of proof necessary to qualify for the 1938 exemption and that "this regulation is irrelevant to a determination of' grandfather' status under the 1938 clause" (Petition at 14-15). We disagree with that position. Although (e)(2) addresses the requirements for establishing that a drg is not subject to the new drug requirements in the context of an administrative hearing process, the evidentiary burden necessar to demonstrate that a drg product is exempt from the new drug provisions of the FD&C Act under the 1938 grandfather clause is the same regardless of the context. Our reference to ( e) is not intended to suggest that any oxycodone HC1 product is currently the subject of an administrative hearing, or that such a hearing process would in all circumstances be necessary to establish whether a particular product meets the requirements of the grandfather clause exemption. We also note that when FDA finalized what is now (e), the Agency addressed a comment arguing that the information being required in the context of an administrative hearing to support a claim of grandfather status exceeded the requirements of the FD&C Act. In its response, FDA stated that it had "thoroughly reviewed the information to be required by the format and conclude(d) that all of it is relevant to the 'grandfather' status of a drug." 39 FR 9750 at 9759 (March 13, 1974). 9 See also USV Pharmaceutical Corp. v. Weinberger, 412 U.S. 655,663 (1973). 10 See United States v. An Article of Drug... "Bentex Ulcerine," 469 F.2d 875, 878 (5th Cir. 1972), cert. denied, 412 U.S. 938 (1973); United States v. Allan Drug Corp., 357 F.2d 713,718 (lath Cir. 1966), cert. denied, 385 U.S. 899 (1966). 5

6 Product meets the requirements of essential fact necessary for invocation of that exemption. the 1938 grandfather clause, you must prove every i 1 You have not met this burden and, therefore, for the reasons discussed below, your request that FDA affrm the status of Lannett's Oxycodone HCI Product as "grandfathered" is denied. 1. The Petition Misconstrues the Requirements of the 1938 Grandfather Clause You correctly indicate that the 1938 grandfather clause, located at section 201 (p) of the FD&C Act, stipulates that a drug... shall not be deemed to be a "new drug" if at any time prior to (June 25, 1938) it was subject to the Food and Drugs Act of June 30, 1906, as amended, and if at such time its labeling contained the same representations concerning the conditions of its use.12 However, you incorrectly interpret the 1938 grandfather clause by indicating that the only two questions relevant to the inquiry are: (1) Was the drug in commercial use between January 1, 1907, the effective date of the 1906 Act, and June 25, 1938, the enactment date of the 1938 Act? (2) Does the drug at issue currently contain "the same representations concerning the conditions of its use" as the drug in commercial use between January i, 1907 and June 25, 1938? Agency's longstanding position, as (Petition at 6.) Your petition fails to recognize the discussed in the 1977 Laetrile Commissioner's Decision, that to qualify for exemption from the definition of a new drug under the 1938 grandfather clause, a manufacturer must demonstrate that: (1) the identical drug (2) bearing labeling containing the identical representations concerning the conditions of its use (3) was introduced into interstate commerce in the United States (or was manufactured in a Federal territory or the District of Columbia) after (January 1, 1907) and prior to the enactment of the act in The exemption applies only to drugs whose labeling with respect to representations as to conditions of use has undergone no changes whatsoever from the labeling utilzed prior to the passage of the 1938 act, and whose composition is completely identical to its composition prior to this passage. If any change in representations for conditions of use in labeling or any change in composition has occurred since the enactment of the 1938 act, such change precludes the applicabilty of the 1938 exemption. The proof required would necessarily involve the production of quantitative 11 See Bentex Ulcerine, 469 F.2d at U.S.C. 321(p). 6

