Antibacterial guidance (including pediatrics): Parallel EMA+FDA updates

Dear All (Wonkish alert! Get some coffee and settle in!),

Almost in parallel, EMA and FDA have released updates to key antibacterial guidance documents! Here are the links you’ll need and I’ve highlighted the key documents. To go deeper, you’ll need to pick through everything and I provide a tour further below in this newsletter: 

EMA’s new documents (n = 2)

  1. [NEW] 2022-05-19 Guideline on the evaluation of medicinal products indicated for treatment of bacterial infections
  2. 2019 draft revision of the original (2012) guidance
  3. comparison .pdf that I created of the new 2022 guidance vs. the 2019 draft
  4. [helpful context] 25 Jan 2019 newsletter discussing the 2019 draft guidance
  5. Webpage discussing the history of the EMA antibacterial guidance
  6. Pediatric addendum
    • [NEW] 2022-05-19 Addendum to the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections to address paediatric-specific clinical data requirements
    • [Key related document, unchanged] 2018-10-07 Reflection paper on the use of extrapolation in the development of medicines for paediatrics
    • Webpage discussing the history of the guidance
    • [helpful context] 2021-04-07 newsletter on pediatric development that discusses both EMA’s extrapolation document as well as FDA’s 2020 draft pediatric anti-infective guidance


FDA’s new document (just one!)

  1. [NEW] 2022-05 (Draft) Antibacterial Therapies for Patients With an Unmet Medical Need for the Treatment of Serious Bacterial Diseases – Questions and Answers (Revision 1)
  2. comparison .pdf that I created of the new 2022 draft vs. the 2017 draft of the same name
  3. A very brief 2017-08-02 newsletter on the 2017 draft guidance
  4. [Key related document, unchanged] The 2020 LPAD guidance and a 2020-08-06 newsletter on same



So, what’s new? What does it all mean? Let me say that I’m not going to repeat everything from the newsletters marked “[helpful context]” … please make time to read them. (Aside: Your reward for doing that bit of homework is that you get to revisit the fabulous quote “So yes, it’s true we didn’t need randomized controlled trials to evaluate penicillin!” as well as a regulatory decision that would have made Solomon proud!). On that note, let’s take a tour of key changes in the new documents:

EMA Antibacterial guideline

  1. [Major] All discussions of idea of underpowered RCTs have moved to Section 6.3.2. This section offers a nicely expanded consideration focused on the idea of developing for a pathogen-specific indication in patients with limited treatment options. The section notes that compliance with guidance on usual NI margins is not needed but rather the developer can seek to justify a trade-off between statistical power, nominal significance, and NI margin.
  2. [Major] The discussion of pathogen-focused development also notes that the program need not be limited to just studies of MDR pathogens – rather, it implies that non-inferiority in the UDR setting is a powerful tool! If this is a new or odd idea for you, please read the 19 Sep 2020 newsletter entitled “In Praise of Non-Inferiority!” or watch the video on that topic.
  3. [Major] Finally, a discussion in Section 6.4 of rare pathogens notes that trade-offs for some indications might include limits due to feasibility — trials that will run longer than ~2 years are seen as potentially too long. Agreed!
  4. [Minor but notable] There is now a very clear statement in Section 5.4.1 on NI designs that the comparator should be “one of the best available treatments” and need not necessarily be something specifically approved for the target indication.
  5. [Minor but notable] Section 5.5.1 adds a new note stating that the primary analysis should remove patients with proven baseline resistance to the test agent before unblinding.



The EMA Addendum for pediatrics has two main ideas

  1. First, most antibacterial development for pediatrics can and should proceed via extrapolation.
  2. Second, there are a handful of indications that are distinctive to children and that would require primary data in children.
    • The addendum provides infection-by-infection guidance on impetigo, infected atopic dermatitis, acute otitis media, acute group A streptococcal pharyngo-tonsilitis, and acute hematogenous osteomyelitis.


