Labeling for Biosimilar Products Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2018 Labeling Labeling for Biosimilar Products Guidance for Industry Additional copies are available from: Office of Communications Division of Drug Information, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: druginfo@fda.hhs.gov https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or Office of Communication, Outreach and Development Center for Biologics Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Bldg. 71, Room 3128 Silver Spring, MD 20993-0002 Phone: 800-835-4709 or 240-402-8010 Email: ocod@fda.hhs.gov https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2018 Labeling Contains Nonbinding Recommendations TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND ............................................................................................................... 1 III. GENERAL PRINCIPLES FOR DRAFT LABELING OF PROPOSED BIOSIMILAR PRODUCTS (BIOSIMILAR PRODUCT LABELING) ................................. 3 IV. SPECIFIC RECOMMENDATIONS ON CONTENT OF BIOSIMILAR PRODUCT LABELING ................................................................................................................................... 5 A. Approaches to Product Identification .......................................................................................... 5 B. Approaches to Content Presentation............................................................................................ 7 C. Approaches to Specific Sections of Biosimilar Product Labeling .............................................. 8 V. FDA-APPROVED PATIENT LABELING .................................................................. 10 VI. REVISING BIOSIMILAR PRODUCT LABELING .................................................. 10 A. Updating Safety Information ...................................................................................................... 10 B. Additional Conditions of Use ...................................................................................................... 11 VII. HOW TO SUBMIT INITIAL AND REVISED LABELING ..................................... 11 VIII. INTERCHANGEABLE PRODUCTS .......................................................................... 12 Contains Nonbinding Recommendations Labeling for Biosimilar Products Guidance for Industry1 This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page. I. INTRODUCTION This guidance is intended to help applicants develop draft labeling for proposed biosimilar products for submission in an application under section 351(k) of the Public Health Service Act (PHS Act) (42 U.S.C. 262(k)). The recommendations for prescription drug labeling in this guidance pertain only to the prescribing information (commonly referred to as the package insert), except for certain recommendations in section V pertaining to FDA-approved patient labeling (e.g., Patient Information, Medication Guide, and Instructions for Use).2 This guidance does not provide specific labeling recommendations for interchangeable products (see section VIII of this guidance). In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. II. BACKGROUND The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was enacted as part of the Patient Protection and Affordable Care Act (Affordable Care Act) (Public Law 111-148) on March 23, 2010. The BPCI Act amends the PHS Act and other statutes to create an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an 1 This guidance has been prepared by the Office of New Drugs, Therapeutic Biologics and Biosimilars Staff, in the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. 2 Unless otherwise specified, the terms biosimilar product labeling and labeling as used in this guidance address only the prescribing information as described in 21 CFR 201.56 and 201.57. 1 Contains Nonbinding Recommendations FDA-licensed reference product3 (see sections 7001 through 7003 of the Affordable Care Act). Section 351(k) of the PHS Act, added by the BPCI Act, sets forth the requirements for an application for a proposed biosimilar product and an application or a supplement for a proposed interchangeable product. Section 351(i) of the PHS Act defines biosimilarity to mean “that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.” To meet the standard for interchangeability, an applicant must provide sufficient information to demonstrate biosimilarity and also to demonstrate that the biological product can be expected to produce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch (see section 351(k)(4) of the PHS Act). Interchangeable products may be substituted for the reference product without the intervention of the prescribing health care provider (see section 351(i)(3) of the PHS Act). An application submitted under section 351(k) of the PHS Act must contain, among other things, information demonstrating that the biological product is biosimilar to a reference product based upon data derived from: • Analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; • Animal studies (including the assessment of toxicity); and • A clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product. Under the PHS Act, FDA has the discretion to determine that an element described above is unnecessary in a 351(k) application. Under FDA regulations, prescription drug labeling must provide adequate information to enable health care providers to “use the drug safely and for the purposes for which it is intended”; and to this end, the approved prescribing information summarizes the essential scientific information 3 Reference product means the single biological product licensed under section 351(a) of the PHS Act against which a biological product is evaluated in a 351(k) application (section 351(i)(4) of the PHS Act). 