7 formulas, labeling, and evidence of marketing both for the pre use and for the present use.13 Your misinterpretation of the 1938 grandfather clause fails to account for one of the key aspects of that clause, namely that in section 201 (p) of the FD&C Act the term "drug" refers to the entire finished drug product,14 and therefore the relevant inquiry is not simply whether "the drug at issue currently contain( s) 'the same representations concerning the conditions of its use' as the drug in commercial use between January 1, 1907, and June 25, 1938; rather, the current drug product must also be the same drug product that was marketed between January 1, 1907, and June 25, As you acknowledge in your petition,15 FDA's interpretation of the scope and application of the FD&C Act's grandfather clauses, as set forth in the Laetrile Commissioner's Decision, was subsequently reviewed and upheld by the Tenth Circuit in Rutherford v. United States, 616 F.2d 455 (loth Cir. 1980).16 In light of this fact, your assertion that 13 See Laetrile Commissioner's Decision, 42 FR at (August 5, 1977). See also Letter from Dennis E. Baker, Associate Commissioner for Regulatory Affairs, FDA, to Paul K10pper and Tod H. Mikuriya, M.D. re: Docket No /CP1 (December 29,2000) ("December 29,2000 CP response") at 1 (to establish that a drg product is not a new drug under the 1938 grandfather clause, "the following two questions must be answered affirative1y: 1) Was the drug product marketed between January 1, 1907, the effective date of the 1906 Act, and June 25, 1938, the enactment date of the 1938 Act? 2) Is the drug product at issue the same drug product that was marketed between January 1,1907, and June 25,1938, and does its labeling describe the same conditions of use?") (That citizen petition was originally assigned 14. Generix, 460 U.S. at 454,460. docket number /CPL. The number was changed to FDA-1999-P-2922 as a result of transition to its new docketing system (Regulations.gov) in January 2008.) FDA's 15 Petition at 14, note We take this opportnity to address your statement on pages of the petition that "FDA should not confuse application of the 1938 'grandfather clause' with that of the 1962 'grandfather clause.'" You contend that "(a)ny attempt by FDA to impose the same requirements with respect to the applicabilty of the 1938 'grandfather clause' and the 1962 'grandfather clause'-despite the clear differences between the language used in the two provisions-is unsupported by the statutory language and is contrary to the above mentioned canons of statutory constrction" (Petition at 14). The petition further claims on page 13 that the "notion" from Allan Drug that '''(w)hile the exempting language of the basic Act (the 1938 "grandfather clause") and the Amendment (the 1962 "grandfather clause") are verbally different, they are undoubtedly intended to mean the same thing'" constitutes a "misstatement in dicta" by the 10th Circuit Court of Appeals. We disagree that the language you quote from the Allan cour constitutes a "misstatement in dicta." The cour in Allan Drug was asked to decide whether a change in a drug's labeling caused it to become a "new drug" within the meaning of the FD&C Act; in order to reach this decision the court of necessity had to make a determination as to whether the drug was grandfathered. Allan Drug Corp., 357 F.2d at The Tenth Circuit noted that the language of the transitional provisions of the 1962 amendments to the FD&C Act was never codified, and that "(t)he 1962 Amendment simply added the words 'and effectiveness' after the word 'safety' and the words 'and effective' after the word 'safe'" to the new drug definition in section 201(p) of the FD&C Act, and thereby "perpetuated verbatim" the 1938 grandfather clause language. d. at 717. As such, the cour reviewed the same labeling evidence and conducted the same analysis in determining that the drug at issue was not entitled to grandfather status under either the 1938 or 1962 clauses. /d. at 719 ("(W)e construe the critical language of the Grandfather Clauses to exempt drugs... if on the effective date of the Act the labeling contained the same representations concerning its use....") (emphasis added). Furthermore, although the

