FDA/CDER s Division of Project Management Office of Regulatory Operations Office of Generic Drugs

Transcription

1 FDA/CDER s Division of Project Management Office of Regulatory Operations Office of Generic Drugs LCDR Kevin Denny, Pharm.D. Regulatory Project Manager Team Lead Division of Project Management Office of Regulatory Operations Office of Generic Drugs CDR Craig Kiester, RPh, M.S., RAC Branch Chief (acting) Office of Program and Regulatory Operations Office of Pharmaceutical Quality November 3,

2 How an ANDA Gets Approved 2

3 3 Topics Covered Recent events affecting approval Overview of the disciplines involved in the approval process Areas for industry assistance

4 4 Early Challenges Implementation of the Informatics Platform (IT) - New archival system used to track and process applications - Went live October 1, 2014 Reorganization - Creation of the Office of Pharmaceutical Quality - Separating several review disciplines from OGD Increase in new staff - Addition of many new reviewers - Experienced reviewers involved in training

5 5 Recent Improvements Informatics Platform has been tailored to meet our needs OPQ settled into the reorganization, new processes in place New hires becoming more productive Experienced reviewers returning to spending more time reviewing applications

6 FY15 Trends (ANDA Originals) Actions Taken by Month (Totals) Complete Response (CR), Approval (AP), & Tentative Approval (TA) CR AP TA Oct 14 Nov 14 Dec 14 Jan 15 Feb 15 Mar 15 Apr 15 May 15 Jun 15 Jul 15 Aug 15 Sept 15 Grand Total AP CR TA

7 7 Emphasis to Reduce Number of Review Cycles Goal to reduce the time for an ANDA to be approved Need improved applications from the applicant Increased number of Information Request (IR)/Easily Correctable Deficiencies (ECD) communications

8 FY15 Trends (ANDA Originals) Actions Taken by Month (Totals) ECD/IR ECD/IR

9 603 FDA Snapshot 54 Pending Filing Review ,115 Filed No Review Comm. + At Least One Review Communication Issued = 2,662 with FDA (Data as of 9/21/2015) Monthly Average (May - August) Complete Response 99 Amendments 83 Info Req. 548 Tentative Approvals 10 + Industry Snapshot 872 Pending Industry Response to the Complete Response Tentative Approval with Industry = 1,148 with Industry Current ANDA Workload of Original Applications 3,810 Total Pre-Y3 Application Cohort (As of 10/1/2012) 1,293 Approva ls + Refuse to Receive 78 Resubmitted in Y3 128 No Resubmission Withdrawal s (from Cohort) + 3,810 = 5,707

10 FILING STAGE 10

11 Division of Filing Review 11

12 12 Office of Generic Drugs Office of Research and Standards Office of Bioequivalence Office of Generic Drug Policy Office of Regulatory Operations Division of Therapeutic Performance Division of Bioequivalence 1 Division of Legal and Regulatory Support Division of Filing Review Division of Quantitative Methods and Modeling Division of Bioequivalence 2 Division of Policy Development Division of Project Management Division of Bioequivalence 3 Division of Labeling Review Division of Clinical Review Division of Quality Management Systems

13 13 Topics Filing Review Process ectd Recommendations Module Specifications

14 14 ANDA Submitted Filing Review Process Application Filing Review Refuse to Receive Letter Acceptable & Complete NO YES Quality Review Labeling Review Bioequivalence Review Facility Inspection

15 15 ectd Requirements Review metric goals only apply to submissions made electronically following the Electronic Common Technical Document (ectd) format in effect at the date of submission Electronic submission of ANDAs in ectd format will be required as of May 2017 (see Guidance for industry Providing Regulatory Submissions in Electronic Format Certain Human Pharmaceuticals Product Applications and Related Submissions Using the ectd Specifications) Electronic format must be in a form FDA can process, review and archive (21 CFR (d)(1)(iii)) See the FDA web site for guidances and technical specifications to ensure documents are submitted correctly

