FNIH’s submission to the HABP/VABP docket

Dear All:

After a multi-year gestation period (my notes on this project go back to 2012!!), a comment on the FDA draft HABP/VABP guidance document has now been submitted by the FNIH (Foundation for the NIH) Biomarkers Consortium HABP/VABP Project Team and posted online. Links to the docket and document are below my signature.

The document is substantial and you should plan to review it in detail if you are interested in studies of Noscomial Pneumonia. I have excerpted below my signature the summary recommendations.

At a high level, the key points are that (a) VABP and ventilated HABP may be studied together, (b) non-ventilated HABP is meaningfully different, (c) all-cause mortality at day 14-28 remains a valid endpoint but also (d) the Standardized MedDRA Query (SMQ) for Toxic/Septic Shock can be used to create a “mortality plus” endpoint that incorporates SAEs & AEs from that SMQ.

Interestingly, it turned out that non-ventilated HABP seems amenable to study with the same symptom-based tool that we use for CABP.

Frustratingly (and despite its obvious biological relevance), the available data on improvement in oxygenation were inadequate to support meaningful analysis. We were all eager for a way to validate this as an endpoint, but the required data were not collected in sufficient detail in the studies avaialble for analysis. The project team recommends that such data be gathered in future trials and perhaps this can be revisited.

Overall, this docket submission is expected to be a substantial boost to finalization by FDA of its guidance on conducting HABP-VABP trials. Establishing the acceptable performance of the “mortality plus” strategy is important as this helps ensure an event rate high enough to allow to allow use of the fixed 10% NI margin recommended for HABP-VABP trials.

It’s a work of many hands, but I would be remiss if I failed to say that the entire commmunity owes thanks to George Talbot for his exemplary leadership of this project. Thank you, George!!

All best wishes,

–jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Chief Strategy Officer, CARB-X | Expert-in-Residence, Wellcome Trust. Follow me on Twitter: @JohnRex_NewAbx


The FDA docket:https://www.regulations.gov/docket?rpp=10&po=0&D=FDA-2010-D-0589
FNIH’s submission in the docket:https://www.regulations.gov/document?D=FDA-2010-D-0589-0027

Summary of Recommendations
1.  VABP and ventilated HABP appear to be similar syndromes that can readily be studied together. Patients with non-ventilated HABP have a lower mortality rate, and this difference should be anticipated if a study seeks to pool data across all three categories of nosocomial pneumonia.

  1. Enriching clinical trials for HABP and VABP with older patients who have higher APACHE Il scores will increase the rate of ACM. When this enrichment cannot be performed, the ACM event rate may be low enough that a fixed NI margin cannot be justified and an odds ratio approach to analysis may be needed. To avoid this statistical eventuality, sponsors could pre-specify a “mortality-plus” primary outcome parameter by incorporating SAEs and AES from the Toxic/Septic Shock SMQ. The same NI margin can be used for analysis of a 28-day ACM endpoint as for a 28-day endpoint comprising ACM plus AES or SAEs as defined by the Toxic/Septic Shock SMQ.
  2. For studies of non-ventilated HABP, the data demonstrate that patient symptoms can be collected and occur with a high enough frequency to allow an endpoint similar to that for trials of CABP. Analysis of resolution of symptoms at Study Days 5-7 appears reasonable. Since the data on symptom resolution in non-ventilated HABP support development of a patient-reported outcome (PRO) instrument, which is currently ongoing, the current FNIH effort will not pursue validation of a symptom-based endpoint in nonventilated HABP.
  3. Sponsors of future trials in these indications should collect the following data:
    1. For VABP and ventilated HABP, oxygenation and ventilation, especially positive end-expiratory pressure settings;
    2. For non-ventilated HABP, symptoms and symptom resolution until Days 7—14; and
    3. Prior antibiotic usage.
  4. If mortality-plus is not used as a primary endpoint, sponsors of future trials in any of these indications should include secondary analyses of the utility of the mortality-plus endpoint based on AES and SAEs from the Toxic/Septic Shock SMQ.

Dear All,
 
The IDWeek 2024 program committee is again seeking programs on novel antimicrobial agents and novel diagnostics for presentation in pipeline sessions! Here’s what is sought:

  • “Industry partners are invited to submit antimicrobials that are in preclinical stages of development (Phase II and III preferred) or recently approved after January 2024.
  • “The pipeline sessions will include antibacterials, antifungals, and antivirals (excluding COVID-19 and HIV).
  • “The committee also invites companies developing novel diagnostic technologies with a minimum of some preliminary proof of concept data to submit.” 

This is a great opportunity to tell the story of your development project! The deadline to submit is Wednesday, June 26 via the application portal. Any questions should be directed to program@idsociety.org. Please share this email with anyone you think might be interested in applying!
 
