Dear All (long note alert … there’s a lot of material below my signature):
Just published today is an IDSA White Paper entitled “Developing Antimicrobial Drugs for Resistant Pathogens, Narrow-spectrum Indications, and Unmet Needs.” The paper is accompanied by an editorial by George Drusano. As the papers are free to download (links below).
The white paper reviews the output from the July 2016 FDA workshop entitled “Facilitating Antibacterial Drug Development for Patients with Unmet Need and Developing Antibacterial Drugs that Target a Single Species” and has the goal of presenting for a pragmatic approach to feasible trial designs for antibacterial agents.
If you were at the July 2016 workshop, you’ll recall that the group worked in detail through the problem of organism-specific clinical trials and identified a group of potential solutions. The discussion was then advanced again during the 1 Mar 2017 workshop. And, we’ve also had since then the 13 April 2017 FDA AMDAC on this topic.
There’s a lot in these various documents … you’ll need to spend some time with them. The briefing book from the 13 Apr 2017 AMDAC is an excellent way to get an overview of whole problem. As a supplemental rough guide, I provide a summary of the core logic below my signature.
As noted before, I suspect (hope!) that FDA is going to turn all this into a guidance document in the near future.
Heady times! See you soon, –jr
John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Chief Strategy Officer, CARB-X | Expert-in-Residence, Wellcome Trust. Follow me on Twitter: @JohnRex_NewAbx
Boucher et al. White Paper:
18-19 July 2016 FDA workshop: Facilitating Antibacterial Drug Development for Patients with Unmet Need and Developing Antibacterial Drugs that Target a Single Species
1 Mar 1017 FDA workshop: Current State and Further Development of Animal Models of Serious Infections Caused by Acinetobacter baumannii and Pseudomonas aeruginosa
13 Apr 1017 FDA AMDAC: Developing Single-Pathogen agents for Acinetobacter baumannii and Pseudomonas aeruginosa
John’s summary of the core ideas
- AMR continues to advance and narrow-spectrum drugs could be valuable tools to address this problem.
- 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
- There are a few (but only a few) settings where narrow-spectrum is / would be pretty easy: S. aureus (skin) and GC (STDs)
- Everything else is / will be hard
- ALL approaches to the general problem of narrow-spectrum drugs have significant flaws
- There is no simple approach: 100+ people attacked this for a day during July 2016 and failed to generate any strong alternatives
- We thus must find ways to use a collection of relatively flawed tools as the basis of registration
- The alternative action of not finding this pathway is also a form of action and would be unacceptable.
- 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
- The needed patients are uncommon … and we want this to remain true, as if they are common then we’ve failed with infection prevention
- Neither non-inferiority-based nor superiority-based approaches are routinely tractable.
- Diagnostics will not solve the problem in that they don’t create patients with the target pathogen – they only help spot them
- 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-focuses studies (McDonnell AM et al. Efficient Delivery of Investigational Antibacterial Agents via Sustainable Clinical Trial Networks. Clinical Infectious Diseases. 2016;63 (Suppl. 2):S57-S9.)
- Excellent preclinical PK-PD programs are now possible and need to be better leveraged
- Multiple isolates and models
- PK in patients with the target syndrome
- Is there a way to use these as an informative Bayesian prior? Not clear, but perhaps worth further study
- To resolve these issue, and despite their flaws, we will need to use elements from these two categories of clinical research tools:
- The concept of validated Animal Models (approaching the ideas of the Animal Rule to the extent possible)
- Validated external controls (e.g., reasonably contemporaneous controls who could actually have been enrolled)
- At a practical level, we need to validate ertapenem for HABP-VABP
- This appears to be the best way to provide a companion for a narrow-spectrum anti-pseudomonal
- There is a paper coming out on this from the Ambrose group
- And to succeed in a sustained fashion, we must make pull incentives work