;

DEPARTMENT 03 HFALTH & HUMAN SERVICES I,~^_ _.i.~.IIx--,~.l.--II __.-. ,-I--1 I ..X ..._. _, _... ,., . _ I~,xI _,.ll__ ._^ __,, ^.I.X llXll I_.,~ .1-1__ 1,, ._ II .^.._, ..,,._. l-. I I _ I _ .xxxI..II _ll

October 14,2003 Katherine M. Sanzo, Esq. Lawrence S. Ganslaw, Esq. Morgan, Lewis & Bockius, LLP 1111 Pennsylvania Avenue, N. W. Wz#ington, DC 20004 Jeffrey B. Chasnow, Esq Pfizer Inc. 235 Ehst 42nd Street New York, NY 10017 Stephan E., Lawton, Esq. Gillian R. Woollett, Ph.D. Vice President and Regulatory Affairs Biotechnology Industry Organization (BIO) suite 400 1225 I Street, N.W. Washington, DC 20005 William R. Rakoczy, Esq. Lord, Bissell & Brook LLP 115 South Lx&the Street Chicago, IL 60603 Re: Dockets Nos. 2001P-0323/CPl& Dear Petitioners: C5,2002P-0447KP1,

Food and Drug Administration Rockville MD 20857

and 2003P-0408KPl

This letter is a consolidated response to the citizen petitions in the dockets referred to above and comments submitted on the petitions. Although each of these petitions has a slightly different focus and concerns different drug products or classes of products, each is, in essence, a challenge to the Food and Drug Administration (FDA interpretation of section 505(b)(2) of the Federal s s) Food, Drug, and Cosmetic Act (the FDCA or the Act)(21 U.S.C. 355(b)(2)). For the reasons
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2001P-0323KPl submittedby Morgan Lewis 0 Bockius, LLP, on behalf of Pfvler Inc. and Pharmacia Corporation(2001 Pfizer petition); 2OOlCP-0323/(Xsubmittedby the BiotechnologyIndustry Organization(BIO) (BIO petition); 2002P-0447/CPlsubmittedby Morgan, Lewis & Bock& LLP on behalf of Pfizer Inc. (2002 Pfizer petition); 2003P-0408/CPl,submittedby Lord, Bissell & Brook LLP on behalf of TorPharm(TorPharmpetition). The BIO petition containsregulatoryand legal arguments challengingFDA implementationof section 505(b)(2) of s the FDCA, as well as scientific and technicalarguments to why biologically derived products,in particular, are as addresses legal and regulatory issues;the unique the not suited for approvalunder section505(b)(2). This response scientific issuesassociated biologically derivedproductspresenta separate of challenges will be with set that a addressed a response be issuedlater. The BIO petition, althoughdesignated citizen petition by RIO, was in to docketedas a comment. FDA is respondingto the documentas a petition, The 2002 Pfizer petition contains this scientific argumentsspecific to a pendingapplication. Because applicationis not approved,FDA caturot commenton the scientific issuesraisedin this petition. (gee 2 1 CFR 3 14.430.)

Docket Nos. 2001P-0323/CPl & C5,2002P-0447/CpI, and 2003P-0408KPl described below, FDA declines to alter its current interpretation of section 505(b)(2). Accordingly, those portions of the petitions seeking such a change are denied. However, the Agency also grants certain specific portions of the petitions as described below (section IV-M) related to therapeutic equivalence ratings for 505(b)(2) drug products. I. INTRODUCTION

Section 505(b)(2) of the Act was enacted as part of the Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch-Waxman Amendments). Section 505(b)(2) provides: An application [may be] submittedunder [section 505(b)(l)] for which the [safety and effectiveness]investigations. . , relied upon by the applicant [to support] approval of the application were not conducted by or for the applicant and for which the applicant has not obtaineda right of reference or use from the
person by or for whom the investigations were conducted (and] shall also include [patent certifications for patents on the drug for which investigations were conducted or a method of use statement].

The Hatch-Waxman Amendments reff ect Congress attempt to balance the need to encourage s innovation with the desire to speed the availability of lower cost alternatives to approved drugs. (S&eEli Lilly and Co. v. Medtronic, Inc., 496 U.S. 66 1 (1990); and Bristol-Myers Squibb %ompany Royce Laboratories, Inc., 69 F.3d 1130,1132,1133-34 (Fed. Cir. 1995).) With v. passage of the Hatch- Waxman Amendments, the Act describes different routes for obtaining approval of two broad categories of drug applications: new drug applications (NDAs), for which the requirements are set out in section 505(b) and (c) of the Act, and abbreviated new drug applications (ANDAs), for which the requirements are set out in section 505(j). These categories can be further subdivided into the following:
e

an application that contains fi.dl reports of investigations of safety and effectiveness that were conducted by or for the applicant or for which the applicant has a right of reference (section 505(b)(l)) (a stand alone NDA); an application that contains full reports of investigations of safety and electiveness, where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference (section 505(b)(2)) (a 505(b)(2) application); an application for a duplicate3 of a previously approved drug that contains information to show that the proposed product is identical in active ingredient(s), dosage form, streng& route of administration, labeling, quality, performance

2 As discussed in greater detail in section 1V.N below, FDA is considering whether to commence a public process to examine the narrow question of whether to change our interpretation of section SOS(b)(Z)as it applies to applications for which the only change from the listed drug is a change in active ingredient. 3 The informal term duplkute is used in this respokse to refer to an application under section 505(i) describing a product that is the same as the listed drug with respect to active ingredient, dosage form, route of administration, strength, and conditions of use, among other characteristics.

Docket Nos. 200 l P-0323/CPl&

CS, 2002P-0447KP I, and 2003P-04OWCP1

characteristics, and intended use, among other things, to a previously approved product, and for which clinical studies are not necesse to show safety and effectiveness (section 505(j))(an ANDA); and an application for a drug that differs from a previously approved drug product in dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient), for which FDA has determined, in response to a suitability petition submitted under section 505(j)(2)(C), that clinical studies are not necessary to show safety and effectiveness (section 505(j))(a petitioned ANDA).

Each type of application may rely on different sources and types of information to support the safety and effectiveness of the drug product. The statute also provides for drug development incentives in the form of marketing protections and patent extensions. The marketing protections available will depend on the type of application submitted. Similarly, some applications will be subject to the marketing protections and patent rights of other applications. A 505(b)(2) application shares characteristics of both ANDAs and stand alone NDAs. Like a stand alone NDA, a 505(b)(2) application is submitted under section 505(b)(l) and approved under section 505(c). As such, it must satisfy the requirements for safety and effectiveness information. A 505(b)(2) application is similar to an ANDA as well because it may rely on the FDA fmding that the listed drug it references is safe and effective as evidence in support of its own safety and effectiveness. However, although an ANDA is generally required to duplicate the innovator product (with a few limited exceptions) 1 and an ANDA therefore may not include new clinical safety or effectiveness information to support approval - a 505(b)(2) application often describes a drug with substantial differences from the listed drug it references. Accordingly, it must support those differences with appropriate safety and effectiveness information. For example, a 505(b)(2) application may seek approval for a new dosage form, indication, or new formulation of a previously approved drug. In such cases, the 505(b)(2) application can rely on the finding of safety and effectiveness of the listed drug only to the extent the product seeking approval and the listed drug are the same. To the etient the products are different, the 505(b)(2) application, like a stand alone NDA, must include sufficient data to demonstrate that the product with those different aspects meets the statutory approval standard for safety and effectiveness. FDA longstanding interpretation of section 505(b)(2) is intended to permit the pharmaceutical s industry to rely to the greatest extent possible under the law on What is already known about a drug. The Agency approach is to use the 505(b)(2) drug approval pathway to avoid requiring s drug sponsors to conduct and submit studies that are not scientifically necessary. The conduct and review of duplicative studies would (1) divert industry resources that could be used to undertake innovative research, (2) increase drug costs, (3) strain FDA review resources, and (4) slow The process for drug approval with no corresponding benefit to the public health.

Docket Nos. 2001P-0323/CPl&

C5,2002P-0447/CPl, and 2003P-0408/CPl

In addition, the conduct of duplicative studies raises ethical concerns because it could subject human beings and animals to medically or scientifically unjustified testing.4 The 505(b)(2) pathway permits sponsors and FDA to determine what studies are necessary to support the approval of the new aspect of a drug. It then allows sponsors to target drug development resources to studies needed to support the proposed difference or innovation. FDA interpretation of section 505(b)(2) is supported by the plain language of that provision, as s well as the overall structure and purpose of the Act and, in particular, the Hatch-Waxman Amendments. As discussed below in section III.& since passage of the Hatch-Waxman Amendments, FDA has approved more than 80 section 505(b)(2) applications for drugs for indications ranging from cancer pain to attention deficit disorder. Many of these drugs would never have reached the market, or would have been significantly delayed, without the 505(b)(2) pathway. II. A. LEGAL AND REGULATORY BACKGROUND

Background on NDAs and ANDAs

The petitions challenge FDA interpretation of section 505(b)(2), not the statutory provisions s related to stand alone NDAs, ANDAs for duplicate drugs, or petitioned ANDAs. To understand how the 505(b)(2) application fits into the drug approval landscape, however, it is important to fully appreciate the characteristics of NDAs, ANDAs, and petitioned ANDAs. A 505(b)(2) application is a subset or variation on an NDA, and it is subject to the NDA approval requirements set out in section 505(b) and (c) of the Act. A 505(b)(2) application also shares certain features with an ANDA. As such, it is subject to the patent certification requirements and many of the exclusivity delays that apply to ANDAs. I. NDAs

Section 505(b)(l) requires that an applicant submit in an NDA: evidence that the drug is safe and effective; a list of the components of the drug; a statement of the drug composition; a s description of the manufacturing, processing, and packaging of the drug; samples of the drug as necessary; and proposed labeling for the drug. Because 505(b)(2) applications, like stand alone NDAs, are submitted under section 505(b)(l) and approved under section 505(c), 505(b)(2) applications must also satisfy these NDA requirements. FDA regulations in 2 1 CFR part 3 14 s describe the NDA approval requirements in detail at 8 3 14.50. Section 3 14.54 specifically describes how 505(b)(2) applications must satisfy these requirements. In 1984, with the Hatch-Waxman Amendments, section 505 was amended to require that an NDA applicant (including a 505(b)(2) applicant) submit to FDA information about any patent that (1) claims the drug, or a method of using the drug, for which the applicant submitted the 4 The ethicsof duplicative studies oneof the concerns was leading passage of Hatch-Waxman. See House Report to 98-857, part 1,9&h Congress Sew June 21,1984 (House Report) at 16: [S]uch retesting is unethical because it 2d. requires that some sick patients take placebos and be denied treatment knownto be effective. 4

Docket Nos. 2001P-0323/CPl&

C5,2002P-0447/CPI, and 2003P-0408/CPl

application and (2) with respect to which a claim for patent infringement could reasonably be asserted if a person not licensed by the patent owner were to engage in the manufacture, sale, or use of the drug (section SOS(b)(l) and (c)(2)). Patents that must be submitted include patents on the drug active inyedient (drug substance), the drug product (formulation or composition), and s the use of the drug. Once the drug product has been approved, FDA must publish the patent information in Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book). Approved drug products listed in the Orange Book with their relevant patent information are referred to in the statute and regulations as listed drugs (section 505@(2)(A)(i)). As explained iin more detail below, the statute requires that 505(b)(2) and ANDA applicants certify whether their proposed products may infringe the patents on the listed drugs they reference in their applications. The ,Hatch-Waxman Amendments also provided different marketing exclusivity periods for drugs approved in NDAs (including drugs approved in 505(b)(2) applications), based on the level of innovation represented by the drug product. While these five- and three-year exclusivity periods are in effect, FDA may not accept or approve certain applications that rely on the protected product for approval (section 505(c)(3)(D)(ii)-(iv) and (i)(S)@)(ii)-(iv)).6 Five-year exclusivity is granted to a drug that contains no active ingredient (including any ester or salt of the active ingredient) previously approved under section 505(b) (section 505(c)(3)@)(ii) and (j)(S)(D)(ii); 6 314.108). During this five-year period that begins with approval, FDA may not receive for review any 505(b)(2) or 505(j) application referring to the listed drug with this protection. However, ifthe NDA holder for the listed drug with five-year exclusivity has submitted a patent for the drug pursuant to section 505(b)(l) or (c)(2), a 505(b)(2) or ANDA applicant wishing to challenge that patent may submit an application referencing the listed drug at the end of four years (section 505(c)(3)(D)(ii) and (i)(S)(D)(ii); 4 314.108). Three-year exclusivity is granted to a drug for which approval of an NDA or NDA supplement requires FDA to review new clinical studies conducted or sponsored by the applicant that are essential to the approval. This exclusivity bars FDA from approving for three years a 505(b)(2) apphcation or ANDA referencing the listed drug (or the change to the listed drug) for which the

5 FDA hasrecentlyissuednewregulations governing patentsubmissions, provision of notice of paragraph the IV certifications,andthe availability of 30-monthmultiple stayson ANDA and 505(b)(Z)approvals(68 FR 36676, June 18,2003). Theseregulationsapply to patentsubmissions madeon or afterAugust l&2003, andto patent certificationsto thosepatents. The mattersaddressed the new regulations not at issuein thesecitizen by are petitions. However,the interpretation section505(b)(2)discussed this response consistentwith both the old of in is andthe new regulations. 6 Title II of the Hatch-Waxman Amendments establishes processfor the extensionof the terms of certain also a patentsfor approvedinnovatordrug products. SpecificalIy,subjectto certaincaps,sponsors seeka patent can extensionequalto one-halfthe drug development plus the lengthof time the productwas underFDA review. time This is to compensate marketingtime lost to the sponsor for while the drug productwas underdevelopment and beingreviewedby FDA. The patentterm extensionprovisionsarecodifled in the PatentCodeat Title 35, sections 156and271.

