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  • 1.  CMC expectations for a Fast Track NDA

    Posted 22-Mar-2020 22:26

    For a small molecule oncology drug, how would you expect Fast Track status to influence FDA's expectations for the CMC package?  I am working with a compound that was only synthesized under GMP one time, with purity and assay values in the low 90% range.  Numerous impurities were qualified due to their presence in nonclinical batches, but not identified.  The manufacturing process and analytical methods were adequate to open an IND and proceed into Phase 2 trials.  If the goal was to file an NDA without any special Fast Track status, we would be expected to optimize the API manufacturing process and the analytical methods, identify some impurities, manufacture registration stability batches and validation batches, identify critical process parameters, and conduct similar activities for the drug product.  Would Fast Track status result in relaxed expectations for any of these CMC activities?  Or would all of the usual CMC activities need to be completed before the NDA could be approved?

     

    John M Wetzel, PhD

    Wetzel Chemistry Consulting, LLC

    4141 Baker Road

    Albany, OH  45710

    740-698-0420

    www.wetzelconsulting.com

     



  • 2.  RE: CMC expectations for a Fast Track NDA

    Posted 23-Mar-2020 09:59
    My sense is that the CMC requirements for approval are less about the amount of time available to perform them then on the risk-benefit assessment for the indication. I have heard several presentations on the review and approval process for Breakthrough Therapy products where FDA has gone out of their way to help companies get their CMC work done while keeping the requirements for quality of the product high. I do see some flexibility for products treating serious and life-threatening diseases and unmet medical need. However, I think it is imperative to plan all that can be done and then discuss with FDA what flexibility there will be. It is possible that some activities could become post-marketing requirements.

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    Glen Park PharmD
    Executive Director, Regulatory Affairs and Quality Assurance
    Jersey City NJ
    United States
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    Original Message


  • 3.  RE: CMC expectations for a Fast Track NDA

    Posted 23-Mar-2020 10:19
    There may be some relative relaxation of some expectations, you will still need to have a full validation package for the API and finished product.  All products, even Breakthrough and Fast-Track still have to meet the same standards for safety and efficacy.  This includes the quality aspects of the product.  Most of the advantages in Fast-Track and Breakthrough relate to clinical development, although you can extrapolate this somewhat to CMC.

    If the company has only manufactured the API once under GMP, this will probably not be adequate.  It may not need to be fully optimized, but a N=1 for production is not enough to even demonstrate that they can produce it more than once with the current specifications.

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    Michael Hamrell, Ph.D., RAC, FRAPS
    Huntington Beach CA
    United States
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    Original Message


  • 4.  RE: CMC expectations for a Fast Track NDA

    Posted 23-Mar-2020 10:28

    FDA's guidance emphasizes the need for safety, with any anomalies having clinical significance, if any, that are offset by the benefit of the drug. The guidance purposefully leaves room for discretion and so provides no real detail.

    In practice, for example, this could mean that impurities that would otherwise be expected to be identified can be, instead, demonstrated to have little to no clinical significance. There should be a scientific and clinical justification for the lack of CMC information and for the low risk, as well as a plan going forward to close the knowledge gaps and monitor patient safety.

    https://www.fda.gov/files/drugs/published/Expedited-Programs-for-Serious-Conditions-Drugs-and-Biologics.pdf



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    Andrea Chamblee Esq., RAC, FRAPS

    This information and views expressed are provided in my capacity as an FDA and compliance professor at Johns Hopkins and George Washington universities, and do not necessarily represent the official views of the agency or the United States. Consult the Agency for an official position.

    Silver Spring MD
    United States
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    Original Message


  • 5.  RE: CMC expectations for a Fast Track NDA

    Posted 26-Mar-2020 01:24
    Thank you all for your very helpful comments.
    Kind regards,
    John

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    John Wetzel
    Principal
    Albany OH
    United States
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    Original Message


  • 6.  RE: CMC expectations for a Fast Track NDA

    Posted 28-Mar-2020 10:26
    None of those CMC requirements will be relaxed, but perhaps shifted out to a later point, such as during NDA review or (if you are lucky) as post-approval commitments.  Take a look at the several Expedited Programs guidance documents available from FDA.

    With your product status, you have an opportunity to engage FDA earlier and more often than for a 'regular' product.  Take advantage of that.  Make sure there is alignment of expectations with FDA well in advance of a pre-NDA meeting.  Request a pre-NDA meeting only AFTER you have engaged FDA on overall expectations.

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    Richard Shansky PhD
    Executive Director, Regulatory Affairs-CMC
    Cambridge MA
    United States
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    Original Message


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