8 Lannett's Oxycodone H Ci Product meets the requirements of the 1938 grandfather clause is specious, in that your conclusion relies on an interpretation of the 1938 grandfather clause that is inconsistent with both applicable case law and FDA's longstanding interpretation and implementation of the FD&C Act. 2. The Petition Fails to Demonstrate that Lannetts Oxycodone HCI Product Was Marketed Between January 1, 1907, and June 25, 1938 Your petition presents information regarding your contention that versions of oxycodone HCI products were marketed between January 1, 1907, and June 25, 1938 (Petition at 4, 6-7, and Attachments A":C). We need not address, for the purposes of this response, whether we agree that versions of oxycodone HCI products were marketed between January 1, 1907, and June 25, 1938, because you concede that Lannett has only been manufacturing, marketing, and sellng its Oxycodone HCI Product since January 2006 (Petition at 4), nor do you present any evidence that Lannett's Oxycodone HCI Product is identical to any of the drug products that were marketed between January 1, 1907, and June 25, Even assuming, arguendo, that Lannett's Oxycodone HCI Product complies with the other provisions of the 1938 grandfather clause (which it does not, as explained more below), you have failed to demonstrate that Lanett's Oxycodone HCI Product was marketed between January 1, 1907, and June 25, Because "failure to meet anyone of the criteria of the grandfather provisions renders compliance with the remaining criteria moot,,,l7 your requests that we affrm the "grandfather" status of Lanett's Oxycodone HCI Product and that we acknowledge that Lanetts Oxycodone HCI Product may be legally marketed based on its "grandfather" status must be denied. You maintain that the plain language of the grandfather clause "requires only that a drug be subject to the 1906 Act, not the drug or a specifc manufacturer's drug(,)" and thus that "Lannett's Oxycodone HCI... Product()need not be the identical drug product() that (was) marketed between January 1, 1907 and June 25, 1938(,)" but that "Lannett need grandfather clause does use different language than the 1938 clause, that is a distinction without a difference, because the language in the 1938 grandfather clause refers to the "labeling contain(ing) the same representations concerning the conditions of its use" (section 201(p)(1) of the FD&C Act), which conceptually is the same as the 1962 clause, which refers to "use under the conditions prescribed, recommended, or suggested in labeling" (Pub , section 107(c)(4), 76 Stat. 780, 789). Both clauses clearly refer to the labeling and conditions of use, and both refer to "such drug." Under Generix, 460 U.S. at 454, 460, the term drug means "drg product" and refers to the finished drg product, which per se includes the composition of the product. Thus both clauses also incorporate a requirement concerning the composition of the drug product. Because Congress presumably was aware of how FDA interpreted the grandfather clause in section 201 (p)(1) of the Act when it enacted the 1962 amendments, FDA believes the grandfather clause in those amendments is appropriately viewed as clarification on the part of Congress as to the meaning of the language in the 1938 grandfather clause, rather than as evidence that Congress intended the two different clauses to have different meanings. Accordingly, the 10th Circuit's statement that "(w)hile the exempting language of the basic Act (the 1938 grandfather clause) and the Amendment (the 1962 grandfather clause) are verbally different, they are undoubtedly intended to mean the same thing'" (Allan Drug Corp., 357 F.2d at 718) (emphasis added) is in fact legally correct, and has not been overtured FR at (May 4,1982). 8

9 only reasonably demonstrate that an oxycodone HCI product... was in commercial use some time between January 1, 1907 and June 25, 1938" (Petition at 8, emphasis in Petition).!8 On page 8 of your petition, you acknowledge that the Court in Generix rejected the contention "that the term 'drug' means only the active ingredient in a product" and instead held that this term refers "to the entire product.,,19 You argue, however, that Generix is inapplicable to Lanett because Generix (l) "evaluate(d) the pre-1962 provision and the 'new drug' regulatory framework, as opposed to the pre-1938 'grandfather clause"'; (2) "deal(t) with a tablet formulation, not a solution"; and (3) "expressly stated that it did not reach the issue of 'whether two demonstrably bioequivalent products, containing the same active ingredients but different excipients, might under some circumstances be the same drug.'" (Petition at 8-9). We disagree that these points distinguish the Supreme Court's ruling in Generix from this case. We find your first point unpersuasive, because, in Generix, the Court considered the term drug in the context of Section 201 (p) of the FD&C Act and as it appeared throughout the FD&C Act, and determined that "(t)he term 'drug' is plainly intended throughout the Act to include entire drug products, complete with active and inactive ingredients.,,2o Moreover, we