FDA Unmet Need Guidance
The updated document retains a Q&A approach to discussing unmet need. FDA’s introductory comments highlight the new ideas. “Significant changes in this draft guidance from the 2017 version include:

  1. “… the possibility to conduct noninferiority trials that include subjects with infections caused by certain drug-resistant pathogens since effective active controls are now available.”
  2. This one appears to be unpacked when FDA now says in Q&A #4 that “As the therapeutic armamentarium and the unmet 181 medical need for serious bacterial diseases are continuously evolving, sponsors are encouraged to discuss their development plans early with the Agency.”
    • In short, your choice of comparator needs to keep up with the times!
  3. And then “More detail is also provided for the currently used noninferiority trial designs that may be used with a wider noninferiority margin, including cases for which the trial population is enriched for subjects with infections caused by certain drug-resistant organisms.”
    • This comes out in the heavily reworked section on non-inferiority clinical trials in Q&A #4.
    • Similar to the ideas from EMA in settings of unmet need (and presumably also rare pathogens), we have “… the characterization of efficacy in a noninferiority trial could be based on a larger noninferiority margin than is typically recommended in the disease-specific guidances, but acceptance of the noninferiority margin would depend on the type and degree of unmet need.”
  4. Finally, there is a silent change in which the idea of superiority based on use of external controls has been deleted from the superiority design discussion in Q&A #4. The entire paragraph is simply gone. This similar to what EMA has done. My guess is that this proved to be so difficult that FDA wants to dissuade sponsors for attempting to follow this approach.


So, let’s summarize. Very helpfully, we are seeing great convergence in thinking between EMA and FDA. Here are the big ideas that I see as having been refined by these documents:

  1. The ideas of underpowered RCTs and the use of external controls to show superiority are not supported by either agency for development of new antibacterial agents.
  2. Both agencies emphasize a willingness to consider less stringent statistical designs. EMA explicitly mentions the idea of trade-offs: Less statistical power but you get a drug for a clear unmet need in a limited population.
  3. Implicitly, both agencies are endorsing the idea of non-inferiority (newslettervideo) in the UDR setting as a reliable path.
  4. And for children, the mantra is EXTRAPOLATE!


Well done to our colleagues at FDA and EMA … these updates obviously reflect many lessons learned in the school of hard knocks! In short, let’s figure out what is really possible, share that insight with each other, and then focus our efforts on those pathways!

All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.

Current funding opportunities (most current list is here)


Upcoming meetings of interest to the AMR community (most current list is here):