Docket Nos. 2001 P-0323KP 1 & C5,2002P-0447/CPl, and 2003P-04081CPl new studies were submitted (section 505(c)(3)@)(iii) and (iv); 505@(5)(D)(iii) and (iv); 8 314.108). As explained further below, 505(b)(2) applications are hybrid applications that receive the benefits of patent listing and marketing exclusivity available to NDAs. They are also subject to the burden of patent certifications and delays in approval to which ANDAs are subject, resulting from the patents and marketing exclusivity protecting the listed drugs they reference. ANDAs Before the Hatch-Waxman Amendments were passed, there was no explicit abbreviated statutory pathway to approve duplicates of post-1962 drugs. In 1962, Congress added an effectiveness requirement as a condition of drug approval. After this change, under the Drug Efficacy Study Implementation (DESI) program, the Agency undertook to review all drugs that had been approved based on safety alone (before the 1962 effectiveness requirement was added) to determine whether there was sufEcient evidence of effectiveness to warrant their continued approval. To ensure that the largest number of drugs possible came under the Agency approval s provisions, unapproved gevteric versions of pre- 1962 drugs were permitted to obtain approval under DES1 without showing independent evidence of safety or effectiveness if they were duplicates of drugs that the Agency determined had sufficient evidence of effectiveness to warrant continued approval (as memorialized by a Federal Register notice) and contained all other information required in a new drug application (34 FR 2673, February 27,1969; 35 FR 6574, April 24, 1970). The preamble to FDA proposed rule implementing the Hatch-Waxman s Amendments briefly describes the DES1 program (54 FR 28872 at 28872 and 28873, July 10, 1989). The DES1 program and abbreviated route of approval for duplicates did not apply to drugs approved after 1962. For post-l 962 duplicates, FDA initially concluded that the statute did not provide an abbreviated pathway for approval. Accordingly, for duplicates of post- 1962 drugs, the Agency created the paper NDA policy. That policy applied narrowly to permit an applicant to rely on evidence from published scientific literature to satisfy the approval Paper NDA requirements for full reports of safety and effectiveness. (See Publication of Memorandum, 46 FR 27396, May 19, 198 1.) The application of this policy to literature-based duplicates was upheld in Burroughs Wellcome Co. v. Schweiker, 649 F.2d 221 (4th Cir. 198 1). Because so few post-l 962 drugs had an adequate quantity of published literature to support the full reports requirement for approval, in 1982 FDA announced that it was reconsidering its initial assessmentof the scope of its authority and was contemplating changing its regulations to create an abbreviated pathway for post-l 962 drugs similar to the DES1 process for pre- 1962 drugs (47 FR 1765 at 1767 January 13,1982). However, the need for such a change was obviated when, in 1984, the Hatch-Waxman Amendments were passed. Among other things, the Hatch-Waxman Amendments established an abbreviated process to approve duplicates of post- 1962 drug products. They also integrated into the drug approval process recognition of the listed drug patent protections and provided patent extensions, as well s as additional periods of market exclusivity, to encourage development of innovative drug 6

Docket Nos. 2OOlP-0323/CPl&

C5,2002P-0447/CPl, and 2003P-0408/CP1

produ&s. In creating an explicit regulatory pathway to approve duplicates of post- 1962 drugs, the Hatch-Waxman provisions ehminated the need to approve duplicates of post- 1962 drugs via the paper NDA route. Specifically, the Hatch-Waxman Amendments established a process, under section 505(j) of the FDCA, to approve duplicates of listed drugs on the basis of chemistry, manufacturing, and bioequivalence data without evidence from Iiterature or chnicai data to establish effectiveness and safety. Under these provisions, if an ANDA applicant establishes that its proposed drug product has the same active ingredient, strength, dosage form, route of administration, labeling, and conditions of use as a listed drug, and that it is bioequivalent to that drug, the applicant can rely on the fact that the FDA has previously found the listed drug to be safe and effective. FDA is not permitted to require safety or effectiveness trials to support 505(j) approval (section 505@(2)(A)). The legislation also permitted ANDA applicants to petition for permission to submit ANDAs for products that differ from the listed drug in any of four specified ways - dosage form, route of administration, streng&, or active ingredient -where such changes do not require review of clinical data (section 505@(2)(C)). If such a petition is granted, the applicant may seek approval for the altered drug product in a petitioned ANDA. Under section 505(j), the approval of both ANDAs and petitioned ANDAs depends upon the ANDA applicant demonstrating that the proposed product is sufficiently similar to the approved product for which safety and effectiveness have already been established so that no additional evidence of safety and effectiveness need be submitted for review. Section SOS(j) also contains procedures whereby the patents and marketing exclusivity protecting the listed drug are considered by FDA during the approval process for ANDAs, including petitioned ANDAs. The proposed drug described in the ANDA may not be finally approved until the patents and marketing exclusivity have expired or until the NDA holder and patent owners for patents on the listed drug have had an opportunity to defend their patent rights in court. These procedures and requirements to protect the patents and market exclusivity rights of listed drugs are duplicated with respect to approval of 505(b)(2) applications. With respect to each patent submitted by the sponsor for the listed drug and listed in the Orange Book, the ANDA, petitioned ANDA, or 505(b)(2) applicant must submit to FDA a certification under section 505@(2)(A)(vii) or 505(b)(2)(A) stating:
(I) that such patent information has not beenfiled,

(II) that such patent has expired,

Two drugsare considered bioequivalent in general, rate and extentof absorptionof the proposeddrug do not if, the show a significant differencefkom the rateand extentof absorption the listed drug (section505(j)(S)@)). of * Under FDA regulations,a changein active ingredientis permittedonly whereone active ingredientis substituted in for one of the active ingredientsin a listed combinationdrug (0 3 14.93(b)).The petitionedANDA route is not availablefor a changein active ingredientin a single active ingredientproduct. 9 If such a petition is deniedbecause clinical studiesarenecessary demonstrate the altereddrug product is to that safeand effective, an applicantmay submit a 505(b)(2)application.

Docket Nos. 2OOlP-0323/CPl& C5,2002P-0447/CPl, and 2003P-O408/CPl

(m) the date on which such patent will expire, or (IV) that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted.

If an ANDA, petitioned ANDA, or 505(b)(2) applicant does not challenge the listed patents, the application will not be approved until all the listed patents claiming the listed drug have expired. If an applicant wishes to challenge the validity of the patent, or to claim that the patent would not be infringed by the product proposed in the ANDA, petitioned ANDA, or 505(b)(2) application, the applicant must submit a paragraph IV certification to FDA. The applicant must. also provide a notice to the NDA holder and the patent owner stating that the application has been submitted and explainin the factual and legal basis for the applicant opinion that the patent is invalid or s not infringed 1% (section 505(b)(2)(B); 505(i)(2)(B)). Once the NDA holder and patent owner have received the ANDA, petitioned ANDA, or SOS(b)(Z)applicant notice and explanation as s to why the listed patent is invalid or till not be infringed by the proposed drug, they have 45 days within which to sue the applicant for patent infringement and thus trigger a 30-month stay of FDA approval of the proposed drug (section 505(c)(3)(C); 505(j)(5)(B)). FDA will approve the proposed drug before the 3%month period expires only if a court finds the patent invalid or not infringed or the court shortens the period because the parties fail to cooperate in expediting the litigation (section 505(c)(3)(C); 505(i)(S)(B)). An ANDA, petitioned ANDA, or 505(b)(2) application will not be approved until all applicable listed drug product exclusivity has expired and the listed patents have expired, have been successfully challenged by an applicant, or any applicable 30-month stay has expired (553 14.107). ANDAs with paragraph IV certifications to a listed patent may also be subject to NO-day exclusivity held by the first ANDA with a paragraph IV certification to that patent; this exclusivity does not apply to petitioned ANDAs or 505(b)(2) applications.

B.

Background on 505(b)(2) Applications

In addition to creating the ANDA approval process, the Hatch-Waxman Amendments also created a new subset of NDA. Section 505(b)(2) of the PDCA permits the filing of an NDA where the sponsor does not have a right of reference to all of the studies supporting approval, as follows: An application submittedunder [section505(b)(l)] for a drug for which the investigationsdescribedin [section SOS(b)(l)(A)] and relied upon by the applicant for approval of the application were not conductedby or for the applicant and for which the applicant has not obtaineda right of re&rence or use from the personby or for whom the investigationswere conductedshall also include -

lo see footnote 5.

Because I petitionedANDAs are for a different drug product(differentstrength,active ingredient,route.of administration,dosage form), they becomea separate listed drug and are not subjectto the 18O-day exclusivity of thefirst ANDA applicant the listed drug. for

Docket Nos. 2001P-0323/CPl&

C5,2002P-0447/CPl, and 2003P-O408/CPl

(A) a certification, in the opinion of the applicant and to the best of his knowledge,with respectto eachpatent which claims the drug for which such investigationswere conductedor which claims a use for such drug for which the applicant is seekingapproval under this subsectionand for which information is required to he tiled under paragraph(1) or subsection(c) of this sectionthat such patent information has not been filed, that such patent has expired, of the date on which such patent will expire, or that such pafent is invalid or will not be intiged by the manufacture, use,or sale of the new drug for which the application is submit&& and

(iii) (iv)

(B) if with respectto the drug for which investigationsdescribedin paragraph (l)(A) were conductedinformation was filed under paragraph(1) or subsection (c) of this sectionfor a methodof use patent which doesnot claim a use for which the applicant is seekingapproval under this subsection,a statementthat the method of use patent does not claim such a use. Thus, this section states that an applicant may rely for approval on investigations not conducted by orfor the applicant and for which the applicant has not obtained a right of reference (emphasis added). It also anticipates that the studies on which a 505(b)(2) applicant can rely may be studies on an approved drug product. This is the case because patent certifications apply only to patents on approved drug products listed in the Orange Book. The statute also was amended throughout, as described above, to ensure that the patent and exclusivity bars to approval that apply to ANDAs apply as well to the approval of 505(b)(2) applications. (See, e.g., section 505(c)(3).) Section 505(b)(2) permits FDA to review applications that are not reviewable under section 505(j) either as duplicates or minor variations of a listed drug and that do not require a full stand alone NDA supported by new scientific studies. Without the 505(b)(2) approval pathway, the available approval routes would be limited to: (I) new studies on all aspects of a drug safety s and efficacy (stand alone NDA) or (2) almost complete reliance on established findings of safety and efficacy (ANDA). For example, a modification to a listed drug (e.g., a novel dosage form) that could not be approved in a petitioned ANDA under section 505(j) because review of new clinical data would be necessary for approval could only be reviewed in a complete new stand alone NDA. This approach is not necessary. Instead, FDA believes that it is reasonable to interpret the statute so that: (1) if a proposed modification may be approved without additional studies, the drug may be reviewed in a 505(j) application that relies entirely on the Agency s finding of safety and effectiveness for the listed drug; and (2) if the proposed modification will require additional data for approval, the drug may be reviewed in a 505(b)(2) application that relies in part on the Agency finding of safety and effectiveness for the listed drug. s

I2 Right of reference or use is defined in 4 314.3(b) as the &ho&y to rely upon, and otherwise use, an investigation for the purpose of obtaining approval of an application, including the ability to make available the underlying raw data from the investigation for FDA audit, if necessary.