2 Contains Nonbinding Recommendations needed by health care providers for the safe and effective use of a drug.4 Prescription drug labeling reflects FDA’s finding of safety and effectiveness5,6 for the drug under the labeled conditions of use and facilitates prescribing decisions, thereby enabling the safe and effective use of drugs, including biological products, and reducing the likelihood of medication errors. III. GENERAL PRINCIPLES FOR DRAFT LABELING OF PROPOSED BIOSIMILAR PRODUCTS (BIOSIMILAR PRODUCT LABELING) The goal of a biosimilar product development program is to demonstrate biosimilarity between the proposed product and the reference product — not to independently establish safety and effectiveness of the proposed product. A demonstration of biosimilarity means, among other things, that FDA has determined that there are no clinically meaningful differences between the proposed product and the reference product in terms of safety, purity, and potency.7 Thus, FDA’s finding of safety and effectiveness for the reference product, as reflected in its FDA- approved prescribing information, may be relied upon to provide health care providers with the essential scientific information needed to facilitate prescribing decisions for the proposed biosimilar product’s labeled conditions of use (e.g., indication(s), dosing regimen(s)). Accordingly, FDA recommends that biosimilar product labeling incorporate relevant data and information from the reference product labeling, with appropriate modifications, such as those described in sections V and VI of this guidance.8 Information and data from a clinical study of a proposed biosimilar product should be described in its labeling only when necessary to inform safe and effective use by a health care provider. As a general matter, it is FDA’s view that biosimilar product labeling should not include a description of or data from clinical studies conducted to support a demonstration of biosimilarity.9 Generally, clinical studies conducted to support a demonstration of biosimilarity 4 See 21 CFR 201.100 and 201.56(a)(1). 5 The standard for licensure of a biological product as potent under section 351(a) of the PHS Act has long been interpreted to include effectiveness (see 21 CFR 600.3(s) and the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products). We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 6 In this guidance, we use the terms safety and effectiveness and safety, purity, and potency interchangeably in the discussions pertaining to biosimilar products. 7 Section 351(i)(2) of the PHS Act. 8 Sections V and VI of this guidance describe examples of areas in which the reference product labeling and biosimilar product labeling might differ. 9 FDA posts on its website certain documents generated by FDA related to its review of a 351(k) application, as appropriate. For products regulated by CDER, see Drugs@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm). For products regulated by CBER, see the CBER Freedom of Information Office Electronic Reading Room 3 Contains Nonbinding Recommendations are not designed to support an independent demonstration of safety or effectiveness of the proposed biosimilar product and thus would generally not be expected to facilitate an understanding of product safety and effectiveness. For example, the endpoints used in a clinical study conducted to support a demonstration of no clinically meaningful differences may not be the same endpoints evaluated to support licensure of the reference product and thus may not inform prescribing decisions regarding safety and effectiveness. Similarly, the patient population may differ from the patient population studied in the clinical trials that supported the determination of safety and effectiveness of the reference product. For example, subjects in a study conducted to support a demonstration of no clinically meaningful differences between the biosimilar product and the reference product may be healthy volunteers, or the condition of use studied may be one for which the reference product is not licensed or for which the applicant of the biosimilar product is not seeking licensure but for which sufficient data indicate that the population or condition of use is adequately sensitive to detect clinically meaningful differences between the products, should they exist. Because clinical studies conducted to support a demonstration of biosimilarity generally are not designed to support an independent demonstration of safety or effectiveness, such studies may be misinterpreted in the context of drug labeling, resulting in an inaccurate understanding of the risk-benefit profile of the biosimilar product. Therefore, studies conducted to support biosimilarity generally should not be included in biosimilar product labeling. Biosimilar product labeling should incorporate relevant data and information from the reference product labeling, including clinical data that supported FDA’s finding of safety and effectiveness of the reference product. As required under 21 CFR 201.56(c)(1), biosimilar product labeling must meet the content and format requirements of the physician labeling rule (PLR) as described in 21 CFR 201.56(d) and 201.57, regardless of the format of the reference product labeling.10 In addition, biosimilar product labeling must meet the content and format requirements of the pregnancy and lactation labeling final rule (PLLR) as described in 21 CFR 201.57(c)(9)(i) through (iii), regardless of whether the reference product must meet these requirements.11 (https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm129132.htm). Health care providers and others can refer to those documents if interested in FDA’s review of data and information submitted in a 351(k) application to support biosimilarity. 10 See the final rule “Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products” (71 FR 3922, January 24, 2006). This rule is commonly referred to as the physician labeling rule because it addresses prescription drug labeling that is used by prescribing physicians and other health care providers. Also see additional labeling guidances at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm084159.htm. 11 See the final rule “Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling” (79 FR 72064, December 4, 2014). The final rule describes the implementation schedule for applications submitted on or after the effective date of the rule, applications pending at the time the rule became effective, and applications approved before the rule became effective (79 FR 72064 at 72095–96). 