  • [Not to be missed!] 8 Dec 2021: “The New Winds Pushing and Pulling Antibacterial Development.” This FABULOUS program featured talks from the UK team behind the NHS “Netflix” pilot, Kevin Outterson’s recently released report documenting the need for global Pull incentives to have a value of $2.2 – 4.8b, and speakers covering PASTEUR and work in the EU on pull incentives. The video is here — please make time to listen to this program!
  • [Required reading!] The stunning 4 Feb 2022 webinar for the GRAM report (Global Research on Antimicrobial Resistance “1.27 million deaths per year are directly attributable to AMR”) is now available for replay. #AMRSOS! 
  • 31 May 2022 (virtual, 15:00-18:00, Finland): “Antibiotics for Life”, a webinar sponsored by TGAR (The Global Antibiotics Resistance Foundation) that will discuss stewardship and innovation from a Nordic perspective. Go here to register.
  • 3 Jun 2022 (virtual, 9a-5p ET): FDA-sponsored workshop entitled “Drugs for the Treatment of Uncomplicated Urinary Tract Infections (UTI)” that will focus on “nonclinical and clinical considerations regarding antimicrobial drug development for uncomplicated UTI.” Go here for more details and to register.
  • 7 Jun 2022 (virtual, 9-10.30a East Coast). CDC-sponsored webinar entitled “Antifungal Resistance: Understanding this Growing Global Threat.” Hosted by the team at CDC’s Mycotic Diseases Division, this looks to be an excellent conversation. Go here to register.
  • 8-9 Jun 2022 (virtual, 15.00-18.00 CEST / 9.00-12.00 EDT on both days): “Expert Workshop on Monoclonal Antibodies for AMR Pathogens” sponsored by the Paul-Ehrlich-Institut, on behalf of the COMBINE project. Day 1 focuses on preclinical development and translation (register here); Day 2 focuses on recurring problems and mitigation strategies in the clinical development (register here).
  • 16-18 June 2022 (Perth, Australia): Australasian Society for Infectious Diseases Annual Scientific Meeting is a hybrid event for adult and pediatric infectious disease and clinical microbiology specialists. Go here for details.
  • 21 Jun 2022 (virtual, 10:00-11:00 ET | 15:00-16:00 BST): Launch of the AMR Register. Sponsored by Vivli with funding from many partners, this is the launch of an open-access repository for industry-generated surveillance data. Looks interesting! Go here to register.
  • 22-23 Jun 2022 (virtual, 10a to approx. 2.30p ET on both days): Workshop entitled “Strategies for Early-Stage Programs Developing Novel Antibacterial and Antifungal Drugs.” Sponsored by NIAID’s Bacteriology and Mycology Branch (BMB), this 2-day webinar features a very strong faculty (including speakers from FDA) discussing tips and insights for early product discovery including in-depth discussions of funding opportunities. The timing is US-centered but video replay will be available. Do not miss this! Go here to register.
  • 11-14 July 2022 (Sydney): Australian Society for Microbiology Annual National Meeting is a hybrid event that will feature a range of lectures and symposium sessions, as well as extensive opportunities for networking. Go here for details.
  • 24-27 July 2022 (Il Ciocco, Tuscany): Gordon Research Conference entitled “New Antibacterial Discovery and Development”. Go here for details, go here for the linked 5-6 Mar Gordon Research Seminar that precedes it.
  • 28-31 July 2022 (Singapore): 10th International Congress of Asia Pacific Society of Infection Control is a hybrid event for professionals in the Asia Pacific region. Go here for details and to register.
  • 12-13 Sep 2022 (virtual, 9a-5p ET): This meeting of PACCARB is going to “identify key issues and critical policy gaps through a series of facilitated discussions examining a hypothetical large-scale disease outbreak scenario based on historic examples and estimates of future AMR outbreaks.” Sounds like pandemic wargaming (Center for Health Security; pre-COVID 19 May 2020 NPR article) to me! Go here for details.
  • 20-24 Sep 2022 (New Delhi): 21st Congress of the International Society for Human and Animal Mycology (ISHAM). Go here for details.
  • 4-7 Oct 2022 (Dublin, Ireland): The 2022 ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. This is an excellent meeting, especially for developers … and if you’ve missed it, the recordings from the 2021 meeting are online. Go here for details on the 2022 meeting.
  • 19-23 Oct 2022 (Washington, DC): IDWeek 2022, the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP). Go here for details.
  • 15-23 Oct 2022 (in person, residential, Les Pensières, Veyrier-du-Lac, France): The 6th edition of Patrice Courvalin’s fabulous ICARe residential training course covering all things AMR is on for 2022! This is a soup-to-nuts training in AMR: it is very intense, very detailed, and always gets rave reviews from attendees. Registration is open 21 Mar 2022 to 21 June 2022 and is limited, so book your slot as soon as you can. Go here for details.
  • 19-23 Oct 2022 (Washington, DC): IDWeek 2022, the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP). Go here for details.
  • 25-28 Oct 2022 (Stellenbosch, South Africa): The University of Cape Town’s H3D Research Centre will celebrate its 10th anniversary with a symposium covering the Centre’s research on Malaria, TB, Neglected Tropical Diseases, and AMR. Go here to register.
  • 17-20 Nov 2022 (Kuala Lumpur, Malaysia): The International Congress on Infectious Diseases will take place for the first time as a hybrid event. Go here for details. 
  • 27-30 Nov 2022 (Perth, Australia): 32nd International Congress of Antimicrobial Chemotherapy is the biennial congress of the International Society of Antimicrobial Chemotherapy (ISAC). Go here for details.

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