Scary, Scarier, Scariest (Part 2): What can YOU do about it?

Long note alert— apologies! Get a cup of coffee and settle in…

Dear All: My 22 Apr 2019 note entitled Scary, Scarier, Scariest: Achaogen / FT editorial / CBS “60 Minutes” on AMR (link) caused a number of you to write expressing your related concerns and frustrations. Many thanks for those thoughts!

A core theme in those notes was “So, what now? What can I / you / we be doing to make a difference?” As you might guess, I’ve also been thinking about this rather a lot.

Provoked by the just-released final IACG recommendations (link) and with the goal of encouraging yet further conversation, here’s a starting point for debate, with ideas broken out by category of actor. Please note that this list is focused on human therapeutics and preventatives. Some of the ideas would apply to diagnostics and perhaps also food agriculture but I’m not trying to be exhaustive in those domains! With more detail below my signature, here we go…

  • Developers: Choose your projects VERY carefully. Novelty and pretty science are not enough — you must realistically envision the entire path to registration and market. See further commentary below my signature.
  • Professional Societies: Update the guidelines! As an immediate action, colistin should appear only at the very bottom of any list along with strong warnings about its relative inefficacy. After this, guidelines must be steadily updated to keep pace with resistance.
  • Academics & Thought Leaders: Come to grips with the inability to generate superiority data, why (as one example consequence) most new Gram-negative agents will be approved first for cUTI, and why this is actually good for your patients!
  • Regulatory agencies and payors: Engage and lead on finding a way to label and reimburse for the true societal value of new products. We know that the primary indication on the label may have been in cUTI but the real value lies elsewhere — how can we take advantage of this within a well-structured, predictable, and widely accepted regulatory and payor framework?
  • Large(r) companies: Be open to alternative R&D and partnership models that cause all parts of the ecosystem to contribute jointly! What is the equivalent of a toll road fee that governments, insurers, patients (tax payers), and companies could each contribute to the creation of a sustainable ecosystem supporting antibiotics?
  • Small(er) companies: Get out there and talk to your local political leadership! Invite your MP (or congressman) to tour your labs … photos (put everyone in a white coat!) and stories about a local company and a good visit with a local CEO can have enormous impact!
  • Public and private philanthropic funders: Thank you for your efforts to date! The early pipeline is still thin (link and link) but at least it exists. That said, it is now time for you to insist that the other parts of the ecosystem step up and take on the task of pulling those molecules through registration and keeping them on the market.
  • Political and economic thinkers: Advance those Pull incentives! Cheer for the UK’s ground-breaking efforts in this regard and then implement something similar in your country! We must plan broadly and continue to think of antibiotics as infrastructure (like fire protection) that is worthy of continued investment.
  • Everybody: Talk less, listen more! Appreciate that everyone comes to this VERY challenging conversation with good intentions but different perspectives. Answers that are quick, simple, and wrong are readily suggested! It is only via thoughtful multi-stakeholder debate that we will find the answers that best balance biases, build trust, and create long-term partnerships!

It takes years to create a new antibiotic and we simply can’t waste any efforts! As an example, PA-824 (a compound for MDR-XDR tuberculosis) was patented in approximately 1997, first described in a paper in 2000 (Stover et al., Nature 405:962-966), and is just now coming to present Phase 3 data at an FDA Advisory Committee (6 June 2019,link). Similarly, the Achaogen effort took 15+ years to come to fruition and then failure (link; I think plazomicin was patented in ~2006 and its discovery must have been based on several years of prior work). There are occasional stories of compounds coming to registration in less than 10 years, but these are exceptions rather than the norm.

Onward! With all best wishes (and with thanks to everyone who wrote and with special thanks to Kevin Outterson, Carol Nacy, Ryan Cirz, Jeremy Knox, and Anand Anandkumar for helping me check facts),

John

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: http://amr.solutions/blog/

Extended details (wonkish and nerdy, without further apology!) by category of actor:
Developers:

  • It’s important to recognize that novelty and clever science are not enough – you also have to be realistic about the view from the patient/prescriber/payor side of the equation
  • In particular, you have to think through the entire path to registration and marketing
    • You must be certain that there is a way to show the utility of your product
    • You should not depend on rosy projections of market share or rapid uptake
  • Every project must be taken on its merits, but this backdrop means that some project ideas are in general non-starters despite their lovely science. Here are examples of projects that face very difficult terrain:
    • IV-only Gram-negative agents with a spectrum limited to Enterobacteriaceae covered by the current crop of BL-BLI combinations (i.e., that do not cover metallo-beta-lactamases, P. aeruginosa, or such)
    • IV or oral products for MRSA
    • Topical products
    • Inhaled antibiotics as add-on therapies (standalones for Cystic Fibrosis are, however, a different story and could well have value)
  • On the other hand, products in these areas appear to have a more tractable commercial path forward (see Alan Carr’s review, link):
    • Oral products for Gram-negative infections (uUTI, cUTI, enteric infections, and various follow-up settings) could be of great interest
    • IV-oral agents that can replace fluoroquinolones for CABP
    • Carefully selected, well-defined gaps (here’s a starter list — perhaps you can add to it):
      • Oral products for non-tuberculous mycobacteria (NTM) — See the recent workshop on this (link)
      • IV or oral products for S. aureus endocarditis / osteomyelitis where the agent has bactericidal activity sufficient to transform treatment
      • IV or oral products for serious infections due to P. aeruginosa and A. baumannii (this is a very tricky area for developers but the distinct nature of these organisms creates a path for a standout product)
      • Perhaps also oral products for TB and GC. That said, the market aspect is tricky for these products.

