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  • 1.  Precedent for CRL Based on Insufficient Dose Optimization?

    Posted 14-Nov-2022 09:42
    Hi all,

    Considering that dose optimization is a big focus of the FDA these days, does anyone know if there is precedent for the FDA issuing a CRL on the basis that a Sponsor did not conduct sufficient Phase 2 / dose optimization studies to support the dose(s) they used in Phase 3? Or does anyone have experience with the FDA bringing insufficient dose optimization up as a concern during the NDA/BLA review process or in an AdCom?

    Thanks in advance!

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    Marissa Berry, Ph.D., RAC
    Senior Manager, Regulatory Strategy
    Durham, NC
    United States
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  • 2.  RE: Precedent for CRL Based on Insufficient Dose Optimization?

    This message was posted by a user wishing to remain anonymous
    Posted 15-Nov-2022 07:33
    This message was posted by a user wishing to remain anonymous

    In the past, if the agency had concerns on dose optimization, it would typically ask the sponsor to do a study as part of the post approval requirement. 
       Nowadays, single-arm design is rarely sufficient for the pivotal trial, so the burden of dose optimization is mainly on the sponsor.  At the selected dose,  the registration trial either meets the endpoints (OS or PFS) with acceptable safety profile or it does not.  Therefore I do not think the FDA is forcing sponsors to do dose optimization against their wishes.
       Would love to hear what others think.
    Original Message


  • 3.  RE: Precedent for CRL Based on Insufficient Dose Optimization?

    Posted 15-Nov-2022 08:32

    hi Marissa--
    I think you would get an earful from FDA long before a CRL - you'd likely hear this at your EOP2 meeting and pre-NDA meeting.  When FDA looks at the overall benefit/risk, it may be hard to justify that it's positive if there is only one dose - how do you know you couldn't go lower to get an even better benefit/risk ratio - ie, what's an acceptable risk profile? FDA will be looking for an exposure/response evaluation in addition to dose response, so if you have inadequate dose finding, you won't be able to show that you fully understand the E-R. A relatively short dose range finding Phase 2 study could save you a lot of headaches in your dossier preparation and defense.  Depending on the drug, it would not have to be a huge, long study and would provide a lot of useful data to help select the best dose(s) for Phase 3 and reassure the Agency that you've selected the dose with the best benefit/risk.  And I think it would definitely be an issue at an Advisory Committee if it got that far.

    Hope you're doing well!
    --Beth



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    Beth Weinberg
    Regulatory Affairs Lead
    Carmel IN
    United States
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    Original Message


  • 4.  RE: Precedent for CRL Based on Insufficient Dose Optimization?

    Posted 15-Nov-2022 08:52
    The most recent public discussion on dose optimization was at the September 22 ODAC for Pozenveo (poziotinib). This follows on with the FDA's Oncology Center of Excellence Project Optimus.

    The briefing books, FDA and Company presentations, roster, questions, etc. can be found at Oncologic Drugs Advisory Committee Meeting Announcement. There are also links to the YouTube recordings of the proceedings.

    The Friends of Cancer Annual Meeting is Thursday of this week and you can attend virtually. You might want to register as one of the panel discussions is on Incorporating Patient Reported Outcomes to Inform Dose Selection and Optimization.


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    Linda Bowen MSC, RAC, FRAPS
    Past Chair, NJ NY RAPS Chapter]
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    Original Message


  • 5.  RE: Precedent for CRL Based on Insufficient Dose Optimization?

    Posted 15-Nov-2022 08:58
    Hi Marissa,

    I am not aware of a precedent where FDA issued a CRL solely because the sponsor did not conduct a sufficient Phase 2 dose ranging or optimization study. During development discussions at EOP2 and preNDA, FDA is likely to question the dose selection (Beth's comments on this point are right on) and make recommendations on dose ranging. However, review of a marketing application will be based on the data submitted and not on the data that theoretically should have been submitted. It is the sponsor's responsibility to select the right dose. If they haven't selected the right dose, there could be an issue with the benefit-risk analysis (low efficacy or adverse safety) and a CRL asking for additional studies could be the outcome.  It could be that the problem was a lack of clarity on picking the right dose for the pivotal study(s). 

    A well designed development program would typically have some kind of Phase 2 dose finding study. However, there are plenty of reasons why it can't be done or is unnecessary. For example, the dose could be selected based on a predictive animal model, or on PK studies that show what dose is needed to achieve a target exposure that is known to provide efficacy.

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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


  • 6.  RE: Precedent for CRL Based on Insufficient Dose Optimization?

    Posted 15-Nov-2022 18:07
    Not all drugs act equally for certain disease conditions. For some drugs, a very small change in dose or blood concentration can lead to drastically different therapeutic outcomes – even the risk of death. One cannot generalize regarding dose optimization (i.e. Your statement "Considering that dose optimization is a big focus of the FDA these days....") thus with narrow-therapeutic index drug development, that small change in dose can have a profound impact therefore the FDA would likely issue a CRL if you have not adequately characterized the dose optimization prior to approval!. If your development is not using a narrow therapeutic index medicine, then you may have flexibility as others pointed out with post approval commitments etc.

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    GRSAOnline
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    Original Message


  • 7.  RE: Precedent for CRL Based on Insufficient Dose Optimization?

    Posted 16-Nov-2022 06:49
    While this is not my area of expertise, I have been following recent events and the following may supplement the discussion so far, which has included some solid advice (EOP2 meeting and agreement on dose/study design to be used in Phase 3 probably being the most critical point).

    • A recent FDA approval (LUMAKRAS, Amgen, NDA 214665, accelerated approval in May 2021) includes a specific PMR (4071-2) related to exploring a lower daily dose (which has a trial completion date that has already passed - Oct 2022), reference the approval letter.
    • From an OCE perspective, Dr. Pazdur has very recently expressed the stance that adequate dose optimization should be conducted during front-end development; reference the recent (Sep 2022) RAPS article (which points to a NEJM perspective piece he wrote on the matter).
    Overall this seems to be a relevant discussion since FDA expectations to seem to be evolving on the matter.

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    Jonathan Amaya-Hodges
    Director, Technical Services
    Sharon MA
    United States
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    Original Message


  • 8.  RE: Precedent for CRL Based on Insufficient Dose Optimization?

    Posted 16-Nov-2022 09:18
    Dear All,

    I totally agree with Beth that it is a critical question for assessing the Benefit-Risk.  FDA will always want to understand the lowest effective dose, and often the highest tolerable/safe dose.  That said, if you bring data to support a single dose for approval, I would think it needs to have a very clean safety profile and have clear efficacy.

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    Kenneth Kassler-Taub
    Belle Mead NJ
    United States
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    Original Message


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