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! 

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. 

Writing Grants - Antimicrobial Screening - 2

 Guest Blogger Lynn Silver of LL Silver Consulting, LLC 

Thanks to Dave Shlaes for the opportunity to contribute to his blog with an entry on grant-writing-and-screening-paradigms.  I have some familiarity with the subject as I worked in antibacterial discovery for 21 years at Merck, including the development and deployment of numerous screens, and I have since been consulting in the pre-clinical discovery sphere.  But, more to the point, I, too, have been doing antibacterial drug discovery peer review for NIH and the EU as well as reviewing for journals. And, in my humble opinion, there is a need for a remedial course in antibacterial screening (and drug discovery in general). Let me emphasize that this is indeed all my opinion – you and others may disagree.

My remit here is to discuss screening paradigms.  I’m not sure if that includes target choice – but I’ll start with a few words on that particular tough nut.  Numerous reviews have covered the various points important for selecting and qualifying targets.  But each author has his or her own POV and will emphasize personal favorites. 

My set: 

1) The target should be essential to the growth, and better, to the survival, of the pathogen [preferably under conditions that can be measured in vitro but that also approximate in vivo conditions].  Genetic proof, preferably with conditional mutants or constructs, is optimum – but demonstration of inviability of knock-outs can suffice.  Don’t pick a target whose product can be supplied by nutrients in the host. I.e. avoid auxotrophic targets in most cases [but there are exceptions].   Anti-pathogenesis targets are a different area; they are interesting – but so far not much has come of them.  Reviewers will be skeptical of them – so if this is your bailiwick, prepare to explain how such an inhibitor would be developed [as a therapeutic? A prophylactic? In combination with a standard antibacterial?]

2) The target should be present in a useful spectrum of pathogens with homologs being structurally and mechanistically closely related.

3) The target should have no human homolog – or there should be a good reason to believe that selectivity [kill pathogen not host] can be achieved.

4) Inhibition of the target should not lead to rapid selection of resistance.  Anl hypothesis to consider: inhibitors of a single-gene encoded target will select for pre-existing resistant mutants in the infecting population.  If the frequency is high enough and the mutants fit enough, then such resistant mutants may compromise therapy.  I have been a proponent of the idea that good monotherapeutic antibacterials target the products of multiple genes or structures produced by multiple gene products (Silver, LL. 2007. Nat.Rev. Drug Disc. 6:41-55) and, as such, select much less frequently for single step, high level target-based resistance than do single-targeted agents.  If you choose a single-gene encoded target, be prepared to defend the choice. 

 

5) Having ways of measuring the activity of the target or function in vitro as well as the phenotype of inhibiting the target in the intact cell are important for screening and/or follow-up. 

6) Ability to produce the target in quantity for structural studies and eventual iterative optimization is a plus - but not a big enough plus to substitute for meeting the other necessary criteria.

7) Druggability.  Does the target have a deep enough, well-defined enough binding site for selective inhibitory ligands?  Does your chemical library contain likely ligands?

8) Read Payne. et al. (2007. Nat. Rev. Drug Disc. 6:29-40) and note that they ran 70 HTS antibacterial campaigns with very little to show for it.  Why will you succeed when GSK failed?

OK – you’ve got a target.  Consider the chemicals to be screened.  Be warned, chemical libraries are often filled with aggregators, detergents, alkylating agents – compounds that will interfere with many types of screens.  Read Babaoglu et al. (2008, J. Med. Chem.51:2502-2511).   And, similarly, the detergents and alkylators and many other types of toxic compounds will have uninteresting, non-specific antibacterial activity.  It is easy to kill bacteria, even multi-drug resistant bacteria, with chemicals.  It is hard to find novel antibacterials that are highly selective for pathogen over host.

Stay Tuned for Part 3 in this series and - coming very soon - FDA and Nosocomial Pneumonia. 

The Pharmacometric Solution: We Told You So!

Paul G. Ambrose, Pharm.D, FIDSA, Sujata M. Bhavnani, Pharm.D, M.S. and George L. Drusano, M.D., FIDSA

It was 11 October 2007 at a US Food and Drug Administration (US FDA) and Infectious Disease Society of America (IDSA) co-sponsored workshop where we first proposed a pharmacometric solution to some of the most vexing problems in antimicrobial drug development [CID 2008;47:S225-31].  First, we described how pharmacometrics could be used to determine the magnitude of treatment effect, which allows for the estimation of non-inferiority margins using contemporary clinical data [AAC 2012;56:1466-70].  This is important, as the alternative is to use historical data.   In our view, the use of historical data is assuredly unwise because of the disparity between modern medical care and that available at the dawn of antimicrobial chemotherapy. Second we described how continuous, numeric endpoints  holds the promise for the evaluation for evaluating the impact of drug exposure on time to event, thereby reducing the number of patients required to detect between-regimen differences, and defining the optimal length of therapy.