Frustratingly, this means that some novel agents may fall into a sinkhole. Consider a novel mechanism IV-only agent with marvelous activity for non-metallo-CRE. Would we like to have this? Yes. But would it be used instead of a BL-BLI? Maybe not. In a sense, this is the story of plazomicin* (same link as for Scary/Scarier, above). Such agents have value but are more dependent than others on actions taken elsewhere in the AMR ecosystem (see next points).

*In passing, please note that I erred in the original Scary/Scarier note when I stated that plazomicin covers bacteria with the metallo-beta-lactamase NDM-1. In fact, NDM-1 frequently circulates on plasmids that also encode methyltransferases which alter the ribosomal RNA so as to prevent binding of plazomicin or other aminoglycosides. Thus, plazomicin is active against some, but not all, metallo-beta-lactamase-producing CRE. See Serio et al. 2019 for a good review of this (link). Many thanks to David Livermore for sorting me out on this!
  

Professional Societies

  • It’s time for colistin to be pushed to the very bottom of all treatment guidelines. We now have MUCH better agents on the market.
  • And while we’re at it, perhaps colistin needs a black box regarding its limited efficacy. The societies should approach the regulatory agencies with this suggestion. Remember that colistin was approved in the US before the 1962 Amendments.
  • And, let’s start to experiment with much more frequent guideline updates. Once a year seems both useful and feasible — and knowing that the next update is in a year makes it a little easier to work with the necessary trade-offs in such processes.
  • And as I was writing this note, David Shlaes wrote to make exactly the same points about guidelines & colistin (link)!

Academics / Thought leaders

  • It’s time for all of us to be realistic about the nature of the data we can routinely develop.
  • In particular, we must all come to grips with the idea that we don’t want it to be readily possible to develop data showing activity in settings where all other drugs have failed. If this logic behind this is not clear to you, please see the discussion on slides 11-15 in the most current version of my Funding, Filing, and Finance talk (link).
  • As a corollary to this, it is not acceptable to criticize a package based on (a) clean non-inferiority data vs. a carbapenem in cUTI study and (b) a limited amount of data in the MDR/XDR setting by saying, “I don’t want another drug for cUTI! I want to see superiority data in MDR/XDR!”
    • As is proven by delivery of a clean cUTI (or other body site) study, the new drug works when used on pathogens susceptible to it.
    • Logically, it will still work when those pathogens are resistant to other compounds.
  • Rather than critique the limits on the data, we should all work steadily to explain to others the nature of development in this space, and in particular the inability to routinely generate superiority data.
  • At the end of the day, something has gone horribly wrong if it is readily possible to ever again be in a position where available active agents are as weak and limited as colistin!

Regulatory agencies and Payors

  • As the flip side of the tasks given to the Academics and Thought Leaders, we must find a way for labels to discuss the fact that antibiotics often find their best use outside of labeled indications.
    • In this sense, it IS true that we don’t need another agent for cUTI. Or, rather, we want it … sometimes for cUTI but even more often for other things.
    • I know this is tricky and the extrapolation is imperfect, but the PK-PD insights that support use of the drug in one body site are the necessary basis for treating infections in other body sites. In my life as a practicing physician, I often found myself needing to make just this kind of extrapolation and any help with this would be greatly appreciated!
  • In parallel, it is certainly correct to note that superiority studies are easily interpreted, but it is important that every such mention carry a commentary on why the ready ability to implement such studies is undesirable at the societal level.
  • These two points connect with the question of reimbursement. If we reimburse only for use within the scope of labeled indications while continuing to wish for superiority data that are actually detrimental to the larger goal of controlling AMR, then we are shooting ourselves in the foot. In effect, we create a Catch-22 in which we’ll only pay for data that can’t routinely be developed!
  • As new economic models are developed, such as the UK pilot, industry, regulators and payers will need to have thoughtful discussions to value a new antibiotic across the range of on- and off-label uses for which we know it will be used. The overall societal value of a new antibiotic is routinely MUCH larger than its direct sales value. We should make more use of the data in Sertkaya et al.: Analytical framework for examining the value of antibacterial products. Report to US DHHS (link).
  • For all of these issues, the agencies and payors are best positioned to lead. EMA has taken a step towards this with its use in some labels of an organism-specific indication (rather than an organism-site-specific indication). Further using this idea as part of a sound, scientific, predictable, well-structured, and widely recognized framework will not be easy, but we need to get started. Perfect data are impossible — we need to work with the routinely possible.