16 16 CTD Modules for ANDAs Module 1 Administrative Module 2 Summaries 2.3 Quality Overall Summary 2.7 Clinical Summary Module 3 Quality Module 4 Nonclinical Study Reports Not Applicable Module 5 Clinical Study Reports

17 17 Module 1: Administrative Forms FDA 356h (21 CFR (a)(1)) 3674 (42 USC 282(j)(5)(B)) 3794 (744B of the Federal Food, Drug & Cosmetic Act (FD&C Act)) 3454 or 3455 (BE financial forms)(21 CFR part 54) GDUFA Obligations met 744B of the FD&C Act Certifications Debarment certification and list of convictions (306(k) and 306(a) and (b) of the FD&C Act) Field copy (21 CFR (d)(5)) Environmental impact statement (21 CFR 25.22) DMF Right to Reference 21 CFR (d) Basis of Submission Reference to the RLD (21 CFR (a)(3)) Suitability petition (21 CFR )

18 18 Module 1: Patent Certification ANDA applicants need to make a patent certification with their application (21 CFR (a)(12) 4 Types of Patent Certifications P1 patent(s) not submitted to FDA PII patent(s) have expired PIII patent(s) will expire on a given date PIV applicant is challenging the validity or enforceability of the patent or is asserting that the proposed product does not infringe

19 19 Module 1: Labeling Same as RLD labeling except for changes required because of differences approved under a suitability petition or because of different manufacturers Permitted differences may include excipients, pharmacokinetic data, how supplied section, and differences due to patent or exclusivity issues Must provide copies of RLD labeling and provide a side-by-side comparison of proposed label versus the RLD label with all differences highlighted and annotated (21 CFR (a)(8)(iv))

20 20 Module 2: Summaries Quality Overall Summary for Chemistry Drug Substance Drug Product BE Summary Tables Any and all applicable summary tables for PK studies should be populated All applicable dissolution studies should be provided, which includes multi-media, alcohol dose dumping, and ½ tablet dissolution

21 21 Module 3: Drug Substance and Drug Product Components and composition (formulation and inactive ingredients) Pharmaceutical development Manufacturing Control of excipients Control of drug product Container closure system Stability Executed batch record(s)

22 22 Module 3: Components and Composition Inactive ingredients DFR performs an initial assessment on the acceptability of the applicant s proposed formulation with regard to regulations and guidance applicable to specific dosage forms This initial assessment is conducted for acceptability for receipt, not for approval of the submission

23 23 Module 3: Pharmaceutical Development Report containing methods and procedure on how the drug product was developed Usually submitted in Question Base Review(QbR) format The impact of experience and knowledge should be thoroughly explained in the submission The risk assessment process is one avenue

24 24 Module 3: Manufacture Theoretical yield for the exhibit as well as the commercial batch records Flow diagram of the manufacturing process Blank Master Production Batch Records Applicants may request a maximum production scaleup of 10x the theoretical yield of the exhibit batch Process Validation Sterility filter validation for aseptically filled drug product

25 25 Module 3 : Control of Excipients Source of inactive ingredients Supplier s certificate of analysis (COA) Analytical procedures Should be submitted if procedures used are not USP/NF procedures Validation of analytical procedures, if applicable Applicant s COA

26 26 Module 3: Control of Drug Product Specifications Analytical Procedures Submit when a non-usp procedure is used Validation of Analytical Procedures Submit when a non-usp procedure is used Samples statement of availability (21 CFR (a)(10)) COA for finished drug product Characterization of Impurities Identification and justification of impurities List any expected impurities

27 27 Module 3: Container Closure System Summary of container closure system Components specification and test data Packaging configuration and sizes Container closure testing Moisture permeation testing, light transmission, etc. Source of supplier and suppliers address(es)

28 28 Module 3: Stability Data Stability protocol and data Include proposed expiration dating period of drug product Tentative maximum of 24 months based on 6 months of accelerated stability data Post Approval stability protocol and commitment