Docket Nos. 2001P-0323/CPl&

C5,2002P-04471CP1, and 2003P-0408/CPl

After passage of Hatch-Waxman, FDA explained its interpretation of the new 505(b)(2) provision in a series of public statements, including an open letter to the drug industry in 1f987 written by Dr. Paul D. Parkman (the 1987 Parkman letter) (enclosed with this response), the 1989-1994 Hatch-Waxman rulemaking process, and a 1999 draft guidance. In addition, the Agency has responded to many inquiries from industry regarding whether specific drug products could be approved through the 505(b)(2) route. 1. The I987 Parkman Letter

The first detailed statement by the Agency explaining the scope of section 505(b)(2) was in the April 10,1987, letter to industry from Dr. Paul D. Parkman, then Acting Director of the Center for Drugs and Biologics. The 1987 Parkman letter addressed the statutory route by which an applicant may make modifications in approved drugs when such modifications require submission of clinical data (1987 Parkman fetter at 1). In assessing the various regulatory options, the Agency rejected the idea of requiring a full NDA for such modifications, which would require duplication of the basic safety and effectiveness research. This course, the letter stated, would be inconsistent with the Hatch-Waxman Amendments in that it would be a disincentive to innovation and require needless duplication of research. The Agency also rejected the option of requiring the submission and approval of an ANDA, followed by a supplement to that ANDA containing the data necessary to support the change. The Agency noted that to generate all of the stability and other data required for ANDA approval, the sponsor would have to take steps to manufacture a product that it had no intention to market. The Agency concluded that the better course was to permit submission of an application under section 505(b)(2) for a change to an already approved drug product without requiring that the applicant fiit obtain approval of an ANDA (the phantom ANDA). The 1987 Parkman letter stated that such changes could include changes in dosage form, strength, route of administration, and active ingredients (for which clinical studies are nessary) as well as new. As described in the 1987 Parkman letter, such applications would rely on the approval of the listed drug together with the clinical data to support the change. The 505(b)(2) applicant will thus be relying on the approval of the listed drug only to the extent that such reliance would be allowed under section 505(j) to establish the safety and effectiveness of the underlying drug. 4 The letter further noted
l3 Much of the initial implementation the Hatch-Waxman of Amendments explantedto the public in a seriesof was lettersto industry,which wereissuedbetween1984and 1988and weremailedto all known NDA and ANDA applicantsaud holders. Theselettersdescribed Agency initial views, as it regulateddire&y from the statute the s beforecompletionof the rulemakingprocess. l4 WhenFDA approves standaloneNDA submittedundersection505(h),the approvalis basedon the dataand a informationsubmittedin the application. Later approvals undersection505(j) of duplicatesor minor modifications to this listed drug will rely on the Agencyconclusionsthat a drug with thosespecific characteristics s (e.g.,active ingredient,strength,dosage form, conditionsof use)was previouslyfound to be safeand effective. Similarly, when reviewing a 505(b)(2)applicationthat relies in part on the earlierapprovalof a listed drug, FDA may rely on its earlier conclusions regardingsafetyand effectiveness whateverextentthe conclusions appropriate the drug to are for underreview in the 505(b)(2)application. Although relianceon an FDA finding of safetyand effectiveness an for NDA is certamlyindirect relianceon the datasubmittedin the original NDA. relianceon the conclusionssupported by that datais not the sameas manipulatingthosedatato reachnew conclusions evident from the existing not approval. For example,if the NDA for the listed drug containedstudiesindicatingthat the drug may be effective for indicationsX andY, but the listed drug is not approved useY, a 505(h)(2)applicantcould not rely on those for

10

Docket Nos. ZOOlP-O323/CP1& C5,2002P-0447EP1, and 2003P-0408KPl that the patent certification and exclusivity bars applicableto ANDA approvalswould also apply to 505(b)(2) applications.
2.

The 1989 Proposed Rule

In 1989,FDA proposedregulationsto implementthe Hatch-WaxmanAmendments,including section 505(b)(2). (SeeAbbreviatedNew Drug Application Regulations;ProposedRule, 54 PR 28872, July 10,1989.) In proposed0 314.54,PDA laid out the requirementsfor submission of an application under section505(b)(2) (54 PR 28919). In the preambleto the proposed regulations,FDA acknowledgedthat the legislative history referredto paper NDAs. The paper NDA policy permitted an applicantto rely on evidencederived primarily from scientific literature to demonstrate safety and effectiveness duplicates. As noted above,before the the of enactmentof Hatch-Waxman,FDA had usedthe paper NDA policy to approveliterature-based duplicatesof certain post-1962pioneer drug products. FDA noted that despitethe referenceto paperNDAs in the legislative history, the text of section505(b)(2) and 505(c)(3)@) is considerablybroader. It doesnot Iimit 505(b)(2) applicationsto applicationsfor literaturesupportedduplicatesof alreadyapprovedproducts(54 PR 28890). PDA further explainedin the preamblethat 505(b)(2) appliesto any applicationthat relies on investigationsthe applicant has not conductedor to which it has not obtaineda right of referenceregardlessof the similarity or dissimilarity of the drug product to the previously approveddrug product(54 PR 28890). Such applicationsmay be for variationsof approveddrug productsor for new chemical entities. i FDA explainedthat 505(b)(2) applicationsshouldbe usedfor never-before-approved changesin approveddrug productsand that it was proposingto treat as a 505(b)(2) application an
application for a change in an already approved drug supported by a combination of literature or new clinical investigations and the Agency sjhihg that a previously approved drug is safe and efictive (54 PR 28891) (emphasisadded). FDA noted, however,that certain applications

that were previously approvableunder the paperNDA policy would no longer be approvable under section505(b)(2). Specifically, PDA statedthat it would not approve505(b)(2) applicationsfor literature-based duplicatesbecause would be inconsistentwith Hatch-Wsxman it purposesto undertakeduplicative review of safety and effectivenessdata when the abbreviated approvalroute under section505(j) is available(54 PR 28890 and 28891). FDA also discussed the patentcertification and exclusivity bars for 505(b)(2) applications,emphasizingthat they are the sameas those that apply to ANDAs (54 PR 28892).
The 1992 Final Rule

The regulation proposedin 1989 is, in all relevantrespects,the sameas the current regulation at 0 314.54, which was finalized in 1992.15 There were two commentson the proposedprovisions
l_l_,_--^.I._-ll^ ^^ ,^,,__,IIXX ^ -,_, ,_,, -,, ~ ,,, -,&.-*~*,I_LII ,I,,

studies to for use x.

getapproval for

indication Y; it could only rely on the fact that the Agency found the drug to be effective

Is Section 314.54 Procedurefor submission of an application requiring investigationsfor approval of a indication for, or other change from, a listed drug provides:

Docket Nos. 2OOlP-0323/CPl& C5,2002P-0447/CPl, and 2003P-O408/CPl regarding505(b)(2) applications,neither of which addressed FDA fundamentalinterpretation s of section 505(b)(2). Thesecommentswere addressed the preambleof the final rule that in established regulation at 0 314.54 governingthe types of applicationsthat could be submitted the under section 505(h)(2) (57 PR 17950at 17954,April 28,1992). FDA regulation at 4 314.54makesclear that FDA interpretssection505(h)(2) to permit s approval of an applicationthat relies on the finding of safetyand effectivenessof a listed drug to the extent such relianceis scientifically justified. Specifically, it providesthat [a]ny person seekingapproval of a drug product that represents modification of a listed drug. . . and for a which investigationsother than bioavailability or bioequivalencestudiesare essentialto approval of the changesmay . . . submit a 505(b)(2)application. This applicationneed contain only that information neededto supportthe modification of the listed drug (0 314.54(a)). It further requiresapplicantsseekingapprovalunder 505(b)(2) to [identify] the listed drug for which FDA
-

(a) The act doesnot permit approvalof an abbreviated drug applicationfor a new indication,nor does new it permit approvalof otherchanges a listed drug if investigations, in otherthanbioavaiIabilityor bioequivalence studies,areessential the approvalof the change. personseekingapprovalof a drug to Any productthat represents modificationof a listed drug (e.g.,a new indicationor new dosage a form) andfor which investigations, otherthanbioavailabilityor bioequivalence studies,areessential the approvalof to the changes may, exceptas providedin paragraph of this section,submita 505(b)(2)application.This (b) applicationneedcontainonly that informationneeded supporttbe modification(s)of the listed drug to [inchuiingl (iii) Identificationof the listed drug for which FDA hasmadea finding of safetyandeffectiveness andon which finding the applicantrelies in seekingapprovalof its proposed drug productby established name,if any, prop&&y name,dosage form, strength, route of administration, name of listed drug applicationholder.and listed drug approved s s applicationnumber. (iv) If the applicantis seekingapprovalonly for a new indicationandnot for the indications approved the listed drug on which the applicantrelies,a certificationso stating. for (v) Any patentinformationrequiredundersection505(b)(1) of the act with respectto any patent which claims the drug for which approvalis soughtor a methodof using suchdrug and to which a claim of patentinfringementcould reasonably asserkdif a personnot licensedby the ownerof be the patentengaged the manufacture, or saleof the drug product. in use, (vi) Any patentcertificationor statement requiredundersection505(b)(2)of the act with respect to any relevantpatentsthat claim the listed drug or that claim any otherdrugson which investigations relied on by the applicantfor approvalof the applicationwereconducted, that or claim a usefor the listed or otherdrug. (vii) If the applicantbelievesthe changefor which it is seekingapprovalis entitledto a period of exclusivity, the informationrequiredunder+j314.50(j). (b) An applicationmay not be submittedunderthis sectionfor a drug productwhoseonly differencefrom the reference listed drug is that: (1) The extentto which its active ingredient(s) absorbed otherwise is or madeavailableto the site of actionis less thanthat of the reference listed drug; or (2) The rate at which its activeingredient(s) absorbed otherwisemadeavailableto the site of actionis unintentionallylessthan is or that of the reference listed drug.

Docket Nos. 2OOlP-0323/CPl&

C5,2002P-0447KP1, and 2003P-04OWCPl

has made a finding of safety and effectiveness and on which finding the applicant relies in seeking approval of its proposed drug product (I$314.54(a)( l)(iii)). 4. The 1994 Final Rule

In 1994, PDA issued regulations governing the patent certification and exclusivity aspects of 505(b)(2) applications (Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions; Final Rule (59 IX 50338, October 3,1994)). Because 505(b)(2) applications are NDAs submitted under section SOS(b)and approved under section 505(c), they are eligible for the same three-year new clinical study exclusivity and five-year new molecular exclusivity as are other NDAs (6 314.108). The sponsors of SOS(b)(Z)applications also must submit the same required information regarding patents that claim the drug, or the use of the drug, described and approved in the 505(b)(2) application (5 314.53). The regulations also addressed the fact that approval of a 505(b)(2) application is, as with ANDAs, subject to the listed patents, as well as the three- and five-year exclusivity protecting the listed drug. A 505(b)(2) application will not be approved until all applicable listed drug product exclusivity has expired, and the listed patents have expired, have been successfully challenged by an applicant, or any applicable 30-month stay has expired (See 00 314.50,314.107, and 314.108.) 5. ZIhe 1999 Draft Guidance

In response to many requests from industry and based upon accumulated agency experience in applying section 505(b)(2), IDA drafted and published in October 1999 a draft guidance for industry entitled Applications Covered by Section 505(b)(2) (1999 draft guidance). The 1999 draft guidance describes existing practice as well as certain possible uses within the scope of section 505(b)(2) that had not yet been employed by industry. It notes that [sleetion 505(b)(2) permits approval of applications other than those for duplicate products and permits reliance for such approvals on literature or on an Agency finding of safety and/or effectiveness for an approved drug product (1999 draft guidance, p. 2). The 1999 draft guidance contains information for industry regarding the type of information an applicant could rely on for approval under section 505(b)(2) as well as the types of changes approvable under that section. The 1999 draft guidance states that an applicant seeking approval under section 505(b)(2) can rely on a combination of published literature, its own clinical studies, and/or the agency finding s of safety and effectiveness for a listed drug (1999 draft guidance, p. 3). The guidance also notes that a 505(b)(2) application can be submitted for different types of applications, including for a new chemical entity, or for a change to a previously approved drug such as a new dosage form, strength, route of administration, substitution of an active ingredient in a combination product, new formulation, new dosing regimen, new active ingredient, new combination product, a new indication, or for a naturally derived or recombinant active ingredient. PDA received a number of comments on the 1999 draft guidance. Some of the comments stated that the approach described in the guidance would result in improper use of data in innovator NDAs. Other comments supported the guidance as describing an appropriate use of section 505(b)(2) to permit approval of innovative drug products without requiring unnecessary

13

Docket Nos. 2001P-O323/CPl& C5,2002P-0447KP1, and 2003P-0408/CPl duplication of research,including clinical research The guidancehas not been publishedin final . form.
TTT.

