Only now, a few days before the actual AMDAC meeting, the FDA’s Briefing Document becomes available to the public. The topic of the December 5th meeting: Reappraisal of the risk/benefit of fluoroquinolones (FQ) in approved but “mild, self-limiting” disease indications in light of new post-approval safety issues.
The document is 617 pages long and provides a thorough review of study data of FQ in the indications challenged: ABS, ABECB-COPD, and uUTI. None of the safety concerns are new; all have found their way into the labels of Cipro, Avelox, Levaquin, and Factive by now. They are: tendonitis, neuropathy, and QTc prolongation.
After providing an excellent, thorough review of the efficacy and safety data of FQ, FDA asks a simple question: Is the use of these drugs justified in light of the mild nature of these diseases? Or should these indications be struck from labels?
The answer is easy: It’s a judgement call. A toss-up with good arguments pro and con. There is no right or wrong answer and certainly different Health Authorities, looking at the same data, would easily come to different conclusions. And yes, it’s also a political ploy by an FDA that would like to get external answers for questions and justification for actions that they cannot get a grip on internally for quite some time.
Of course the FDA is right: These drugs are being overused in these indications. But – I would argue – not because of bad intentions by doctors, or as a result of the marketing muscle of Big Pharma. They are overused because of our state of collective ignorance.
Nobody can argue with the FDA’s razor-sharp logic that antibiotics should be reserved for those that need them. The only problem: We just don’t know when to use them correctly each time. Diagnostics are just not in place that would help even with seemingly basic determinations of antibiotic need.
First FDA tenet: Antibiotics should only be used if and when bacteria are involved in the disease process.
- Sinusitis etc: As of Nov. 2015, we still cannot properly distinguish between viral and bacterial sinusitis. The same is true for otitis media and CAP (see Dr. Bartlett’s recent comments). For all the respiratory infections, there is just no diagnostic or imaging tool that distinguishes bacterial from all other possible etiologies not amenable to antibiotics which make up the list of differential diagnoses.
Even if we had the diagnostics to positively identify bacterial disease, the FDA may still think that trivial diseases should be left untreated. Here I beg to differ: it is not up to the FDA to tell doctors which bacterial infections in private practice warrant antibiotic therapy.
Second FDA tenet: Antibiotics should not be used in self-limiting mild diseases because the benefits don’t outweigh the risks:
- ABS, ABECB-COPD, uUTI: It is correct that prior to the advent of antibiotics, patients survived these diseases in most cases. This does not make them trivial: the potential for a mild form of sinusitis to turn severe, for an otitis media to result in hearing loss or mastoiditis, and for a walking pneumonia to become a walk to the graveyard is real. How about the development of septic complications?
Going a step further: Does FDA believe prophylaxis has a place for certain situations or is it always tantamount to treating colonization?
Third FDA tenet: Antibiotics should not be approved / used when a benefit cannot be proven in a well-controlled, unbiased clinical trial setting:
- ABS, ABECB-COPD, uUTI: All FQ were approved for these indications following the Guidelines in existence at the time. More recently, FDA has pushed hard to obtain objective data demonstrating efficacy over placebo, instead of relying on non-inferiority studies and worrying about biocreep.
This information has now become available for sinusitis in which placebo studies have helped define which patients are likely to benefit (e.g., Lindbaeck). For uUTI, FDA acknowledges that such data exist as well.
FDA is to be commended for their critical reappraisal of approved indications in light of new data. There is not much work these days at the agency with the review of new NDAs for anti-infectives, so we are treated to this retrospective re-evaluation of the therapeutic index. As we all know, time is not kind to antibiotics: they lose efficacy over time, and their safety profile statistics can only get worse over time. Of course, the benefit/risk ratio will seemingly become worse over time.
But there are other trends as well which should not be neglected. The increasing resistance of uropathogens to FQ has already led to a change in the Practice Guideline for uUTI (a main area of use for ciprofloxacin). Nitrofurantoin and fosfomycin are now first-line agents for uUTI. The medical experts have downgraded FQ already, and we can expect a dramatic shift in antibiotic use patterns for this indication.
What does the FDA action mean for industry, esp. for Bayer and Johnson, the main players in this arena? A big yawn there, not much is at stake for them. The recognition that antibiotics are ‘undervalued’ will drive up prices for the few we still have, including the FQ class. Remember, the pipeline is pretty empty.
If AMDAC recommends removal of the indications for uUTI, ABS and ABECB-COPD and if FDA follows this advice, commercial losses will be minor. Companies can always ‘adjust’ the price to compensate. Internally, Big Pharma managers will feel justified in their decision to leave the field and move to more lucrative markets. Without a competitor in sight, Bayer and J&J stand to lose nothing.
The US is not living in ‘splendid isolation’. Not even Donald Trump can build a wall defending us from bad bugs entering the US without an FDA visa. Hence, any FDA action – like so many other antibiotic stewardship actions – will have little overall economic impact. However, in the quest to ‘protect the public’, individual patients will suffer.
Stay tuned for Part 2…
