Cover Letter Attachments for Controlled Correspondence and ANDA Submissions Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) June 2023 Generic Drugs Cover Letter Attachments for Controlled Correspondence and ANDA Submissions Guidance for Industry Additional copies are available from: Office of Communications, 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/guidance-compliance-regulatory-information/guidances-drugs U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) June 2023 Generic Drugs Contains Nonbinding Recommendations TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND ............................................................................................................... 1 III. USING THE COVER LETTER ATTACHMENTS ..................................................... 3 APPENDIX 1: COVER LETTER ATTACHMENT FOR CONTROLLED CORRESPONDENCE ................................................................................................................. 4 APPENDIX 2: COVER LETTER ATTACHMENT FOR ORIGINAL ANDAS, AMENDMENTS TO ORIGINAL ANDAS, AND GENERAL CORRESPONDENCE RELATED TO ORIGINAL APPLICATIONS.......................................................................... 7 APPENDIX 3: COVER LETTER ATTACHMENT FOR SUPPLEMENTS TO APPROVED ANDAS, AMENDMENTS TO PENDING SUPPLEMENTS, AMENDMENTS TO TENTATIVELY APPROVED PEPFAR ANDAS, AND GENERAL CORRESPONDENCE RELATED TO THESE SUBMISSIONS.......................................... 13 Contains Nonbinding Recommendations Cover Letter Attachments for Controlled Correspondence and ANDA Submissions Guidance for Industry1 This guidance represents the current thinking of the Food and Drug Administration (FDA or the 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 assist prospective applicants, applicants, and holders of abbreviated new drug applications (ANDAs) with optional attachments that can be used when preparing cover letters that accompany controlled correspondence,2 original ANDAs, amendments to ANDAs, and supplements to approved ANDAs submitted to FDA. These attachments do not replace the recommendations for the content of cover letters provided in other FDA guidances.3 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 Generic Drug User Fee Amendments of 2012 (GDUFA I)4 amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) to authorize FDA to assess and collect user fees to provide the 1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research at the Food and Drug Administration. 2 Controlled correspondence is correspondence submitted to the Agency, by or on behalf of a generic drug manufacturer or related industry, requesting information on a specific element of generic drug product development. See GDUFA Reauthorization Performance Goals and Program Enhancements fiscal years (FYs) 2023-2027 commitment letter (GDUFA III Commitment Letter), available at https://www.fda.gov/media/153631/download. See also the guidance for industry Controlled Correspondence Related to Generic Drug Development (December 2020). We update guidance periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 3 Recommended content of cover letters (or first page of submission) is provided in the following guidances for industry: Controlled Correspondence Related to Generic Drug Development (December 2020); ANDA Submissions-Content and Format (June 2019); ANDA Submissions-Amendments to Abbreviated New Drug Applications Under GDUFA (July 2018); and ANDA Submissions-Prior Approval Supplements Under GDUFA (October 2017). 4 Generic Drug User Fee Amendments of 2012, Title III of the Food and Drug Administration Safety and Innovation Act (Public Law 112-144, Title III). 1 Contains Nonbinding Recommendations Agency with resources5 to help ensure patients have access to quality, affordable, safe, and effective generic drugs. GDUFA fee resources bring greater predictability and timeliness to the review of generic drug applications. GDUFA has been reauthorized every 5 years to continue FDA's ability to assess and collect GDUFA fees, and this user fee program has been reauthorized two times since GDUFA I, most recently in the Continuing Appropriations and Ukraine Supplemental Appropriations Act, 2023.6 As described in the GDUFA III commitment letter applicable to this latest reauthorization,7 FDA has agreed to performance goals and program enhancements regarding aspects of the generic drug assessment program that build on previous authorizations of GDUFA. New enhancements to the program are designed to maximize the efficiency and utility of each assessment cycle, with the intent of reducing the number of assessment cycles for ANDAs and facilitating timely access to generic medicines for American patients. The enhancements described in the GDUFA III commitment letter include expansion of the types of correspondence that can be submitted as controlled correspondence,8 as well as other submission and communication enhancements designed to improve the efficiency of ANDA assessment. The recommendations in this guidance are intended to aid applicants in preparing cover letters