29 29 Module 3: Stability Data Stability Data See guidances for industry: ANDAs: Stability Testing of Drug Substances and Products (June 2013) and ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers (May 2014) Executed Batch Records Provided for each strength

30 30 Module 5: Clinical Study Reports Tabular Listing of Clinical Studies Comparative BA/BE Study Reports For products requiring bioequivalence studies, the study information is submitted in folder In-vivo studies In-vitro studies Studies with Clinical Endpoints Skin Irritation/Sensitization Studies Pharmacokinetic studies must meet BE criteria (90% CI of , Cmax, AUC) FDA will refuse to receive (RTR) an application without a passing study having been provided or a reference-scaled approach for the failed parameter

31 31 Questions Any questions related to filing may be directed to

32 REVIEW STAGE 32

33 Regulatory Project Manager (RPM) 33

34 34 Office of Generic Drugs Office of Research and Standards Office of Bioequivalence Office of Generic Drug Policy Office of Regulatory Operations Division of Therapeutic Performance Division of Bioequivalence 1 Division of Legal and Regulatory Support Division of Filing Review Division of Quantitative Methods and Modeling Division of Bioequivalence 2 Division of Policy Development Division of Project Management Division of Bioequivalence 3 Division of Labeling Review Division of Clinical Review Division of Quality Management Systems

35 35 Regulatory Project Manager Oversee the review of ANDAs - Provide oversight across all review disciplines - Work to ensure all reviews are complete - Work to ensure OGD meets GDUFA goal dates Triage all amendments from receipt of ANDA to approval - Assign received amendments to the applicable disciplines Communicate key events in the approval process MAPP Rev. 1 Serve as point of contact - All communications will go through RPM - Exception: responding directly, as requested by a discipline

36 36 Communications ANDA assigned to an RPM introductory ANDA reassigned to another RPM Target Action Dates (TADs) (pre-year 3 planning date) Application status updates Major deficiency expected

37 37 Communications Complete Responses (CR) Post CR meetings (clarification) CR Response Acknowledgements Inform application is in the clearance phase Issue Approvals and Tentative Approval Letters

38 OPQ ANDA Approval Process

39 39 OPQ Immediate Office Acting Director: Janet Woodcock Deputy Director: Lawrence Yu Office of Program and Regulatory Operations Acting Director: Giuseppe Randazzo Office of Policy for Pharmaceutical Quality Acting Director: Ashley Boam Office of Biotech Products Director: Steven Kozlowski Office of New Drug Products Acting Director: Sarah Pope Miksinski Office of Lifecycle Drug Products Acting Director: Susan Rosencrance Office of Testing and Research Director: Lucinda Buhse Office of Surveillance Acting Director: Russ Wesdyk Office of Process and Facilities Acting Director: Robert Iser

40 OPQ office structure OPQ Immediate Office (IO) Office of Program and Regulatory Operations (OPRO) Office of New Drug Products (ONDP) Office of Life Cycle Drug Products (OLDP) Office of Process and Facilities (OPF) Office of Testing and Research (OTR) Office of Surveillance (OS) Office of Policy for Pharmaceutical Quality (OPPQ) Office of Biotechnology Products (OBP)

41 OPQ office structure OPQ Immediate Office (IO) Office of Program and Regulatory Operations (OPRO) Office of New Drug Products (ONDP) Office of Life Cycle Drug Products (OLDP) Office of Process and Facilities (OPF) Office of Testing and Research (OTR) Office of Surveillance (OS) Office of Policy for Pharmaceutical Quality (OPPQ) Office of Biotechnology Products (OBP)

42 OPQ - Responsibilities Responsibilities include: Review of Chemistry, Manufacturing, & Controls portion for: New Drug Applications (NDA/ANDA/BLA) Post-approval CMC changes Annual Reports Pre-Approval Inspection decisions Evaluation of Compendia standards Development of Guidance and Policy 42

43 Team Based Review Integrated Quality Assessment (IQA) Team based review Kick off meetings begin each application Communication between disciplines throughout the review

