Draft EMA antibacterial guidance: Analysis

Dear All:

wrote previously that EMA posted an extensively updated and consolidated version of their previously separate Guideline (CPMP/EWP/558/95 Rev.2) and Addendum (EMA/CHMP/351889/2013) documents into a single draft antibacterial guidance document.

I’ve now had a chance to read it in detail and thought I would share my thoughts as a way to provoke discussion. As a reminder, the draft is open for public consultation until 31 July 2019.

At a high-level, there’s a lot to like here. Many threads have been drawn together into a unified source document, linkages to other recent summary documents (e.g., the July 2016 EMA PK-PD guidance) are made clear, and the tripartite (FDA, EMA, and PMDA) efforts to seek harmonization are frequently visible. 

That said, there are important clarifications as well as important ideas that have remained stable. Here is a list of the points I found most notable:

  1. Section 4.1.1: A relatively current surveillance survey is needed. This section recommends submission of surveillance database based on isolates collected within the 5 years prior to submission of an application. In its guidance on Microbiology Data for Systemic Antibacterial Drugs, FDA recommends data on isolates within the 3 years prior to submission. Whichever it is, you need to plan in advance for this one!
  2. Section 5.1.2: Use of rapid diagnostic tests to enrich trial populations. The role of screening tests (sometimes investigational) as ways to maximize the rate of culture-positive subjects is a recurring question that is clearly discussed here. Yes, it’s OK to do this provided you follow some fairly simple rules.
  3. Section 5.1.3: How much prior therapy? As always, the answer is “not much” with 24 hours being the recommended limit unless there is clear evidence of failure of a prior therapy. This remains a challenge as prior therapy can have enough of an impact to alter results. For more on this, see Knirsch et al. 2016 (link) as well as the now-classic daptomycin paper by Pertel 2008 (link).
  4. Sections 5.4.1 and 6.3.2: An RCT (Randomized Controlled Trial) is really desirable, but what if you really can’t do one due to the infrequent nature of the pathogen or infection? This issue was addressed in the 2013 Addendum in a detailed discussion entitled “Circumstances in which limited clinical data may be accepted.”
    • The key update to the 2013 text is that EMA is now very firm that a randomized trial must be conducted if even remotely feasible and even if a statistically useful sample size cannot be obtained.
    • On this point, the new draft suggests that sample size could be driven by feasibility within a reasonable time frame (2 years is suggested).
    • The idea of using external controls that was offered in 2013 does not appear at all in this draft, at least not to my eye — instead, a discussion of very rare pathogens in Section 6.4 speaks of using the totality of clinical and non-clinical data.
  5. Section 5.4.2: What about superiority trials? As before, the draft indicates that certain settings (e.g., acute otitis media) must be studied as superiority trials. 
  6. Section 5.4.5: Endpoints. As before, EMA retains its preference for non-mortality clinical endpoints throughout vs. FDA’s effort to use all-cause mortality in some settings.
  7. Section 6.1: Detailed designs for ABSSSI, UTI, etc. This section walks through all major designs: ABSSSI,CABP, HABP-VABP, cIAI, cUTI+pyelonephritis, uUTI, and uncomplicated gonorrhea. Other than the difference in endpoints, the EMA’s guidance looks similar across the board to that from FDA. I do note that the non-inferiority margins for CABP and HABP-VABP seem flipped relative to FDA: this draft gives them as 10% and 12.5%, respectively vs. 12.5% and 10% for FDA (links to FDA on CABP and on HABP-VABP; see also Rex-Talbot et al. 2017, link). Perhaps this is a typo.
  8. Section 6.3: Unmet need and pathogen-specific indications. This section expands on the problem of studying specific rare pathogens in patients with limited treatment options. Section 9 discusses how this type of work may lead to a standard indication at a standard body site or to an indication just for the pathogen without reference to a body site.
  9. Section 6.5.1: Bacteremia is not an indication on its own. Bacteremia from a primary site is entirely within scope (e.g., you can show that your compound works for CABP as well as CABP with bacteremia), but bacteremia just by itself is not a thing. The setting where I have long thought this might be possible was S. aureus bacteremia, but even there it is usually possible to spot a primary source.
  10. Section 6.5.2: Eradication of carriage (almost always) requires a clinical correlate. Not a change from the past, but the guidance makes it really clear that simply showing clearance of a pathogen will not lead to approval except in a few well-defined settings (e.g., eradication of nasal carriage of the meningococcus). In most other cases, clearance must be linked to a measurable clinical benefit.

Overall, no real surprises and a lot of useful clarity. The strongest shift (to my eye) is the firming up of the idea that an RCT is really, really required even if it is small and underpowered. It is my understanding that this follows from frustration with prior open-label data sets as well as very substantially from the problems with interpreting clinical data during the recent Ebola outbreak. 