believe your second point has no merit because the Court did not arive at its holding in Generix as a result of the formulation in question. Indeed the Supreme Court's opinion does not even refer to whether the drug(s) in question were tablet or solution formulations?! Finally, we disagree with your third point, because the issue at is You reference a letter dated September 13, 1991, to Greg Loosely from Harold Davis, Consumer Safety Offcer ofcder and assert that "FDA's own correspondence reflects this understanding" (Petition at 8). We do not agree with your interpretation. The letter you reference stated: Colloidal silver is considered to be a pre-1938 drg. These products may continue to be marketed without submitted evidence of safety and effectiveness (required of all prescription drugs marketed after 1938) as long as they are advertised and labeled for the same use as in 1938 and as long as they are manufactured in the original manner. Your suggestion that this letter supports your claim that "Lannett need only reasonably demonstrate that an oxycodone HC1 product (...) was in commercial use some time between January 1, 1907 and June 25, 1938" (Petition at 8, emphasis in Petition) is contrary to FDA's stated position regarding the 1938 grandfather clause criteria both before and after the 1991 letter was written.. Furthermore, regardless of whether the language in this letter could be construed in a manner contrary to longstanding FDA policy, the letter is an informal communication that represents the best judgment of that employee at that time, with respect to the particular drg at issue, but it does not constitute an advisory opinion or necessarily represent the formal position of FDA, and it does not bind or otherwise obligate or commit the Agency to the views expressed. 21 CFR 10.85(k). As such, the 1991 letter has no bearing on any current determination with respect to whether Lannett's Oxycodone HC1 Product is "grandfathered" under the 1938 grandfather clause. Moreover, in 1999, FDA issued a Federal Register notice observing that it had not received "any evidence to show that the composition and the labeling of colloidal silver or silver salt drug products have remained unchanged since 1938 or 1962" and stating that "(w)ithout such evidence, the products cannot qualify for either (1938 or 1962) grandfather exemption." 64 FR at (August 17, 1999). 19 Generix, 460 U.S. at 454, d. at 459 (emphasis added). 21 You further suggest, referencing 21 CFR (b)(3), that the Generix "holding is distinguishable with respect to Lannett's oral and aqueous solution formulations for which excipients are not usually evaluated in ANDAs" (Petition at 9). You also maintain that "a change in an inactive ingredient should not, by that 9

10 hand here is not "whether two demonstrably bioequivalent products, containing the same active ingredients but different excipients (are) the same 'drug.''' An inquiry into whether a drug product is exempt from the new drug definition under the 1938 grandfather clause does not require a showing of bioequivalence. 22 Instead, as stated above, to qualify under the 1938 grandfather clause, a manufacturer must prove (in part) that the identical drug, including all inactive ingredients, was on the market between fact alone, render a drg, particularly in oral or aqueous solution dosage form, a 'new drug'" and that if such a drug "is the same 'drg' for purposes of a generic ANDA, it should be the same 'drug' for puroses of the (1938) 'grandfather clause'" (Petition at 9). 21 CFR outlines the criteria for waiving evidence of in vivo bioavailability or bioequivalence in drug applications. Under 21 CFR (b )(3) a drug product's "bioequiva1ence may be considered self-evident based on other data in the application if the product"... is (i) "an oral solution" and "(ii) (c)ontains an active drug ingredient in the same concentration and dosage form as a drug product that is the subject of an approved full (NDA) or (ANDA); and (iii) (c)ontains no inactive ingredient or other change in formulation from the drug product that is the subject of the approved full (NDA) or (ANDA) that may significantly affect absorption of the active drg ingredient or active moiety for products that are systemically absorbed, or that may significantly affect systemic or local availabilty for products intended to act locally." (21 CFR (b)(3)) (emphasis added). This provision only applies to a pending application for a drug product that "contains no inactive ingredient