44 Seamless Integration of Review, Inspection, Surveillance, Policy, and Research Drug Substance Product Experts Experts One Quality Voice Technical Advisors OPQ Laboratories Policy Surveillance Others as needed Process Experts Facility Experts Application Technical Lead (ATL) oversees the scientific content of the assessment Business Process Manager (BPM) manages the process, adhering to the established timelines 44

45 Integrated Quality Assessment Team IQA team will provide an aligned, patient-focused and risk-based drug product quality recommendations for BLAs, NDAs, and ANDAs, inclusive of drug substance, drug product, manufacturing, and facilities. IQA Teams consist of: Application technical lead (ATL) Regulatory business process manager (RBPM) Discipline reviewers Advisors, if needed lab (OTR), policy (OPPQ), surveillance (OS), etc.

46 Team-based Integrated Quality Assessment (IQA) Drug Substance Inspection Drug Product Surveillance Team-based Integrated Quality Assessment Biopharm Microbiology Process facility 46

47 Previous Review Process No formal risk assessment process to define scope and extent Discipline reviewers worked in isolation Independent reviews (or assessments) Separate review templates Rare communications between review functions and facility inspections Team-based Integrated Quality Assessment Formal risk assessment process to enhance efficiency and effectiveness of review and inspection Team of discipline reviewers with constant communication A single collaborative review (or assessment) Consolidated review template Integration of review with inspection for more informed decisions on facility acceptability and application approvability 47

48 IQA Team Roles Role / Task Scientific Content / Initial Risk Assessment Process and Timeline IQA Executive Summary Assessment of Drug Substance Assessment of Drug Product Assessment of the Manufacturing Process Assessment of Facilities Assessment of Biopharmaceutics Assessment of Microbiology Assessment of Environmental Analysis Facility Inspections FDA Labs Others as needed Responsible* -- OPQ Sub-office ATL OLDP RBPM OPRO ATL / IQA Team OLDP DS Reviewer ONDP DP Reviewer -- OLDP Process Reviewer OPF Facility Reviewer OPF Biopharm Reviewer ONDP Micro Reviewer OPF EA reviewer ONDP ORA Leads / SMEs participate OTR OS, OPPQ, etc * Represents General Cases 48

49 ANDA Original Process Current state: OPQ and OGD working to meet Cohort Year (CY) 3/4 15 mth GDUFA date. Proposed example of 10 mth CY 5 timeline: Filing Review (OGD) Review Team Assignmen t Kick-Off Meeting Assessment #1 and Cumulative IR #1 IR #1 Response Received and Reviewed Complete Inspection IR #2 Response Received and Final Review completed RBPM finalizes IQA/sends to OGD 0 60d Within 70d Within 90d Within 120d 4mo 6.5mo Within 7.0mo 6.5mo 8.5mo Within 9.0mo OPQ believes, in working with OGD and Industry, by CY5 the 1 st cycle approvability rate for ANDAs can be improved. This goal is achievable provided the ANDA submissions we receive are of high quality and complete upon first submission. 49

50 Office of Program and Regulatory Operations RBPMs Co-leads along with the Application Technical Lead (ATLs) for ANDAs. Responsible for leading and managing all processes associated with drug quality review and facility inspections. Coordinates with all OPQ offices to monitor and track all applications to ensure completion by goal dates Serves as the internal and external liaison for quality related products Triage all incoming submissions

51 Office of New Drug Products Division of Life Cycle API Drug Master File review Primarily reviewing Type II DMFs for GDUFA applications Only review DMFs which are referenced by an ANDA/NDA. DMF communications include major deficiencies, IR s, deficiencies, ECD s and No Further Comment Letters. The RBPM for quality responsible for issuing these letters Drug Substance (in general) Characterization (structure, physico-chemical properties, etc.) Manufacturing Issues Quality Control Container-Closure System Stability (shelf life)

52 Division of Biopharmaceutics Responsible for the Biopharmaceutics component of ANDA reviews. This entails release testing for quality control (e.g. dissolution) as well as biopharmaceutics related assessments to quality due to SUPAC related post approval changes

53 Office of Life Cycle Drug Product Original application drug product review Division of Immediate Release Products I Division of Immediate Release Products II Division of Modified Release Products Division of Liquid Products Post approval drug product review Division of Post Marketing Activities I Division of Post Marketing Activities II

54 OLDP Responsibilities Manage the lifecycle of both brand and generic drugs Evaluate and assess product quality Make risk-informed recommendations Evaluate post-marketing activities for Approved brand and generic drugs Assists OGD on certain Pre-ANDA meeting/request packages, responding to consults related to product quality.

