Long note alert: Set aside at least 30 minutes for this one … there’s a lot of important material here.

Last week’s workshop entitled “Enhancing the Clinical Trial Enterprise for Antibacterial Drug Development in the United States” was an unusual and unusually instructive meeting. You can go here for the meeting materials but as there are 23 presentations to review, I suggest you use instead the annotated guide to the presentations that you’ll find just below my signature.

Sponsored by FDA, IDSA, NIH (NIAID), and Pew Charitable Trusts, the idea for the workshop arose out of the oft-heard and intertwined critiques that (i) new approvals are for indications that aren’t really the best use of the drug (“We don’t need another drug for cUTI!”), (ii) the approved label does not contain data on how the drug performs vs. really difficult pathogens or in challenging body sites, and (iii) “We don’t have much data on US patients.”

With this as a backdrop, the meeting’s three main goals were to

• Review the current state of antibacterial drug development
• Obtain stakeholder perspectives on what data would be most informative from development programs for new antibacterial drugs
• Evaluate strategies to support generation of the desired data from antibacterial drug development programs

Drawing on the summary deck (link) prepared for the end of the meeting, I offer this 3-part synopsis of the meeting’s very rich discussions:

Part 1: Different stakeholders want different things. This may seem obvious, but we’ve not always (or even often) made sure that we were hearing each other. Because the discussants at the workshop included diverse stakeholders (patients, journals, societies, physicians, charitable funders, government funders, companies), an instructive dialogue arose regarding their different needs.

In particular, there is a real tension between the US legislative requirement that the approved product label contain only very well supported data (the formal description is “Adequate and Well-Controlled”, A&WC) and the value that physicians place on having access to any and all hints about how to treat difficult organisms and unusual sites of infection, even if incomplete. Further, patients may well value outcomes differently — not all adverse events and outcomes are created equal!

In summary form, the different groups want the following:

• (ID) physicians want access to all the data, even if incomplete
• Payors, P&T committees want ways to judge data quality
• Patients want to be heard. Outcomes should include measures of how patients feel!
• Companies want validated, acceptable mechanisms for promoting based on data on resistant pathogens and difficult infections
• FDA must label products per regulations: “Adequate and well-controlled” data are required

Part 2: There are better ways to share the data we have. So, how do we address these conflicting needs? Intriguingly, four groups of implementable ideas emerged at the workshop for plausible approaches to making better use of the data we have:

• First, we must be clear on the limits on data generation
  • Because we work so hard to make rare pathogens and rare infections be (and remain!) rare, the choices reduce to either no data or making do with small datasets.
  • Even with unlimited time and money, there is no easy fix for this — and while you await those data, what do you tell today’s patient?
  • We need to explain the limits to ourselves and our peers – it’s so easy to wish for more data, especially when the constraints on data generation are not obvious.
• Second, we must all be clear on FDA’s limits on labeling
  • Without rules, we would have arbitrary unpredictable decisions
  • “Adequate and well-controlled” (A&WC) is the standard (but see Part 3 for further notes on this)
• Third, official society guidelines need to be updated much more often. Because the current update process is so onerous, guidelines can lag practice by years. Alternative approaches (e.g., the rapid guidance updates used in the HCV community, link) should be explored and implemented.
• Finally, and recognizing that some very interesting data will never be A&WC, we need to make other data and analyses accessible to the community.
  • Publishing data in a major journal about a new drug is of course a good start. Journals need to support this by recognizing that smaller datasets should not be denigrated as “small” when such datasets are the best that can be done.
  • In parallel, IDSA (or more broadly, the various professional societies) could publish informed integrated critiques of the available primary and secondary data on new drugs.
    1. Such reviews might be called “Guidance for using Drug X for Difficult Infections and Difficult Pathogens.” 
    2. Each by-drug analyses would draw on the FDA label, the FDA medical/statistical reviews, and all other published data to provide a society-led review of all of the available information, both complete and incomplete.
    3. The vision would be for the guidance to be the sort of thing that one peer would tell another about approaches to difficult situations and would be infinitely better than the haphazard data you might find if you went to Medline and searched to find tidbits.
    4. The point here is to recognize that patients present with infections and pathogens that are not (and will never be) discussed in ANY label. When this occurs, it is not an option to say “Sorry, your organism (or infection) is not in the FDA label — please come back when you have a conforming illness.”
    5. Such reviews would / should be appropriate for discussions with payors, discussions with insurers, and (maybe) promotional use. This could be very helpful when, for example, a physician needs to obtain reimbursement approval for use of an agent for an unusual situation.

