Push! Pull! Push! Pull! / Highlights from Davos 2018

Dear All: Three important documents were released at / during / around the World Economic Forum meeting that occurred this week in Davos.

First and foremost, we have the final report from DRIVE-AB. It’s a substantial document and you’ll need to set aside an afternoon to read it. As a way to get started, my 11 Sep 2017 blog post provided a good overview of DRIVE-AB’s conclusions and also offers a downloadable PowerPoint lecture containing the key ideas. In brief, the multidisciplinary DRIVE-AB team has:

  • Created 3 blocks of insight: (1) a common language for measuring things like sustainable use, (2) models to predict emergence & spread of AMR, and (3) new HTA metrics for antibiotic value and
  • Used these insights to propose four types of pragmatic and effective incentives
    • Two types of Push incentives (Grants and a Pipeline coordination)
    • Two types of Pull incentives (Market Entry Rewards and a Long-Term Continuity Model)
  • Given us three key takeaway messages:
    • It’s an ecosystem: We need Push and Pull. No single thing fixes it.
    • Push: Given the weakness in the overall pipeline (see my 5 Jan 2018 blog summary of the recent pipeline analysis by Pew), DRIVE-AB suggests that current global Push funding (~$550m/year) should be increased ~50%.
    • Pull: Detailed modeling by the DRIVE-AB team shows that a global market entry reward of ~$1b per new antibiotic would mean we’d have ~16-20 new novel antibiotics over the next 30 years rather than just the ~4 we’d currently expect.

That we’re making at least some progress on AMR-related work already is shown by the second report on our tour, 2016 R&D summary released by the AMR Industry Alliance. Per their progress report, Alliance companies invested > USD 2 billion during 2016 in R&D dedicated to a wide range of AMR-related products that include therapeutics, vaccines, diagnostics, and other preventative products. This is of course good to see, but the 48 traditional and the 32 non-traditional antibiotics in all phases of development as of Sep 2017 is certainly dwarfed by comparison with the more than 600 oncology drugs in Phase 2 or beyond (I could not find a good number for Phase 1).

The third report on our tour doesn’t speak to direct incentives but rather to the important role that planning for stewardship and access for new antibiotics will play in acceptance and implementation of meaningful Pull incentives. Provided by the Access to Medicines Foundation, the first AMR Benchmark Report shows that companies are working on priority pathogens, setting limits on antibiotic discharges, decoupling bonuses from sales volume, and tracking resistance. It’s not a surprise that the efforts are somewhat uneven across companies, but the trends are there and are encouraging.

Putting it all together, this figure from the DRIVE-AB reports shows that we’ve seen an impressive array of Push efforts implemented in the past two years:

But, you’ll immediately note that the Pull side of this figure is pretty lonely with only the GAIN Act in the United States keeping the box from being entirely empty.

The real question now is thus about global creation of strong Pull incentives and that’s where I hope that ripples from Davos will begin to drive this during 2018 and beyond. Every report reaches the same conclusion about the critical role of Pull incentives:

  • DRIVE-AB: “The effective stimulation of antibiotic innovation requires a balanced combination of both “push” incentives (those designed to support R&D directly) and “pull” incentives (those designed to reward successful outcomes from R&D). Push incentives, such as grants, are important but not sufficient to fill the pipeline.
  • AMR Industry Alliance: “There was near-total consensus that progress on pull incentives is needed to change internal investment decisions. … Pull incentives must be sustainable and sufficient to stimulate R&D across the full R&D lifecycle, from discovery through development, to see an impactful long-term change on the pipeline of new products.”
  • DRIVE-AB (again): “The G20 should work with member states and other like-minded countries to agree to implement and finance a market entry reward for a 20-year period including common sustainable use and equitable availability provisions.”
  • AMR Industry Alliance (again): “Responding companies clearly articulated their current views of incentives, citing new and substantial pull incentives as the greatest need. In the words of one responding company, echoed by many others, Now is the time to drive theoretical discussions to action.’
  • AMR Benchmark: “Governments and other funders must act to ensure the antimicrobial market can offer sufficient commercial incentive to keep pharmaceutical companies active in this space: for example by acting on commitments to develop additional and robust market-shaping mechanisms that support access objectives, stewardship, global supply and quality.”
  • And even before this week, don’t forget the very similar conclusions on Pull incentives provided by TATFAR (the government-level Trans-Atlantic Task Force on Antimicrobial Resistance) in their 2017 paper on incentives, the UK AMR review in their May 2015 recommendations on incentives, and the Duke-Margolis team in their PAVE policy paper.
  • (30 Jan 2018 update): Also of note is the 16 Nov 2017 multi-company-authored report from the BEAM Alliance that “emphasises key role of small and medium-sized enterprises (SMEs) as major innovators and presents a set of guidelines on how to more effectively reinforce and support antibacterial research and development (R&D) by SMEs.” ​