55 Responsible for the following product quality components of applications: Formulation/product design Identifying potential failure modes Risk assessment Quality standards Clinically-relevant specifications Product characterization Method validation Control strategy related to product attributes Container/closure system stability

56 Office of Process and Facilities Division of Process 1,2 and 3 Oversees the scientific review and quality evaluation of the manufacturing process Participates PAIs as Subject Matter Experts when needed (based on risk) Division of Microbiology Assessment Reviews the Sterility portion of the application Responsible for the microbiological issues related to product quality and drug manufacturing Participates PAIs as Subject Matter Experts for large molecules or when needed (based on risk) for other products

57 Office of Process and Facilities (cont.) Division of Inspectional Assessment Responsible for reviewing the Facility portion of the application and making decisions/recommendations for PAIs/facility status. Works with Office of Regulatory Affairs (ORA) to prioritize inspection requests Participates PAIs as Subject Matter Experts when needed (based on risk)

58 Office of Testing and Research Method Validation Program (OPQ/OTR/DPA): Perform method validation on applicant methods as requested by reviewers Submit report detailing whether methods are acceptable, acceptable with modifications, or unacceptable for quality control and regulatory purposes Common methods evaluated: Assay, Impurities, Degradants, Dissolution DPA has averaged completed method validations (NDA/ANDA) for the past 4 years 58

59 OPQ disciplines complete At this point, the RBPM will compile all of the OPQ discipline recommendations, and communicate that status to the OGD RPM. If it is adequate, OGD can move towards an approval or tentative approval if their disciplines are also adequate. If there are deficiencies which were not satisfied with the IR response, they will be communicated to industry via CR from OGD.

60 Frequent Deficiencies Missing/unclear facility information and responsibilities ensure that the 356H shows the most current and complete facilities for your application. Failure to link the development work to the proposed commercial process/product. This includes the scale up plan. Ensure you have the data to justify potential future scale ups. Missing in-process controls or inadequate justification for in-process criteria based on development studies.

61 Frequent Deficiencies (cont.) Insufficient process/product knowledge. Address the issue of microbiological growth and controls during manufacturing of non-sterile oral dosage forms. Contact the RBPM for all questions related to Quality-only correspondences received (IR). Continue to use the OGD/OND RPM as the point of contact for general inquiries.

62 Frequent Deficiencies (cont.) Be aware of your information request response deadline. Only respond to IR with requested information. Additional unsolicited information may impact review time and goal dates. Correctly code all submissions and amendments to ensure accurate triage and goal dates applied. Changes to facilities, either additions or withdrawals, at or near patent expiry dates or close to approval.

63 Frequent Deficiencies (cont.) Deficiencies related to facilities (OAI/POAI or data integrity issues.) Failure to make timely payments for facility user fees.

64 Divisions of Bioequivalence 64

65 65 Office of Generic Drugs Office of Research and Standards Office of Bioequivalence Office of Generic Drug Policy Office of Regulatory Operations Division of Therapeutic Performance Division of Bioequivalence 1 Division of Legal and Regulatory Support Division of Filing Review Division of Quantitative Methods and Modeling Division of Bioequivalence 2 Division of Policy Development Division of Project Management Division of Bioequivalence 3 Division of Labeling Review Division of Clinical Review Division of Quality Management Systems

66 66 Divisions of Bioequivalence (DB): Structure Three Divisions. Each Division has a Director, Deputy Director, and an Associate Director. Directors: Division of Bioequivalence I: Dr. Bing V. Li, Acting Director Division of Bioequivalence II: Dr. Ethan M. Stier, Director Division of Bioequivalence III: Dr. Nilufer Tampal, Acting Director Six teams per Division, with each team headed by a Team Leader (Lead Pharmacologist). Approximately four primary reviewers per team.