Part 3: We can make better use of the data we do routinely generate. The ideas here require a bit more work but also seem within reach:

• First, we can reduce our angst about the need for data from patients in the United States. We would still like at least some such data, but FDA has done a deep review of this topic (see this talk) and it turns out that the studies generalize pretty well across national lines.
• Second, we must all be clear on the power of the standard indication (e.g., cUTI) based on a modern non-inferiority (NI) trial
  • Modern NI studies are powerful tools that readily detect inferior agents (go here for more details)
  • NI trials provide clear safety and efficacy comparisons
  • NI trials facilitate initial approval and thus provide a basis for additional indications
• Third, we can probably do more with the data we do have, up to and possibly including the scope of the data we can put in labeling
  • Please look closely at the 4 statistical talks in the last section of the meeting agenda!
  • As one path, we need to learn to apply statistical methods of borrowing data (information) across sites of infection.
  • As another element, we also need to think about the words Adequate and Well in the idea of A&WC. The same thresholds for validity do not apply to all settings — we must make accommodations for rarity.
  • Finally, don’t forget PROs (Patient-Reported Outcomes) and other patient-oriented measures! These can be incorporated into endpoints by use of advanced statistical methods thereby adding some additional information to otherwise dichotomous success/fail endpoints.
• Finally, we can run trials more efficiently
  • They are not a panacea, but platform trials show real potential to reduce cost and speed data generation. This seems particularly true after initial approval is achieved: studies in pediatrics and rare infections would seem a particularly good fit
  • And trial process improvements are also possible. As one example, obtaining consent in high-risk patients before they develop an infection seems workable!

All in all, this was an excellent conversation that leaves us with some clear actions. Some of the actions can be taken promptly and would have immediate benefit to the community. In particular, I am very excited about the ideas of (i) more frequent guideline updates and (ii) society-led “Guidance for using Drug X for Difficult Infections and Difficult Pathogens.” Others ideas (e.g., ordinal endpoints and data borrowing) will require more conversation be seem well positioned for use.

Nothing is set in stone, but I am hopeful that we’ll have the next iteration of this conversation at a follow-up workshop in the not too far distant future.

Many thanks to FDA, IDSA, Pew Trusts, and NIAID for organizing this workshop! 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: https://13.43.35.2/blog/

Outline of presentations at the 18-19 Nov 2019 FDA-IDSA-NIH-Pew Public Workshop.
The home page for the meeting is here and the links below are drawn from that web page. The presentation order is slightly re-arranged from the actual meeting so that talks are grouped logically for this summary. Panel discussions did not include slides and hence are not captured here.

• Introductory Comments, Meeting Summary, and related notes
  • Welcome and Panel Introduction (John Farley, FDA; link)
  • Meeting Summary (John Rex, F2G; link)
  • Agenda (link)
  • Speakers and Panelists (link)