In addition, I’ll also note that those with a more general story to tell should look at the BugHub Stage (and the Global BugHub stage). Both BugHub variants seek “presentations that touch on your experience of working in infectious diseases and presentations that ultimately lead to a greater understanding of our diverse field” via a TED Talk-esque speech about your work. The deadline for applications is 26 June, the same as for the pipeline sessions.

I look forward to seeing you there! All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.

John’s Top Recurring Meetings

Virtual meetings are easy to attend, but regular attendance at annual in-person events is the key to building your network and gaining deeper insight. My personal favorites for such in-person meetings are below. Of particular value for developers are the AMR Conference and the ASM-ESCMID conference. Hope to see you there!

  • 27-30 April 2024 (Barcelona, Spain): 34th ECCMID, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. Go here for details. 
  • 17-20 Sep 2024 (Porto, Portugal): ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. Go here for the meeting’s general website. You can’t register (yet) for the 2024 event, but save the date!
  • 16-20 Oct 2024 (Los Angeles, USA): IDWeek 2024, the annual meeting of the Infectious Diseases Society of America. Save the date! More details to come!
  • 25-26 February 2025 (Basel, Switzerland): The 9th AMR Conference 2025. Go here to register

Upcoming meetings of interest to the AMR community:

  • [NEW]  9 Apr 2024 (virtual, 830a-10a ET): GARDP’s next REVIVE webinar entitled “Progressing a discovery project – Criteria and challenges.” Register here.
  • [NEW] 9 Apr 2024 (virtual, 10a-1130a ET): CDC webinar “Impacts of Antimicrobial Resistance on Cancer Care.” Click here for details and to register.
  • 10-11 Apr 2024 (virtual): Sepsis Alliance AMR Conference, a 2-day conference focused on “Practical technologies to manage sepsis and counteract the expanding challenge of antimicrobial resistance.” Go here for details and to register.
  • 26 Apr 2024 (Barcelona, Spain): ESCMID workshop entitled “Using Data Science and Machine Learning for Infection Science: A Hands-on Introduction.” Click here to register or here for more details. 
  • 27-30 April 2024 (Barcelona, Spain): 34th ECCMID, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
  • 26-31 May 2024 (Montreal, Canada): EDAR7, the McGill AMR Centre’s 7th edition of their Environmental Dimension of Antimicrobial Resistance conference. Go here for details; final abstract deadline is 21 Dec 2023.
  • 28-29 May 2024 (in person, Uppsala, Sweden): Uppsala Antibiotic Days, a broad-ranging 2-day program hosted by the Uppsala Antibiotic Center. Go here for details and to register.
  • [NEW] 30-31 May 2024 (face-to-face in Rockville, Maryland as well as online, 8.30-5.30p ET on 30 May, 9-2.40p on 31 May): NIAID-sponsored workshop entitled “Towards realizing the promise of adjunctive immune therapy for invasive fungal infections”. The agenda covers host immunity to invasive fungal infections, immune modulators in the context of fungal infections; and strategies for testing immune modulators as adjunctive therapy. Go here for more details and to register.
  • 9-13 June 2024 (in person, Ascona, Switzerland): “New Approaches to Combat Antibiotic-Resistant Bacteria, 2nd Edition” is a Sunday-Thursday residential workshop focused on the deep biology of AMR. Sponsored by NCCR AntiResist (a Swiss National Science Foundation consortium), the scientific program has the feel of a Gordon Conference. Space is limited, so you are encouraged to apply promptly — go here for details.
  • 13-17 June 2024 (Atlanta, Georgia): ASM Microbe, the annual meeting of the American Society for Microbiology. You can’t register yet, but you can go here for general details.
  • 17-20 Sep 2024 (Porto, Portugal): ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. See Recurring Meetings list, above.
  • 16-20 Oct 2024 (Los Angeles, USA): IDWeek 2024, the annual meeting of the Infectious Diseases Society of America. See Recurring Meetings list, above. 
  • 19-27 Oct 2024 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance). Now in its 8th year, Patrice Courvalin directs the program with the support of an all-star scientific committee and faculty. The resulting soup-to-nuts training covers all aspects of antimicrobials, is very intense, and routinely gets rave reviews! Seating is limited, so mark your calendars now if you are interested. Applications open in March 2024 — go here for more details.
  • 4-5 Dec 2024 (in person, Washington, DC): “Fungal Dx 2024: Fungal Diagnostics in Clinical Practice” is a 2-day in-person workshop organized by ISHAM‘s Fungal Diagnostics Working Group. The program and registration links are available at https://fungaldx.com/; the agenda is comprehensive and features an all-star global list of speakers.

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