ANALYSr!s

FDA long-standinginterpretationof section505(b)(2) permits the Agency to approvedrug s applicationsthat rely on studiesnot conductedby or for the applicantand which the applicant has not receivedpermissionto use from the sponsor,so long as the 505(b)(2) applicantcomplies with the applicablestatutoryrequirementsregardingpatentprotection and new drug exclusivity. The 505(b)(2) processpermits an applicant seekingapprovalfor a drug product that differs from the approveddrug product to obtain approvalwithout conductingnew studiesto demonstrate to the Agency what has alreadybeendemonstrated.This approachis basedon the broad statutory language,its historical context, and its place within the Hatch-Waxmanstatutory scheme,as well as relevant policy and public health considerations. The linchpin of FDA interpretationof 505(b)(2) is that a 505(b)(2) applicantmay rely on the s FDA finding of safety and effectiveness a listed drug only to the sameextent an ANDA s for applicant may rely on such a finding under sectionSOS(i).(See54 FR 28872 at 28892: The [505(b)(2)] applicant will thus be relying on the approvalof the listed drug only to the extent such reliance would be allowed under 505(j) of the act.) In the 505(j) approvalprocess,the ANDA applicant seekingapprovalof either a duplicateto the listed drug, or a petitioned modification, relies solely on the previousfinding of safety and effectivenessfor the listed drug; the ANDA must be approvablewithout additional clinical or preclinical evidenceof safety or effectiveness.In the 505(b)(2) process,the applicant also relies on the previous finding of safety and effectivenessfor the listed drug. But such reliancewill be appropriateonly to the extent that the proposedproduct in the 505(b)(2) application sharescharacteristics (active ingredient,dosage form, strength,route of administration,indications,and conditions of use) in common with the listed drug. The safety and effectivenessof any differencesbetweenthe listed drug and the drug proposedin the 505(b)(2) applicationmust be supportedby additional data,including clinical or animal data, as appropriate(0 314.54). Since the Agency beganimplementing sectionSOS(b)(Z) the 1987 Parkmanletter, FDA with s approachto 505(b)(2) applicationshas beengovernedby consistentscientific principles. In enactingthe Hatch-WaxmanAmendments,CongressauthorizedFDA to rely on information about the safe and effective use of an approveddrug product to approveanotherdrug with similar characteristics, because duplicative clinical testing to reestablishwhat has alreadybeen shown is wasteful, unnecessary, may raise ethical issues. In the 505(b)(2) context, the and applicantcan rely on established conclusionsabout the approveddrug to the extent these conclusionsare applicableto the proposedproduct. However, the applicantmust supply data to support any differencesbetweenthe two products. Preciselywhat additional data will be necessary approvalof a drug will vary from caseto for caseand is generallythe subjectof discussionbetweenthe sponsorand FDA during the drug developmentprocess. For example,a 505(b)(2) application for a new dosageform (such as a transdermalpatch or a novel drug delivery mechanism)that cannot be approvedas a petitioned
4

Docket Nos. 2OOlP-O323/CPl& C5,2002P-0447/CPl, and 2003P4408/CP1 ANDA - because clinical studiesare necessary demonstrate to safety and/or effectiveness must contain whateverdata are necessary demonstrate the new dosageform is safe and to that effective to u-eatthe indications approvedfor the listed drug. Similarly, approval of a drug product for a new indication with the samestrengthand dosing regimen as a previously approved drug product will require evidenceestablishingthat the drug is effective for the new indication. But new safety information may not be necessary because underlying drug has alreadybeen the shown to be safe at the approveddosing level. Thus, the nature and extent of the relianceon the agencyconclusionof safety and effectiveness a listed drug am the samefor applicantsunder s for section505(b)(2) and 505(j); it is only the amountof additional data necessary supportthe to approval of the proposeddrug product that may differ. Relianceon FDA conclusionthat an approveddrug is safe and effective doesnot involve s disclosureto the ANDA or 505(b)(2) applicant- or to the public -of the data in the listed drug NDA. Instead,it permits the ANDA or 505(b)(2) applicantto rely on the fact that FDA s found a drug product with certain characteristics be safe and effective and, in the caseof a to 505(b)(2) applicant,to target its studiesto prove how changesfrom this previously approved drug product also meet the FDA safety and effectiveness s standards. FDA interpretationis supportedby the text of section505(b)(2), the structureof the Hatchs Waxman Amendments,and the purposesof that legislation. The interpretationis also supported by policy considerations.By permitting appropriaterelianceon what is alreadyknown about a drug, thereby saving time and resources the drug developmentand approvalprocess,FDA in s interpretationallows the pharmaceutical industry to target investmenton innovative drug development. It avoids the ethical concernsassociated with unnecessary duplicative testing that could deny effective treatmentto sick patientstaking placebosor ineffective dosages.And it allows improved productsto reachthe market that may not otherwisehave been developed,such as modifications to productsneededfor a small patient population. Thus, FDA current s interpretationis in the interest of the public health. A. Statute and Legislative History
1 The Language and Legislative History of Section .50.5(b)(Z)

FDA interpretationis basedon and supportedby the plain languageof the statute. Section s 505(b)(2) permits applicantsto rely on studieswhich were not conductedby or for the applicant and for which the applicanthas not obtaineda right of referenceor use. This provision doesnot limit the sourcesof the studieson which 505(b)(2) applicantsmay rely. The statutorylanguage doesnot suggestCongressintendedto codify the paperNDA policy in effect before the statute s passage to limit 505(b)(2) approvalsto literature-based or duplicatesor changesthat could be approvedunder an ANDA followed by a supplement.Thus, on its face, the statutegoesbeyond the old paperNDA policy. Even if the statutewere consideredambiguous,however,FDA has reasonablyconstruedthe broad languageof section505(b)(2). The legislative history of the SOS(b)(Z) provision doesnot require a contrary interpretation. The House Report definesPqer NDA as any application submittedunder section505(b) of the 15

Docket Nos. 2001P-0323KP18zC5,2002P-O447KPl, and 2003P-0408KPl PDCA in which the investigationsrelied upon by the applicantto show safety and effectiveness were not conductedby or for the applicantand the applicanthas not obtaineda right of reference or use from the personwho conductedthe studiesor for whom the studieswere conducted (HouseReport at 32). Notably, this definition makesno mention of either literature or duplicate products,the two hallmarks of the paper NDA under the paper NDA policy in effect when Hatch-Waxmanwas passed. (See Publication of PaperNDAMemorandum(46 PR 27396).) Had Congressintendedto use section 505(b)(2) to codify the paper NDA policy then in existence,it presumablywould not have defined a 505(b)(2) application or paper NDA in a way that was considerablybroaderthan its preexistingdefinition. Rather,given that the broad definition of paperNDA in the HouseReport mirrors the broad statutorylanguage,it is reasonable presumethat Congressintendedthat section505(b)(2) extend beyond the to literature-based duplicatespermissibleunder the paperNDA policy. This seemsespecially 6 likely given that when IHatch-Waxman passed, was widely recognizedthat few, if any, was it additional applicationscould be approvedbasedon publishedliterature alone, given the stateof such literature (HouseReport at 16: [Paper NDA policy] is inadequate, however, because FDA estimatesthat satisfactoryreports are not availablefor 85% of ail post-1962drugs). In assessing role of section505(b)(2) in the drug approvalprocess,it is important to bear in the mind that, in the Hatch-WaxmanAmendments,Congresscreateda specific, detailed abbreviated route for approval of duplicatesthrough sectionSOS(i), which permits relianceon the previous finding of safety and effectivenessfor a listed drug. Thus, codification of the inadequateand ineffective paperNDA processfor literature-based duplicateswould have been unnecessary and supeffluous. In addition, section505(b)(2) would have beenunnecessary an approvalroute as for changesto drug productsfor which a petition can be filed seekingapproval as a petitioned ANDA under section SOS(i) because additional safetyor effectivenessdata are necessary no to the approval in that case. Thus, Congresscreateda new type of application, a 505(b)(2) application, to fill specific gapsleft by the other approvalpathways: a 505(b)(2) application can be usedfor approvalof thosechangesthat are not so significant that they require a standalone NDA, but that are significant enoughthat they may require additional safety or effectivenessdata (and, therefore,are not eligible for approvalunder sectionSOS(i)). As describedin the 1987 Pa&man letter, an applicantwishing to make a changeto an approved drug could submit an ANDA for a duplicate of the listed drug (or a petitioned ANDA for a petitioned changeto that drug). Once the ANDA applicantreceivedapproval of the ANDA, that ANDA holder could submit a supplemental applicationunder 505(b) to make a changeto the approveddrug, and include in that supplementwhateverinformation and studiesare neededto Although there is no statutorybarrier to permitting an ANDA holder to approvethe change.17
l6 Because Congress specificallydefinedwer NDA in the legislativehistory in a way that was broaderthanthe definition that FDA had usedpreviousIy,the prea~ption that Congress gavethe term the samemeaningas the Agency had previouslydoesnot apply.
I7 FDA haslong interpreted the term application as usedin section505 to includenew NDAs, amendment& and supplements 3 14.3(b),3 14.50). Thus, for example,when the holderof an approved ($0 applicationseeksapproval for a supplement changethat drug, it must submit a supplement meetsthe relevantapplicationrequirements to that in !j 314.50(8 314.71(b)).

16

Docket Nos. 2OOlP-O323/CPl& C5,2002P-0447KP1, and 2003P4408/CP1 requestapprovalunder sectionSOS(b) a supplementto that ANDA, as describedin the 1987 for Parkmanletter, the Agency decidedthat it is not necessary torequire that an applicant obtain approval of a phantomANDA when the applicantseeksto make a changeto a listed drug. In this situation, the section505(b)(2) mechanismprovides an appropriateregulatory pathway that also ensuresadequate marketingprotectionsfor the listed drug. The languageof the statutedoesnot limit 505(b)(2) approvalsto thosechangesthat could be proposedin a supplementto an approvedANDA under section505(i). The changes(such as a new indication, new dosageform, new strengthor new formulation) that may be submittedin a supplementrather than requiring a separate application (i.e., what productsmay be bundled) are a matter of PDA administrativepolicy and practice,not a function of statutoryrequirements. Nor doesthe languageof section505(b)(2) necessarilyprohibit approvalof a 505(b)(2) application before an ANDA for the listed drug has beenor could be approved. If a 505(b)(2) application could only be approvedafter an ANDA referencingthe listed drug had been approved,or after all patent and exclusivity rights have expired (as somehave contended),the independentpatentcertification obligationsthat apply under section505(b)(2) (and the opportunity to challengea listed patentand obtain approvalupon a finding of noninfringementor upon expiration of the 30-month stay) would be superfluous.(SeeGmtafson v. AZZoydCo., 115 S. Ct. 1061, 1069 (1995) (courts should avoid interpretationsthat rendersome words of statute redundant).) Similarly, if Congresshad wantedto imposesuch a limitation on 505(b)(2) approvals,it likely would have placedthe relevantprovision in section505(j) rather than in section505(b) of the statuteor would have otherwisesignaledthat only this limited subsetof applicationscould be submittedand approvedunder section505(b)(2).
2. Diflerences Between Section SOS(b)(Z) and 505cj)

The differencesbetweensection505(b)(2) and 505(i) of the statute(and the references one or to the other type of application in other parts of the statute)further supportPDA interpretation. s Thesedifferencesinclude differencesin disclosureand withdrawal provisions, among others, and reflect the fact that drugs approvedunder 505(b)(2) applications,unlike those approved under 505(j) applications,are not requiredto be duplicatesof listed drugs.I8 The disclosureprovisions of section505(l) are a casein point. Under section505(l)(5), absent extraordirwy circumstances, all safety and effectiveness data in an NDA shah be disclosedto the public upon requestwhen an ANDA has beenor could have been approved. There is no comparableprovision requiring disclosure,absentextraordinarycircumstances, when a 505(b)(2) application is approved. This differencereflects Congressunderstanding 505(b)(2) s that applications,in contrastto ANDAs, may rely on someaspects a listed drug approval (such as of s the toxicology profile) but not on others. Given the possibility that the product under a 505(b)(2) application could have significant differencesfrom the listed drug referenced,approval of a 505(b)(2) application based,in part, on a previous approvalof an NDA would not give rise to a
,.. .,. .^_, ._ ____ -n----v

In fact, FDA regulations state that section 505(b)(Z) is not an appropriate approval pathway for an application for * a duplicate eligible for approval under section 505(j). See $6 314.54(b), 314.101(d)(9).

