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IND CMC amendments

  • 1.  IND CMC amendments

    This message was posted by a user wishing to remain anonymous
    Posted 12-Jul-2022 15:49
    This message was posted by a user wishing to remain anonymous

    For manufacturing of marketed products, there is PAS, CBE-30, CBE-0, and annual report.  On the other hand, if there are moderate or major changes to the CMC in the IND stage, you file an IND amendment and request the FDA to respond.  If you do not hear back from the agency after 30 days, can you implement the change ?

    More broadly, in your experience, how often does the FDA respond to IND CMC amendments ?  10% of the time ?  Or does it depend on the stage of the development, e.g. you almost never hear back from the agency on a CMC change before pivotal trials ?


  • 2.  RE: IND CMC amendments

    Posted 13-Jul-2022 06:45
    Hi Anon

    I have submitted several IND CMC Amendments and have actually never seen an acknowledgement or approval letter from FDA in at least Phase 1 or phase 2 stages. We used to implement the change after 30 days. Not sure if that's how it is about IND amendments with FDA. Others can also share their experiences.

    Thanks!

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    Sharry Arora, M.Ph, RAC
    Ireland
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    Original Message


  • 3.  RE: IND CMC amendments

    Posted 13-Jul-2022 08:16
    It is my experience that FDA reviewers do not respond to ANY kind of amendment to an IND unless there is a safety issue that requires intervention. Unless the change you are making has a high risk of a safety issue (i.e., reduction in product quality) I also don't see any reason to wait 30 days to implement the change. But then, why would you make such a change?

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    Glen Park PharmD
    Vice President, Regulatory Affairs and Quality Assurance
    New York NY
    United States
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    Original Message


  • 4.  RE: IND CMC amendments

    This message was posted by a user wishing to remain anonymous
    Posted 13-Jul-2022 09:44
    This message was posted by a user wishing to remain anonymous

    Thank you all for the responses !
        We simplified an assay to qualify a raw material that has some presumed implications to safety for an early phase autologous product (the potential risk here is pure theoretical and not supported by clinical experience to our knowledge).  Would waiting for 30 days to give the agency a chance to review be a good practice ?  We have actually waited for some 60 days now.
        Thanks again.

    OP
    Original Message


  • 5.  RE: IND CMC amendments

    Posted 13-Jul-2022 11:12
    30 days is more than necessary for the change you have described!

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    GRSAOnline
    ------------------------------

    Original Message


  • 6.  RE: IND CMC amendments

    Posted 14-Jul-2022 06:19
    I concur with the input by others in this thread, no need to wait (even a single day) after submitting an amendment to an active IND, and I can also share the same experience, the Agency will never comment unless they have serious safety concerns about the change(s) you intend to implement.
    If you, the Sponsor, have concerns and are not confident about the potential impact of the change, then I'd consider engaging them in a formal interaction and ask for guidance (this might become even easier under PDUFA VII, with the new Type D meetings). Doesn't seem the case here, though.

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    Maurizio Franzini
    Regulatory Affairs CMC, Director
    San Francisco CA
    United States
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    Original Message


  • 7.  RE: IND CMC amendments

    Posted 27-Mar-2024 08:47

    Hello, 

    I am currently trying to assess a change control for a biological origin material and I was wondering is there any FDA and/or ICH guidance for Clinical Quality Amendment describing which changes are reportable as an amendment and which as Annual Report? Similar to Post-Approval Changes guidance for Commercial?

    Thank you.

    PV



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    Parita Varma MSRA
    Senior Manager Regulatory Affairs -CMC
    Bristol Myers Squibb - ENTERPRISE
    Boston MA
    United States
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    Original Message


  • 8.  RE: IND CMC amendments

    This message was posted by a user wishing to remain anonymous
    Posted 27-Mar-2024 09:20
    This message was posted by a user wishing to remain anonymous

    You need to file an amendment whenever there is a CMC change during IND phases! CMC annual report for INDs is not the same thing as for post approval Annual report! IN IND CMC Annual report you summarize all the CMC amendments made during the year plus you can submit any updates (NOT new changes) to the CMC amendments made during that year! Update to stability data etc.....


    Original Message


  • 9.  RE: IND CMC amendments

    Posted 27-Mar-2024 09:24

    For FDA there is INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information | FDA. The information is rather scattered throughout the text and is pretty high level, but it's all we have from them.

    EU has Requirements for quality documentation concerning biological investigational medicinal products in clinical trials - Scientific guideline | European Medicines Agency (europa.eu). Generally if the EU considers it a substantial amendment, FDA would want an IND amendment.

    Canada has Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications - Canada.ca which includes a section on CMC changes and whether they would be amendments or notifications. Again, if it's an amendment in CA, then it's safe to assume you should do an amendment to FDA. One difference is shelf-life extensions: those are always AR assuming you submitted the stability protocol.

    Hope that helps.



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    Rachel Thornton
    Director
    Smyrna GA
    United States
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    Original Message


  • 10.  RE: IND CMC amendments

    Posted 27-Mar-2024 09:39

    Thank you, Rachel. That's what I figured that there is no straight forward FDA guidance for IND Information Amendment/ Quality Amendment. As suggested, I am planning to leverage information from CA guidance to assess this change control.