4 Contains Nonbinding Recommendations IV. SPECIFIC RECOMMENDATIONS ON CONTENT OF BIOSIMILAR PRODUCT LABELING FDA recommends that biosimilar product labeling incorporate relevant data and information from the reference product labeling, with appropriate modifications, as explained in sections V and VI of this guidance. The relevant data and information from the reference product labeling that should be incorporated into the biosimilar product labeling will depend on whether the applicant is seeking licensure for all conditions of use (e.g., indication(s), dosing regimen(s)) or fewer than all conditions of use of the reference product for the biosimilar product.12 In sections of the biosimilar product labeling that are based on the reference product labeling, it is anticipated that the text will be similar to the corresponding text in the reference product labeling. Text based on the reference product labeling need not be identical to the reference product labeling and should reflect currently available information necessary for the safe and effective use of the biosimilar product. Certain differences between the biosimilar and reference product labeling may be appropriate. For example, biosimilar product labeling conforming to PLR and/or PLLR may differ from reference product labeling because the reference product labeling may not be required to conform to those requirements at the time of licensure of the biosimilar product. In addition, biosimilar product labeling may include information specific to the biosimilar product that is necessary to inform safe and effective use of the product, including administration, preparation, storage, or safety information. This information may differ from that of the reference product labeling when it reflects differences between the biosimilar product and the reference product that do not preclude licensure of the biosimilar product. A. Approaches to Product Identification In biosimilar product labeling, the approach to product identification depends on the context of the information being presented. FDA acknowledges that there will be variations on the general concepts outlined in this section because the approach to product identification will depend on the specific statements. The illustrative examples in this section use a fictional reference product JUNEXANT (replicamab-hjxf) and a fictional biosimilar product NEXSYMEO (replicamab- cznm). 12 A biosimilar product applicant generally may seek licensure for fewer than all conditions of use for which the reference product is licensed. The 351(k) application must include information demonstrating that the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling submitted for the proposed biosimilar product have been previously licensed for the reference product (see section 351(k)(2)(A)(i)(III) of the PHS Act). 5 Contains Nonbinding Recommendations 1. When use of the biosimilar product name is recommended: The biosimilar product name should be used in labeling text that is specific to the biosimilar product or that refers solely to the biosimilar product. If a biosimilar product has a proprietary name, the proprietary name (e.g., NEXSYMEO) should be used in the appropriate sections. However, if a proprietary name is not available, or if referring to the drug substance (as discussed below), the biosimilar product’s proper name (e.g., replicamab-cznm) should be used.13 The biosimilar product’s proprietary name (or, if a proprietary name is not available, the biosimilar product’s proper name) should be used in circumstances such as the following:  In sections where the information described is specific to the biosimilar product — This includes, but is not limited to, the following sections: INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, DESCRIPTION, and HOW SUPPLIED/STORAGE AND HANDLING.  For directive statements and recommendations for preventing, monitoring, managing, or mitigating risks (e.g., “Discontinue NEXSYMEO in patients with [adverse reaction]”) — Such statements are typically included in, but are not limited to, the BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS sections. The biosimilar product’s proper name should be used when referring to the drug substance. An example would be to use the biosimilar product’s proper name in the DESCRIPTION section. 2. When use of the reference product name is recommended: When clinical studies or data derived from studies with the reference product are described in biosimilar product labeling, the reference product’s proper name (e.g., replicamab-hjxf) should be used. This information would typically be included in sections such as, but not limited to, ADVERSE REACTIONS (Clinical Trials Experience subsection) and CLINICAL STUDIES. 3. When use of the core name is recommended:14 The overall risk-benefit profile of the reference product is relevant to the biosimilar product, even if a particular serious adverse reaction or other risk included in the reference product labeling may not have been reported with the biosimilar product at the time of licensure. In labeling sections where the risk applies to both the biosimilar product and the reference product 13 The proper name is the nonproprietary name designated by FDA in the license for a biological product licensed under the PHS Act (see section 351(a)(1)(B)(i) of the PHS Act and 21 CFR 600.3(k)). 14 Two examples of a core name are filgrastim and epoetin alfa. The proper name for biological products will include a distinguishing suffix composed of four lowercase letters attached to the core name with a hyphen. 