or other change in formulation from the drug product that is the subject of (an) approved full (NDA) or (ANDA.) The provision is not relevant here, because Lannett is arguing that the company is not required to fie a new drg application or an abbreviated new drug application for its Oxycodone HCl Product, because its product may be legally marketed based on "grandfather" status under the 1938 grandfather clause. In addition, you do not claim in your Petition that Lannett's Oxycodone HC1 Product "(c)ontains no inactive ingredient or other change in formulation from (a) drug that is the subject of (an) approved full "bioequivalence" with what is required to (NDA) or (ANDA.)" Further, you have conflated the concept of qualify as a drug exempt from the new drug requirements under the 1938 grandfather clause. According to 21 CFR 320.1(e), (b )ioequiva1ence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. The main focus of a bioequiva1ence study is whether "pharmaceutical equivalents or pharmaceutical alternatives" are behaving in a suffciently similar way in the same subject; however, a drug need not be identical in its composition to the drug against which it is being compared in order to be deemed "bioequivalent." By contrast, "(t)he (1938 "grandfather") exemption applies only to drugs... whose composition is completely identical to its composition prior to (passage of the 1938 FD&C Act)" (Laetrile Commissioner's Decision, 42 FR at (August 5, 1977)) (emphasis added). Moreover, "as an exemption to a comprehensive regulatory statute concerned with public safety, the grandfather clause is to be strictly constred, and (a drug manufacturer) bears the burden of proof as to each condition." United States v. Articles of Drug... 5,906 Boxes, 745 F.2d 1 as, 113 (1 sl Cir. 1984); see also Allan Drug Corp., 357 F.2d at 718 ("Since we are dealing with a Grandfather Clause exception, we must construe it strictly against one who invokes it."); Durovic v. Richardson, 479 F.2d 242,250 (7th Cir. 1973) (same); USV Pharm. Corp. v. Richardson, 461 F.2d 223, (4th Cir. 1972) (same); United States v. An Article of Drug... "Bentex Ulcerine", 469 F.2d 875,878 (5th Cir. 1972) (same). 22 Regardless of whether this issue is relevant here, we note that you have not provided any evidence to support a claim that Lannett's Oxycodone HC1 Product is "demonstrably bioequiva1ent" to any particular oxycodone HC1 product that was marketed in the United States between January 1, 1907, and June 25,

11 January 1, 1907, and June 25, Thus, the reasons you have offered in support of your claim that the Generix holding is inapplicable to Lannett are not persuasive?3 As we stated above, it is FDA's long-held position, supported by various court decisions, that to qualify for exemption from the new drug provisions of the FD&C Act under the 1938 grandfather clause a manufacturer must demonstrate that the identical drug... was introduced into interstate commerce in the United States (or was manufactured in a Federal territory or the District of Columbia) after (January 1, 1907) and prior to the enactment of the act in The exemption applies only to drugs... whose composition is completely identical to its composition prior to (passage of the 1938 FD&C Act). If... any change in composition has occurred since the enactment of the 1938 act, such change precludes the applicabilty of the 1938 exemption. The proof required would necessarily involve the production of quantitative formulas, labeling, and evidence of marketing both for the pre use and for the present use.24 (Emphasis added) Lanett has not provided evidence of a specific pre drug product whose composition is identical to Lanett's Oxycodone HCI Product in the Petition or the Attachments thereto. In fact, Attachments A, B, and C provide no reference to an oral 23 You also highlight as "noteworthy that the term used in the 'grandfather clauses' is not 'drug product' but 'drg'" and that under section 20 1 (g)(1)(a) of the FD&C Act, "the term 'drg' means 'articles recognized in the offcial United States Pharmacopeia, offcial Homeopathic Pharmacopeia of the United States, or offcial National Formulary, or any supplement to any of them'" (Petition at 9). You furher observe that "(t)hose compendia tyically list the drug in terms of only the active pharmaceutical ingredient, irrespective of any excipients contained in the drg product" (Petition at 9). However, your analysis of the term drug under section 201 (g)( 1) is incomplete in its focus on only