FDA analysis of 40-years of antibacterial development: Dheman et al.

What we have in the upper graph is the # of antibacterials in development during each of the last 40 years (key point: the analysis was limited to systemic antibacterials … agents for C. difficile, H. pylori, and M. tuberculosis were excluded). Note how antbacterial R&D began to again gather momentum after the lull around 2000 … but then note the steam seems to going out of the efforts: As of 31 Dec 2019, only 25 antibacterials were in development, a number below that of 1980.

And there’s yet further bad news: the average time from IND to approval rose from 6 to 8.3 years (and trends in more recent data suggest that average time will ultimately exceed 9 years), the success rates fell from 40% to 23%, and the number of large companies involved fell steadily: Finally, only 3 large-company sponsored INDs were in active development as of 31 December 2019, the lowest level observed over the entire 40-year survey window (lower graph).

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As noted above, these findings were foreshadowed in 2014 by the paper by Kinch (link) … and none of this will come as a surprise to those of us working in this space. Thus, our accompanying editorial (link) surveys both the challenges of this space and our evolving thinking:

• Finding compelling new antibacterial agents is very, very hard
  • Both the science and the economics are challenging (link to a relevant newsletter)
• Calls for action have been raised and have led to some concrete actions
  • We’ve seen IDSA’s 10×20 initiative, ND4BB, CARB-X, and much more (link to a survey of incentive reports)
• But, company-crushing post-approval economic pressure on antibacterial development remains unabated
  • The failures of Achaogen (newsletter), Melinta (newsletter), and Tetraphase (newsletter)…
• And (perhaps a surprise), there is hope that Worst of Times might be transformed into the Best of Times
  • The UK Subscription Pilot (newsletter), the DISARM Act (newsletter), and more (Hint! Sign up here for that 9 July webinar on the new global AMR initiative)

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And to complete our tour of the challenges of R&D, please also review Darrow 2020 (link). Based on external data on drugs approved during 1984-2018, these authors have compared the application of regulatory flexibility to antimicrobial vs. non-antimicrobial products. In a very important difference from the FDA analysis, the scope of this review includes all types of antimicrobials, not just antibacterials. These authors found that antimicrobial products as a whole:

• were more likely to benefit from priority review, fast-track designation, and accelerated approval; 
• were less likely to have Orphan Drug Act designation; and
• had a median time from investigational new drug application to approval of 5·9 years vs 7·6 years for other drug classes.

But when you dig closely (see the paper’s Figure 1), you see that this seemingly favorable pattern is dominated by these advantages playing out mostly for antivirals, antiprotozoals, antimycobacterials, and antifungals. Antibacterials, on the other hand, fall behind these other groups in their use of every type of expedited designation: Orphan Drug, Priority Review, Fast Track, Accelerated Approval, and Breakthrough Therapy Designation.

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OK, so what does all this mean? Well, antibacterials are hard. Really, REALLY hard. And, we need more of them. So, and to quote the title of our editorial: We’ve pushed as hard as we can … now we need to start pulling! It’s time to create some delinked incentives!

All best wishes, John & Kevin

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.

Kevin Outterson, JD, Professor of Law, Boston University & Executive Director, CARB-X (these views are personal and do not necessarily reflect the views of CARB-X or any of its funders) @koutterson