for controlled correspondence and common ANDA submissions to help ensure these cover letters include pertinent information to aid FDA's assessment of the submission. A cover letter is generally included with controlled correspondence to the Office of Generic Drugs (OGD) and submissions to an ANDA file. While a cover letter is not required content for an ANDA, the cover letter is a part of the electronic common technical document (eCTD) hierarchy and is included in Module 1 of an ANDA submission.9 The cover letter provides an overview of the submission and helps FDA ensure that the submission is properly triaged and assigned to the appropriate assessors. In an effort to ensure that submissions are effectively managed by FDA and acted upon within the performance review goal dates agreed to in the GDUFA III commitment letter, FDA has developed cover letter attachments to accompany, not replace, the applicant's10 cover letter for the following common submissions: controlled correspondence, original ANDAs and amendments to ANDAs, and supplements to approved ANDAs. Use of the cover letter attachments contained in the appendices of this guidance is voluntary, and the absence of a cover letter attachment in a submission would not be a basis for a submission to be considered deficient or for a refuse-to- receive (RTR) determination. 5 User fees are available for obligation in accordance with appropriations acts. 6 See Division F, Title III of the Continuing Appropriations and Ukraine Supplemental Appropriations Act, 2023 (Public Law 117-180). 7 The GDUFA III commitment letter, available at https://www.fda.gov/media/153631/download. 8 See GDUFA III commitment letter at 11. 9 See The Comprehensive Table of Contents Headings and Hierarchy, available at https://www.fda.gov/media/76444/download. 10 Use of the term applicant in this guidance includes prospective ANDA applicants, ANDA applicants, and ANDA holders. 2 Contains Nonbinding Recommendations III. USING THE COVER LETTER ATTACHMENTS The cover letter attachments provided in this guidance have been developed by the divisions that receive and respond to controlled correspondence and that assess ANDAs (including amendments and supplements). The cover letter attachments have been designed as a checklist to reflect common types of information applicants are expected to address in the cover letter for their submission. Please note that these checklists are not an exhaustive list of the information needed from applicants for a particular submission. There may be additional items that need to be submitted with a particular submission; for example, information related to patents and exclusivities may need to be submitted with some ANDA submissions. Prospective ANDA applicants, ANDA applicants, and ANDA holders may complete and submit the appropriate attachment(s) along with their cover letter. Applicants are not required to submit an attachment with their cover letter; however, the optional cover letter attachment can be a useful guide to help applicants prepare their cover letters, particularly in situations covered in Appendices 2 and 3. The format of the cover letter attachment may be adapted by the applicant for their convenience. The main purpose of the cover letter attachment is to help applicants ensure that they are addressing relevant information in any cover letter submitted to FDA for the submissions covered in this guidance. Completing a relevant checklist and attaching it to the cover letter submission is helpful to FDA in the triage of applications and management of submissions. The cover letter attachment provided in Appendix 1 of this guidance is intended for use with controlled correspondence submitted to OGD. The cover letter attachment provided in Appendix 2 of this guidance is intended for original ANDA submissions, amendments to original ANDAs, and any general correspondence associated with that original ANDA. The cover letter attachment provided in Appendix 3 of this guidance is for supplements to approved ANDAs, amendments to pending supplements, submissions to tentatively approved ANDAs under the President's Emergency Plan for AIDS Relief (PEPFAR) program,11 and any general correspondence related to these submissions. 11 Under PEPFAR, certain antiretroviral products that have been granted a tentative approval may be distributed for use outside of the United States, even when there is still patent and/or exclusivity protection in the United States. See FDA's PEPFAR web page, available at https://www.fda.gov/international-programs/presidents-emergency- plan-aids-relief-pepfar. 