sub-section 201(g)(1)(A). In Generix, the Supreme Court criticized the earlier Cour of Appeals opinion for its incomplete analysis of the definition of the term drug as provided in section 201(g)(l). The Cour observed that (i)n examining this statutory definition, the Court of Appeals was persuaded that only active ingredients come within the terms of subsection (A)(.) Unfortunately, the cour did not analyze the entire definition. If it had done so, it would have noted both that the terms of subsections (A), (B), and (C) are plainly broad enough to include more than just active ingredients, and that they must do so unless subsection (D) is to be superfluous. (Generix, 460 U.S. at 459). 24 Laetrile Commissioner's Decision, 42 FR at (August 5, 1977). As previously noted, FDA's interpretation of the scope and application of the FD&C Act's grandfather clauses set forth in the Laetrile Commissioner's Decision was subsequently reviewed and upheld by the Tenth Circuit in Rutherford v. United States, 616 F.2d 455, 457 (lath Cir. 1980). See also Drug Products Containing Papaverine or Ethaverine and Similar or Related Drugs; Hearing, 44 FR 22180,22193 (April 13, 1979) ("Papaverine/Ethaverine Notice") (stating that, when referring to the 1938 grandfather clause, the exemption applies only to drugs whose current composition is identical to its composition before the passage of the 1938 Act. See United States v. Allan Drug Corp., 357 F.2d 713 (loth Cir. 1966), cert denied, 385 U.S. 899 (l966); United States v. An Article of Drug... "Entrol-C Medicated", 513 F. 2d (9th Cir. 1975)). 11

12 concentrate solution of20 mg per ml manufactured by any company, much less by Lannett, before Furher, these attachments do not discuss the composition of a finished drug product (e.g., they provide no list of inactive ingredients included in the formulation of any pre-1938 oxycodone HCI drugs) The Petition Fails to Demonstrate That Lannetts Oxycodone HCI Product Bears Labeling Containing Representations Concerning the Conditions of Its Use Today That Are Identical to Such Representations in the Labeling Used Between January 1, 1907 and June 25, 1938 Your petition also fails to demonstrate that Lannett's Oxycodone HCI Product bears labeling containing representations concerning the conditions of its use that are identical to those before the enactment of the FD&C Act in Because "failure to meet any one criteria of the grandfather provisions renders compliance with the remaining criteria moot,,,27 we again find that your requests that we affrm the "grandfather" status of Lannett's Oxycodone HCI Product and that we acknowledge that Lannett's Oxycodone HCI Product may be legally marketed based on its "grandfather" status must be denied. As an initial matter, and as stated previously, an exception (such as the 1938 srandfather clause) to a general policy is strictly construed against the person invoking it. 8 The 1938 grandfather clause requires that the.labeling of the product "contain() the same representations concerning the conditions of its use" as the product that was marketed between January 1, 1907 and June 25, As we stated above in Section II.B.1, it is FDA's long-held position that The (1938 grandfather clause) exemption applies only to drugs whose labeling with respect to representations as to conditions of use has undergone no changes whatsoever from the labeling utilzed prior to the passage of the 1938 act... If any change in representations for conditions of use in labeling... has occurred since the enactment of the 1938 act, such change precludes the applicability of the i938 exemption. The proof required would necessarily involve the production of... labeling... for the pre-1938 use and for the present use Further, your statement that the document attached to the Petition arid designated as "Attachment A" "reflects dosages within the ranges of20 mg/inl" (Petition at 4) is incorrect. It appears your assertion may have resulted from confusing the concentration of Lan nett's Oxycodone HCl Product (20 mg/ml) with the dosage (Le., the actual amount, for example, weight in mg, administered to an individual patient in a single dose) referenced in Attachment A. 26 FDA assumes, for puroses of this response, that "Eucoda1," "dihydroxycodeinon hydrochloride," "Eukoda1," "dihydroxy codeinone hydrochloride," and "dihydroxy-codeinene" (the names included in Attachments A-C) constituted alternative names for oxycodone HCl prior to FR at (May 4, 1982). 28 Spokane & Inland Empire Railroad Co. v United States, 241 U.S. 344, 350 (1916); Allan Drug Corp., 357 F.2d at 718; Bentex Ulcerine, 469 F.2d at Laetrile Commissioner's Decision, 42 FR at (August 5, 1977). See Rutherford, 616 F.2d at 457 (upholding FDA's interpretation ofthe scope and application of the FD&C Act's grandfather clauses 12

