Monday, May 8, 2017

Antibiotic Development - the IDSA Stands Up!

I take pen (computer keyboard) in hand today along with John Rex who has agreed to be my co-author of this blog. Because John is currently very busy, the retired guy (me) gets the last word.

Last week, the Infectious Diseases Society of America (Boucher et al) published a white paper on the development of antibiotics for resistant pathogens, narrow spectrum indications and unmet needs.  An editorial by George Drusano accompanies the paper. These are important discussions that are based on the myriad of workshops and advisory boards held by the FDA over the last several years. The white paper represents clearly the views of the IDSA. We are grateful that the IDSA has taken this step (full disclosure – JR is a co-author).

A summary (credit to JR here) of core concepts of the paper might be –

1.       AMR continues to advance and narrow-spectrum drugs could be valuable tools to address this problem.
2.       But, developing narrow-spectrum drugs is surprisingly difficult when you want to do so for less common pathogens or forms of resistance – and these are precisely the settings where we most need new drugs.
a.       There are a few (but only a few) settings where narrow-spectrum is / would be pretty easy: S. aureus (skin) and GC (STDs).
b.       Everything else is / will be hard.
3.       ALL approaches to the general problem of narrow-spectrum drugs have significant flaws.
a.       There is no simple approach: 100+ people attacked this for a day during July 2016 and failed to generate any strong alternatives.
4.        We thus must find ways to use a collection of relatively flawed tools as the basis of registration.
5.       The alternative action of not finding this pathway is also a form of action and would be unacceptable.
6.       In this/the/an alternative plan, comparative clinical data will be needed on each new agent but generating these comparative data is (and should be!) very hard.
a.       The needed patients are uncommon … and we want this to remain true, as if they are common then we’ve failed with infection prevention.
b.       Neither non-inferiority-based nor superiority-based approaches are routinely tractable.
c.       Diagnostics will not solve the problem in that they don’t create patients with the target pathogen – they only help spot them.
d.       That said, screening for such rare patients would be facilitated by layering study of such drugs on top of a clinical trial network that is actively running UDR-focused studies.
7.       Excellent preclinical PK-PD programs are now possible and need to be better leveraged.
a.       Multiple isolates and models.
b.       PK in patients with the target syndrome.
c.       Is there a way to use these as an informative Bayesian prior? Not clear, but perhaps worth further study.
8.       To resolve these issue, and despite their flaws, we will need to use elements from these two categories of clinical research tools:
a.       The concept of validated Animal Models (approaching the ideas of the Animal Rule to the extent possible).
b.        Validated external controls (e.g., reasonably contemporaneous controls who could actually have been enrolled).
9.       At a practical level, we need to validate ertapenem for HABP-VABP
a.       This appears to be the best way to provide a companion for a  narrow-spectrum anti-pseudomonal.
b.       There is a paper coming out on this from the Ambrose group.
10.   And to succeed in a sustained fashion, we must make pull incentives work.

One quibble – (see this prior blog)  the paper uses the term “superiority studies” in a very specific way.  They mean prospective randomized controlled trials designed to determine if one treatment is superior to another. The IDSA argues that such trials are not feasible outside a large outbreak of infection caused by virtually pan-resistant bacteria – something we work hard to avoid.  They also point out the difficulty of randomizing patients to treatments that, in that situation, are likely to be inferior. We agree. But there are other ways of running superiority trials. As the paper also points out, the use of validated external controls (something I have been pushing for the last two years) can help here. Whether or not such a trial will be able to enroll sufficient patients to achieve statistical superiority or not is not yet clear – but the external controls will clearly increase the power of such a study. (On a personal note, I am very gratified that the idea of validated external controls seems to have taken hold among my colleagues).

The other aspect of the paper we would like to emphasize involves the use of animal models.  We agree with the FDA and the IDSA that exploring models that might more clearly reflect the human situation as compared to our current mouse models is a good idea.  But to achieve the validation of any new model, as clearly stated by both the IDSA and Drusano, will take years of effort and is not a guaranteed result. All agree that the existing models are well validated and are likely to provide reliable dosage predictions when combined with appropriate human pharmacokinetic studies. 

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