Yesterday I spent the day in front of my computer screen
watching theatre of the macabre – the FDA Anti-Infectives Drug Advisory
Committee’s latest review of Theravance’s telavancin for nosocomial
pneumonia. I watched this in light of
all the activity going on at FDA to make their trial designs more feasible and
to draw companies back into antibiotic R&D (more on this below). Yet 95% of what was said at the meeting
focused on the completely infeasible design of an all cause 28 day mortality
endpoint with a 10% non-inferiority margin (see my previous blog on this). I noticed that Tom Fleming wasn’t
there (I hope that’s a permanent change).
But that didn’t stop one of the statistician committee members from
justifying a no vote by saying that there was no clear evidence that the
comparator drug, vancomycin, worked better than placebo. Of course he’s right – but there is no clear
evidence that parachutes work better than placebo either!
NO ONE WILL EVER RUN TRIALS IN NOSOCOMIAL PNEUMONIA UNDER
THE FDA’S CURRENT GUIDANCE. NO ONE.
Those of you who have been following this blog (and some who
haven’t) are familiar with the now-famous FDA reboot announced by Janet
Woodcock of the FDA in May of this year.
Changes in FDA requirements for trial designs focusing on feasibility of
non-inferiority designs as well as approaches to the rapid development of
antibiotics active against multiply-resistant pathogens have been discussed now
at two Brookings meetings and a separate FDA task force meeting. I attended both Brookings meetings. In fact, the change in FDA attitude seemed to
be foreshadowed by Ed Cox’s presentation at the Gordon Research Conference on
New Antibacterial Discovery in April of this year. Since then, I have been on a high drinking in
all of the optimistic and forward-looking pronouncements from FDA top
management.
In this context, I was astounded, flabbergasted,
disappointed, distressed and angry watching the AIDAC meeting yesterday. I had
hoped that FDA might even hint that they were going to drop this completely
unrealistic trial design requirement for nosocomial pneumonia. But no. In light of yesterday’s meeting, if this
is the FDA reboot for antibiotic development, what we need is the nuclear
option.
Of course, this is
not the first time the FDA has pulled the rug out from under us and it won’t be
the last. But what this means is that I cannot pass the red face test
recommending that clients even approach FDA to discuss trials in pneumonia – at
least not before the clients have discussed designs with European regulators.
It also means that until the FDA comes out with some concrete proposals, (which
may have to wait another year or two for actual guidance documents), the
reboot, as far as I’m concerned, is on hold.
And I don’t understand the FDA’s dilemma here. We don’t have to wait for guidance. In fact,
I think hasty development of guidance is a bad idea. A quick way forward would
be a workshop or series of workshops or even an AIDAC meeting where they
present potential designs and get comments.
These meeting presentations and summaries frequently serve as “FDA current
thinking” for sponsors to plan trials and provide a starting point for
discussion with FDA. Of course, the FDA
may not be ready for such public meetings as yet. But right now – we have
NOTHING other than optimistic discussions that have now been undermined by FDA
action at their own advisory committee meeting.
David- Well said. I do think we have is a knowledge gap in AIDAC members; few of the members have been involved in "reboot" discussions or aware of them, and those that have will adhere to a rigid frequentist statistical worldview. Where are the Bayesians?
ReplyDeleteThe public representative said it best: there was sufficient information in this package for a clinician and even a patient (as he described his own experience with VAP and blinking to communicate) to make decisions on the risk-benefit of a drug to treat life-threatening infections.
From a news item I read,the implication that the vote against telavancin was toxicity- and not efficacy-based. Is this not true? (http://www.medpagetoday.com/InfectiousDisease/Pneumonia/36177)
ReplyDeleteThank you both for your comments. I am less concerned about the specifics of the telavancin debate and more concerned that all the effort we have spent with the FDA since their announcement of a "reboot" has come up short. Although I still truly believe that the FDA will change - they certainly showed no evidence of that during the AIDAC meeting. Hence my red face since I have been telling everyone that the will, in fact, reboot.
ReplyDeleteOn the positive side, as I said, there was a recommendation for a limited use label for telavancin - consistent with what we are discussing in our meetings with FDA at Brookings.