Friday, November 30, 2012

Suspending Disbelief - The FDA Reboot and Nosocomial Pneumonia

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! 


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. 


  1. 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?

    The 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.

  2. From a news item I read,the implication that the vote against telavancin was toxicity- and not efficacy-based. Is this not true? (

  3. Thank 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.

    On 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.