3 Contains Nonbinding Recommendations APPENDIX 1: COVER LETTER ATTACHMENT FOR CONTROLLED CORRESPONDENCE Controlled Correspondence (CC) Background Submission Date Subject Person Submitting the CC Name Title Entity (e.g., corporate affiliation) Note here if this is a U.S. Agent, Prospective Applicant, or Applicant Address Phone number Email Relevant Reference Listed Drug (RLD)/Reference Standard (RS) Information Application number Proprietary (brand) name Manufacturer Established Name Dosage form Strength(s) CC Information Concise statement of the inquiry Applicant or prospective applicant's recommendation of the appropriate FDA review discipline Additional Background Yes No or N/A Are copies of relevant prior research, background information, and supporting materials included with the CC submission? Drug-Device Combination Product Yes No or N/A Is the product or proposed product a drug-device combination product? Note: If this is a combination product, mark the corresponding box to identify it as such on line #24 of the FDA Form 356h. 4 Contains Nonbinding Recommendations Previous CC History • If this is related to a previous CC that was accepted for substantive review and response, provide the FDA-assigned CC number and submission date. • Include copies of all previous, related CC(s) accepted for substantive review and response and the Agency's response. Previous CC Submission Concise Statement of Concise Statement of Agency's Number Date Inquiry Response Related Submissions • If this is related to a submitted abbreviated new drug application (ANDA) or a pre-assigned ANDA, provide the information below. ANDA Number Submission Date Submission Status 5 Contains Nonbinding Recommendations Previous Meeting and PSG Teleconference (TCon) History • If this is related to a previous meeting and/or PSG TCon, provide the assigned ANDA number, meeting type, and meeting date. • Include copies of all previous, related meeting and PSG TCon requests and the Agency's response(s). ANDA Number Meeting Type Meeting Date List of attachments provided: 1. 2. 3. 6 Contains Nonbinding Recommendations APPENDIX 2: COVER LETTER ATTACHMENT FOR ORIGINAL ANDAS, AMENDMENTS TO ORIGINAL ANDAS, AND GENERAL CORRESPONDENCE RELATED TO ORIGINAL APPLICATIONS12 ANDA Background Abbreviated New Drug Application (ANDA) Number Applicant Submission Date Authorized Representative's Email Submission Type (e.g., Original, Amendment) Proposed Product Established Name Dosage Form Strength(s) Reference Listed Drug (RLD) (proprietary name (brand name), application number) Reference Standard (RS) (proprietary name (brand name), if any, established name, and application number) RLD/RS Application Number Used to Conduct Bioequivalence Studies Note: If priority review is being requested, please refer to the Agency's Manual of Policies and Procedures (MAPP) 5240.3 (Rev. 6), Prioritization of the Review of Original ANDAs, Amendments, and Supplements13 12 Note that there may be multiple submissions falling under this particular category related to a particular ANDA. Applicants should utilize the checklist for each specific submission and only include information relevant to the current submission, not previous submissions. 13 The cover letter should clearly state "Priority Review Requested"; reference the ANDA number; provide the basis for the request, including the prioritization factor(s); and include sufficient supporting documentation for the request. For additional information, see FDA's MAPP 5240.3 (Rev. 6), available at https://www.fda.gov/media/89061/download. 7 Contains Nonbinding Recommendations Select all applicable information included in the submission  Administrative General  Bioequivalence  Biopharmaceutics  Clinical Correspondence14  Scientific General Correspondence15  Drug Substance  Drug Product  Labeling  Microbiology (Drug Master File) DMF  Carve-out16 #: __________________  Patent (Section viii statement)  Exclusivity  Dosage Form  Patent or  Pharm/Tox  Manufacturing: Exclusivity  Facility  Active Pharmaceutical Ingredient (API)  Finished Dosage Form (FDF) (including packaging and labeling)  Testing  Request for  Other (e.g., storage, device Reconsideration constituent)  Ready for Inspection17  Process  Facility-Based Major CRL Amendment Request for Reclassification 14 An administrative general correspondence is a general correspondence to FDA that does not include information required for review of the ANDA. For example, it may include a change in the point of contact, applicant address, etc. 15 A scientific general correspondence is a general correspondence from an applicant to FDA requesting scientific advice after a complete response letter has been issued by the Agency. 16 Labeling carve-outs should be prominently identified (e.g., bolded) in the cover letter for these types of submissions. 17 FDA recommends that applicants state in their cover letters "Facility Ready For Inspection" along with the ANDA number, if applicable. 8 Contains Nonbinding Recommendations Additional background Yes No or N/A 1. Is the email secure? If no, apply for a secure email with the FDA by contacting secureemail@fda.hhs.gov 2. Was a Pre-Submission Facility Correspondence (PFC) submitted? 3. If a PFC was submitted, have any significant changes been made to the pre-submitted facility information? 4. Does the submission contain any technology that has been accepted into or may qualify for the Emerging Technology Program18? 