So, we now must work hard to make Pull happen and this requires us to focus on the pivotal role of antibiotics as the fire extinguishers of medicine.

Without antibiotics, there is no treatment for cancer, no ability to care for premies, hip replacements are high-risk ventures, and much more.

But, we don’t pay for fire extinguishers only when we use them — indeed, we much prefer to admire them and NOT use them … except in the knowledge that they are available. Similarly, we simply must stop paying for antibiotics on a per fire basis … this simply makes no sense and is not sustainable.

And while ~$1b per new antibiotic sounds like a lot of money, it’s important to look at other examples of cooperative international funding. The International Space Station had a cost in 2010 of $150b (and an astronaut/day cost of $7.5m). The CERN Large Hadron Collider cost ~9b to build and requires another $1b/yr to operate. So, it is possible!

I don’t exactly know how the needed Pull incentives will come about and there are still questions to be answered: Should all antibiotics get the same reward? If not, how do we created and adjudicate a suitable differential scale? Once you decide to provide a reward, how do you deliver it to the innovator? Different mechanisms would seem likely to be required in different territories (e.g., transferable exclusivity seems to make a lot of sense in the US due to its 100s of payors but single-payor countries would likely use a single central mechanism). And, how do you connect all this stewardship and access provisions in the developing world?

14 Apr 2018 update: Kevin Outterson has written an excellent Op-Ed in STAT News on these themes. Please check it out!

OK, so lots of questions! But, that fact that we’re talking about it so openly is a huge advance over where we were 5 years ago. It really takes my breath away when I think about how far we’ve come. Yes the next steps are hard, but the path is open … and the journey of a 1,000 miles does indeed begin with its first few steps! Push! Pull! Push! Pull! Heave! Ho! Onward!

At right, Dr. Doolittle’s mythical Pushmi-Pullyu.

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://amr.solutions//blog-index.html

Upcoming meetings of interest to the AMR community:

Dear All,
The IDWeek 2024 program committee is again seeking programs on novel antimicrobial agents and novel diagnostics for presentation in pipeline sessions! Here’s what is sought:

  • “Industry partners are invited to submit antimicrobials that are in preclinical stages of development (Phase II and III preferred) or recently approved after January 2024.
  • “The pipeline sessions will include antibacterials, antifungals, and antivirals (excluding COVID-19 and HIV).
  • “The committee also invites companies developing novel diagnostic technologies with a minimum of some preliminary proof of concept data to submit.” 

This is a great opportunity to tell the story of your development project! The deadline to submit is Wednesday, June 26 via the application portal. Any questions should be directed to program@idsociety.org. Please share this email with anyone you think might be interested in applying!
In addition, I’ll also note that those with a more general story to tell should look at the BugHub Stage (and the Global BugHub stage). Both BugHub variants seek “presentations that touch on your experience of working in infectious diseases and presentations that ultimately lead to a greater understanding of our diverse field” via a TED Talk-esque speech about your work. The deadline for applications is 26 June, the same as for the pipeline sessions.

I look forward to seeing you there! 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.

John’s Top Recurring Meetings

Virtual meetings are easy to attend, but regular attendance at annual in-person events is the key to building your network and gaining deeper insight. My personal favorites for such in-person meetings are below. Of particular value for developers are the AMR Conference and the ASM-ESCMID conference. Hope to see you there!

