`SEPTEMBER 19TH, 2019
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`Listen to our Audio Podcast
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`Abbreviated Approval Pathways for Drug Products:
`505(b)(2) or ANDA?
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`Determining the right abbreviated approval pathway for submitting a drug
`product application to FDA requires an understanding of the options available
`and what types of data are permitted to support a selection.
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`The Drug Price Competition and Patent Term Restoration Act of 1984 (also known
`as the Hatch-Waxman Amendments) added sections 505(b)(2) and 505(j) to the
`Federal Food, Drug, and Cosmetic Act (FD&C Act), establishing abbreviated routes
`for obtaining approval for new drug applications (NDAs) and abbreviated new
`drug applications (ANDAs). FDA’s final guidance for industry “Determining
`Whether to Submit an ANDA or 505(b)(2) Application” assists prospective
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`applicants and provides direction in determining which one of these pathways is
`more appropriate.
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` A
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` 505(b)(2) application is an NDA that contains full reports of investigations of
`safety and effectiveness, 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 or use, including, for example,
`the Agency’s finding of safety and/or effectiveness for a listed drug or published
`literature. NDAs requiring full 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 or use, known as “stand-alone” NDAs, are submitted under section
`505(b)(1) of the FD&C Act.
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`An ANDA is an application submitted and approved under section 505(j) of the
`FD&C Act for a drug product that is a duplicate of a previously approved drug
`product. It relies on FDA’s finding that the previously approved drug product (the
`reference listed drug or RLD), is safe and effective, and may not be submitted if
`clinical investigations are necessary to establish the safety and effectiveness of
`the proposed drug product. An ANDA generally must contain information to show
`that the proposed generic product is the same as the RLD with respect to the
`active ingredient(s), conditions of use, route of administration, dosage form,
`strength, and labeling (with certain permissible differences) and is bioequivalent
`to the RLD.
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`Featuring Elizabeth Friedman, JD, LLM
`Regulatory Counsel, Office of Generic
`Drugs
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`Resources:
`1. Determining Whether to Submit
`an ANDA or 505(b)(2) Application
`– Guidance for Industry
`2. 2019 Generic Drug Forum
`Conference Presentation:
`505(b)(2) NDA or ANDA?
`3. Drug Competition Action Plan
`
`Upcoming Events:
`1. REdI and CERSI Workshop:
`Current State and Future
`Expectations of Translational
`Modeling Strategies to Support
`Drug Product Development,
`Manufacturing Changes and
`Controls – Sept. 23-25 - College
`Park, MD
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`2. REdI: 2019 Complex Generic
`Drug Product Workshop – Sept.
`25-26 – College Park, MD
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`3. REdI: Pharmaceutical Quality
`Symposium – October 16-17 -
`College Park, MD
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`AQUESTIVE EXHIBIT 1147 Page 0001
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`PAGE 2
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`Considerations for submission of ANDAs and 505(b)(2) applications include the following situations:
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`Drug product is a duplicate of the RLD: FDA generally will refuse to file a 505(b)(2) application for a drug that is a duplicate
`of an already listed drug and eligible for approval as an ANDA.
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`Drug product differs from the RLD: An applicant may submit a suitability petition to FDA requesting permission to submit an
`ANDA for a generic drug product that differs from an RLD in its route of administration, dosage form, or strength or that has
`one different active ingredient in a fixed-combination drug product (see 21 CFR 314.93).
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`Multiple drug products contain the same active ingredient(s): An applicant may seek approval for multiple drug products
`containing the same active ingredient(s) when some of these products would qualify for approval under the section 505(j)
`pathway and some would qualify for approval under the 505(b)(2) pathway. In this case, the applicant may bundle these
`drug products by submitting a single 505(b)(2) application. For example, an applicant seeking approval for multiple
`strengths of a product, only some of which are included in the Orange Book as listed drugs, may submit one 505(b)(2)
`application for all of the proposed strengths.
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`The types of studies, data and Information that may be necessary to support the approval of drugs proposed in ANDAs
`compared to 505(b)(2) applications may differ. For example, 505(b)(2) applications may include clinical investigations to
`establish the safety and/or effectiveness of a product. Generally, ANDA applicants have significant flexibility in the types of
`studies, data, and information they may submit in an ANDA to support the requirements for ANDA approval, so long as
`clinical investigations are not submitted to establish the safety or effectiveness of a product. The precise scope and type of
`information necessary for approval will vary and may be the subject of discussion between the applicant and FDA during the
`drug development process.
