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.