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1、Request for Reconsideration Under GDUFA III Overview and Experience from a Bioequivalence PerspectiveYi Zhang,Ph.D.Associate Division DirectorDivision of Bioequivalence III/Office of BioequivalenceOffice of Generic Drugs|CDER|US FDA2025 Generic Drug Forum April 9,2025fda.gov/cdersbiafda.gov/cdersbia

2、2Learning ObjectivesTo define a Request for Reconsideration(RfR)To differentiate what it means to Accept vs.Not Accept and Grant vs.Deny for RfRsTo understand FDAs process for reviewing/responding to RfRsTo understand Office of Bioequivalence(OB)s current perspective and experience when reviewing Rf

3、Rsfda.gov/cdersbiafda.gov/cdersbia3Disclaimer:This presentation reflects the views of the author and should not be construed to represent FDAs views or policies.fda.gov/cdersbiafda.gov/cdersbia4What is a Request for Reconsideration(RfR)and why it is needed?A procedure between FDA and ANDA applicants

4、 to resolve scientific and/or regulatory issues or matters.-Guidance for Industry:RfR at the Division Level Under GDUFA(Finalized 10/2024)GDUFA III Commitment Letter:The applicant may pursue a request for reconsideration(RfR)within the assessment discipline at the division level or original signator

5、y authority,as needed.fda.gov/cdersbiafda.gov/cdersbia5Related Guidance:Two FDA guidance related to RfR published in 2024:-Guidance for Industry:ANDA Submissions Amendments to Abbreviated New Drug Applications under GDUFA(Finalized 9/2024).-Guidance for Industry:Requests for Reconsideration at the D

6、ivision Level Under GDUFA(Finalized 10/2024).fda.gov/cdersbiafda.gov/cdersbia6Initially published in 2017Current version to reflect GDUFA III updatesRecommendations to ANDA applicants on pursuing a RfR within the review discipline.Appropriate matters for RfRs.FDAs timelines and procedures for review

7、ing and responding to RfRs.fda.gov/cdersbiafda.gov/cdersbia7Section VII.RfR of major amendment classification Other related information:-How to classify ANDA amendments as major vs minor,and corresponding assessment Goal dates under GDUFA III?-Examples of“Potential Major Deficiencies”across differen

8、t review disciplines e.g.,Pharmaceutical Quality,Bioequivalence(BE),Labeling,et al.fda.gov/cdersbiafda.gov/cdersbia8RfR received by FDAAssign RfR to RPM in OROAccept/Not Accept EvaluationInitial assessment by RPM;Review discipline(s)may be consulted Discipline(s)review RfR Attend T-con if requestedD

9、iscipline(s)provide finalized internal memo for grant/deny decision and written response to RPMFinal grant/deny decision letter signed and email courtesy copy to the applicantFDAs Process for Reviewing/Responding to a RfR:Initial Assessment(Agencys action upon submission of the request):Accept:RfR s

10、atisfies the accept criteria(Section IV.C of guidance)and a grant/deny decision letter will be provided.Not Accept:RfR does not satisfy the accept criteria(Section IV.C of guidance)and does not receive a grant/deny decision letter Applicant will be informed with reason(s).A grant/deny decision lette

11、r(Agencys action after acceptance and review of the request)Grant:The signatory authority agrees with the applicants proposal for the reconsideration request(Applicable shortened goal dates may apply).Deny:The signatory authority does not agree with the applicants proposal for the reconsideration re

12、quest and the reason(s)will be provided.-Per Guidance for Industry:RfR at the Division Level Under GDUFAfda.gov/cdersbiafda.gov/cdersbia9RfRs Triaged to Office of Bioequivalence(OB)and Outcomes63423124202629 Survey data collected based on Fiscal Year for GDUFA II(10/2017-9/2022)and GDUFA III(10/2022

13、-9/2024).Total#of RfR reviewed by OB per year from FY18 to FY24.Outcome/Subcategory of RfR:Accept vs.Not Accept(to review by OB);Grant vs.Deny(after accepted and reviewed by OB).fda.gov/cdersbiafda.gov/cdersbia10FY 2018-2024Total#Not AcceptableGrantedDeniedWithdrawn#of RfR Assessed by OB(%Percentage

