LPAD/Limited Use insights; NI margins for TB and candidiasis

Dear All, 

I want to call your attention to next week’s AMDAC (Antimicrobial Drugs Advisory Committee) for rezafungin. This meeting is Tue 24 Jan 2023, 9a-4.30p ET and the meeting materials are provided here

Rezafungin is an antifungal but please don’t let that dissuade you from attending: this AMDAC promises to be an important discussion of the limited use / limited population concept that is fundamental to the LPAD pathway!

As a reminder, the central concept of the LPAD pathway (Limited Population Antibacterial and Antifungal Drug Pathway, add the extra As to make it LPAAAD and then sing it aloud to appreciate the great melisma!) is that “FDA’s determination of safety and effectiveness take into account the severity, rarity, or prevalence of the infection a drug is intended to treat and the lack of alternative treatment in the limited population for which the drug is intended.”

Although you won’t find LPAD mentioned directly in the pre-meeting materials, the idea of defining a limited use population is clearly raised. And, this in turn, should make you think of LPAD. So that you’ve got all the background in mind, I suggest you review these documents in advance of the AMDAC:

  1. August 2020: FDA’s final LPAD guidance itself.
  2. 6 Aug 2020: This brief newsletter surveys the final LPAD guidance.
  3. 22 Jul 2019: Based on discussions at the 12 July 2019 Public Meeting organized by FDA on the LPAD, this very wonkish newsletter digs deeply into the ideas behind LPAD. Even though dated July 2019, the posted version of the newsletter has been kept current with post-newsletter addenda.


As an added benefit, the briefing documents from both FDA and rezafungin’s sponsor discuss the question of the non-inferiority (NI) margin for active agents vs. placebo for candidemia / invasive candidiasis. Net, an effect size (M1) of around 30% on Day 30 All-Cause Mortality is supported … and this leads to support for NI margins of 10-20% in clinical trials depending on the target population.

While we’re on the topic of NI margins, you might find value in these related papers:

  • A draft guidance for TB drugs was release mid-Dec 2022 and it proposes an NI margin justification for a trial of a 4-month regimen for drug-susceptible TB. 
  • 26 May 2017 newsletter that reviews a 2017 paper on non-inferiority margins for bacterial infections. 
  • A 19 Sep 2020 newsletter entitled “In praise of non-inferiority.” This is a wonkish dive into the power of NI studies in the UDR setting and the reason(s) why we actively avoid superiority designs studies when developing new antibiotics. This theme is so fundamental that there is also a detailed 15-minute YouTube explainer.


Lots of important ideas here — happy reading! 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)

  • FDA have announced five RFPs spanning antifungal animal models, usability of antimicrobial drug labeling, urine PK-PD, and interpretive breakpoints. Applications are due dates of 23 Jan 2023 — see this newsletter for more details.
  • CDC have announced a very eclectic BAA that covers topics as diverse as surveillance and novel endpoints! White papers are due 3 Feb 2020 — see this newsletter for more details.
  • Current funding rounds from CARB-X are as described in this newsletter!
  • The AMR Action Fund is now open to proposals for funding of Phase 2 / Phase 3 antibacterial therapeutics. Per its charter, the fund prioritizes investment in treatments that address a pathogen prioritized by the WHO, the CDC and/or other public health entities that: (i) are novel (e.g., absence of known cross-resistance, novel targets, new chemical classes, or new mechanisms of action); and/or (ii) have significant differentiated clinical utility (e.g., differentiated innovation that provides clinical value versus standard of care to prescribers and patients, such as safety/tolerability, oral formulation, different spectrum of activity); and (iii) reduce patient mortality. It is also expected that such agents would have the potential to strongly address the likely requirements for delinked Pull incentives such as the UK (NHS England) subscription pilot and the PASTEUR Act in the US. Submit queries to contact@amractionfund.com.
  • BARDA’s long-running BAA-18-100-SOL-00003 offers support for both antibacterial and antifungal agents. This BAA has offered 4 deadlines/year since 2018 … check the most current amendment for details.
  • INCATE (Incubator for Antibacterial Therapies in Europe) is an early-stage funding vehicle supporting innovation vs. drug-resistant bacterial infections. The fund provides advice, community, and non-dilutive funding (€10k in Stage I and up to €250k in Stage II) to support early-stage ventures in creating the evidence and building the team needed to get next-level funding. Details and contacts on their website (https://www.incate.net/).
  • It’s not a funder, but AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
  • The Global AMR R&D Hub’s dynamic dashboard (link) summarizes the global clinical development pipeline, incentives for AMR R&D, and investors/investments in AMR R&D.
  • In addition to the lists provided by the Global AMR R&D Hub, you might also be interested in my most current lists of R&D incentives (link) and priority pathogens (link).