• Current State of Play 
  • Overview of Antibacterial Trials (Sumathi Nambiar, FDA; link)
    • Why are we here today? Lessons learned and Rules of the Road for FDA
  • Geographic Shifts in Antibacterial Drug Trial Enrollment: Implications for Generalizability (Stephen Bart, FDA; link):
    • US data are important, but demographic, clinical, and microbiological similarities across regions lessen generalizability concerns for antibacterial drug trials 
  • Current Constraints in Antibacterial Drug Development: Clinician’s Perspective (Helen Boucher, Tufts Medical Center; link)
    • The crisis of AMR is here NOW! ID physicians need new drugs and know how to work with incomplete data
  • Role of Antibiotic Stewardship Programs in Utilization of Antibacterial Drugs (Sara Cosgrove, Johns Hopkins University; link)
    • A review of real-world challenges with positioning new antibacterials in hospitalized patients
  • Patient Perspective on Clinical Trial Participation (Amy Leitman, NTM Info and Research; link)
    • Patients both have things to tell us (please incorporate patient-reported outcomes and wish for better messaging from their caregivers
  • Review of Antibiotics in Clinical Development Pipeline (Wes Kim, Pew Charitable Trusts; link)
    • Most compounds currently in clinical development are based on known classes. Of the 13 candidates in Phase III development, three are based on novel classes (but one has now been discontinued) and (ii) only six have expected activity against a CDC ‘Urgent’ threat.
  • Current Federal Efforts to Support Antibacterial Drug Development (Dennis Dixon, NIAID, link; Erin Duffy, CARB-X, link ; Mark Albrecht, BARDA; link)
    • Collectively, BARDA, NIAID, and CARB-X have deployed an impressive array of resources
  • Economic Challenges and Considerations in Antibacterial Drug Development (Kevin Outterson, CARB-X; link)
    • The “Check Engine” light is flashing on the AMR enterprise — all our hard work is at risk unless we act now

• Realistic Options for Enhancing the Antibacterial Trial Enterprise
  • What Do We Need, What Should We Be Doing, Who Should be Doing It? (John Rex, F2G; link)
    • It’s time for Antibiotic R&D 3.0: Let’s all row the boat together … and in the same direction
  • Impact of Publications on Clinical Care and Research of Antibacterial Drugs (Lindsey Baden, Harvard University; link)
    • Publishers face competing demands from different stakeholders: Data mean different things depending on your point of view. Publishers should facilitate, air, and provoke discussion from all perspectives
  • Updating Professional Society Guidelines for Bacterial Infections (Cynthia Sears, Johns Hopkins University; link)
    • Guidelines and Guidance: Upholding methodological rigor while meeting a reduced development timeframe
  • Pitfalls and Progress in Getting Clinicians the Trials They Need (Vance Fowler, Duke University; link)
    • Registrational Trials are necessary but not sufficient, Strategy Trials will give clinicians what they want, and 
      Clinical Networks can improve US participation in both types of studies
  • Enhancing Clinical Trial Enrollment Strategies (Pamela Tenaerts, CTTI; link)
    • Process improvement is possible in HABP-VABP trials! With some limitations, CTTI has validated a way to obtain consent from high-risk patients in advance of the onset of an infection.
  • International Clinical Trial Networks (Chibuzor Uchea, Wellcome Trust; link)
    • International Trial Networks and Continuous Master Protocols are mutually supportive ways to enhance efficient trial implementation

• Innovative Statistical Approaches
  • FDA Statistical Perspective (Dan Rubin, FDA; link)
    • Areas for improvement include (i) Ordinal endpoints (e.g., Death < Survival with major morbidity < Survival without major morbidity), (ii) Borrowing of data across body sites, and (iii) Techniques for incorporation of resistant pathogen data into trial programs
  • Statistical Approaches for Antibiotic Trials (Roger Lewis, Berry Consultants; link)
    • A multi-infection-site, multidrug, platform trial could efficiently address non-inferiority and superiority evaluations of new agents targeting highly resistant pathogens
  • Radical Pragmatism: DOOR and SMART COMPASS for the Evaluation of Antibiotics (Scott Evans, George Washington University; link)
    • Simple Success/Fail endpoints lose valuable information that matters to patients and doctors. We can do better
  • An Alternative Design for Trials of Patients with Rare Pathogens: Conducting Trials with Difficult to Find Cases (Aaron Dane, DaneStat Consulting Limited; link)
    • Small studies (40-50/arm) efficiently detect inferior and superior drugs. Recognizing this enables better use of limited data.