14、)235(100%)14(6%)77(33%)142(60%)2(1%)Accumulative data for RfRs reviewed by OB(FY18-FY24)and overall outcomes.Appeal Reasons:Of 235 RfRs reviewed by OB,-Requests for reclassification from major to minor,96%of RfRs.i.e.,Reclassification of a major CRL(complete response letter);Reclassification of a ma

15、jor amendment-Requests to reconsider BE deficiency(4%)and others(1%;e.g.,Downgrade“TE”code from A*to B*),4%of RfRs.RfRs Triaged to OB and Outcomesfda.gov/cdersbiafda.gov/cdersbia11Guidance for Industry:ANDA Submissions Amendments to ANDAs under GDUFA(9/2024).APPENDIX A:Potential Major Deficiencies:B

16、1.BE a.Inadequate or insufficient in vivo or in vitro BE studies requiring submission of new studiesb.Inadequate physicochemical datac.Deficiencies related to device comparability for nasal/inhalation products that require consult to other offices within the Agency or require additional BE studiesd.

17、Insufficient validation data that would require extensive review of resubmitted data and/or development of new analytical procedures with full validation datae.Reintegration of chromatograms that may result in method revalidationf.Reanalysis of samples required due to contract/clinical research orga

18、nization issue,site issue,analytical issue,inadequate justification for reanalysis of samples,or other significant issuesg.Insufficient justification for protocol deviations that could impact the BE determinationh.Submission contains an in vivo study with a serious adverse event(s)or death(s)possibl

19、y related to test producti.Inadequate in vitro dissolution testing or in vitro alcohol dose dumping study data resulting from,for example,the use of aged or expired batches or inadequate study methodologyj.Information needed to address the impact of significant Office of Study Integrity and Surveill

20、ance inspectional or review findingsk.Inadequate formulation and/or recommendation to reformulatel.Deficiencies identified during the technical review related to excipient intake above the limit in the Inactive Ingredient Database without adequate justificationm.Deficiencies related to sugar alcohol

21、 content in a drug product formulation in cases where an in vivo comparative study is not conducted,or adequate justification is not providedn.Consult-related deficiencies found including,but not limited to:insufficient information submitted to address safety issues;insufficient information to addre

22、ss tablet size,or a change in device/container closure;and insufficient information to support alternative study designs in relation to the product-specific guidanceo.Deficiencies related to changes in FDAs guidances for industry that result in inadequate in vivo and/or in vitro BE studiesp.Inadequa

23、te information to support that the alternate method is acceptable for demonstrating BE between productsq.Unacceptable study data due to a concern about study conduct or data integrityMajority of RfRs reviewed by OB are Reclassification Requests(major to minor)for either major CRL or major amendment.

24、A non-exhaustive list of examples of major BE deficiencies.The determination of a major or minor deficiency will be in the judgment of the relevant assessment discipline.FDA attempts to resolve possible deficiencies identified during the assessment cycle through information requests(IRs)and discipli

25、ne review letters(DRLs)prior to sending them in a CRL.In general,a CRL classification will advise the applicant whether a CRL response will be classified as a major or minor amendment.However,FDA may change its classification of the CRL response based on the content of the amendment.Potential Major

26、BE Deficienciesfda.gov/cdersbiafda.gov/cdersbia12Case Studies-RfRs Reviewed by Office of Bioequivalence(OB)fda.gov/cdersbiafda.gov/cdersbia13BE deficiency in CRL classified as major due to a failed in vitro BE study and a new BE study was requested.RfR requesting reclassification of CRL deficiency m

27、ajor to minor with reanalysis of previously submitted BE data in the RfR.OBs assessment:-Reanalysis of previously submitted data using a different approach is considered as new information.-RfR is not acceptable(Recommended to submit new information as CRL amendment).Key Considerations:-Applicant sh

28、ould not submit new information as part of a RfR because FDAs decision must be based on the same information that was used to make the original decision(i.e.,information already in the ANDA file).-FDA considers new analyses of previously reviewed data submitted by the applicant to be new information

29、.Case#1:RfR Not Acceptablefda.gov/cdersbiafda.gov/cdersbia14BE deficiency in CRL classified as major due to an inadequate in vivo BE study and a new BE study was requested.CRL amendment submitted along with a RfR requesting reclassification of amendment major to minor.Additional information/data sub