  • 27-30 April 2024 (Barcelona, Spain): 34th ECCMID, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. Go here for details. 
  • 17-20 Sep 2024 (Porto, Portugal): ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. Go here for the meeting’s general website. You can’t register (yet) for the 2024 event, but save the date!
  • 16-20 Oct 2024 (Los Angeles, USA): IDWeek 2024, the annual meeting of the Infectious Diseases Society of America. Save the date! More details to come!
  • 25-26 February 2025 (Basel, Switzerland): The 9th AMR Conference 2025. Go here to register

Upcoming meetings of interest to the AMR community:

  • [NEW]  9 Apr 2024 (virtual, 830a-10a ET): GARDP’s next REVIVE webinar entitled “Progressing a discovery project – Criteria and challenges.” Register here.
  • [NEW] 9 Apr 2024 (virtual, 10a-1130a ET): CDC webinar “Impacts of Antimicrobial Resistance on Cancer Care.” Click here for details and to register.
  • 10-11 Apr 2024 (virtual): Sepsis Alliance AMR Conference, a 2-day conference focused on “Practical technologies to manage sepsis and counteract the expanding challenge of antimicrobial resistance.” Go here for details and to register.
  • 26 Apr 2024 (Barcelona, Spain): ESCMID workshop entitled “Using Data Science and Machine Learning for Infection Science: A Hands-on Introduction.” Click here to register or here for more details. 
  • 27-30 April 2024 (Barcelona, Spain): 34th ECCMID, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
  • 26-31 May 2024 (Montreal, Canada): EDAR7, the McGill AMR Centre’s 7th edition of their Environmental Dimension of Antimicrobial Resistance conference. Go here for details; final abstract deadline is 21 Dec 2023.
  • 28-29 May 2024 (in person, Uppsala, Sweden): Uppsala Antibiotic Days, a broad-ranging 2-day program hosted by the Uppsala Antibiotic Center. Go here for details and to register.
  • [NEW] 30-31 May 2024 (face-to-face in Rockville, Maryland as well as online, 8.30-5.30p ET on 30 May, 9-2.40p on 31 May): NIAID-sponsored workshop entitled “Towards realizing the promise of adjunctive immune therapy for invasive fungal infections”. The agenda covers host immunity to invasive fungal infections, immune modulators in the context of fungal infections; and strategies for testing immune modulators as adjunctive therapy. Go here for more details and to register.
  • 9-13 June 2024 (in person, Ascona, Switzerland): “New Approaches to Combat Antibiotic-Resistant Bacteria, 2nd Edition” is a Sunday-Thursday residential workshop focused on the deep biology of AMR. Sponsored by NCCR AntiResist (a Swiss National Science Foundation consortium), the scientific program has the feel of a Gordon Conference. Space is limited, so you are encouraged to apply promptly — go here for details.
  • 13-17 June 2024 (Atlanta, Georgia): ASM Microbe, the annual meeting of the American Society for Microbiology. You can’t register yet, but you can go here for general details.
  • 17-20 Sep 2024 (Porto, Portugal): ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. See Recurring Meetings list, above.
  • 16-20 Oct 2024 (Los Angeles, USA): IDWeek 2024, the annual meeting of the Infectious Diseases Society of America. See Recurring Meetings list, above. 
  • 19-27 Oct 2024 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance). Now in its 8th year, Patrice Courvalin directs the program with the support of an all-star scientific committee and faculty. The resulting soup-to-nuts training covers all aspects of antimicrobials, is very intense, and routinely gets rave reviews! Seating is limited, so mark your calendars now if you are interested. Applications open in March 2024 — go here for more details.
  • 4-5 Dec 2024 (in person, Washington, DC): “Fungal Dx 2024: Fungal Diagnostics in Clinical Practice” is a 2-day in-person workshop organized by ISHAM‘s Fungal Diagnostics Working Group. The program and registration links are available at https://fungaldx.com/; the agenda is comprehensive and features an all-star global list of speakers.


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