Novel Biology, Novel Utility, & the Illusion of Skill: What to develop? What to reward?

Dear All (wonk-ish note alert and also with particular thanks as always to Kevin Outterson for helping to refine this newsletter):

Sparked at least in part by the innovation metrics in recent pipeline analyses (specifically, the ideas of No Cross-Resistance, New Chemical Class, New Target, and New Mechanism of Action) used in the 2018 pipeline analysis by Theuretzbacher et al. (link, and note that I plead guilty to being part of the et al. in this publication), I have been pulled of late into conversations that consider the idea that we should ONLY consider COMPLETELY novel products as having value. No Me-Too products, no extensions of known classes.

I can certainly see the attraction of this idea. If nothing else, requiring complete scientific or biologic novelty is both a very easy metric and is a good way to encourage developers to pursue diversity.

That acknowledged, I want to argue that this view suffers from the “Illusion of Skill,” and that we should instead maintain a focus on both Novel Biology* and Novel Utility. I talked a bit about this in my recent commentary on the WHO review of the preclinical and the clinical antibacterial pipeline (link) and I don’t want these ideas to get lost. (*Aside: Note that I struggle with the best word to use here and have settled for purposes of this newsletter on Novel Biology as a way to encompass multiple variations on the idea of novel mechanism, chemistry, etc.)

But before we look further at Novel Biology vs. Novel Utility, let’s first spend a moment on the idea of the Illusion of Skill as discussed by Nobel laureate Daniel Kahneman in his fabulous book Thinking, Fast and Slow. (If you don’t know his work, please take a look: here is the link to the book on Amazon.com and a link to a New York Times Magazine article by him — his ideas take time to digest but are mind-bending!) In brief, the Illusion of Skill is the idea that we consistently over-estimate the extent to which skill in one domain transfers to another domain. Stated differently, it is easy to believe that true skill in a complex but generally consistent domain (e.g., ability to diagnose an obscure medical syndrome based on deep understanding of human biology) translates into equal skill in a less consistent/more chaotic domain (e.g., predicting which antibiotic will be useful 15 years from now). Kahneman summarizes this forcefully in his New York Times Magazine article:

“We often interact with professionals who exercise their judgment with evident confidence, sometimes priding themselves on the power of their intuition. … How do we distinguish the justified confidence of experts from the sincere overconfidence of professionals who do not know they are out of their depth? … Overconfidence arises because people are often blind to their own blindness.”

With that in our heads, why does the Illusion of Skill matter in the Novel Biology vs. Novel Utility debate? Well, we are using Novel Biology/Utility as surrogates for the thing we really want: Useful antibiotics that last as long as possible in the clinic. In short, these are our rules of thumb as we think about what to research, fund and reward. But, the Illusion of Skill is a reminder that we should be cautious in our application of these rules. As I said in that prior note about the WHO pipeline:

  1. Really compelling novel antibacterials are rare. Seriously rare. Rocking horse manure rare. I love the idea of novelty and we should keep looking (Go CARB-X with its willingness to fund ~15 projects that could produce new class agents, together with a similar number of extensions on approved classes!), but we also need to deal with reality and recognize that …
  2. Improved versions of existing-class compounds can be really interesting and are generally easier to find (e.g., oral variants of known classes for difficult Gram-negatives). Over time, these improvements can be substantial: see my timeline chart (link) looking in particular at the idea that decades passed between first and subsequent fluoroquinolones and beta-lactams.

So, where does this leave us? How can we use the ideas of Novel Biology vs. Novel Utility? Let me now point to a paper that Kevin Outterson and I wrote a few years ago (link to the paper and link to a slide deck about the paper). In it, we suggested a point-scoring system for judging the value of a new antibiotic with the intent of using the resulting score to set the size of a pull incentive. The core idea was to create a simple metric based on rules that a drug developer could apply very early in an R&D program. Here is a distillation of the rules we proposed:

  • Everything started with achieving FDA and EMA approval for one or more indications and at least one pathogen on a threat list.
  • For the threat list, we used the then-available CDC 2013 list and said that a product got more points by covering pathogens that were rated as increasingly of concern.
  • We also proposed points for having a novel mechanism of action. Further, we suggested that at least a few 2nd-in-class products could earn at least some points.
  • We proposed points for having an oral route of administration.
  • We also had features to cover pediatrics and 2nd indications, but these are not relevant to this debate.