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

  • [NEW] 24 Jan 2023 (virtual, 9a-4.30p ET): Rezafungin NDA AMDAC. Go here for the meeting materials as well as connection instructions.
  • 24 Jan 2023 (virtual, 17.00-18.30 CET) Webinar entitled “Delivery systems in antibacterial drug discovery.” Sponsored by GARDP, this webinar will survey the use of phage, DNA nanostructures, and nanocarriers for drug delivery. Go here for details. 
  • 27 Jan 2023 (virtual, 10.00-14.00 ET): “The Challenges,” part 1 of a 2-part series entitled “Improving the Investigation of New Antibacterial Agents for Use in Children.” Convened by I-ACT (Institute for Advanced Clinical Trials for Children) and chaired by I-ACT’s Chief Medical Officer (Gary Noel), this webinar series features an outstanding faculty from Industry, Academia, and Regulatory (both FDA and EMA). Go here for details and to register.
  • 1-2 Feb 2023 (virtual): Antimicrobial Chemotherapy Conference by GARDP and BSAC in collaboration with ReAct Africa and Africa CDC. Go here for details.
  • 2 Feb 2023 (virtual, 10.00-14.00 ET): “Addressing The Challenges,” part 2 of a 2-part series entitled “Improving the Investigation of New Antibacterial Agents for Use in Children.” Convened by I-ACT (Institute for Advanced Clinical Trials for Children) and chaired by I-ACT’s Chief Medical Officer (Gary Noel), this webinar series features an outstanding faculty from Industry, Academia, and Regulatory (both FDA and EMA). Go here for details and to register.
  • [NEW] 14 Feb 2023 (virtual, noon-1.30p CET): Webinar entitled “WHO People-centred framework on addressing AMR” from WHO’s series entitled “WHO Global Webinar Series to Support Implementation of National Action Plans on Antimicrobial Resistance (AMR).” Go here to register.
  • [NEW] 16 Mar 2023 (virtual, noon-1.30p CET): Webinar entitled “WHO AMR Costing & budgeting tool: A review and country experiences” from WHO’s series entitled “WHO Global Webinar Series to Support Implementation of National Action Plans on Antimicrobial Resistance (AMR).” Go here to register.
  • 16-17 Mar 2023 (timings suggest hybrid EU-US): 7th AMR Conference, hosted by the BEAM Alliance with many co-sponsors. This has historically been a very good networking event. Go here for details.
  • [NEW] 23-24 March 2023 (virtual, 10a-4p ET): 23rd Meeting of the Presidential Advisory Council on Combating Antibiotic Resistance (PACCARB). The PACCARB will vote on the report from the Pandemic Preparedness Working Group (PPWG) on how to strengthen defenses against AMR pathogens in the face of a potential future, large-scale disease event. Go here for details and to register.
  • 14 Apr 2023 (Copenhagen, Denmark; 3-6.30p CEST): ECCMID and the Global Leaders Group on AMR will jointly sponsor a symposium entitled “Forging partnerships between science and policy in Antimicrobial Resistance (AMR).” Go here to register.
  • 15-18 Apr 2023 (Copenhagen, Denmark): 33rd ECCMID. Go here for details and to register.
  • [NEW] 26 Apr 2023 (virtual, noon-1.30p CET): Webinar entitled “WHO Human health AMR research agenda” from WHO’s series entitled “WHO Global Webinar Series to Support Implementation of National Action Plans on Antimicrobial Resistance (AMR).” Go here to register.
  • 8-12 May 2023 (Lisbon, Portugal): 41st Annual Meeting of the European Society for Paediatric Infectious Diseases. Go here for details.
  • [UPDATED DATES] 7-15 Oct 2023 (residential, Annecy, France): ICARe, the Interdisciplinary Course on Antibiotics and Resistance. Now in its 7th year, this course is a deep-dive into the world of antibiotic development. Intense, rigorous, and HIGHLY recommended. Seats are always limited … apply sooner rather than later! Go here for details.
  • 20-23 Oct 2023 (Athens, Greece): 11th TIMM (Trends in Medical Mycology). Go here for details.

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