5. For all submissions: Was a Competitive Generic Therapy (CGT) designation granted for a drug product or drug products under this ANDA? 6. For original ANDAs: Is a CGT designation request being made concurrently with the original ANDA submission? If yes, please refer to the guidance for industry Competitive Generic Therapies (March 2020) for additional information on what to include in the cover letter.19 Drug-device combination product Yes No or N/A 7. Is the proposed product a drug-device combination product? If yes, answer questions #8 and #9. Note: If this is a combination product, mark the corresponding box to identify it as such on line #24 of the FDA Form 356h. 8. Does the submission include comparative analyses for a drug-device combination product? If yes, then specify location in the submission: __________________ 9. Does the submission include additional data and/or information, such as data from a comparative use human factors study, to support differences in user interface? If yes, then specify location(s) in the submission: __________________:__________________:__________________ 18 See the guidance for industry Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization (September 2017). 19 This guidance recommends including a statement supporting the request for designation and information supporting the assertion that there is inadequate generic competition for the drug product under section 506H of the FD&C Act (21 U.S.C. 356h). 9 Contains Nonbinding Recommendations Study Information Yes No or N/A 10. Does the submission include an alternate method for demonstrating bioequivalence (BE) (e.g., modeling, in vitro testing) that deviates from the current recommendations in a Product-Specific Guidance? 11. Does the submission include a request for a waiver under 21 CFR 320.22? If yes and referencing a BE study submitted under a different application, then include the original BE study's ANDA number, submission date, and the module for the BE study referenced in support of the waiver request in the current submission: _________________________________________ 12. Are there any additional data and/or information from comparative studies (e.g., in vitro studies, failed BE studies) included in other modules besides module 5? If yes, then specify study type and location in the submission: __________________________________________________ _________________________________________________________ 13. Does the submission include a Pharmacology/Toxicology (safety) justification, for example, nonclinical studies as defined in 21 CFR 58.3(d)? If yes, then specify justification/study type and location in the submission: ____________________________________________________________ Proposed product development history • For original ANDAs: ensure that copies of all related pre-ANDA communications accepted for substantive review and the Agency's response (e.g., controlled correspondence, pre-ANDA meeting written responses) are included in your submission • For subsequent amendments: only include updates or new information since last submission, as applicable Complete this section to document any prior FDA communications Yes No or N/A for this ANDA, as appropriate 1. Controlled correspondence(s) If yes, include #(s) and date(s): _______________________________ 2. Protocol review(s) If yes, include #(s) and date(s): _______________________________ 3. Bio-investigational new drug (Bio-IND) protocol review(s) If yes, include #(s) and date(s): ______________________________ 4. Approved suitability petition for the basis of submission, as per 21 CFR 314.94(a)(3)(iii) 10 Contains Nonbinding Recommendations If yes, include docket number and a copy of FDA's correspondence approving the petition: _____________________________________ 5. Approved citizen petition requesting a specific basis of submission20 If yes, include docket number: _______________________________ 6. Pre-ANDA meeting(s) If yes, include #(s) and date(s): ______________________________ 7. Scientific General Correspondence(s) after complete response letter (CRL) response (for amendments only) If yes, include #(s) and date(s): ______________________________ 8. Device related communication(s) (for drug-device combination product only) If yes, include #(s) and date(s): ______________________________ For Amendments Only Type of amendment Date of FDA correspondence Is this a response to a or action that elicited the CRL? amendment (e.g., CRL, discipline review letter (DRL), Yes No or N/A information request (IR), or tentative approval (TA) Unsolicited Solicited Post-TA amendment Post-TA Request for Final Approval Request For Reconsideration (RFR) Facility-Based Major CRL Amendment to Minor Reclassification Request Patent Certification/Statement Yes No21 1. Does the submission contain any of the following changes? (i) To add a new indication or other condition of use; (ii) To add a new strength; (iii) To make other than minor changes in product formulation; or 20 See section III.C.3 in FDA's guidance for industry Referencing Approved Drug Products in ANDA Submissions (October 2020). 