    Best,

    Parita



    ------------------------------
    Parita Varma MSRA
    Senior Manager Regulatory Affairs -CMC
    Bristol Myers Squibb - ENTERPRISE
    Boston MA
    United States
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    Original Message


  • 11.  RE: IND CMC amendments

    This message was posted by a user wishing to remain anonymous
    Posted 13-Jul-2022 09:42
    This message was posted by a user wishing to remain anonymous

    During IND stage, only if there is a safety related issue they would respond within 30 days else they can take their own time i.e. no time limits for amendments.
    Original Message


  • 12.  RE: IND CMC amendments

    This message was posted by a user wishing to remain anonymous
    Posted 14-Jul-2022 11:56
    This message was posted by a user wishing to remain anonymous

    Thank you all again for the comments and insights !
        1) If the sponsor does not hear back from the agency after 30 days, can it assume that the FDA will not likely to ever respond ?  In other words, if the sponsor implements the change after 30 days with no response from the FDA, the agency will never respond after, say 90 days, and say the change is not a good idea ?  We understand the FDA is the gatekeeper, but the sponsor has the ultimate responsibility for patient safety.
        2) Related to the question above, we plan on making some significant changes to the manufacturing process of a complex biological product in phase I.  There is no reason for us to believe that the changes will impact patient safety.  Can we file an IND amendment, then implement the changes immediately, or to be on the safe side, wait 30 days ?

    OP
    Original Message


  • 13.  RE: IND CMC amendments

    Posted 14-Jul-2022 13:26
    As mentioned before, only safety impacted change will be responded within 30 days, else they will take their own time to respond or they may never respond if all the data submitted in support of that change is adequate, else they would ask for additional supportive information/or clarification etc. even after several months! 

    Second question: I'd wait 30 days because of how you describe your product and the change i.e. "complex biologic" (autologous) and "significant changes". I assume these changes will be made after you initiated the Phase 1 human study with the previous or original IND material. Plus you are dealing with OTAT not CDER for small molecules and therapeutic biologics. so 30 day wait is reasonable.

    Contact me privately if you need any help!

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    GRSAOnline
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    Original Message


  • 14.  RE: IND CMC amendments

    This message was posted by a user wishing to remain anonymous
    Posted 18-Jul-2022 09:22
    This message was posted by a user wishing to remain anonymous

    Thanks Narayan !
          It does not seem to be regulations, MAPPs, or SOPPs that mandate or recommend the 30-day wait period for safety impacted changes.  This wait period is just an unwritten rule ?

    OP
    Original Message


  • 15.  RE: IND CMC amendments

    Posted 18-Jul-2022 11:59
    By regulation, you do not have to wait any amount of time after filing an IND amendment. Their primary concern at this point is safety. If they have a serious safety concern, such that they would stop the trial, they will get back to you ASAP as they know there is no requirement to wait. I have seen, on occasion, questions come back on CMC IND amendments at some point, but you just answer their questions... they have never been such that they would stop the trial or forbid us from using that material in the study. One thing they will never do is send an "approval letter" for a CMC change.

    I do not have experience in cell or gene therapy, and I realize there can be additional safety issues at play, so I can't really comment on how conservative FDA might be in your case. If you have are able to wait 30 days, that should be safe. But it's not a regulatory requirement. You just need to assess the business risk (impact x probability) of the worst case scenario.

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    Rachel Thornton
    Associate Director
    Smyrna GA
    United States
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    Original Message


  • 16.  RE: IND CMC amendments

    This message was posted by a user wishing to remain anonymous
    Posted 19-Jul-2022 09:33
    This message was posted by a user wishing to remain anonymous

    Hi Rachel

        Thank you for the comments. 
        One follow-up question that is not directly related to my original one: PDUFA mandates a review timeline of 6 months of a CBE-30 post-marketing approval change.  Theoretically, it is possible for the sponsor to implement the change after 30 days, then some months later, the agency comes back to say they do not agree with the change, and the sponsor has to reverse it ?

    OP
    Original Message


  • 17.  RE: IND CMC amendments

    Posted 19-Jul-2022 09:52
    Yes, there is the possibility that you implement a change after 30dys and then the Agency comes back with questions or even a CRL (that happened to us once). So you have to weigh the business risk of waiting for the approval vs. dealing with the fallout if they don't approve. FYI, there is a MAPP (Manual of Policies and Procedures) on drug product distribution after a CRL action to a CBE supplement (Drug Product Distribution After a Complete Response Action to a Changes Being Effected Supplement (fda.gov))

    At least for a CBE-30 they do eventually issue an approval letter! 


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    Rachel Thornton
    Associate Director
    Smyrna GA
    United States
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    Original Message


  • 18.  RE: IND CMC amendments

    Posted 30 days ago

    Hi

    If you intend to make significant changes to the manufacturing process for a cell-based product then I would advise that you request advice from OTP at CBER regarding the comparability assessment that you intend to perform to demonstrate that pre- and post-change product batches are comparable.

    Note the current draft guideline: Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products

    https://www.fda.gov/media/170198/download

    And also use other gene and cell therapy guidance to gain insight into expectations, e.g. the recent CAR-T guidance:

    https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances

    Alexis



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    Alexis Cockroft
    Lex Regulatory Ltd
    Royston
    United Kingdom
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    Original Message


  • 19.  RE: IND CMC amendments

    Posted 27-Mar-2024 11:36

    In the FDA Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) guidance, there is the following text related to information amendments and a "recommended" waiting period:

     For amendments containing numerous or significant changes (e.g., manufacturing process, assays for critical quality attributes (CQAs), new manufacturing site or manufacturer, etc.), we recommend that you include a "Reviewer's Guide," as described in FDA's "eCTD Technical Conformance Guide: Technical Specifications Document," (Ref. 4) or a document with all changes tracked, and that you allow sufficient lead time (e.g., 30 days) for FDA review before release of a new lot of clinical trial material.



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    Scott Burian RAC, PhD
    Sr. Dir. Regulatory Affairs CMC
    Mallinckrodt Pharmaceuticals (Specialty Brands Principal Office)
    Chapel Hill NC
    United States
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    Original Message


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