So, the key to our scoring system was that the merit of a new compound was judged both on what it did (e.g., pathogens, being oral) and how it did it (e.g., new mechanism, new target). The weighting of these two elements can be adjusted but the core idea was that both are valued – and you could make a guess very early in an R&D program whether one or both of these would be achieved. 

Notably, we excluded expert evaluations about whether the new antibiotic was “great.”  Such expert opinions involve a lot of judgment, but most importantly reliance on such a subjective standard makes it impossible for a drug developer to make rational choices in the early stages of an R&D program.  

So, and with a sincere desire to avoid the Illusion of Skill, let’s close the loop by coming back to Theuretzbacher et al. (same link as above) and note that the analytical table in that paper ALSO included columns for spectrum (aka, Novel Utility). Being oral was not used for product ratings but was noted in the comments about each product.

So that’s it. Novel Biology matters. But, Novel Utility also matters. The perfect should not be the enemy of the merely good — there is room for both in analyses of value. We should be careful when making guesses about which products will be of greatest value in 15 years … for now, I simply know that while I would love to have Novel Biology, I can get a lot value from Novel Utility.

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/

 

Current funding opportunities:

  • Open now through 28 Feb 2020: FDA call for applications to create rabbit models of ventilator-associated bacterial pneumonia (VAP or VABP, depending on your preferred abbreviation) due to carbapenem-resistant strains of A. baumannii and P. aeruginosa. Go here for details.
  • Open now through 16 Mar 2020: CC4CARB, NIAID’s call for applications to fund an innovative Chemistry Center for Combating Antibiotic-Resistant Bacteria (CC4CARB). Go here for details.
  • Open now through 9 Apr 2020: NIAID Broad Agency Announcement (BAA) soliciting contract proposals for preclinical and clinical development of vaccines, therapeutic, and diagnostics for microbial pathogens. Go here for more.
  • Dates for the 2020 funding rounds for Novo REPAIR Impact Fund will be announced May 2020. Go here for current details.
  • 2020 funding rounds for CARB-X have not been announced.

Upcoming meetings of interest to the AMR community:

  • 12 Feb 2020 (Alderley Park, UK): “2020 Bioinfect Conference” sponsored by Bionow (link), the NW England life science accelerator. 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.
  • 24 Feb 2020 (London, UK): One-day workshop hosted by Royal College of Nursing and the Longitude Prize entitled “Developing point-of-care diagnostics for urinary tract infections (UTIs): addressing clinical need in the UK.” Register here.
  • 26-27 Feb 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
  • 27 Feb 2020 (1700-1830 CET, online): GARDP-sponsored webinar entitled “PK/PD murine infection models: Focus on study elements, variability, and interpretation of results.” Go here to register.
  • 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.
  • [NEW] 5 Mar 2020 (FDA, White Oak Campus, 8.30a-5.00p EST): FDA workshop entitled “Advancing Animal Models for Antibacterial Drug Development.” FR notice is here and registration is here. The workshop will be webcast.
  • 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. 
  • 26-30 Mar 2020 (Atlanta, GA): CDC- and SHEA-sponsored 6th International Conference on Healthcare Associated Infections. Go here for details.
  • 30 Mar 2020 (everywhere): Deadline for applications for the Molecular Mycology pathogenesis course at Marine Biological Laboratory, Woods Hole. Now in its 24th year, the hands-on residential course runs 17 July to 2 Aug and gets rave reviews. Go here for more.
  • 9 Apr 2020 (everywhere): Final date for applications for NIAID/DMID call (link) for AMR-related vaccines, therapeutics, and diagnostics.
  • 18-21 Apr 2020 (Paris): Annual ECCMID meeting (#30)
  • 25-30 May 2020 (Rotterdam), Annual ESPID meeting (European Society for Pediatric ID, #38)
  • 18-22 Jun 2020 (Chicago), ASM Microbe 2020. Go here for details.
  • 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, antibiotic resistance, and antibiotic R&D. 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)
  • 3-7 Jun 2021 (Anaheim), ASM Microbe 2021. Go here for details.

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