21 "N/A" does not apply for Patent Certification/Statement. Under 21 CFR 314.96(d), an amendment to an unapproved ANDA must contain either (1) an appropriate patent certification or statement (or recertification), or (2) a verification that the proposed changes described in the amendment is not one of the types of amendments described in 21 CFR 314.96(d)(1). 11 Contains Nonbinding Recommendations (iv) To change the physical form or crystalline structure of the active ingredient If yes, please address this according to 21 CFR 314.96(d)(1) If no, please provide a statement according to 21 CFR 314.96(d)(2) within the cover letter Does the amendment submission include any of the following? Yes No or N/A 2. New strength (including new fill volume for parenteral products) 3. Modified formulation 4. New batch 5. Specification change(s) 6. New container closure system 7. Active Pharmaceutical Ingredient (API) source change If yes, then include Drug Master File (DMF) #: __________________ 8. Changes or additions to the manufacturing/quality facilities? 9. For a request for final approval, is new data being submitted? 10. New bioequivalence (BE) study/studies If yes, then specify the following for each new BE study: a. Select study type: in vivo or in vitro, including failed study b. Study number: __________________ c. Study site (clinical, analytical, in vitro testing) Name and address: ______________________________________________ d. Location of new BE study in the submission: _____________________________________ 11. Updated labeling due to a new or revised patent or exclusivity currently listed in the Orange Book22 22 The publication Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known as the Orange Book) identifies drug products approved on the basis of safety and effectiveness by FDA under the FD&C Act and related patent and exclusivity information. For more information on the Orange Book, see the Agency's web page https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic- equivalence-evaluations-orange-book. 12 Contains Nonbinding Recommendations APPENDIX 3: COVER LETTER ATTACHMENT FOR SUPPLEMENTS TO APPROVED ANDAS, AMENDMENTS TO PENDING SUPPLEMENTS, AMENDMENTS TO TENTATIVELY APPROVED PEPFAR ANDAS, AND GENERAL CORRESPONDENCE RELATED TO THESE SUBMISSIONS23 ANDA Background Abbreviated new drug application (ANDA) number Applicant Submission Date Email Established Name Dosage Form Strength(s) Reference Listed Drug (RLD) (proprietary name (brand name) and application number) Reference Standard (RS) (proprietary name (brand name), if any, established name, and application number) If priority review is being requested, please refer to FDA's Manual of Policies and Procedures (MAPP) 5240.3 (Rev. 6), Prioritization of the Review of Original ANDAs, Amendments, and Supplements24 Select all applicable information included in the submission  Administrative General  Bioequivalence  Biopharmaceutics  Clinical Correspondence25  Scientific General Correspondence26 23 Note that there may be multiple submissions falling under this particular category related to a particular ANDA. Applicants should utilize the checklist for each specific submission and only include information relevant to a particular application, not previous submissions. 24 The cover letter should clearly state "Priority Review Requested"; reference the ANDA number; provide the basis for the request, including the prioritization factor(s); and include sufficient supporting documentation for the request. For additional information, see FDA's MAPP 5240.3 (Rev. 6), available at https://www.fda.gov/media/89061/download. 25 An administrative general correspondence is a general correspondence to FDA that does not include information required for review of the ANDA. For example, it may include a change in the point of contact, applicant address, etc. 26 A scientific general correspondence is a general correspondence from an applicant to FDA requesting scientific advice after a complete response letter has been issued by the Agency. 13 Contains Nonbinding Recommendations  Drug Substance  Drug Product  Labeling  Microbiology DMF #:  Carve-out 27 __________________  Patent (Section viii statement)  Exclusivity  Dosage Form  Patent or  Pharm/Tox  Manufacturing: Exclusivity  Facility  Active Pharmaceutical  Request for Ingredient (API) Reconsideration  Finished Dosage Form (FDF) (including packaging/labeling)  Testing  Other (e.g., storage warehouse, device constituent parts)  Ready for Inspection28  Process  Facility-Based Major CRL Amendment Request for Reclassification  Notice of Commercial Marketing 27 Labeling carve-outs should be prominently identified (e.g., bolded) in the cover letter for these types of supplements and amendments. 28 FDA recommends that applicants state in their cover letters "Facility Ready For Inspection" along with the ANDA number, if applicable. 14 Contains Nonbinding Recommendations Additional Background Yes No or N/A 1. Is the email secure? If no, apply for a secure email with the FDA by contacting secureemail@fda.hhs.gov. 2. Was a Pre-Submission Facility Correspondence (PFC) submitted? 3. If a PFC was submitted, have any significant changes been made to the pre-submitted facility information? 