67 67 DB Responsibilities and Process Review of bioequivalence data submitted in ANDAs Identify and request inspections for analytical and clinical BE sites requiring an Office of Study Integrity and Surveillance (OSIS) inspections Coordinate, draft, and inform ANDA applicants of BE IRs and ECDs

68 68 DB Responsibilities and Process (cont d) Reviews may be two-tier (i.e., a primary and secondary review) or three-tier (i.e., a primary, secondary, and tertiary review) depending on the complexity of the submission Assist in product-specific recommendation development/revision Review of protocols Involved in projects pertaining to regulatory science

69 69 Examples of Common Deficiencies Incomplete bioanalytical report (e.g., missing validation studies, 100% raw analytical data not provided) Incomplete and/or inadequate justification of repeat analyses Standard operating procedures not provided Composition of colorant or flavor used in the test formulation not submitted

70 Division of Clinical Review (DCR) 70

71 71 Office of Generic Drugs Office of Research and Standards Office of Bioequivalence Office of Generic Drug Policy Office of Regulatory Operations Division of Therapeutic Performance Division of Bioequivalence 1 Division of Legal and Regulatory Support Division of Filing Review Division of Quantitative Methods and Modeling Division of Bioequivalence 2 Division of Policy Development Division of Project Management Division of Bioequivalence 3 Division of Labeling Review Division of Clinical Review Division of Quality Management Systems

72 72 Division of Clinical Review (DCR) Involved primarily in two types of reviews - Drug products that exert some or all of their activity directly at the site of application (such as topical dermatological products or nasal sprays) - Consults regarding clinical or safety concerns

73 Division of Clinical Review (DCR) Elements of topical drug product reviews Review clinical endpoint studies and studies related to skin irritation and adhesion for transdermal films and patches Contingent on satisfactory clinical site inspections when OSIS determines those inspections are necessary

74 DCR Consults Pharmacology/toxicology consults - Safe levels of impurities, degradants, and residual solvents - Excipient issues Clinical consults - Review excipients that have biologic activity - Safety concerns raised by containers/devices - Tmax concerns Can seek input from other disciplines for complex consults including: - Office of New Drugs - Office of Surveillance and Epidemiology

75 Suggestions to Improve Applications Ensure novel excipients are not in the DMF - Not reviewed at filing - Typically requires preclinical and clinical safety data outside the scope of an ANDA submission Ensure that differences in proposed container closure system or drug-device product does not require clinical studies to establish safety or effectiveness or necessitate labeling differences from the RLD beyond those permitted in an ANDA

76 Suggestions to Improve Applications Consider the clinical aspects of the excipients Some have biologic activity May present safety issues Examples: Sugar in a product used to treat diabetes Agents that cause osmotic diarrhea in a product to treat irritable bowel syndrome Known migraine triggers in a product to treat migraines Failed studies Avoid the temptation to do a post hoc analysis and submit it as a pivotal study in support of your product

77 Risk Evaluation and Mitigation Strategy (REMS) 77

78 78 Risk Evaluation and Mitigation Strategy (REMS) Does your ANDA require a REMS? Look up the RLD on FDA s REMS website at:

79 Once an ANDA is Received You will receive a REMS notification letter (RNL) instructing you on: Who to contact if there is a shared system REMS or if a shared system needs to be developed The required elements of the REMS Follow the instructions on how the REMS should be submitted Your REMS is NOT complete without a REMS supporting document Title your cover letter as instructed and ensure your Form 356h Submission Type matches the cover letter title You do NOT need to wait for RNL to submit your REMS