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`Active ingredient sameness is evaluated to demonstrate that the proposed generic drug product is the same as the RLD with
`respect to active ingredient(s). As scientific understanding and technology evolve, FDA may be able to receive, review, and
`approve ANDAs where it previously lacked the scientific basis to do so.
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`Intentional differences between the proposed drug product and the RLD, such as differences in formulation, bioequivalence
`and/or bioavailability, and conditions of use should be considered.
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`• Formulation: An ANDA generally may differ from the RLD in inactive ingredients. However, the ANDA must include
`information regarding the identity and quantity of all active and inactive ingredients of the proposed drug product. It
`must also include a characterization of any permitted differences between the formulations of the proposed drug
`product and the RLD, along with a justification demonstrating that the safety and effectiveness of the proposed drug
`product is not adversely affected by these differences. If the proposed drug product contains changes to its
`formulation that are not permissible in an ANDA, the applicant should consider submitting a 505(b)(2) application.
`For example, a proposed drug product that contains an excipient that requires clinical investigations to establish
`safety of the excipient would not be permitted in an ANDA but may be submitted in a 505(b)(2) application.
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`• Bioequivalence/bioavailability: An ANDA must contain information to show that its rate and extent of absorption
`does not show a significant difference from that of the RLD. If there is an intentional difference in rate (such as in
`certain extended-release dosage forms), certain pharmaceutical equivalents or alternatives may be considered
`bioequivalent if there is no significant difference in the extent of absorption. A 505(b)(2) application may be
`submitted if the rate and/or extent of absorption exceed, or are different from the ANDA standards, and may
`require studies to show safety and efficacy. However, FDA a 505(b)(2) application is generally not appropriate for a
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`AQUESTIVE EXHIBIT 1147 Page 0002
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`PAGE 3
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`drug product that should have been submitted under the ANDA pathway, but would have failed to meet the 505(j)
`standards. For example, a 505(b)(2) application may not be appropriate if the proposed drug product is a duplicate
`of a listed drug but is unintentionally less bioavailable and fails to demonstrate bioequivalence to the listed drug.
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`• Conditions of Use: An ANDA must include a statement that the conditions of use in the labeling for the proposed
`drug product have been previously approved for the RLD. If the proposed labeling reflects different conditions of use
`than the RLD labeling, such as a new indication, the application could not be approved as an ANDA. However, the
`ANDA labeling may exclude (or “carve out”) conditions of use approved for the RLD that may be omitted from the
`proposed ANDA labeling because of patents or exclusivity.
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`Clearly, some differences are permitted between an RLD and a proposed product in an ANDA. For example, certain
`differences in labeling between generic drug products and RLDs, such as differences in expiration date, formulation,
`bioavailability, or pharmacokinetics, labeling revisions made to comply with current FDA labeling guidelines or other
`guidance, or omission of an indication or other aspect of labeling protected by patent or accorded exclusivity, may be
`allowed. However, products that differ considerably from the RLD or require submission of data that could be considered
`beyond the scope of studies that can be reviewed in an ANDA are generally not candidates for approval under the 505(j)
`pathway.
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`Requesting assistance from FDA: FDA encourages prospective applicants with questions about whether their proposed drug
`product is appropriate for submission in an ANDA to contact the Office of Generic Drugs before submission. Controlled
`correspondence should be used if the applicant has a specific question about the generic drug development process. A pre-
`ANDA meeting is appropriate when a prospective applicant would like to discuss with the Agency a particular matter that
`would fall outside the scope of controlled correspondence. Questions about submission of an application through the
`505(b)(2) pathway should be directed to the appropriate Office of New Drugs review division.
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`The guidance was published as part of the agency’s Drug Competition Action Plan, and to assist in clarifying the ANDA
`submission process, provide assistance to potential applicants, and ultimately expand access for patients to lower cost, while
`providing high quality medicine. In addition to the guidance for industry “Determining Whether to Submit an ANDA or
`505(b)(2) Application,” learn more about this topic in our 2019 Generic Drug Forum Conference presentation.
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`Cheers,
`Renu Lal, Pharm.D.
`CDER Small Business and Industry Assistance
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`Issues of this newsletter are archived at http://www.fda.gov/cdersbiachronicles
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`This communication is consistent with 21CFR10.85(k) and constitutes an informal communication that represents our best
`judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of the FDA,
`and does not bind or otherwise obligate or commit the agency to the views expressed.
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`AQUESTIVE EXHIBIT 1147 Page 0003
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