Delafloxacin approval / Good example of a modern label

Dear All:

FDA’s approval of delafloxacin (BAXDELA) was announced on 20 June 2017 and the label can be found here. In brief, delafloxacin is a fluoroquinolone with coverage for MRSA as well as key Gram-negative pathogens.

The label is attached is worth reading as a good example of a modern label – reading closely will give you a feel for the breadth and depth of material that is required above and beyond the pivotal (Phase 3) program. Some reading notes are found below my signature (and with thanks to regulatory gurus Krissy Haeckl and Uzma Anwar for helping me proof same).

Congratulations to Eugene Sun and his team at Melinta on bringing this one to fruition!

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

Reading the BAXDELA label – a brief tour

  1. Start at the bottom of page 18 in Section 14, Clinical Studies
    • There were two identical pivotal trials of dela vs. vancomycin + aztreonam. One of the trials used IV therapy throughout and one switched from IV to PO delafloxacin after 6 doses (3 days) of delafloxacin.
    • Success is reported at two time points and assessed in two different ways.
    • First, Table 7 reports reduction in peri-infection erythema at 48-72h by digital planimetry in an ITT (all randomized) analysis. This early endpoint is sensitive measure of drug effect that is known to all physicians … you really can watch the erythema begin to recede. The importance of this endpoint is that it validates the non-inferiority trial. The patient is not cured at this point, but detailed review of prior responses has shown that there is a strong treatment effect at this point in time.
    • Second, Table 8 then shows overall clinical judgment of success at 14 days, an endpoint that will feel more intuitively relevant. This endpoint is the one most important to the patient (got better and stayed better), but it is not the primary endpoint due to its reliance on a subjective decision by the physician. This analysis is done both for the ITT population (all randomized) and a CE analysis (effectively, all who adhered closely to the protocol).
    • All 6 of these endpoints show non-inferiority within a lower bound of -10%
    • Look also at Table 9: They have a good collection of Gram-positive bacteria (both MSSA and MRSA) as well ≥ 10 infections due to each of several key Gram-negatives. The number of ≥10 organisms is not written into guidance anywhere but is a typical threshold.
  2. Now go to Page 1 of the label
    1. First, you’ll see a boxed warning. This is class labeling for all the fluoroquinolones and is now going to be standard for this class. There was an AdComm on the adverse events associated with FQs on 5 Nov 2015.
    2. Then, look at Indications and Usage. Delafloxacin has a standard indication for ABSSI: “BAXDELA is a fluoroquinolone antibacterial indicated in adults for the treatment of acute bacterial skin and skin structure infection (ABSSSI) caused by designated susceptible bacteria.”
    3. The unmet need language from the Unmet Need Guidance (“As only limited clinical safety and efficacy data for NEWDRUG are currently available, reserve NEWDRUG for use in patients who have limited or no alternative treatment options.”) does NOT appear as dela has two adequate and well-controlled trials supporting this indication.
    4. The second bit about “To reduce the development of drug-resistant bacteria…” is standard boilerplate.
  3. Now go to bottom page 2/top of Page 3
    1. Here in Section 1 (“Indications and Usage”) we find the fully expanded version of the approved indication.
    2. This version also shows the list of bacterial species for which adequate data was produced to show activity of delafloxacin … this matches Table 9.
    3. While looking at that list of species, you should also look at Section 12.4 (“Microbiology”) where you’ll again see that list of species. You’ll also see the so-called “List 2” of other bacteria which look like they should be treatable because their MIC looks reasonable but where there is little or no clinical experience.
  4. All the sections (1-14) are consistently structured in all FDA labels
    1. I’ve above discussed Sections 1, 14, and part of 12.
    2. If you’ve not looked at labels before, the material in Section 2 to 13 is worth scanning. To my eye, the text in these sections is pretty typical.
    3. Note the page space devoted to clinical pharmacology (presentation, dosing, PK, drug-drug interactions, special populations). This label is a good example of why these materials are typically about half the label.

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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