13 You have not provided any pre-1938 labeling for any specific oxycodone HCI drug product against which Lannett's Oxycodone HCI Product's labeling can be compared. The Petition references historical treatises/compendia containing general statements regarding "Eucodal" (Dihydroxycodeinon Hydrochloride), "Eucodal"/"Eukodal" (Dihydroxy codeinone hydrochloride), and "Eukodal" (dihydroxy-codeinene)) (Petition at 4, and 6-7, referencing Attachments A - Cto the Petition).3o Although you state on page 11 of the Petition that "pursuant to the definition of the term 'labeling' as defined in the (FD&C Act), written, printed, or graphic matter accompanying (Section) 201(m) of the drug product should be considered when determining the conditions of use for Oxycodone HCI between 1907 and 1938(,)" the examples you provided in the documents you designate as Attachments A through C to the Petition do not appear to meet the statutory definition of "labeling" in section 201(m) of the FD&C Act, much less constitute examples of any specific oxycodone HCI product's labeling.31 There is no indication that they were used "upon any article or any of its containers or wrappers," or that they "accompan(ied) such article." Rather, they are "treatises" that "include entries for oxycodone HCI and discuss its use for pain relief," and appear to have been used by pharmacists to compound a drug "to prescriber order at various strengths based on the stated needs of the patient" (Petition at 4). Moreover, it is clear, based on a side-by-side comparison of Lannett's Oxycodone HCI Product labeling (supplied in Attachment D to the Petition) with Attachments A through C, that, regardless of whether the information in Attachments A through C constitute labeling, Lannett's' Oxycodone HCI Product is not labeled for the same conditions of use as presented in Attachments A through C. As stated above, FDA has previously explained that "(c)onditions of use include, among other things, what the drug is set forth in the Laetrile Commissioner's Decision). Furthermore, as noted above, in the Papaverine/Ethaverine Notice FDA stated that the exemption in the 1938 grandfather clause "applies only use has undergone no changes to drugs whose labeling with respect to representations about conditions of whatsoever from the labeling utilzed before the passage of the 1938 act.... See United States v. Allan Drug Corp., 357 F.2d 713 (loth Cir. 1966), cert denied, 385 U.S. 899 (1966); United States v. An Article of Drug... "Entrol-C Medicated", 513 F. 2d (9th Cir. 1975)." Papaverine/Ethaverine Notice, 44 FR at (April 13, 1979). 30 As stated above, supra note 26, FDA wil assume, for purposes ofthis response, that "Eucodal," "dihydroxycodeinon hydrochloride," "Eukodal," "dihydroxy codeinone hydrochloride," and "dihydroxycodeinene" constituted alternative names for oxycodone HCl before We do not accept the proposition that in making a determination about whether a drug meets the criteria of the 1938 grandfather clause, the Agency should accept in lieu of the labeling for specific drug products the "(m)any treatises (that) state... the conditions of use for which oxycodone HC1 has been widely accepted since before 1938" (Petition at 4). You claim that oxycodone HC1 was "not marketed or dispensed with modem product 'labels' or product inserts, but rather (was) compounded by pharmacists to prescriber order at various strengths based on the stated needs of the patient" (Petition at 4). The fact that a product (or class of products) did not have pre-1938 labeling that meets the definition in section 201(m) of the FD&C Act does not mean that a sponsor therefore does not need to demonstrate that the labeling contains the identical representations concerning the conditions of its use (see Laetrile Commissioner's Decision, 42 FR at (August 5, 1977)). Rather, it means that the product does not meet the requirements for being grandfathered under the 1938 grandfather clause. 13