30、mitted to justify the acceptability of original BE study.OBs assessment:-Major CRL classification aligning with FDA Guidance,ANDA Submissions-Amendments to ANDAs Under GDUFA.-Significant new information/data(including modeling data)submitted in CRL amendment requiring a substantial assessment,includ

31、ing potential consultation to other office.FDA uphold the initial decision,and no change to be made to the classification of CRL amendment.Key Considerations:-The major classification of an amendment is based on a determination by FDA that the content of the information or data provided will require

32、 extensive assessment.Case#2:RfR Deniedfda.gov/cdersbiafda.gov/cdersbia15CRL classified as major due to inadequate in vivo BE study related to quality concerns of test product(including bio-bath)identified by Office of Pharmaceutical Quality(OPQ),and a new BE study was requested.CRL amendment submit

33、ted along with a RfR requesting reclassification of amendment major to minor.Applicant stated that new BE study is not warranted as the quality concerns had been resolved with additional supportive information/data submitted to OPQ.OBs assessment:-OB agrees that no substantial information/data or un

34、solicited information is provided in this amendment.-RfR is granted(GDUFA goal date will be revised accordingly if applicable).Key Considerations:-OB may grant a RfR(major to minor)provided that no substantial information is submitted in the amendment that requires extensive assessment by OB.-Accept

35、ability of justification will be evaluated during the scientific assessment of amendment.Case#3 RfR Grantedfda.gov/cdersbiafda.gov/cdersbia16Challenge Question#1If the BE deficiencies are issued as major in a discipline review letter(DRL),can the applicant submit a RfR to request reclassification of

36、 this DRL from major to minor?A.Yes B.Nofda.gov/cdersbiafda.gov/cdersbia17Advice communicated during meetings or in meeting minutes,and in other correspondence(e.g.,information requests,discipline review letters)is not a regulatory action taken by FDA;therefore,such advice would not be an appropriat

37、e subject for a request for reconsideration by an applicant.Challenge Question#1-Guidance for Industry:RfR at the Division Level Under GDUFA(Finalized 10/2024)fda.gov/cdersbiafda.gov/cdersbia18Challenge Question#2Which of the following statements is NOT true?A.FDA will schedule and conduct the telec

38、onference and decide 90%of such reclassification requests within 30 days of the receipt date,when request for reconsideration submitted within 7 calendar days from the date of the regulatory action taken by FDA.B.An applicant may request a change in the assessment classification at any time during t

39、he assessment.C.The major BE deficiency must be listed in“APPENDIX A:Potential Major Deficiencies”of Guidance for Industry:ANDA Submissions Amendments to ANDAs under GDUFA.D.If the eligible request cannot be resolved through the request for reconsideration process at the division level or original s

40、ignatory authority,the applicant may pursue formal dispute resolution above the division level.fda.gov/cdersbiafda.gov/cdersbia19SummaryRfR is a procedure between FDA and ANDA applicants to resolve scientific and/or regulatory issues or matters.Most RfRs received and reviewed by OB are reclassificat

41、ion requests(major to minor)for either major CRLs or major amendments.A non-exhaustive list of potential major BE deficiencies has been updated in the Guidance for Industry:ANDA Submissions Amendments to ANDAs under GDUFA(9/2024).All initial amendment classifications and any changes to those classif

42、ications will be made at FDAs discretion.Typically,a CRL classification will advise whether a CRL amendment is major or minor.However,FDA may change its classification based on the content of the amendment reviewed on a case-by-case basis.FDA will inform the applicant of the reason(s)if a RfR is not

43、 accepted(to review)or denied.fda.gov/cdersbiafda.gov/cdersbia20April Braddy,Ph.D.,RAC,SEPDirector,Division of Bioequivalence IIIKe Ren,Ph.D.Deputy Director,Division of Bioequivalence IIILCDR Martin Yoon,Pharm.D.Lead Program Manager,Division of Bioequivalence Process ManagementCDR Chitra Mahadevan,Pharm.D.,M,S,BCPS,PMP Director,Division of Bioequivalence Process ManagementPartha Roy,Ph.D.Director,Office of BioequivalenceACKNOWLEDGEMENTS