6 Contains Nonbinding Recommendations (e.g., BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS (Postmarketing Experience subsection)), it would be appropriate to use the core name of the reference product followed by the word “products” (e.g., replicamab products) to convey, for instance, that a risk or other information necessary for the safe use of the product applies to both the biosimilar product and the reference product (see section IV.B of this guidance). For example, in WARNINGS AND PRECAUTIONS: Reference Product Labeling Biosimilar Product Labeling Treatment with JUNEXANT increases Treatment with replicamab products the risk of serious infections involving increases the risk of serious infections various organ systems and sites that may involving various organ systems and sites lead to hospitalization or death. that may lead to hospitalization or death. 4. When use of more than one product name is recommended: There may be text appropriately based on the reference product labeling where more than one of these product identification approaches should be used to convey information accurately. Therefore, all text in biosimilar product labeling, even sections that have been based on reference product labeling, should be carefully evaluated for the most appropriate product identification approach. In some cases, such as the following example, more than two of the approaches may be used: Replicamab products can cause hepatoxicity and acute hepatic failure. In clinical trials of replicamab-hjxf, 10% of patients developed elevated ALT or AST greater than three times the upper limit of normal and 5% progressed to acute hepatic failure. Evaluate serum transaminases (ALT and AST) and bilirubin at baseline and monthly during treatment with NEXSYMEO . . . B. Approaches to Content Presentation The labeling for the biosimilar product should be specific to the conditions of use (e.g., indication(s), dosing regimen(s)) sought for the biosimilar product and should be consistent with language previously approved for the reference product for those conditions of use. When a biosimilar product applicant obtains licensure for fewer than all conditions of use (e.g., indication(s), dosing regimen(s)) for which the reference product is licensed, certain text in the reference product labeling related to condition(s) of use for the reference product that are not licensed for the biosimilar product would generally not be included in the biosimilar product labeling.15 However, in certain circumstances it may be necessary to include information in the biosimilar product labeling relating to an indication(s) for which the biosimilar product is not 15 See Q.I.7 in the guidance for industry Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. 7 Contains Nonbinding Recommendations licensed, in order to help ensure safe use (e.g., when safety information in the reference product labeling is related to use of the product and is not specific to a particular licensed indication(s) or when information specific to only the biosimilar product’s indication(s) cannot be easily extracted).16 Such text should be written in a manner that does not imply that the biosimilar product is licensed for a reference product indication(s) or use(s) that has not been licensed for the biosimilar product. In these circumstances, specific sections of labeling that could be affected include BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, DRUG INTERACTIONS, and USE IN SPECIFIC POPULATIONS. For example, for sections such as WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, the reference product labeling may pool and categorize events from all the reference product clinical trials for all the indications for which the reference product is licensed. In cases where the biosimilar product applicant is not seeking licensure for all the indications for which the reference product is licensed, the pooled data described in the reference product labeling should be included in the biosimilar product labeling in a manner that is not indication- specific. However, any text that refers to an indication for which the biosimilar product applicant is not currently seeking licensure and is included to ensure safe use of the biosimilar product should be revised to avoid an implication that the biosimilar has been licensed for that indication(s). C. Approaches to Specific Sections of Biosimilar Product Labeling 1. HIGHLIGHTS OF PRESCRIBING INFORMATION (Highlights) a. Initial U.S. approval The initial U.S. approval in the Highlights section is the year that the biosimilar product is licensed. b. Biosimilarity statement FDA recommends including a statement, placed on the line immediately beneath the initial U.S. approval in the Highlights section, that the product is biosimilar to the reference product. It should read as follows: [BIOSIMILAR PRODUCT’S PROPRIETARY NAME (biosimilar product’s proper name)] is biosimilar* to [REFERENCE PRODUCT’S PROPRIETARY NAME (reference product’s proper name)]. The asterisk should appear as a footnote symbol inserted after the word “biosimilar.” 16 See also 21 CFR 201.57(c)(6)(i). 8 Contains Nonbinding Recommendations For example, for the fictitious product NEXSYMEO, the statement should read as follows: NEXSYMEO (replicamab-cznm) is biosimilar* to JUNEXANT (replicamab-hjxf). The footnote should appear at the end of the Highlights section (but above the Revision Date) and state the following: *Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of [BIOSIMILAR PRODUCT’S PROPRIETARY NAME] has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. 2. INDICATIONS AND USAGE Information in the INDICATIONS AND USAGE section should be specific to the licensed indications for the biosimilar product and should be consistent with information previously approved for the reference product. The biosimilar product labeling should include text from the reference product labeling regarding any Limitations of Use relevant to the biosimilar product’s indication(s) (see section IV.B of this guidance for recommendations regarding text that refers to an indication for which licensure has not been sought by the biosimilar product applicant). 