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FDA workshop on non-traditional antibacterials (21-22 Aug 2018)

 Please be sure to look closely at the events calendar: Q&A with Scott Gottlieb, Lipinski on Lipinski, and more!

Dear All: FDA’s 21-22 Aug 2018 workshop on the development of non-traditional antibacterial agents was an excellent discussion of core challenges in this area. The agenda plus all the meeting materials (including the public comment slides and replays of the webcasts) are available on this web page. There’s a lot here to digest, so let me offer this guided tour:

  • In the opening session,
    • Kevin Outterson and I provided an initial overview that discusses the core problem of showing value, the challenges with defining the idea of a Non-Traditional (NT) product, and why this matters to CARB-X.
    • Helen Boucher brought the challenges in the clinic together with the promise of NT products in her discussion of two powerful case vignettes. Any of us could be the patient who needs these products!
    • Owen McMaster provided a summary of key Pharmacology and Toxicology issues — my takeaway here was that the guidelines for NT products were not uniform but you should attempt where possible to apply the usual rules. When this is not possible, well-reasoned adaption is the order of the day.
    • Similarly, Tracey (Xiaohui) Wei discussed Clinical Pharmacology issues with a focus on highlighting some of the unusual ADME and dose-selection issues that may arise, especially with biological products.
    • Kalavati Suvarna rounded out the session by surveying the microbiology issues that arise with NT products.
  • The heart of the meeting was then a series of hypothetical but realistic case scenarios:
    • Drug X-1: A monoclonal for preventing VABP (Mary Beth Dorr and Mayurika Ghosh)
    • Drug Z-2: An approach to preventing gut microbiome disruption (and hence C. difficile infection) due to beta-lactam drugs (Michael Kaleko and Ramya Gopinath)
    • Drug Z-3: Reducing the risk of infection due to an MBL-producer by preventing acquisition of same (John Rex)
    • Drug Z-4: A chimeric bacteriophage endolysin as an adjunct for S. aureus infections (Cara Cassino and Ed Weinstein)

My takeaway messages from the day are as listed just below. An expanded slide deck on this topic is found here.

  • “Non-Traditional” is a very broad term and requires qualification
    • Sub-dividing into NT Structure vs. Goal (see also the opening Outterson-Rex talk) may help a bit
  • Current development tools are often suitable
    • There may be gaps around measures of delayed (indirect) benefit
    • There may be gaps around evaluation of combination products
  • The lack of a tool (or path) can be managed
    • New approaches have been / can be developed
  • The product’s whole effect must be considered
    • Don’t be seduced by a pretty mechanism
  • A high-level guidance document might be useful
    • But we’re not ready to commit to many details

My closing thought is that I think that 10-15 years from now we will view many non-traditional products as “business as usual.” This rather reminds me of the comment that “All Art was once Contemporary.”  If you want to dig a little deeper into the philosophy side, you could even (re)read Thomas Kuhn’s The Structure of Scientific Revolutions in which he discusses the contrast between small incremental changes and significant paradigm shifts. Some of the products we are discussing are incremental, but ideas around products with delayed (indirect, or community-level) benefits could represent a substantial shift in perspective.

Meditatively yours, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Expert-in-Residence, Wellcome Trust. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://13.43.35.2/blog/

General notes of interest for the AMR community

  • Novo’s REPAIR Impact fund will re-open for proposals during the window 4 Sep – 11 Oct. Watch for further news here.
  • IMI AMR Accelerator programme Pillar A within IMI Call 15: Capability-building network to manage the whole accelerator and strengthen AMR science. This is a two-stage call, with letter of intent from applicants expected on 24 Oct 2018.
  • IMI AMR Accelerator programme Pillar B: Tuberculosis drug development network within IMI Call 15: Tuberculosis drug development network to collaboratively progress TB compounds and validate new tools for TB drug development. This is a two-stage call, with letter of intent from applicants expected on 24 Oct 2018.
  • IMI Call 16: A series of individual programs where a single EFPIA partner works with a consortium to progress compounds for for TB, non-tuberculous mycobacteria, and Gram-negatives. This is a one-stage call, with full proposal from the EFPIA and applicant consortium expected on 24 Oct 2018.

Upcoming meetings of interest to the AMR community:

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