Docket Nos. 2OOlP-O323/CPl&C5,2002P-0447KP1, and 2003P-0408KPl presumptionthat all of the NDA data ceaseto retain their value and should be availablefor public disclosure. In contrast,because ANDA is for a duplicateof an approveddrug, it is an logical to presumethat once a SOS(i)applicationhas been approved,the information in the original application ceases retain much of its value and thus may be availablefor public to disclosure. This differenceexplains why section505(l)(5) usesANDA approvalsas a disclosure trigger, but has no comparabletrigger basedon 505(b)(2) approval. Similarly, there are no analogues section505(b)(2)to the provisions in section505(j) in requiring that the product under the 5051j)applicationbe bioequivalentto, have the same conditions of use as, and use the samelabeling as the listed drug referenced. Thesedifferences do not suggestthat 505(b)(2) applicationscannotrely, in part, on FDA conclusionthat a listed s drug is safe and effective. Rather,they supportFDA longstandinginterpretationthat the s productsunder 505(b)(2) applications,unlike thoseunder ANDAs, need not be duplicatesof the listed drugs referenced. If 505(b)(2) applicationswere limited to literature-based duplicates, surely Congresswould have required that, like thoseapprovedin ANDAs, productsapprovedin 505(b)(2) applicationsbe bioequivalentto, have the sameconditionsof use as, and the same labeling as the listed drugs referenced. No such sameness requirementwas included, however, becausesection505(b)(2) was never intendedto be limited to literature-based duplicates. Furthermore,differencesin withdrawal provisionsreflect the differencesin the two types of applications. BecauseANDAs ate, by definition, for duplicates(or minor variations) of a referencelisted drug, drug productsapprovedin ANDAs are expectedto have the samesafety and effectivenessprofile as the listed drugs they reference. Thus, it is not surprisingthat ANDAs must be withdrawn when the listed drug is withdrawn for safety or effectivenessreasons(section 505(j)(6)). In contrast,because product under a 505(b)(2) applicationcan differ significantly the from the listed drug referenced,there is no comparablewithdrawal requirementwhen the listed drug is withdrawn for safety or effectiveness reasons. B. Drug Approvals Under Section SOS(b)(Z)

Since 1984,505(b)(2) applicationshave beenusedby a wide rangeof sponsorsin the pharmaceutical industry (including petitioner Pfizer and membersof petitioner BIO) to obtain approval of more than 80 drug products. Over 30 additional 505(b)(2) applicationsare currently under review by the Agency. Most of theseapplicationshave not been solely literature-based 505(b)(2) applications. The 505(b)(2) approvalpathwayhas been particularly important in certain areasof drug developmentwhere a limited or uncertainmarket warrantsmaximum leveragingof current knowledge about a drug. The Agency has approved505(b)(2) applicationsfor drugs for treatmentof exposureto radiation and chemicalwarfare,drugs targetedto pediatric populations, novel dosageforms, and new formulationsfor antibiotics and cancerdrugs, amongothers. In many of theseareas,drug developmentresources scarce. Creating an abbreviatedpathway are that allows sponsorsto focus theselimited resources develop data on the innovation has led to to the creation of new therapeuticoptions that otherwisemight not have been available. For example,certain patient groups,such as children, may have trouble swallowing capsulesor 18

Docket Nos. 2OOlP-O323/CPl& C5,2002P-O447/CPl,and 2003P-WWCPl tablets. But the size of that patient populationmay not supportthe expenseof a stand alone NDA to seekapproval for a pediatric-friendly dosageform. Section 505(b)(2) provides a more efficient and cost-effectivepathwayto bring such innovationsto market. The following noncomprehensive provides someexamplesof SOS(b)(Z) list applicationsthat the Agency has approved:
1. Treatments for Exposure to Radialogical or Chemical Terrorism or Warfare

* The U.S. Army 505(b)(2) applicationfor pyridostigminebromide was approvedin 2003 s as a pretreatmentto increasesurvival after exposureto the nerve agentSoman. This applicationrelied on animal efficacy data to supportthe effectivenessof pyridostigmine bromide to treat exposureto nerve gas;it relied for safety on the fact that pyridostigmine bromide had been approvedand usedfor many yearsas Mestinon at a higher doseto treat myestheniagravis. @ The U.S. Army 505(b)(2) applicationfor atropine/pralidoximeautoinjectorswas s approvedin 2002 for treatmentof poisoning by nerve agentsand relied on the previous approvalsof a&opineand pralidoxime products. Before approval of this 505(b)(2) application,there had beentwo approvedNDAs for the separate autoinjectors,and mihtary personnelwere requiredto carry separate injectors for atropineand pralidoxime. This 505(b)(2) application approvedone autoinjectorthat administersboth drugs in a single injection. 0 The U.S. Army 505(b)(2) applicationfor a diazepamautoinjectorwas approvedas an s anticonvulsantin December1990.When the Army enteredinto discussionswith the Agency about approvalof an autoinjectableanticonvulsant, Agency concludedthat, the because necessary of variationsfrom innovator labeling, such an application would not be appropriatefor an ANDA through the suitability petition process. Section 505(b)(2) provided for a prompt approvalto meet an immediateneed. 0 Heyl 505(b)(2) applicationfor Radiogardase s (prussianblue) was approvedin 2003 for use in patientswith known or suspected exposureto thallium or radioactivecesium, an orphan indication. Prussianblue was approvedas new chemical entity (a drug in which no active moiety has beenpreviously approved).
2. Pediatrics

0 Mallinckrodt 505(b)(2) applicationsfor chewabletablet and oral solution forms of s methylphenidatewere approvedin 2002 and 2003, respectively,to treat attentiondeficit disorder.
l

Ascent 505(b)(2) applicationfor trimetboprim hydrochloridein oral solution was s approvedin 1995 for treatmentof urinary tract infections. 19

Docket Nos. 2OOlP-0323/CPl& CS, 2002P-0447/CPl,and 2003P-O408KPl Wyeth ConsumerHealthcare505(b)(Z) applicationfor Children Advil Cold s s Suspension(ibuprofen and pseudoephedrine) approvedin 2002 for the temporary was relief of cold, sinus, and flu symptoms. 3.
New Drugs, Alternative Dosage Forms and New Formulations for Antibiotics and Cancer Drugs

0 Bryan Corporation 505(b)(2) applicationfor Sclerosol(sterile talc powder) was s approvedin 1997 to treat malignantpleural effusion. Sclerosolwas approvedas a new chemical entity (a drug in which no active moiety has beenpreviously approved). 0 Elan 505(b)(2) applicationfor Duraclin (clonidine HCI) was approvedin 19% for s epidural administrationto treat cancerpain. The 505(b)(2) approachalso has been usedto approveless toxic formulations of cancer drugs, for example,a chemotherapyagentthat is madewithout.a toxic excipient. Use of the 505(b)(2) pathway has allowed somesponsorsto avoid using scarcecancerresearch resourcesto conductunnecessary trials to re-demonstrate efficacy for such a product. 4.
Other Exumples ofSection 505(b)(2) Applications

Pfizer 505(b)(2) application for Zyrtec D (certirizine and pseudoephedrine) s was approvedin 2001 as a new combinationfor the relief of nasal and non-nasalsymptoms associated with seasonalor perennialallergic rhinitis. Pfizer 505(b)(2) application for Rid Mousse(piperonyl butoxide and pyrethins) was s approvedin 2000 for the treatmentof head,pubic, and body lice. Andrx 505(b)(2) applicationfor Altocor (lovastatin)was approvedin 2002 as an s extendedreleaseformulation for lowering cholesterollevels. Galderma505(b)(2) applicationfor clindamycin phosphatewas approvedin November s 2000 as a once daily gel (others are twice daily) for the treatmentof acne. Orion Pharma 505(b)(2) applicationfor Stalevo(carbidopa,levodopa,and entacapone) s was approvedin 2003 as a new combinationproduct for treatmentof Parkinsondisease. s Novartis Consumer505(b)(2) applicationfor Tavist, a new combination of s acetaminophen, clemastine,and pseudoephedrine, approvedin 2001 for the was temporaryrelief of symptomsassociated with hay fever, allergic rhinitis, and the common cold.

20

Docket Nos. 2OOlP-0323/CPl& C5,2OK?P-0447/CPl, and 2003P-0408/CPl * Dey Labs 505(b)(2) application for Duoneb (albuterol sulfate and ipratropium) was approved in 2001 for the treatment of bronchospasms associated with chronic obstructive pulmonary disease in patients requiring more than one bronchodilator.

0 Duramed Cenestin (synthetic conjugated estrogens) was approved in 1999 for the s treatment of moderate-to-severe vasomotor symptoms associated with menopause and the treatment of vulvar and vaginal atrophy. 0 Celegene Thalomid (thalidomide) was approved 1998 to treat erythema nodosum s leprosum (leprosy) (an orphan indication). OPR Cafcit (caffeine citrate) was approved in 1999 for treatment of apnea of s prematurity (an orphan indication).

The pharmaceutical industry continues to rely on the 505(b)(2) pathway for drug development and innovation. l?DA has identified more than 30 pending 505(b)(2) applications, and the Agency is currently in discussions with many additional sponsors about their development and research plans for 505(b)(2) applications.

IV. A.

FDA RESPONSE TO ARGUMENTS IN THE S PFIZER, BIO, AND TORPIURM CITIZEN PETITIONS The Language of Section 505(b)(2)

Petitioners argue that FDA interpretation of section 505(b)(2) is inconsistent with the statutory s language. They argue that section 505(b)(2) simply permits a sponsor to rely on studies in the published literature to support approval, or that such approval is limited to duplicate products. They assert that section 505(b)(2) does not permit a sponsor to rely on FDA~findings that an approved drug is safe and effective when those fmdings are based on the listed drug nonpublic s studies (2001 Pfizer petition at 3, TorPharm petition at 8). FDA Response: As explained above, the plain language of 505(b)(2) does not support petitioners narrow construction. Section 505(b)(2) permits applicants to rely on studies which were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use. The statute does not limit the sources of the studies on which 505(b)(2) applicants may rely to published literature or other publicly available studies - even though Congress could easily have added such a limitation. Indeed, peetioner Pfizer appears to concede in its April 28,2003, submission that the broad language of section 505(b)(2) permits more than approvai of literature-based duplicates. Specifically, Pfizer acknowledges that the principle expressed in the 1987 Parkman letter is a permissible interpretation of the statute (April 2003 comment at 2). lg l9 In the 1987Pa&manletter, the Agency explainedthat section 505(b)(2) allowedsubmission an application of for a change an already in approved product,withoutrequiringthatthe applicant obtainapproval an ANDA drug first of andthensupplement approval that with a 505(b) supplement the change.However,Pfizer construes 1987 for the 21

Docket Nos. ZOOlP-0323/CPl& C5,2002P-0447KP1, and 2003P-0408KPl

B. The Legislative History of Section 505(b)(2)

Petitionerscite to legislative history in which a 505(b)(2) applicationis referred to as a paper ADA to supporttheir argumentthat the statutecodified - rather than expandedon or replaced - the paperNDA policy in effect before the passage the Hatch-WaxmanAmendments. of PetitionersTorPharmand BIO assertthat section505(b)(2),like the paperNDA policy, is intendedto permit approvalof NDAs for duplicatesof approveddrugs that are fully supported by publishedliterature. In petitioners views, no relianceon previous approvalsor previous findings of safety and effectiveness contemplatedunder section 505(b)(2) (I is orPharm petition s at 9-10; BIO petition at 17). PetitionerBIO notesthat court decisionsexaminingFDA paper NDA policy before the passage section505(b)(2)found that FDA could not approvean of application in which one manufacturerrelied on anotherproprietary information. BIO contends s that it is improbablethat Congresswould have changedthe law in this field without an explicit statementin the statute,or, at the very least,the legislative history (BIO petition at 17).
FDA Response: As explainedabove,petitionersselectivelyexcerpt from the legislative history. Although the House Report usesthe phrasepaper ZVDAto describea 505(b)(2) application,the

HouseReport definespaperNDA far more expansivelythan the then-existingpaper NDA policy. Specifically, the HouseReport definedpaperNDA as any application submittedunder section505(b) of the PDCA in which the investigationsrelied upon by the applicantto show safety and effectivenesswere not conductedby or for the applicantand the applicanthas not obtaineda right of referenceor use from the personwho conductedthe studiesor for whom the studieswere conducted (HouseReport at 32). This definition doesnot mention either literature or duplicates,just as the languageof section505(b)(2) doesnot mention either limitation. Thus, contrary to BIO contention,the statuteand the legislative history indicate a changefrom s existing policy by describinga 505(b)(2) application and defining a paper NDA, respectively, more broadly than the preexistingdefinition of a paperNDA.
C. Limitations on Section 505(b)(2) from Statute as a Whole

Petitioner Pfizer arguesthat, readingthe statuteas a whole, there are two important limitations on the subsetof approvalsthat constitutepermissiblechanges listed drugs under section to 505(b)(2). First, accordingto Pfizer, the opportunity to use section505(b)(2) to seekapproval for a changeto a listed drug is only availableat or after the time an ANDA for that listed drug s has been or could be approved. In Pfizer view, the Agency may not approveany 505(b)(2) application that relies on the finding of safety and effectiveness an approveddrug before a for SOS(j)application referencingthat drug has beenor could be approved(April 2003 commentat 13). Second,Pfizer suggests that, regardless the timing of approval,a 505(b)(2) application of cannot be usedfor a changeto a listed drug that could not be madethrough submissionof an ,, .- _ xI,-,,-~--~-I-, -----a-,
Parkman letter narrowly to sanction use of the 505(b)(2) pathway to approve only limited types of changes and then argues that only this limited use is a permissible statutory interpretation. Thus, in Pfizer view, changes that would s require submission of a separate application under PDA current bundling policy are not within section 505(b)(2) s s scope and FDA exceeds the authority granted under the statute when it uses section 505(b)(2) as a pathway for . approval of such changes.