In December of last year, the European Medicines Agency (EMA) released a guideline for the development of antimicrobial drugs, which questioned the usefulness of historical data [EMA guideline 2011] and, importantly, explicitly mentioned the pharmacometric solution.  The EMA guideline said “Historical data are often used to estimate the no-treatment effect but the relevance of these data to current medical practice may be questionable.  Sponsors are encouraged to explore alternative and emerging methods for estimating the no-treatment effect (e.g., using pharmacometric-based approaches)."  We applauded the EMA for taking an important step towards ensuring the development of new antimicrobial agents and urged others to support the pharmacometric-based approach [Lancet ID 2012;12:265-6].  In October 2012, IDSA published recommendations on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections associated with drug-resistant bacteria [CID 2012;55:1031-46].   Therein, IDSA suggested a pharmacometric-based approach to defining the no-treatment effect using contemporary data.

The 22^nd October EMA workshop further highlighted the rising importance of pharmacometric approaches in the development of antimicrobial regimens for the treatment of drug-resistant bacteria.  There we made two presentations.  The first described how the use of in vitro and animal models as well as mathematical models can be used to identify treatment regimens that hold the promise to slow or prevent the amplification of drug-resistant pathogens, while the second described a paradigm where high-quality pharmacometric information obtained from pre-clinical and clinical data sources supported approval and balanced unmet medical need and data quantity.

The in vitro models provide insight into the relationship between drug concentration and cell kill as well as resistant subpopulation response to drug pressure. The animal models allow the impact of drug penetration to the infection space to be elucidated and also allow some insight into the impact of the immune system, which is completely missing from the in vitro system. The mathematical modeling ties this information together to allow delineation of exposure profiles that are linked to specific endpoints (2 Log kill, resistance suppression, etc). Human pharmacokinetic information, including penetration into specialized spaces such as ELF allow the final bridging between pre-clinical data and the clinic. This also allows the generation of optimal approaches to study patients in the clinic so that exposure-response relationships may be developed.

Given the rising tide of resistance to our existing antimicrobial armamentarium, a risk-benefit approach for the assessment of the effectiveness of is appropriate.  Simply put, it is unacceptable to have an absence of active antimicrobial agents for the management of infections associated with drug-resistant pathogens.  The EMA is listening and acting.  The FDA is clearly listening.

All the President's Men and Antibiotics

A recent article by Matt Herper in Forbes caught my attention.  The article provides a nice, historical review of the politics of how the FDA got where it now is on antibiotics – it’s a great read  (but not as good as my book).   He makes two key points.  (1) Presidents rarely directly influence FDA activities on the ground.  Its not a subject that comes up in campaigns because there are no political points to be scored here.  (2) Congressional politics, however, have become very much a part of how the FDA behaves.  Since the Ketek scandal, the Anti-infectives division has been spending about 50% of its time responding to congressional inquiries.  Is that a waste of time or what?

Lessons I have learned – In dealing with the FDA – there is no higher authority there to receive an appeal.  Congress has been useless – more of an obstruction than a help.  The GAIN act, other than its language offering the FDA some political cover for accelerating antibiotic approvals and aside from its aid to a few antibiotics with short patent lives, is one example.  The other is the constant meddling in FDA considerations that provides more of a distraction from real business than anything else. The administration is another false hope. At one point, when I thought I was not getting any response from the FDA in dealing with its completely infeasible guidance documents for antibiotic development, I believed that our only way forward was to appeal to the head of the Department of Health and Human Services.  This certainly worked for the anti-abortion folks when HHS overruled FDA on Plan B. But for antibiotics it was a non-starter.  There was no (or not enough) political gain in supporting the development of new antibiotics.

At the end of the day, somehow, between the IDSA, I will take some credit here, and the pharmaceutical industry, the FDA itself realized that they truly were going to oversee the end of antibiotics in the US unless they changed course.  Was this Rachel Sherman, a pediatric infectious disease physician in the FDA commissioner’s office?  Was it Peggy Hamburg herself – a public health advocate with intimate familiarity with the scourge of resistance through her experience in New York with multiply-resistant TB?  Was it Janet Woodcock?  Ed Cox?  I have no idea.  What I think it was not was congress, HHS or Obama.

Why did it take the FDA so long to get to this point?  Who knows?  How long will they now take to complete their reboot process for antibiotics?  Same answer.  They do tell me that they are making good progress on new approaches for “unmet needs” – new antibiotics targeted at treating small numbers of patients with serious infections caused by extensively resistant organisms – those for whom little or no other therapy is available.  They are having a harder time revamping their old and still infeasible guidance documents on more traditional infections disease indications like skin infections, pneumonia and others.

As always – we await further developments.

Next on the Blog list – a continuation of our series on writing grants on antibiotic discovery with Guest Blogger Lynn Silver! And – a summary of the recent European Medicines Agency’s  Workshop on their Addendum to the Guidance for the Development of Anti-Bacterial Drugs with another Guest Blogger who was actually there!