3. ADVERSE REACTIONS, Immunogenicity Immunogenicity information for therapeutic protein products is usually placed in a subsection in the ADVERSE REACTIONS section entitled Immunogenicity. To help health care providers interpret the significance of the information, the following or a similar statement should be included as the first paragraph in the subsection, preceding the immunogenicity data based on the reference product labeling: As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other [core name] products may be misleading. 9 Contains Nonbinding Recommendations V. FDA-APPROVED PATIENT LABELING If a Medication Guide is required, applicants must follow existing Medication Guide regulations for biosimilar product labeling.17 If the FDA-approved patient labeling for the reference product includes Patient Information, applicants should develop Patient Information for the biosimilar product, incorporating relevant information from the Patient Information for the reference product, with appropriate modifications. If the FDA-approved patient labeling for the reference product includes Instructions for Use (IFU), the IFU for the proposed biosimilar product should incorporate relevant information from the IFU for the reference product and present the information in a similar manner. The proposed IFU may differ from the IFU for the reference product where, for example, modified language or images are needed to describe the biosimilar product accurately. If other changes are proposed beyond those necessary to describe the biosimilar product accurately, applicants should discuss proposed changes with the Agency, including whether such changes are appropriate and whether additional data to support such changes are warranted. Additionally, if there are plans to conduct a human factors study and the applicant intends to submit a protocol for FDA’s review, the applicant should seek FDA input on the proposed IFU when the human factors study protocol is submitted for FDA review. A full and final review of proposed product labeling, including the IFU, will occur in the context of the planned 351(k) application and may be informed by any human factors study findings submitted or other relevant data included in the application. VI. REVISING BIOSIMILAR PRODUCT LABELING A. Updating Safety Information During the lifecycle of a biological product, changes in the labeling may be necessary to provide updated information needed for the safe and effective use of the product. As the reference product and biosimilar product are used more widely or under diverse conditions, new information may become available. This may include new risks or new information about known risks. A biosimilar product application holder must comply with applicable requirements regarding adverse experience review, reporting, and recordkeeping (see 21 CFR 600.80). When new information becomes available that causes information in labeling to be inaccurate, false, or misleading, the application holder must take steps to change the content of its product labeling, in accordance with 21 CFR 601.12.18 All holders of marketing applications for biological products have an ongoing obligation to ensure their labeling is accurate and up to date.19 A biological product is misbranded, in violation of the Federal Food, Drug, and Cosmetic 17 See 21 CFR part 208. 18 See, e.g., 21 CFR 201.56(a)(2): “In accordance with . . . [21 CFR 601.12], the labeling must be updated when new information becomes available that causes the labeling to become inaccurate, false, or misleading.” 19 Ibid. 10 Contains Nonbinding Recommendations Act (FD&C Act), when its labeling is false or misleading; does not provide adequate directions for use and adequate warnings; or prescribes, recommends, or suggests a dosage, manner, frequency, or duration of use of the drug that is dangerous to health (see 21 U.S.C. 331(a) through (b) and 352(a), (f), and (j)). B. Additional Conditions of Use FDA recognizes that a biosimilar product application holder may be interested in seeking licensure for an additional condition(s) of use after product licensure in the following scenarios:  The biosimilar product applicant originally obtained licensure for fewer than all of the conditions of use for which the reference product is licensed and is seeking licensure for one or more of the remaining licensed conditions of use of the reference product.  The biologics license application (BLA) holder for the reference product received licensure for a new condition of use for the reference product after the original licensure of the biosimilar product. The biosimilar product applicant may seek licensure for an additional condition(s) of use of the reference product in these scenarios by submitting a prior approval supplement(s) to the 351(k) application that contains the necessary data and information, including draft labeling revised to include the additional condition(s) of use sought. For more information on how to support licensure of the biosimilar product for an additional condition(s) of use for which the reference product is licensed, refer to the guidance documents on biosimilar product development on FDA’s website.20 VII. HOW TO SUBMIT INITIAL AND REVISED LABELING New BLAs and supplement submissions for biosimilar product labeling should include the following:  A clean version of reference product labeling that was used to develop the biosimilar product labeling  A tracked changes and annotated version of proposed biosimilar product labeling explaining the differences from the reference product labeling  A clean version of the proposed biosimilar product labeling 20 https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm 11 Contains Nonbinding Recommendations VIII. INTERCHANGEABLE PRODUCTS Any specific recommendations for labeling for interchangeable products, including any interchangeability statement similar to the biosimilarity statement described in section IV.C.1.b of this guidance, will be provided in future guidance. 12