22

Docket Nos. 2001P-0323/CPl& C5,2002P-0447/CPl, and 2003P-0408EPl ANDA followed by a supplementto that ANDA (April 2003 commentat 13). In this view, the Agency may only rely on the finding of safety or effectiveness a given drug if the change for proposedis one that could be madein a supplement an ANDA rather than requiring an to entirely separate application. In the limited circumstances where an applicantcan obtain approvalof an ANDA and file a supplement a changeto that ANDA, the applicantmay for collapsethe processand file a single applicationunder section505(b)(2) (April 2003 commentat 3).
FDA Response: There is no temporal languagein the statutelimiting 505(b)(2) approvalsto

thoseoccurring after an ANDA has beenapproved,nor is there any sequentiallanguagein the statutethat limits changesto thosethat could be approvedunder section505(j) followed by a supplement. As explainedabove,if a 505(b)(2) applicationcould only be approvedafter an ANDA referencingthe listed drug had beenapproved,or after all patent and exclusivity rights have expired, the independentpatentcertification obligations that attachunder section505(b)(2) (and the related opportunity to challengea listed patent with a paragraphIV certification and obtain approvalupon a finding of noninfringementor invalidity, or upon expiration of the 30month stay) would be superfluous. Similarly, if Congresshad wantedto imposeeither proposed limitation on 505(b)(2) approvals,it likely would haveplaced the relevant provision in section 505(j), rather than in section505(b) of the statute,or would have otherwisesignaledthat only this limited subsetof applicationscould be submittedand approvedunder section 505(b)(2). Instead,as discussed above,the plain languageof section505(b)(2) is broad, strongly suggesting that Congressintendedto createtwo different pathwaysfor approval,rather than to have section 505(b)(2) function simply as an offshoot of section505(j).
D. Differences Between Section 505(b)(2) and 505(j)

In support of their statutoryinterpretationargumentsthat section505(b)(2) only contemplates relianceon the finding of safety and effectiveness an approveddrug, if at all, in limited for circumstances, petitionerscite differencesbetweenprovisionsin section505(j) and 505(b)(2) and in references the two sectionsin other provisionsof the statute. Both Pfizer and to s TorPharm emphasize differencesbetweensection505(b)(2) and 505(j) to arguethat IDA the interpretationof section 505(b)(2) to allow relianceon the finding of safety or effectivenessof a listed drug is unreasonable.TorPharmarguesthat the languagein section505(j)(2)(A)(i) that requiresan ANDA to contain information to show the conditions of use prescribed, recommended, suggested the labeling have beenpreviously approvedfor a listed drug or in permits PDA to rely on a previousfinding of safety and effectivenessto approvea SOS(i) application. Becausesection505(b)(2) containsno comparableprovision, TorPharmarguesthat no such relianceis permitted in the 505(h)(2)context (TorPharmpetition at 13). Similarly, Pfizer notes that section505(i)(6) requiresapprovalof an ANDA to be withdrawn if the listed drug is withdrawn for safety or effectiveness reasons.Pfizer arguesthat section505(b)(2) does not contain an analogouswithdrawal provision because Congressnever intendedfor 505(b)(2) applicantsto rely in whole or part on the finding of safetyor effectivenessof a listed drug. Accordingly, a 505(b)(2) application would not be expectedto face withdrawal when a listed drug is withdrawn (2001 Pfizer petition at 8).

23

Docket Nos. 2OOlP-O323/CPl& C5,2002P-0447/CPl, and 2003P4408/CP1 F Response: As discussedabove,the differencesin section505(b)(2) and 505(j) (or in DA referencesto one or the other type of applicationin other parts of the statute)do not indicate that Congressprecludedsponsorsfrom relying on the finding of safety or effectivenessof an approveddrug in supportof a 505(b)(2) approval. These differencesmerely reflect that 505(b)(2) applications,unlike 505(j) applications,are not required to be duplicatesof listed drugs. For example,in responseto TorPharmargumentthat there is no 505(b)(2) analogueto s the provision in section505(i) requiring that the applicantseekapproval for the sameconditions ofuse as the listed drug, the differencereflects that 505(b)(2) applications,unlike ANDAs, may seek approval for different conditions of use than the listed drugs they reference. Thus, the 505(b)(2) applicationmay not need information on the sameconditions of use; however,l?DA may require that other appropriateinformation be submitted. The differencesnoted by petitionersdo not establishthat 505(b)(2) applicationsmay not rely on the finding of safety or effectivenessfor a listed drug. Similarly, the differencesin withdrawal provisionsnoted by Pfizer reflect the differencesin the two types of applications. BecauseANDAs are, by definition, for duplicatesor minor variations of a referencelisted drug and are,by definition, approvedwithout submissionof clinical or preclinical studiesto establishsafetyor effectiveness, they are statutorily presumedto have the samesafety and effectivenessprofile as the listed drug they reference. Thus, it is not surprising that an ANDA must be withdrawn when the listed drug it referencesis withdrawn for safety or effectivenessreasons(section505(j)(6)). In contrast,because drug describedin a 505(b)(2) the applicationcan differ significantly from the listed drug it references, withdrawal of the latter for safety or effectivenessreasonsdoesnot necessarilyrequire automaticwithdrawal of the former. Under thesecircumstances, is appropriateto approachwithdrawal of a 505(b)(2) application on it a case-by-case basis,even in the face of the withdrawal of the listed drug it references.
E. Section 505(l)

Pfizer contendsthat the disclosureprovision at section505(l)(5) establishesthatANDA approval (or the expiration of all patentson the listed drug) is a prerequisiteto approval of a 505(b)(2) application. Pfizer notes that section505(l)(5) provides that, absentextraordinarycircumstances, safety and effectivenessdata in an NDA are availablefor public disclosureat the time an ANDA has been,or could be approved. Basedon this provision, Pfizer contendsthat it is only after an ANDA has been,or could be, approvedthat the data in NDA are availablefor any purpose, including supportfor a 505(b)(2) approval. Pfizer thus arguesthat, to give meaningto section 505(l)(5), if no ANDA for a listed drug has been approved(because, example,the sponsorof for the listed drug has a patent on someaspectof the drug that has not been challengedby an ANDA applicant),then no 505(b)(2) applicationis eligible for approval (2001 Pfizer petition at 9). Pfizer arguesthat this interpretationof section SOS(l)(S) consistentwith the approval scheme is under sectionSOS(i) becausesectionSOS(i)authorizesrelianceon data in an innovator companyNDA once other patent and exclusivity rights have expiredto support approval of an s ANDA. Pfizer arguesthat it logically follows that an approval under sectionSOS(i) triggers PFtzeropines that there is no comparabledisclosure releaseof thosedata under section505(l). provision that triggers broader disclosureof data in the NTJA of a listed drug when a 505(b)(2) 24

Docket Nos. 2OOlP-O323/CPl Bz C5,2002P-0447/CPl, and 2003P-04081cPl application is approved because section 505(b)(2), itself, does not authorize reliance on the proprietary data in another company NDA to support a 505(b)(2) approval. Pfizer contends s that FDA interpretation of section SOS(b)(Z)- permitting reliance on the finding of safety and s effectiveness for an approved NDA before the raw data in the NDA are fully disclosable under section 505(l) - renders section 505(l) meaningless, upsets the settled expectations of NDA holders, and is inconsistent with Congress intent (2001 Pfizer petition at 9). s FDA Response: As noted, section 505(l)(5) is silent as to the effect of 505(b)(2) approval on disclosure of innovator data because applications approved under section 505(b)(2), in contrast to those approved under section 505(j), need not be duplicates. Given that a drug approved under section 505(b)(2) can differ significantly from the listed drug it references, an approval of a 505(b)(2) application does not-and logically cannot-give rise to the presumption that the data in the listed drug NDA cease to retain commercial value. s Moreover, Pfizer contention is not supported either by the language of section 505(l) or by its s place in the statutory scheme. Section 505(l) provides in relevant part: Safety and effectivenessdata and information which has been submitted in an application under [section SOS](b) a drug and which hasnot previously been disclosedto the for public shall be made availableto the public, upon request,unlessextraordinary circumstances shown . . . (5) upon the effective date of the approval of the first are application under [section 505](i) which refers to such drug or upon the date upon which the approval of an application under [section 505](i) which refers to such drug could be made effective if such an appiication had beensubmitted. This provision is exactly what it appears to be - a public disclosure provision stating the outer limits after which public disclosure of safety and effectiveness data must occur absent extraordinary circumstances. It does not provide that FDA may not rely on the finding of safety and effectiveness for an approved drug before this outer limit - in this case 505(j) approval is reached. Moreover, section 505(l) deals with public disclosure of raw safety and effectiveness data in an application, not with its use by the Agency to support approval of another application. The Agency need not disclose proprietary data for an applicant or FDA to rely on the fact that a particular drug with particular characteristics has been found safe and effective. In fact, FDA routinely approves ANDAs by relying on the safety and effectiveness of a listed drug without triggering fhll disclosure of raw data under section 505(l)(5). Pfizer premise that its reading of section 505(l) makes sense because A.NDAs cannot be s approved until all patents and exclusivities have expired is also faulty. Approval is possible under section 505(j) even when patent rights are still in force. If, for example, an ANDA applicant were to file a patent challenge, be sued within 45 days, and the patent litigation were ongoing, approval would be possible during the pendency of the litigation if the 30-month stay were to expire. Similarly, an ANDA is eligible for approval during the pendency of patent litigation over a listed patent if that litigation was not commenced within the 45day period that the statute provides. Furthermore, a patent on a dosage form that prevents approval of a

25

Docket Nos. ZOOlP-O323/CPl&CS, 2002P-0447/CPl,and 2003P-04OWYl duplicate under section 505(j) will not bar approvalof a petitioned ANDA for a different, noninfringing dosageform. In eachof thesecases,approvalunder section SOS(b)(Z) not correlatedwith expiration of the is innovator patentrights. Thus, Hatch-Waxmancontemplates someapplicationsreferencing s that a listed drug could be approvedwhile a patenton the listed drug is in force. Like 505(i) applicants,505(b)(2) applicantsare subjectto patentcertification requirementsand patent and exclusivity bars to approval. Theseare the requirementsthat protect the listed drug intellectual s property rights, and bar approvalsof competitorproducts,until certain conditions are met.
Section 505(l) cannotbear the weight that:Pfizer ascribes it. Under Pfizer interpretation, to s approvalof a 505(b)(2) application would be blocked before ANDA approval (or expiration of all patent and exclusivity rights) even if the 505(h)(2)applicant were to describea drug product that differs significantly from the listed drug, and the 505(b)(2) applicantwere to certify to the listed patentsas requiredby the statuteand succeed avoiding a lawsuit or in proving in noninfringement. To interpret section505(l) as placing this additional implicit barrier to 505(b)(2) approval,even after all of the patentand exclusivity bars to 505(b)(2) approvalthat are explicit in the statutehave expired, would unduly stretchthe languageand structureof the HatchWaxman Amendments. Section 505(l) is exactly what it appearsto be on its face - a statutory provision governing disclosureof raw safety astdeffectiveness in an NDA. It doesnot data createan additional barrier to 505(b)(2) approval. F. Pfizer Suitability Petition Argument s

PetitionersTorPharmand Pfizer eachraise distinct and incompatiblechallengesto FDA s interpretationof section505(b)(2)basedon the relationshipof section505(h)(2) to the suitability petition processdescribedin section505(j)(Z)(c). Pfizer arguesthat it would be illogical to use section 505(b)(2) as a pathway to approvechanges could not be approvedunder a suitability that petition because changesraise potential safetyor effectiveness the issuesthat require further exploration. Pfizer assertsthat the suitability petition processis a public processbecause Congressrecognizedthe importanceof changesthat can be approvedunder a petition and wantedto give the public the opportunity to weigh in beforeFDA could concludethat those changesare permitted without requiring a full standaloneNDA. Pfizer notesthat certain changes,such as a changeto a new salt of the approvedactive ingredient,is not a petitionable changebecause particular salt usedcan have relatively significant effects on the safety or the effectivenessof a new product. Pfizer contendsit would renderthe suitability petition process meaningless FDA were to require a public processfor relatively minor changesapprovable if through a petition, while allowing more significant changes,such as a changeto a new salt, to be made through the 505(b)(2) route without the benefit of any formai or public process(2002 Pfizer petition at 6-7).
FDA Response: FDA jnterpretationof sectionSOS(b)(Z) s doesnot undermineand render

meaningless suitability petition process. The suitability petition processdescribedin section the 505(i)(2)(C) specifically de&mines whether a particular changeto a listed drug is suitablefor approval under section SOS(i) without submissiun of any additional studiesoutside of section
26