4. Does the submission contain any technology that has been accepted into or may qualify for the Emerging Technology Program29? Drug-device combination product Yes No or N/A 5. Is the proposed product a drug-device combination product? If yes, answer questions #6 through #9. 6. Does the supplement propose a change to the drug-device combination product that may impact quality or labeling? 7. Does the supplement propose a change to the drug-device combination product that may impact the user interface? 8. Does the submission include comparative analyses for a drug-device combination product? If yes, then specify location in the submission: _________________ 9. Does the submission include additional data and/or information, such as data from a comparative use human factors study, to support differences in user interface? If yes, then specify location(s) in the submission: _______________ Does the submission (supplement or amendment to the supplement) Yes No or include any of the following? N/A 10. New strength (including new fill volume for parenteral products) 11. Modified formulation 12. Specification change(s) 13. New container closure system 29 See the guidance for industry Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization (September 2017). 15 Contains Nonbinding Recommendations 14. Request for a Prescription (Rx) to over-the-counter (OTC) switch 15. A reactivation/reintroduction request as noted in MAPP 5200.7 (Rev. 1)30 16. Revised and/or new patent certification and/or exclusivity statement 17. Updated labeling due to a new or revised patent or exclusivity currently listed in the Orange Book 18. A new facility that has never been inspected for similar operations to those proposed in the supplement 19. Removal of a facility 20. Active Pharmaceutical Ingredient (API) source change If yes, then include Drug Master File (DMF) #: __________________ 21. A Pharmacology/Toxicology (safety) justification for example nonclinical studies as defined in 21 CFR 58.3(d) If yes, then specify justification/study type and location in the submission: __________________ 22. New bioequivalence (BE) study/studies If yes, then specify the following for each new BE study: a. Select Study type: in vivo or in vitro, including failed study b. Study Number: __________________ c. Study Site (clinical, analytical, in-vitro testing) Name and Address: __________________ d. Location of new BE study in the submission: __________________ 23. An alternate method for demonstrating BE (e.g., modeling, in vitro testing) that deviates from the current recommendations in a Product- Specific Guidance 24. A waiver request under 21 CFR 320.22? If yes, include the module where your waiver is located: __________ Select one filing category corresponding to the highest risk of all proposed supplemental changes, ranked by supplement filing category (PAS, CBE-30, CBE-0) per 21 CFR 314.70  PAS  CBE-30  CBE-0 30 FDA's MAPP 5200.7 (Rev. 1), ANDA Amendments and Supplements Reviewed by the Division of Filing Review, is available at https://www.fda.gov/media/94417/download. 16 Contains Nonbinding Recommendations For Amendments Only Type of amendment Supplement # Date of FDA Is this a response to a correspondence or CRL? action that elicited the amendment (e.g., Yes No or Complete Response N/A Letter (CRL), discipline review letter (DRL), information request (IR), or tentative approval (TA)): Unsolicited Solicited President's Emergency Plan for AIDS Relief Program (PEPFAR) Post- TA31 Request for Reconsideration (RFR) Facility-Based Major CRL Amendment Reclassification Request 31 Under PEPFAR, certain antiretroviral products that have been granted a tentative approval may be distributed for use outside of the United States, even when there is still patent and/or exclusivity protection in the United States. See FDA's PEPFAR web page, available at https://www.fda.gov/international-programs/presidents-emergency- plan-aids-relief-pepfar. 17 Contains Nonbinding Recommendations Proposed Changes • For all supplemental changes proposed, populate the table below, ranked by supplement filing category (PAS, CBE-30, CBE-0) per 21 CFR 314.70 # Change Filing Scale-Up and Post Approval Justification for filing category description category Changes (SUPAC) level (1, based on current guidances and/or 2 or 3), as applicable32 risk assessment If the same change has been previously approved, include ANDA # and approval date for the same change. 1 2 3 4 5 32 SUPAC guidances are available for modified-release solid oral dosage forms, immediate-release solid oral dosage forms, and nonsterile semisolid dosage form products (see the guidances for industry SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation (October 1997); SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (November 1995); and SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation (May 1997)). These guidances define levels of change (i.e., SUPAC levels 1, 2, and 3) for the covered products, along with recommended tests and documentation that should support the change. 18