Upcoming meetings of interest to the AMR community:

• 26 Nov 2019 (webinar, 9:30-11:00 CET): REVIVE webinar entitled “Innovation in point-of-care diagnostics for sepsis and bloodstream infections.” Go here to register.
• 28-29 Nov 2019 (Birmingham, UK): BSAC workshop entitled “ARM (Antibiotic Resistance & Mechanisms)”. This meeting is a research forum for UK-based researchers at all levels, including PhD students and technicians. Go here for details.
• 5 Dec 2019 (Monthey, Switzerland): The BioArk technology park is holding a one-day workshop on AMR. Entitled “The Ark Life Sciences Series #1”, you can get more details here.
• 16-18 Dec 2019 (Bangkok, Thailand): 3rd International Symposium on Alternatives to Antibiotics in Animal Production. Go here for details: https://www.ars.usda.gov/alternativestoantibiotics/
• 16 Jan 2020 (Washington, DC): Duke-Margolis meeting entitled (approximately) “improving Payment Policies for Antibiotics.” This meeting will run 10:30am – 4:30pm ET. Go here to register.
• 20 Feb 2020 (London, UK): Westminster Health Forum conference entitled “Antimicrobial resistance – coordinating a global response and progress on the UK strategy.” Go here for details.
• 26-27 Feb 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
• 1-6 Mar 2020 (Il Ciocco, Tuscany, Italy): Gordon Research Conference (GRC) on Antibacterial Discovery and Development: “Now is the time to re-boot antibiotic R&D before it’s too little, too late.” Go here for details.
• 12-13 Mar 2020 (Basel): BEAM-, Novo REPAIR-, CARB-X-, DZIF-, ND4BB-, ENABLE-supported (among a long list!) Conference on Novel Antimicrobials and AMR Diagnostics. Details are here, poster deadline is 12 Dec 2019.  
• 16-17 Mar 2020 (London): BSAC Spring Conference entitled: “Bridging the gap between science, policy and effective antimicrobial use.” Go here for details. 
• 18-21 Apr 2020 (Paris): Annual ECCMID meeting (#30)
• 25-30 May 2020 (Rotterdam), Annual ESPID meeting (European Society for Pediatric ID, #38)
• 27-28 Jun 2020 (Bryant University, Rhode Island): Drug Resistance Gordon Research Seminar entitled “Mechanisms and Approaches to Overcoming Drug Resistance in Cancer, Infectious Disease and Agriculture” for graduate students and postdoctoral scientists. Go here for details … this immediately precedes the GRC listed just next
• 28 Jun-3 Jul 2020 (Bryant University, Rhode Island): Gordon Research Conference (GRC) entitled “Strategies to Disrupt Drug Resistance in Infectious Disease, Cancer and Agriculture.” Go here for details.
• 1-4 Sep 2020 (Dublin): Annual ASM-ESCMID Conference on Antibiotic Development #5! Mark your calendar now and go here for details.
• 9-10 Sep 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
• 22-25 Sep 2020 (Albuquerque, New Mexico): Biannual meeting of the MSGERC (Mycoses Study Group Education and Research Consortium). Save-the-date announcement is here, details to follow.
• 17-25 Oct 2020 (Annecy, France): Interdisciplinary Course on Antibiotics and Resistance (ICARe). This is a soup-to-nuts residential course on antibiotics and resistance. The course is very intense, very detailed, and gets rave reviews. The date is set for 2020 and the program will ultimately appear here. Registration is limited to 40 students and opens 15 Mar 2020.
• 10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)

Please mark your calendar now to be in the Washington, DC area on 18-19 Nov 2019 for a 2-day workshop at FDA’s White Oak Campus focused on enhancing the clinical trial enterprise for antibacterial drug development.

Jointly co-sponsored by FDA, IDSA, NIAID, and Pew Trusts, this meeting will have a particular focus on (a) multi-stakeholder challenges and (b) changes that could be made in the United States to enhance the development of antibacterial drugs.

The program is expected to cover these topics:

• What data do various stakeholders (clinicians, patients, developers, FDA) need?
• Where there are gaps in data, what data are possible?
• How can we use innovative trial design elements (e.g., novel statistical methods) to generate better data?
• Can we facilitate trial conduct via such tools as trial networks?
• What is the role of scientific journals in spreading the word on what is known, not known, and possible to know?
• Likewise, what is the role of scientific societies educating the community? Can guideline updates be more frequent and timely?

I think this will be an important meeting and I would encourage the developer community to make every effort to attend either in person or by webcast. The general webpage for the meeting is here and the registration page is here. The meeting to runs 8.30a-5.30p on Day 1 and then 8.30a-1.00p on Day 2.