80 80 No Shared System REMS Established? Clearly state in your cover letter, what contact you have made with the RLD sponsor to develop a shared system REMS We encourage you to NOT wait for your RNL to begin discussions with the RLD sponsor In addition to the RNL, the OGD REMS Coordinator will send you a disclosure authorization letter, allowing the Agency to begin discussions with the ANDA and RLD sponsor regarding the development of a shared system REMS Expect a meeting invitation (will include the RLD sponsor and all received ANDAs) from the Office of Surveillance & Epidemiology (OSE) Project Manager to discuss developing a shared system REMS

81 81 What if I Receive a CR? If you are joining an already established shared system REMS, it is important that you RESUBMIT the most current version of the REMS in your response to the CR If you were involved in discussions toward developing a shared system REMS, you will continue to be involved in these discussions Not participating in REMS discussions after you receive a CR, may cause delays in your approval

82 Division of Labeling Review (DLR) 82

83 83 Topics Division of Labeling Review Organization Labeling Review Process Receiving Deficiencies BPCA/PREA Carve-outs Helpful Links Labeling Points of Contact

84 84 Office of Generic Drugs Office of Research and Standards Office of Bioequivalence Office of Generic Drug Policy Office of Regulatory Operations Division of Therapeutic Performance Division of Bioequivalence 1 Division of Legal and Regulatory Support Division of Filing Review Division of Quantitative Methods and Modeling Division of Bioequivalence 2 Division of Policy Development Division of Project Management Division of Bioequivalence 3 Division of Labeling Review Division of Clinical Review Division of Quality Management Systems

85 85 Application Process ANDA application acceptable & complete Regulatory Project Manager (RPM) Routes to Labeling Project Manager (LPM) Quality Review Labeling Review Bioequivalence Review Facility Inspection

86 Labeling Review Process 86

87 87 Receiving Labeling Deficiencies ECD Sent via to contact listed on the 356h by the labeling project manager (LPM) For application specific questions, contact the LPM listed in the ECD Do not respond to the ECD directly as it is a send-only account

88 88 Receiving Labeling Deficiencies CR Reflects full division-level review of deficiencies from all relevant review disciplines Amendments submitted late in the review cycle may be deferred and reviewed with the CR response Direct Communication by LPM Communicated via phone or Clarifies labeling only submission questions

89 89 Labeling BPCA/PREA Carve-outs LPM will issue model labeling template once finalized Template typically addresses pediatric information only Disclaimer should be replicated verbatim Please ensure all patent and exclusivity statements are up to date If template does not apply to your application do not revise labeling

90 Helpful Labeling Links last approved labeling D= &CFTOKEN=efcc9740da7b781f-BE6C3C0A-F263-A15C- F9871BDEAE083C69 Orange Book-for patent, exclusivity information Antibiotic Breakpoint Labeling Updates dtobacco/cder/ucm htm

91 DLR Points of Contact Any questions can be directed to the Labeling Project Management staff below: Original Submissions Julie Call at Juliette Larmie-Gyamfi at Carrie Lemley at Sunny Pyon at Danielle Russell at Labeling Supplement Submissions Kyle Snyder at Carol Yun at 91

92 92 ENDORSEMENT STAGE (CLEARANCE PHASE)

93 Division of Legal and Regulatory Support 93

94 94 Office of Generic Drugs Office of Research and Standards Office of Bioequivalence Office of Generic Drug Policy Office of Regulatory Operations Division of Therapeutic Performance Division of Bioequivalence 1 Division of Legal and Regulatory Support Division of Filing Review Division of Quantitative Methods and Modeling Division of Bioequivalence 2 Division of Policy Development Division of Project Management Division of Bioequivalence 3 Division of Labeling Review Division of Clinical Review Division of Quality Management Systems

95 Review of Hatch Waxman related information by Patent/Exclusivity Team Purpose: OGD, in a ministerial role, ensures that ANDA applicants have addressed all listed patents and exclusivities prior to the issuance of TA or Full Approval OGD ensures that all required documentation related to patents and exclusivities has been provided by applicants OGD ensures consistent application of Hatch Waxman policy and precedents across applicants