Docket Nos. 2001P-0323/CPl& C5,2002P-0447KP1, and 2003P-0408KP1 505(j) scope. If FDA approvesa suitability petition, it has concludedthat the proposedANDA s fan be submitted and approvedunder section SOS(j) without further review of clinical or preclinical studies(other than bioavailability studies). However, becausea 505(b)(2) application is a type of MIA, under section 505(b)(l), FDA has the authority to requestany and all clinical and nonclinical studiesit deemsnecessary support approval. Given that the 505(b)(2) to pathway gives FDA the flexibility to specify the types and numbersof clinical and preclinical studiesnecessary supportapproval,no public processto determinesuitability for approval to without additional studiesis required. Similarly, no public processis requiredto determine suitability for approval of a standalone NDA submittedunder section 505(b)(l) because FDA has the opportunity to specify what studiesare required for approvaland to refuse to approveif those studiesdo not adequatelydemonstrate safety and effectiveness. FDA interpretationof section 505(b)(2) complements, s rather than supplants,the suitability petition process. For example,if a suitability petition for a new dosageform of a previously approvedproduct were deniedbecauseFDA believesbioequivalencealone is insufficient to support safety and effectiveness, section505(b)(2) provides a route for FDA to determinewhat additional studiesmay be required for approval.
G. TorPharm Suitability Petition Argument s

TorPharm arguesthat FDA interpretationof section505(b)(2) rendersthe suitability petition s processmeaningless entirely different reasons. TorPharmsuggeststhat becausea changeto a for new salt is a changein active ingredient, the suitability petition processestablishedin section 505(i)(2)(C) provides the proper abbreviatedpathway for approval of a new salt. According to TorPharm,interpreting section505(b)(2) to permit approvalof a new salt (or other changeto an active ingredient in a single ingredient product) rendersthe petition processsuperfluous (TorPharmpetition at 12). that FDA Response: Although TorPharm suggests a changeto a new salt should be reviewed, if at all, in an ANDA submittedthrough the petition process,FDA doesnot interpret the statuteto permit an applicantto changethe active ingredientin a single active ingredient product by this route. Section 505(j)(2)(C) describesin generalterms the submissionof a petition to changean active ingredient. However, section505Q)(2)(A)(ii)(I) statesthat if the listed drug referencedin an ANDA has only one active ingredient,the ANDA must contain information to show that the active ingredient of the new drug is the sameas that of the listed drug. It is only in the provision related to submissionof ANDAs referencinga listed drug with more than one active ingredientthat the ability to use the petitions processin section505(j)(Z)(C) for a changein an active ingredient is referenced(section505(j)(2)(A)(ii)(III)). The preambleto FDA proposed s s rule implementing the Hatch-WaxmanAmendmentscontainsa lengthy discussionof FDA interpretationof theseprovisions. (See54 PR 28872 at 28878 and 28879,28881, July 10, 1989.) FDA regulationsimplement the statuteby permitting the use of a suitability petition for s a changein active ingredient only where one active ingredient is substitutedfor one of the active ingredientsina listed combinationdrug (yj 314.93(b). Thus, a changeto a new salt is not a petitionable changeunlessit: is substitutedin a combinationproduct where the remaining ingredientsremain the same. Becausesection505(b)(2) is the only abbreviatedroute available
27

Docket Nos. 2OOlP-0323/CPl& C5,2002P-O447KPl, and 2003P-O408/CPl for approval of such a changein a single ingredientproduct, it is essentialrather than supeffluous.
II.

Exclusivity

TorPharm contendsthat use of the 505(b)(2) processto approvea drug product whose only changefrom the listed drug is the substitutionof a different salt of the approvedactive ingredient undercutsthe right to 180&y exclusivity under section505(i)f5)(B)(iv) awardedto the first ANDA applicant to challengea listed patent,because180-dayexclusivity doesnot block approvalof 505(b)(2) applications. TorPharmarguesthat Congressdid not intend that the 505(b)(2) approvalprocesscould be usedto obtain approvalof a bioequivalentdrug product when the 180&y exclusivity would block approvalof a 505(j) application for a duplicate (TorPharmpetition at 3). FDA Reap~nse: PDA interpretationof section505(b)(2) doesnot undercutthe 180-day s exclusivity incentive. The Ml-day exclusivity awardedto the first generic applicantto challenge a patent on a listed drug is not a monopoly that preventsFDA from approving any similar or potentially competingdrug product. The provision has beenconsistentlyinterpretedto prevent approval only of anotherapplication submittedunder sectionSOS(i) a pharmaceutical for equivalent that relies on the finding of safety and effectiveness the listed drug and includes a for paragraphIV certification to the listed patent. Put anotherway, 180&y exclusivity blocks approval of later-submittedANDAs for duplicate drug products. An AND A 18O-day s exclusivity would not block approvalof a standalone NDA for a duplicate of the listed drug. Nor would it block approvalof a pharmaceuticalalternative(such as a different dosageform) approvedunder a petitioned ANDA, even though theseproductsmight be marketplace competitorsto the ANDA with exclusivity. Thus, like thesetypesof appIications,a 505(b)(2) application for a bioequivalentand potentially competingdrug product can be approvedwithout undermining the 180&y exclusivity incentive in ways that Congressdid not intend. In fact, the limitation of 505(b)(2) approvalsto literature-based duplicatesthat petitioners BIO and TorPharm advocatewould undercut 180-&y exclusivity significantly more than the interpretationFDA has adopted. To ensurethat section505(b)(2) is not usedto circumvent 180day exclusivity, FDA regulationsprovide in two separate placesthat section505(b)(2) may not be used for duplicates. (See 83 3 14.54(b)and 314.101(d)(9).) If section 505(b)(2) were available for approval of duplicates,including literature-based duplicates,applicantscould circumvent 18Oday exclusivity by filing for the approvalof a duplicate under section 505(b)(2); such an application, even if a true duplicate,would not be blocked from approval under the HOday exclusivity provisions in section505@(5)(b)(iv). I. Section 314.54 and the 1999 Draft Guidance

Petitioner BIO arguesthat the 1999 draft guidanceimproperly creatednew law. BIO argueson Administrative ProcedureAct groundsthat FDA can only adopt a broad interpretationof section 505(b)(2) (such as that spelled out in the 1999draft guidance),if at all, through notice-andcomment rulemaking. BIO arguesthat FDA regulationsat 0 314.54 do not adequatelyadvise 28

Docket Nos. 2OOlP-O323/CPl& CS, 2002P-0447KP1,and 2003P-O408/CPl industry that FDA would interpret section505(b)(2) to permit SOS(b)(Z) applicantsto rely on the finding of safety and effectivenessfor an approvedapplication. Specifically, BIO suggeststhat the broad languageof 0 314.54,coupled with the 1989 preamblestatementthat section 505(b)(2) permits FDA to approvean applicationthat relies on investigationswhich the applicanthas not conducted,sponsored, obtaineda right of referenceto, regardlessof the similarity or or dissimilarity of the drug product to an alreadyapproveddrug product,did not adequatelysignal to industry that FDA intendedto interpret section505(b)(2) to extendbeyond the paperNDA policy as well as the narrow principle that 505(b)(2) applicationscan be usedto approve modifications to a listed drug that could otherwisebe made through submissionof an ANDA followed by a supplement. Given this allegedambiguity in the regulations,BIO arguesthat the 1999 draft guidancecreatednew law when it madeexplicit the usesto which section505(b)(2) had been and could be put. BIG further arguesthat because madenew law, the 1999 draft it guidanceshould have been promulgatedas a regulation and subjectedto notice and comment before implementation. In supportof its argumentsthat tbe regulationsat 0 314.54 did not inform industry of PDA broad interpretationof section505(b)(2),BXOnotesthat FDA received s only two commentsafter publication of the proposedregulations,neither of which addressed issuesas to the provision scope(BIO petition at 26-39). s
FDA Response: As discussed above,the 1999 draft guidanceis not the first time FDA

announcedits intention to interpret section505(b)(2) broadly to extend beyond the paperNDA policy. FDA announcedits interpretationof section505(b)(2) in the 1987 Parkmanletter and the 1989 proposedand 1992final regulations.Although BIO arguesthat the scopeof $314.54 is unclear and that industry did not understand section505(b)(2) would be usedin ways that that extend beyond literature-based duplicates,industry extensiveuse of this provision over time s (including use by membersof BIO and by Pfizer) belies BIO assertion. Moreover, the s implementing regulationsat 5 314.54 and their preamblemake clear that FDA has long interpretedsection 505(b)(2) to permit approvalof NDAs that rely on the finding of safety or effectivenessof an approveddrug to the extent such relianceis scientifically justified. As discussedabove,the regulationsprovide that, where an application seeksapproval under section 505(b)(2) of a drug product that represents modification of a listed drug, . . . the application a need contain only that information neededto supportthe modification(s) of the listed drug (0 314.54). Indeed,FDA preambleto the 1989 proposedrule explicitly revokesthe paperNDA s policy and statesthat section 505(b)(2) has broaderapplicability [than the paper NDA policy] (54 FR 28872 at 28875, July 10,1989). FDA explainedin the 1989 preamblethat FDA intendedto use section505(b)(2) to approvemodifications to listed chugsif they were adequately supportedby appropriatedata. FDA further statedin the preamblethat applicationsfor literature-based duplicates(which would previously have beenapprovedunder paper NDAs) should be approvedunder section505(j), not section505(b)(Z)(54 FR 28890). Thus, FDA has never relied on the 1999 draft guidanceas law; the guidancemerely seeksto make explicit and transparentthe ways in which FDA has interpretedthe law set out in the statuteand regulation. The public had the opportunity to commenton the proposedregulationswhen they were issued and declinedto do so; BIO cannot reasonablyarguethat additional public processis required before this regulation is implemented.

29

Docket Nos. ZOOlP-O323/CPl&CS, 2002P-0447EP1,and 2003P-0408KPl

J.

Section 314.54(a)(l)(i)

TorPharmcites FDA regulation at 0 31454(a)(l)(i) in supportof its argumentthat section s 505(b)(2) doesnot automaticallyauthorizean applicantto rely on proprietary data from another applicant MDA. TorPhatnt notesthat 8 3 14.54(a){ statesthat 505(b)(2) applicationsmust s l)(i) comply with 5 314.50(g). Because0 314.50(g)statesthat a referenceto information submitted by a personother than the applicantmust contain a written and signedstatementof authorization by the submitter,TorPharmarguesthat an applicant submitting an application under section 505(b)(2)cannot referencea listed drug application(or the finding of safety and effectiveness s for a listed drug) without permissionof the NDA holder (TorPharmpetition at 9). F Response:TorPharm reliance on the languagein $314.54 referencing0 314,50(g)is DA s misplaced. Under 6 314.50(g),[a] referenceto information submittedto the agencyby a person other than the applicantis requiredto contain a written statementthat authorizesthe reference and that is signedby the personwho submittedthe information. This provision was not intendedto refer to situationswhere a sponsoridentified a listed drug and soughtto rely on IDA finding of safety or effectiveness the listed drug. If the applicantwere required to and s of succeeded obtaining a right of referenceto the applicationon which it relied to support in approval,the application would be a standaloneNDA, not a SOS(b)(Z) application. Thus, TorPharmreading of this provision would write section505(h)(2) out of existence. Instead,the s regulation is intendedto addressthe circumstancewhere certain information about the proposed drug that is neededfor PDA to review and approvethe specific 505(b)(2) application (e.g., information about the chemistry of the bulk drug substance the applicantplans to use in that manufacturingits drug product) is containedin a place separate from the application (e.g., in a drug masterfile owned by the supplier of the bulk drug substance).In this case,for FDA to considerthis information in approvingthe application,a right of referenceto that external source is required. In other circumstances, when one applicanthas receivedpermissionfrom the sponsorof anotherapplicationfor FDA to rely on information (including the raw data) in the applicant NDA, the regulationdescribesthat such a right of referencemust be in writing and s signed. (Seefootnote 12.) As noted above,if such a right of referenceis given, the application is a stand alone NDA and none of the patentcertification requirementsor exclusivity bars will apply.