In brief, the general view is that external (historical) controls can be useful when the effect of the new therapy relative to available therapy is really strong … but this is not the usual case and hence an RCT is strongly encouraged. A good review on the value of RCTs is Fleming and Ellenberg 2016 (link, worth reading for the wonderful quote “So yes, it’s true we didn’t need randomized controlled trials to evaluate penicillin!”

While I agree that an RCT is very helpful, I’ll admit that I’m still concerned that we may be making it (nearly) impossible to bring new agents forward with a strong focus on resistant pathogens. To make this consistently possible, it still seems to me that we need a path that makes maximal use of small datasets and PK-PD insights. These ideas have been discussed in many ways and under various names: Adaptive Licensing (2012 papers x 3), Tier C (the 2013 and 2017 papers), and Adaptive Pathways (2015):

  • Eichler HG et al. (2012). “Adaptive licensing: taking the next step in the evolution of drug approval.” Clin Pharmacol Ther 91(3): 426-437 (link).
  • Woodcock J. (2012). “Evidence vs. Access: Can Twenty-First-Century Drug Regulation Refine the Tradeoffs?” Clin Pharmacol Ther 91(3): 378-380. (link)
  • Alemayehu DJ et al. (2012). “A paradigm shift in drug development for treatment of rare multidrug-resistant gram-negative pathogens.” Clin Infect Dis 55(4): 562-567 (link). Discusses the idea of Adaptive Licensing
  • Rex JH et al. (2013). “A comprehensive regulatory framework to address the unmet need for new antibacterial treatments.” Lancet Infect Dis 13(3): 269-275 (link).
  • Eichler HG et. (2015). “From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.” Clin Pharmacol Ther 97(3): 234-246 (link)
  • Boucher HW et al. (2017). “White Paper: Developing Antimicrobial Drugs for Resistant Pathogens, Narrow-spectrum Indications, and Unmet Needs.” J Infect Dis 216: 228-236 (link).

It feels like the conversation on this idea has slowed down and I think it needs to be revived. If it is possible to register a new drug for rare diseases in other therapy areas with very small datasets, I think we should be able to find a way to do this in Infectious Diseases!

In any case, start reading and thinking … as noted above, comments on EMA’s draft guidance are due 31 July 2019.

All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Expert-in-Residence, Wellcome Trust. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future:

Upcoming meetings of interest to the AMR community:

  • 4-5 Feb 2019 (London): Hamied Foundation UK-India Antimicrobial Resistance Meeting 2019. This is a 2-day meeting focused on building research links between the UK and India with the specific aim of jointly addressing the challenge of AMR. Register here.
  • 14-15 Mar 2019 (Berlin): BEAM-, CARB-X-, Novo REPAIR-, DZIF-, ND4BB-ENABLE-sponsored (among a long list!) Berlin Conference on Novel Antimicrobials and AMR Diagnostics. Details here. Poster submissions are being accepted through 9 Jan (details here).
  • 21-22 Mar 2019 (Birmingham, UK): BSAC Spring Conference.
  • 26 Mar 2019 (London, UK): Sponsored by The Economist, a 1-day symposium entitled “Antimicrobial Resistance: Preventing an antibiotic apocalypse.” Register here.
  • 28 Mar 2018 (REVIVE webinar, 4-5.30p GMT): “Clinical development for non-developers Part 3: Antibacterial Drug Enhancer Combinations and Non-traditional Products.” Register here.
  • 13-16 Apr 2019 (Amsterdam): Annual ECCMID meeting
  • 16-18 Apr 2019 (Utrecht): ICOHAR, International Conference on One Health Antimicrobial Resistance. Organized by the ESCMID Study Group for Veterinary Microbiology (ESGVM).
  • 24-26 Apr 2019 (Boston): Annual SHEA (Soc. for Hospital Epidemiology of America) Spring meeting
  • 6-11 May 2019 (Ljubljana, Slovenia): 37th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID). Details here.
  • 3-6 Jun 2019 (Philadelphia): Annual BIO meeting
  • 10-11 June 2019 (Research Triangle Park, NC): AMR Action Summit on R&D and Commercialization. Sponsors include the British-American Business Council, the UK Gov’t, CARB-X, the NC Biotechnology Center, and others. Details here.
  • 20-24 June 2019 (San Francisco): Annual ASM Microbe meeting.
  • [Mark your calendar now!] 3-6 Sep 2019 (Boston). Annual ASM-ESCMID Conference on Antibiotic Development. The Bootcamp series will continue on 3 Sep with the main meeting on 4-6 Sep. Mark your calendar now and check back here for details.
  • 6-8 Sep 2019 (Bilbao, Spain): 5th ESCMID conference on Vaccines. Check back here for details.
  • 2-6 Oct 2018 (Washington, DC): IDSA’s annual IDWeek meeting.
  • 19-27 Oct 2019 (Annecy, France): International Course on Antibiotics and Resistance (ICARe) – A soup-to-nuts intensive residential training program on all things AMR, especially R&D for new antibiotics. See this link for details.


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