96 Review of Hatch Waxman related information by Patent/Exclusivity Team Purpose: (Cont d) OGD ensures that all grants of 180 day exclusivity are consistently applied and compliant with the Forfeiture Provisions of 505(j)(5)(D)(I)-(VI) of the FD&C Act Creates a record of ANDA status at the time the action was taken Conducted during endorsement phase of all actions for Tentative or Full Approval

97 Information Reviewed Original submission including Basis of Submission, all patent certifications, exclusivity statements, and aspects of labeling that may have been omitted All patent and exclusivity amendments Certifications/statements to newly listed patents Changes to certifications and impact on labeling/timing of approval All information required by (e)-notice requirements and (e)-court actions

98 Information Reviewed Any labeling amendments potentially related to changes in certification, submission of section viii statement(s) or which address a new exclusivity and/or change in exclusivity statement All new strength amendments Significant formulation changes Other: potential eligibility for 180 day exclusivity pre/post MMA drug product potential for forfeiture of exclusivity by First Filer(s) Late listed statements under (a)(12)(vi) Applicability of CPs

99 99 Outcome of Review If required documentation is missing, information is requested from sponsor generally via ANDA will NOT receive final action until all required documentation has been submitted Questions may be posed of the sponsor if something is unclear Calculation of relevant prospective actionable dates for all ANDAs 30 month stay 7.5/8 year stay of approval Patent expiry Ensure consistency between labeling and patent certifications/statements and exclusivity statements

100 100 Outcome of Review Analyze and confirm late-listed status as defined by 21 CFR (a)(12)(vi) Sponsor must assert their belief that patent is late-listed via letter to their ANDA. Overall recommendation of TA or full approval (FA) based on facts submitted by applicant. Reason for TA identified when applicable Recommendation for grant of 180 day exclusivity when applicable Identification of actual or potential forfeitures Review of TA or FA letter for accuracy

101 101 Frequent Problems/Omissions Sponsor has not addressed ALL patents and/or exclusivities PIV certifications to later-listed patents Sponsors must still submit documentation that notice was sent to NDA holder and patent assignees Inconsistencies between patent certifications or between patent certifications and labeling. Labeling must match manner in which sponsor has addressed listed patents Sponsor must generally address patent(s) which are associated with the same use code(s) in the same manner. Sponsors may need to provide split-certifications for patents to maintain consistency

102 102 Frequent Problems/Omissions Sponsors do not submit all information required by 21 CFR (e) and (f)(2) All court decisions/orders MUST be submitted to the application This includes dismissal orders and adverse court decisions Sponsors do not convert certifications from PIV to PIII Required by 21 CFR (a)(12)(viii)(A) when a final judgment has been entered finding the patent infringed

103 103 Opportunities for Improvement by Industry Submission of all required documentation related to notice (21 CFR (e)) Submission of all Court Decisions in a timely manner Late submission of Court Decisions can impact timing of approvals. Submission of Launch notices for applicants eligible for 180 day exclusivity (21 CFR (c)(4))

104 104 Opportunities for Improvement by Industry Submission of Court Orders that resolve litigation within 10 days of issuance Submission of Pediatric Waivers Applicable when ANDA applicant intends to be approved during 6 month period of pediatric exclusivity associated with a patent Pediatric Waivers MUST be provided even with settlement agreements General Awareness of Agency s rules and applicability of pre-mma 180 day exclusivity

105 105 Future State Additional reminders to industry regarding missing information Potential incorporation of Hatch Waxman information in other letters Additional information available internally for RPMs and others regarding eligibility for Full Approval and timing of TAs This information is only as good as the documents provided by the ANDA sponsor.

106 106 Disciplines Verify all relevant submissions reviewed Verify reviews are up to date - RLD labeling updates - Compendial changes - DMF status - Facilities status - All patents and exclusivities addressed

107 107 Approval Final Signature by Office of Regulatory Operations Deputy Director (or designee) RPM call and of approval letter Official approval letter mailed Orange Book updated

108

109 We All Win!