Any FDA meeting is a high-stakes game for industry: One never knows how the discussions will go. Some oddball issue may take center stage and usurp much time, creating an unbalanced perspective. At other times, simple issues seem to create controversy, questions are not properly understood in the context of the ‘regulatory terminology’.
All company representatives spoke in support of current ATS/IDSA/AUA/ERS guidelines even though they are much stricter than existing Product Labels. They pointed out that fluoroquinolones (FQ) were already ‘held in reserve’, that doctors have experience with this drug class for over 30 years, that labels were regularly updated and that nothing new has come to the fore which would require yet another change.
Correct, amoxicillin or macrolides are recommended as first line drugs for ABS and ABECB, and nitrofurantoin,TMP/SMX and fosfomycin for uUTI. Why then, you may ask, are FQ still so often used in these indications? Doctors have become very comfortable, maybe too comfortable, prescribing this powerful class of drugs which are overkill for most of these self-limiting, often viral infections. In essence, the guidelines are not followed, and FQ are overprescribed for these 3 indications.
FDA presented a series of 178 cases extracted from the FAERS system which showed a constellation of side effects with disability in its wake, creating the moniker of ‘fluoroquinolone-associated disability’, or FQAD for short. It seems that this new entity is not as much a concern to health care providers as to patients.The fact that an unusually high 85% of these reports came directly from patients, not from health care providers, is significant as we are dealing with nothing but subjective claims of damage / disability. There are no objective markers for diagnosis and the syndrome has been self-diagnosed without independent corroboration.
When 30+ former patients gave their very personal testimony, they had a powerful message: Don’t use FQ for trivial infections. It swayed the committee’s thinking just the way it was intended. We heard from panel members how much they were ‘impressed’ with the stories of ‘suffering’, and how ‘inappropriate’ use of FQ in wider populations somehow brings out a higher frequency of adverse events.
We did not hear from the millions of patients telling the panelists that their lives had been improved or saved by the FQ wonder drugs. I am sure they are out there in huge numbers, but they were not asked to testify at the AMDAC and were not heard, leading to a lopsided ruling in favor of the plaintiffs claiming injuries. Why didn’t industry bring some of these people to the hearings?
FDA presented data analyses with figures, numbers and percentages, but at the end, it was not a day for ‘evidence-based medicine’ and balanced analysis. Nobody asked how often patients taking amoxicillin develop a hypersensitivity reaction, or had Stevens Johnson syndrome after TMP/SMX. Do the well-known AEs for these older drugs even make it into the FAERS database?
Other antibiotics may be associated with fewer disability reports but have other severe AEs instead. If we restrict the indications for FQ, perhaps we should do so for all antibiotics in use for these indications. They all carry serious AE in some patients. Some of the side effects of amoxicillin and macrolides can be pretty dramatic (C. difficile infection, QT prolongation). In the case of fosfomycin, we are dealing with a drug much less tested than any FQ.
At the end we got a skewed vote based on testimonials of those who claimed harm from FQ therapy. Industry had a ‘low energy’ defense team at hand and was not prepared for the phalanx of patient advocates presenting their experiences. Industry could have given us examples of cases that developed complications because of watchful waiting or had poor outcomes with amoxicillin or TMP/SMX. We should have heard from families that lost a loved one from meningitis, pneumonia and urosepsis because a 2nd line FQ was withheld in line with Guideline recommendations.
As we said above, it was not a day for a balanced comprehensive analysis.