14 recommended for, how it is to be administered, and in what quantities itis to be administered.,,32 The labeling for Lanett's Oxycodone HCI Product states, for example, that (l) this product is indicated for "the relief of moderate to moderately severe pain(,)" (2) "(t)his drug is given orally(,)" and (3) "(t)he usual adult dosage is 5 mg (, also known as Gm,) every 6 hours or as needed for pain." However, the phrase "moderate to moderately severe pain" is absent from the relevant portions of Attachments A through C, as is any reference to oral administration,33 and the relevant portions of Attachments A and B make reference to a range of possible dose administrations while no dose is described at all in the relevant portion of Attachment C.34 Further, Attachments A through C make reference to several conditions of use that are not included as conditions of use in the labeling for Lannett's Oxycodone HCI Product.35 Finally, we note that oxycodone HCI is currently listed in Schedule II under the CSA and that Lannett's Oxycodone HCI Product's labeling bears the "CII" symbol,36 however Attachments A 32 Laetrile Commissioner's Decision, 42 FR at (August 5, 1977). 33 For example, Attachment A only references Eukodal's intravenous, subcutaneous, and suppository uses. 34 With respect to descriptions regarding quantities of administration in Attachments A through C, the doses described for the use of Eucoda1 in Attachment A range from Gm (e.g., the described dose for the product's use as an analgesic is a range of Gm); the recommended dose for Eucoda1 (Eukodal) in Attachment B is a range of Gm; and no dose is specifically described for Eukoda1 in Attachment C. 35 For example, Attachment A makes reference to Eucodal's use for "relie(f of) irrit(atio)n in nervous colds & hay fever"; Attachment B makes reference to use of Eucoda1 (Eukodal) for "the relief of... cough"; and Attachment C makes reference to Eukodal's use "as an analgesic", which would include the treatment of mild pain. These are all conditions of use not included in Lannett's Oxycodone HC1 Product's label. We note that the court in 5,906 Boxes stated that "even if particular uses ofa drug are the same, a change in the suggested conditions for its use wil suffce to remove the drug from the protection of the grandfather clause." 5,906 Boxes, 745 F.2d at i 15. In that case, the labeling of the product at issue stated that it was "'indicated in the symptomatic treatment of nausea and vomiting,' without apparent qualification as to cause," whereas the 1962 labeling listed 11 specific causes of nausea and vomiting under "indications." Because nothing before the court indicated that those 11 causes were the only possible causes of nausea and vomiting, the cour concluded that the current labeling suggested that the drg be used for conditions not listed in the 1962 labeling (because it was no longer limited to use for treating the 11 previously listed causes of nausea and vomiting).!d. As noted earlier, supra notes 7 and 16, the 10th Circuit concluded that "(w)hile the exempting language of the basic Act (the 1938 grandfather clause) and the Amendment (the 1962 grandfather clause) are verbally different, they are undoubtedly intended to mean the same thing'" (Allan Drug Corp., 357F.2d at 718); thus, the court's reasoning in 5,906 Boxes is equally applicable to the interpretation and application of the 1938 grandfather clause and, therefore, to the oxycodone HC1 product(s) that is(are) the subject of this petition. The attachments to your petition refer broadly to the use of "Eucodal" /"Eukodal" as an analgesic (see Attachments A and C) and "for relief of pain, cough, and other conditions, in which morphine is employed" (see Attachment B). The curent indication for Lannett's Oxycodone HC1 Product is, per the labeling supplied in Attachment D to your petition, "for the relief of moderate to moderately severe pain." Thus, although Lannett's Oxycodone HC1 Product is, broadly speaking, used as an analgesic, the conditions of its use are limited to a specific level of pain, namely moderate to moderately severe pain. In contrast, regardless of whether the references in Attachments A through C referred to specific products marketed between January 1, 1907, and June 25, 1938 and one of those products was the "identical drug" as Lanett's Oxycodone HCl Product, the statements in Attachments A through C contain no such limitation with respect to the specific 1eve1(s) of pain - or conditions - under which "Eucodal"/"Eukoda1" should be used. Accordingly, the "conditions of (Lanett's Oxycodone HCl Product's) use" (per section 201 (p)(1) of the FD&C Act) would have changed. 36 The labeling for all Schedule II drugs is required to bear the "CII" or "C-II" symbol (21 CFR ). 14