Large(r) companies

  • Be open to alternative R&D and partnership models. As part of this, recognize that some form of broad social contract is likely necessary if the needed Pull incentives are to come into being.
  • Stated a little differently, can we find a way to talk about how all the players in the ecosystem contribute something to get to agreeable Pull incentives? What is the equivalent of a toll road fee that governments, insurers, patients (tax payers), and companies could each contribute to the creation of stable ecosystem? What could a “compromise solution” that is workable for all parties look like, at least in the interim, until Pull incentives are delivered?
  • I think that taking leadership on the idea of joint contributions could well be the key to turning the corner in the Pull incentive discussions.
  • In parallel, call loudly and clearly to the Governments you know best for new Pull incentives. Work together via trade associations (link) and also work to involve companies not currently active in the antibiotics business.
  • Finally, and if your company is not currently involved with antibiotic R&D, you should take note of the increased stakeholder pressure to find a solution to the broken economics for antibiotic biotech and use this as encouragement to get involved in efforts to develop solutions

Small(er) companies

  • Be ambassadors for AMR with your local/regional political leadership! Local companies and their leadership are always of interest.
  • Your Member of Parliament or Congressman would probably enjoy a visit to your labs. With everyone in a white coat, you can talk about job creation, the challenge of AMR, and get to show the interesting colors of a petri dish or two..

Public and private philanthropic funders:

  • Your efforts to date have been impressive: The funds injected by/via government and philanthropy in the US and EU have had a stunning effect. Although the pipelines are still too thin and novel mechanism agents too few (link and link), the global community has made a good start.
  • Given this emerging momentum, now is the time for you to use the lesson of Achaogen to focus the attention of the other parts of the ecosystem on their roles. As was stated in Jeremy Farrar’s recent Financial Times editorial (link), we must find “creative new models to stabilise the antibiotics market and stimulate private sector innovation without exposing public funders to all the risk.”

Political and economic thinkers

  • Continue to advance Pull incentive (link) discussions and legislative efforts. We need to use the recent IACG recommendations (link) as impetus to keep this on the agenda at the UN and G20.
  • I know it feels like we’ve analyzed this area ad nauseum, but building region-specific analyses is also needed and is very powerful. The process of implementing Pull incentives will occur one country at a time.
  • To that end, let’s all cheer for the UK’s ground-breaking efforts to undertake a pilot delinked purchase model! This is a wonderful effort. But, it’s only a first effort — we need this across the G20, if not beyond!
  • If the large drug companies continue to retreat, and if substantial market-based incentives remain politically unpalatable, perhaps we do need to consider the question of Plan B as mentioned in Farrar’s recent Financial Times editorial (link). What shape this would take is unclear as yet, but it is simply not acceptable to allow all the work to date to founder for lack of a back-end that can maintain (and continue to develop) new antibiotics that reach the market.

Everybody

  • Appreciate and listen for the good intent behind all conversations in this space. Everyone comes to the table with different perspectives and it takes time to learn that the surface detail of the problem obscures a much more challenging underlying complexity.
  • This is a hard, hard, HARD problem and hence subject to suggestions of answers that are quick, simple, and wrong.
  • It is only via thoughtful debate that one comes to see the true picture.
  • Finally, please engage with the literature — learning the background context is very instructive!

Upcoming meetings of interest to the AMR community:

  • 6-11 May 2019 (Ljubljana, Slovenia): 37th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID). Details here.
  • 20 May 2019 (everywhere): Application deadline for NIAID solicitation (HHS-NIH-NIAID-BAA2019-1) for proposals to support new vaccine or therapeutics candidates targeting antibiotic-resistant bacterial infections. Go here for more details.
  • 3-6 Jun 2019 (Philadelphia): Annual BIO meeting
  • 20-24 June 2019 (San Francisco): Annual ASM Microbe meeting.
  • 10-11 Jul 2019 (Madison, WI): Tiny Earth Symposium, a teaching consortium that uses crowd-sourcing of antibiotic-producing microbes to improve undergraduate education. Details here.
  • 12 July 2019 (FDA, White Oak Campus): Public workshop to discuss the 2018 LPAD guidance. Register here.
  • [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 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 2019 (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.
  • [Application link now active!] 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 (Berlin?): 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. 
  • [NEW] 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)
  • 10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)

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