PetitionersPfizer and BIO suggestthat the statutorylanguage,legislative history, and implementingregulationsgave them a reasonable investment-backed expectationthat data in an approvedNDA would not be usedto supportapprovalof a 505(b)(2) application for a change that could not be made through an ANDA and supplemented (and would not be usedfor any purposebefore an ANDA had beenor could be approved). Petitionerscontendthat nothing in the 1987 Parkmanletter or in the regulationsimplementingsection505(h)(2) signaledthat FDA would permit 505(h)(2) applicantsto rely on a pioneerNDA data before an ANDA approvalor s to approvemodifications that could not be approvedin an ANDA followed by a supplement. Petitionersclaim that FDA suggestionin the 1999 draft guidancethat section505(b)(2) is an s appropriateapprovalroute for a new salt or for a follow-on to a biological product submitted 30

Docket Nos. 200 lP-O323/CPl& C5,2002P-0447/CP and 2003P-04OWCPl 1, under section505(b)(l) was a radical departurefrom past practiceand was directly contrary to the industry understanding section505(b)(2) and congressional s of intent when enactingthat provision. Accordingly, petitionerscontendthat the policy announced FDA 1999 draft in s guidance(and FDA approvalof a new salt of paroxetineunder section505(b)(2)) amountsto an s unconstitutionaltaking of petitioners property without adequate compensation(BIO petition at 37; 2001 Pfizer petition at 17). three significant factors as a guide to FDA Response: The SupremeCourt has established determiningwhether a taking has occurred:(1) the characterof the Governmentaction; (2) the extent to which it has interferedwith reasonable investment-backed expectations;and (3) its economicimpact (Concrete Pipe and Prods. of Cal& Inc. v. Con&r. Laborers Pension Trust, 508 U.S. 602,64346 (1993)). With regardto the secondfactor, to be reasonable, expectations must take into accountthe power of the stateto regulatein the public interest (Pace Resources, Inc. v. Shrewsbury Township, 808 F.2d 1023, 1033 (3d Cir.), cert. dknied, 482 U.S. 906 (1987)). Reasonable expectationsmust also take into accountthe regulatory environment,including the foreseeabilityof changesin the regulatory scheme. In an industry that long has beenthe focus of great public concernand significant governmentregulation(Ruckelshaus Monsanto Co., v. 467 U.S. 986,1008 (1984)), the possibility is substantialthat there will be modifications of the regulatory requirements. Those who do businessin the regulatedfield cannot object if the legislative schemeis buttressed subsequent by amendments achievethe legislative end to (Connolly v. Pension Benefit Guar. Corp., 475 U.S. 211,227 (1986) (citation omitted); Branch v. United Sta&es,69 F.3d 1571, 1579 (&A. Cir. 1995) (same),cert. denied, 519 U.S. 810 (1996); cf: Lucas v. South Carolina Coastal Council, 505 U.S. 1003,1027-28(1992) ([I& the caseof personalproperty, by reasonof the Statetraditionally high degreeof control over commercial s dealings,[the property owner] ought to be awareof the possibility that new regulation might even render his property economicallyworthless. . . .I Participantsin a highly regulated )). industry are on notice that [they] might be subjectedto different regulatory burdensover time (California Housing Sets., Inc. v. United States, 959 F.2d 955,959 (Fed. Cir. 1992),cert. denied, 506 U.S. 916 (1992)). Petitionersshould have been well awarethat the Agency would permit a 505(b)(2) applicantto rely on the finding of safety and effectiveness an approvedNDA, basednot only on the broad for statutory languagefirst enactedin 1984,but also on the Agency subsequent s publicly announced interpretationand applicationof section505(b)(2). FDA written pronouncements the s on statutescopeembodied,among other places,in proposedand final regulationshave further s any provided public notice of that broad scope. Consequently, purportedexpectationthat the Agency would not permit a 505(b)(2) applicantto rely on the finding of safety and effectiveness for an approvedNDA is unreasonable cannotprovide the basisfor a takings claim. and
L. New Salts

Pfizer contendsthat new salts are traditionally and statutorily beyond the reach of section 505(b)(2). Pfizer relies largely on the 1987Parkmanletter to arguethat the 1999 draft guidance went further than ever before in stating that new salts may be appropriatefor approval under section505(b)(2). Pfizer assertsthat the 1987 Parkmanletter, which discussedsection505(b)(2)
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Docket Nos. ZOOlP-0323/CPl& C5,2002P-0447/CPl, and 2003P-O408/CPl as a way to shortcutthe ANDA approvaland supplementation process,represents outer limits the of 505(b)(2) approvals.Given that a drug product containing a new salt cannot be approved through an ANDA and supplement(because ANDA is required to have the sameactive an inment as the listed drug and, under FDA bundling pohcy, a changeto a different active s ingredientrequiresa separate application),Pfizer arguesthat the 505(b)(2) route is also unavailablefor such a change(April 2003 commentat 14).
FDA Response: Pfizer argumentlacks supportin the statute,reguiations,or FDA history of s s

implementation. Although Pf?zeris correct that the 1987Parkmanletter discussed specific the inefficiency associated with requiring an applicantto obtain approvalfor an ANDA before seekinga changeto a listed drug, and changesto an active ingredient are not changespermitted in a supplementto an ANDA, the 198Parkmanletter specifically mentionedsection505(b)(2) 7 as an approvalroute for changesin active ingredients. When read in its entirety, the 1987 Parkmanletter standsmore generallyfor the propositionthat an applicantseekingany changeto a listed drug can rely on the listed drug approvalto establishthe safety and effectivenessof the s listed drug and need only provide data to supportthoseaspects the proposeddrug that differ of from the listed drug. The policy expressed that letter - to eliminate unnecessary in and potentially unethical duplication of research- appliesequally to changesthat can be approved through an ANDA and a postapprovalsupplement, well as to thosechanges(such as changes as to new salts) that have generallybeenconsideredto fall outsideof the type of changesthat may be approvedin a supplement. In addition, in section735(1)@)(i) of the statute,as part of the statutoryprovisions regarding userfees adoptedin the PrescriptionDrug User Fee Act enactedin 1992,Congressexplicitly included as examplesof the type of applicationsthat could be approvedunder section505(b)(2), applicationsfor new active ingredients. Section735(l)(B)(i) states term human drug the application meansan applicationfor . . . approvalof a new drug submittedunder section 505(b)(2) after September30,1992, which requestsapprovalof a molecularentity which is an active ingredient (including any salt or esterof an active ingredient).. . that had not been approvedunder an applicationsubmittedunder section505(b). la
Therapeutic Equivalence

Pfizer contendsthat FDA may not assignan A therapeuticequivalencecode rating to a drug product that - because differs in salt - is a pharmaceutical it alternativeto, not a therapeutic equivalentof, the referencelisted drug (2001 Pfizer petition at 25).
FDA Response: FDA agrees. Becauseit containsa different salt, Synthonparoxetine s

mesylateproduct will not be A rated with respectto either GlaxoSmithIUinePaxil s (paroxetinehydrochloride)or to any paroxetinehydrochlorideproduct that is rated to Paxil. A including TorPharmparoxetinehydrochlorideproduct. s Where there is more than one approvedapplicationfor a particular active ingredient and a particular dosageform, FDA providestherapeuticequivalenceevaluationsin the OrangeBook, Single sourceproductsdo not receivea therapeuticequivalencecode. To obtain an A
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Docket Nos. 2001P-0323/CPl& C5,2002P-0447KP1, and 2003P-0408/CP1 therapeuticequivalencerating from FDA, a sponsormust show that its drug is pharmaceutically equivalent and bioequivalentto a listed drug and that it is expectedto have the sameclinical safety and effectivenessprofile when administeredunder the conditionsof use describedin the labeling (OrangeBook at viii). FDA has defined pharmaceuticallyequivalentdrug productsas drug productsthat contain the sameamount of the sameactive ingredient (i.e., the samesalt or esterof the sametherapeutic moiety) in identical dosageform, but not necessarilycontainingthe sameinactive ingredients, and that meet the compendialstandards identity, strength,quality, purity, and potency, and for where applicable,content uniformity, disintegrationtimes, and/or dissolution rates. Drug productsdenotedas pharmaceutical equivalentsmust be adequatelylabeled and manufactured under current good manufacturingpractice. Different salts of the sameactive moiety are considereddifferent active ingredients,so that drug productscontaining different salts are not pharmaceuticalequivalents. (See44 FR 2932 at 2937 and 2938, January12,1979;5 320.1(c).) Drug productsare consideredto be pharmaceutical alternativesif they contain the same therapeuticmoiety (or its precursor)but not necessarilyin the sameamount or dosageform or as the samesalt or ester where eachdrug product individually meetseither the sameor its own respectivecompendialor other applicablestandardof identity, strength,quality, purity, and potency, and, where applicable,contentuniformity, disintegrationtimes, and/or dissolution rates. (See44 FR 2932 at 2938; 9 320.1(d).) Pharmaceutical alternativesare not consideredto be therapeuticequivalentseven where they have demonstrated bioequivalence(44 FR 2938). BecausePaxil and TorPharmproductsboth contain the hydrochloridesalt of pamxetine and are s bioequivalent,they are consideredpharmaceutical equivalentsand therapeuticequivalents. product containsthe mesylatesalt of paroxetine,it is considereda However, becauseSynthon s pharmaceuticalalternative,not a pharmaceutical equivalent,to Paxil. As such, Synthon s product is not eligible to obtain an A therapeuticequivalencerating to Paxil or to the products to which Paxil is A rated.
N. Marketplace Confusion and Incentives for Development

Both Pfizer and TorPharmraise challengesto the 505(b)(2) policy in the context of approvalof drug productsthat differ from the innovator product only in active ingredient. Such approvals also raise concernsabout inappropriatemarketplacesubstitutionof theseproductsfor the innovator drug when the drugs have not been rated as therapeuticallyequivalentby FDA. TorPharm is also concernedthat approvalof Synthonparoxetineproduct will underminethe s 18O-daygenericdrug exclusivity TorPharmhas earnedpursuantto section 5O(j)(S)(B)(iv)by virtue of having beenone of the first applicantsto challengepatentslisted for Paxil (TorPharm petition at 5). Finally, this type of applicationraisesquestionsabout whetherpermitting approval of pharmaceuticalalternativesbefore therapeuticallyequivalentdrugs are approvedby FDA will discourageinvestmentin innovative new drug products.
FDA Response: The application of section505(b)(2) to productsthat differ from the innovator

product only in the active ingredient has been very limited. FDA believesthat its decisionsto

Docket Nos. 2OOlP-0323/CPl& C5,2002P-0447/CPl, and 2003P-04081CPl date on theseapplicationshave beenjustified by the languageof the statute,the legislative history, and the purposesof the Hatch-WaxmanAmendments. However, the Agency may wish to considerfurther whether theseis somenarrow subsetof applicationsthat should be exempted from the scopeof section505(b)(2) in the future. FDA is particularly interestedin examining the use of 505(b)(2) applicationsto obtain approval of drug productsfor which the only difference from the listed drug is in the form of the active ingredient, such as a changein salt. Theseare productsthat have the samedosageform, route of administration,strength,conditions of use, and labeling as the listed drug. The only reasonthese productsmay not be reviewed and approvedin ANDAs submittedunder section 505(j) is that they contain a different active ingredient from the listed drug. This use of section505(b)(2) doesnot result in the approvalof an innovative drug product that offers a new therapeuticbenefit or alternative,such as a new indication, novel dosageform, or improving administrationfor a new patient population. Nor do such changesin the active ingredient generallyrepresentan improvementin terms of safety or effectiveness. PDA is concernedthat, in addition to not representing innovative drug development,this use of 505(b)(2) applicationsmay have undesirablepolicy and public health consequences: 1. It may underminecurrent incentivesfor developmentof promising new active moieties that Congressincluded in the Hatch-WaxmanAmendments. 2. It may lead to proliferation of pharmace utical alternativedrug products,with resulting confusion in the marketplace. 3. It may divert resources, otherwiseavailablefor innovative drug research,to the developmentand patentingof alternativeactive ingredients,where such patentsare used solely either to establisha barrier to competition or to preemptthe holder of the listed drug from establishingsuch a barrier. Accordingly, FDA is reserving for further review the issuesraisedby this narrow use of section 505(b)(2), and is consideringwhetherto begin a public processto seekinput from interested parties,including the pharmaceuticaland health care industries,as well as consumergroups. V. CONCLUSION

FDA consistentand long-standinginterpretationis that section505(b)(2) permits an applicant s to rely on literature and/or the Agency finding of safety and effectiveness support approval s to of a new drug product. l?DA approachis consistentwith the text of section 505(b)(2) and the s structureof the statute,as well as with the policy balancestruck in Hatch-Waxmanbetween protecting innovator pharmaceutical investmentand promptly approving ANDAs and 505(b)(2) applicationsonce thoseprotectionsare no longer barriers. The 1987Pa&man letter, the regulatory preambles,and l?DA regulation at (3314.54 describedthe types of changesto s approveddrug productsfor which approval may be soughtunder section505(b)(2). In addition, 34

Docket Nos. 2OOlP-0323/CPl& C5,2002P-0447/CPl, and 2003P4408/CP1 in 1999, PDA published its draft guidance, which consolidated and made public detailed information on the types of applications that had been or could be reviewed under section 505(b)(2). As demonstrated by the number and variety of 505(b)(2) approvals over the 19 years since the Hatch-Waxman Amendments were passed, the pharmaceutical industry has been well aware of the scope of section 505(b)(2). Moreover, as is clear from the partial list of drug products approved under section 505(b)(2) included in this petition, the Agency scientific s considerations, the policy implications for the current and future use ofsection 505(b)(2), and there are substantial public health benefits to the Agency approach, as it allows for leveraging s past research and targeting new research investment on innovative drug products, while at the same time protecting innovator patent rights and marketing exclusivity. Sincerely yours, 6 Janet Woodcock, M.D. Director Center for Drug Evaluation and Research

il c-Enclosure:

April 10,1987, letter from Dr. Paul D. Parkman, then Acting Director, Center for Drugs and Biologics, to NDA and ANDA holders and applicants.

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