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: https://13.43.35.2/blog/

Upcoming meetings of interest to the AMR community:

• 8 Oct 2019 (London): Launch of “Reviewing Antimicrobial Resistance: Where Are We Now and What Needs to Be Done?”, a follow-up to the UK AMR Review‘s report and recommendations. Go here to register. 
• 10 Oct 2019 (online): Deadline for feedback to the Global AMR R&D Hub on their draft Collaboration Framework. Go here to tell them what you think! 
• 11 Oct 2019 (online): Deadline for Novo REPAIR’s 2019 US-Canada investment round. Go here for details — you need to dig all the way to the bottom of the web page.
• 16 Oct 2019 (FDA, White Oak): Advisory Committee for NDA 209445, cefiderocol lyophilized powder for intravenous administration, submitted by Shionogi Inc., for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis due to gram-negative bacteria in patients with limited or no alternative treatment options. Go here for details.
• 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.
• 4 Nov 2019 (FDA, White Oak): Public hearing on FDA’s proposed rules for “Use of Fecal Microbiota for Transplantation to Treat Clostridioides (Clostridium) difficile.” Go here for the online FR notice and here for the .pdf version.
• 7 Nov 2019 (webinar, 17:00-18:30 CEST): REVIVE webinar entitled “Converting Gram-positive-only compounds into broad-spectrum antibiotics.” Go here to register.
• 14-15 Nov 2019 (Hamilton, Ontario): “Fueling the Fight Against Antimicrobial Resistance”, a 2-day Gairdner Foundation-sponsored symposium in collaboration with the Michael G. DeGroote Institute for Infectious Disease Research and the David Braley Centre for Antibiotic Discovery at McMaster University. Go here for details.
• [NEW] 18-19 Nov 2019 (FDA, White Oak Campus): FDA-IDSA-NIAID-Pew-sponsored workshop: “Enhancing the Clinical Trial Enterprise for Antibacterial Drug Development in the United States.” Mark your calendar now, details to follow.
• 19 Nov 2019 (London): BSAC seminar entitled “Into clinical practice: Meeting the challenges of Gram-negative infection management”. A one-day conference on treatments for Gram-negative infections. Go here for details.
• 28-29 Nov 2019 (Birmingham, UK): BSAC workshop entitled “ARM (Antibiotic Resistance & Mechanisms)”. This meeting is a research forum for UK-based researchers at all levels, including PhD students and technicians. Go here for details.
• 16-18 Dec 2019 (Bangkok, Thailand): 3rd International Symposium on Alternatives to Antibiotics in Animal Production. Go here for details: https://www.ars.usda.gov/alternativestoantibiotics/
• 21 Jan 2020 (London): BSAC’s 2nd Antimicrobial Chemotherapy Conference – An ABC for everyone involved in developing new antimicrobials. Go here for details.
• 20 Feb 2020 (London, UK): Westminster Health Forum conference entitled “Antimicrobial resistance – coordinating a global response and progress on the UK strategy.” Go here for details.
• 26-27 Feb 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
• 1-6 Mar 2020 (Il Ciocco, Tuscany, Italy): GRC on Antibacterial Discovery and Development: “Now is the time to re-boot antibiotic R&D before it’s too little, too late.” Go here for details.
• 12-13 Mar 2020 (Basel, I’m told): BEAM-, Novo REPAIR-, CARB-X-, DZIF-, ND4BB-, ENABLE-supported (among a long list!) Conference on Novel Antimicrobials and AMR Diagnostics. Final location is TBD, details will appear here, and you should mark your calendar now. 
• 16-17 Mar 2020 (London): BSAC Spring Conference entitled: “Bridging the gap between science, policy and effective antimicrobial use.” Go here for details. 
• 18-21 Apr 2020 (Paris): Annual ECCMID meeting (#30)
• 25-30 May 2020 (Rotterdam), Annual ESPID meeting (European Society for Pediatric ID, #38)
• 10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)
• 1-4 Sep 2020 (Dublin): Annual ASM-ESCMID Conference on Antibiotic Development #5! Mark your calendar now and go here for details.
• 9-10 Sep 2020 (Washington, DC): US PACCARB public meeting. Go here for details.