FDA and EMA regulatory updates / Fireside chat during the 4th AMR Conference

Dear All (lots and lots of wonkish detail here, be sure your blood caffeine level is adequate!),

During the 24-28 Aug 2020 BEAM Alliance-sponsored AMR Conference (go here or see below my signature for more), I had the opportunity on 27 August to chat with Sumati Nambiar (FDA) and Marco Cavaleri (EMA) about ongoing regulatory activities. The conversation broadly covered (i) guidance updates, (ii) upcoming workshops, (iii) developing products for rare pathogens, (iv) pediatrics, and (v) working in the era of COVID. Here’s a summary of the conversation

Let’s start our tour with comments made by Sumati and Marco on guidelines and workshops:

FDA (Sumati Nambiar)

1. The guidances for HABP-VABP and CABP (hospital/ventilator-associated and community-acquired bacterial pneumonia) are now final with few surprises relative to the drafts. Go here for a prior newsletter on the update.
2. Ditto for the guidance on LPAD (Limited Population Antibacterial and Antifungal Drug pathway)– the final version is now out with minor clarifications from the draft. Go here for a newsletter on the final guidance; go here for a wonkish newsletter on LPAD itself.
3. There’s a recently released draft guidance on anti-infectives for children (link to my newsletter on same). The big ideas are (i) efficacy can often be extrapolated from adult data provided the syndromes are similar, (ii) cohorts can be by weight as well as age (and 12+ children can often be enrolled in adult studies), (iii) cohorts can be enrolled in parallel, and (iv) there is an intent to be flexible on inclusions/exclusions, comparators, and laboratory testing. Comments on this guidance are invited!
4. A recent pair of workshops on systemic antifungal agents covered both development in general (4 Aug, link to materials) and coccidioidomycosis in particular (“Valley Fever”, 5 Aug 2020, link to materials), highlighted challenges with developing antifungals and included discussions of topics such as the use of external data as controls for rare pathogens and the possible value of PROs (Patient-Reported Outcomes) as endpoints. The links for the meetings give you access to webcasts, slides, and transcripts — everything is now posted.
5. A workshop on developing inhaled antifungals has been announced for 25 Sep 2020. Go here to register.
6. A workshop on drugs for treatment of gonorrhea is planned for 27 Oct 2020. Go here to register.
7. Finally, Sumati commented on these two recent papers authored by FDA:
   • Bart, S. M., et al. (2020). “Geographic shifts in antibacterial drug clinical trial enrollment: implications for generalizability.” Clin Infect Dis. (link). Quick summary: Data from different parts of the world are more similar than different and can often be generalized. Given that enrolling in the US can be difficult, being able to generalize from non-US data is important; although this paper was FDA-centric, the analysis would also imply that you can generalize in other directions.
   • Bart, S. M., et al. (2020). “Concordance of early and late endpoints for community-acquired bacterial pneumonia trials.” Clinical Infectious Diseases. Quick summary: The title really says it all … go here for a wonkish newsletter on the importance of this insight.

 
EMA (Marco Cavaleri)

1. An update to the EMA antibacterial guidance is in revision but has encountered COVID-related delays (link to prior newsletter).
2. Similarly, an updated pediatric guidance for anti-infectives is underway but delayed (COVID, again). Broadly, the approaches of EMA are similar to those of FDA. See the key links and further commentary in this prior newsletter.
3. EMA is considering a web-based approach to providing interpretive criteria (breakpoints) for susceptibility testing that sounds a lot like the approach FDA has taken with its susceptibility testing website (the website is here and a newsletter on it is here).
4. An EMA Network Strategy to 2025 consultation is underway. A previous newsletter discussed the call. Excitingly, part of this document recognizes the financial challenges of new antibiotics and the need for new business models! The deadline for comments is past but you can see the comments that Keven Outterson and I submitted here; there is also a related newsletter on the failure of new antibiotics to come to Europe in a timely manner.

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On the topic of developing for rare pathogens, interpreting small datasets, and labeling to support use of products in (as yet) unstudied circumstances, we have these interwoven comments from both Marco and Sumati:

1. As broad context, the conversation on rare pathogens focused here on products that have use ONLY for those rare pathogens. An example might be a product that uses a monoclonal antibody to target a single uncommon species.
2. FDA recognizes the need for such products, the challenges with developing same, and seeks to use the flexibility provided by LPAD to enable product progression.
   1. But, flexibility is not a free-for-all: Adequate & Well-Controlled trial data are still required for inclusion of the clinical data in Section 14 of the product labeling, approved indications are linked to specific infections at specific body sites (e.g., urinary tract infection), and wording in the label as a whole cannot imply use for an unapproved indication (site of infection).
   2. That noted, more uncertainty with both safety and efficacy is permitted if a limited population with an unmet need can be clearly defined. In particular, margins (M2) can often be broadened to the maximum effect size (M1); see above-cited wonkish newsletter on LPAD.
   3. And, there has been some flexibility applied to the use of animal model data to support PK-PD-based insights mentioned in the label. Go here for a very wonkish note about the 5 Mar 2020 FDA workshop on using animal models to support antibacterial development.
   4. Also note the very exciting release by IDSA of a living document guidance to supplement formal guidelines for the treatment of infections due to resistant Gram-negative bacteria (link). This new approach provides an opportunity for prompt expert commentary on clinical challenges for which there are no good answers.
3. EMA similarly recognizes the need for products for rare pathogens and likewise seeks comparative data for new agents if at all possible. EMA doesn’t apply the language of Adequate & Well-Controlled and also can in circumstances of unmet need and with sufficient justification grant an indication focused on a pathogen (e.g., “XYZ is indicated for treatment of infections due to Genus species“) rather qualifying the indication for a specific body site (e.g., “XYZ is indicated for treatment of urinary tract infection due to Genus species.“)
4. Both speakers commented on the number of organisms needed for any given species to be mentioned in product labeling. Both commented in particular on the way that small programs make it more difficult to get to the traditional cut-off of ~10 cases; no clear resolution to this conundrum is as yet evident.
5. Both speakers acknowledged the potential role of external (historical) control data in some circumstances. Both noted there have been relatively few examples of such products, that insight on best approaches is accruing, and that further conversation is needed.
6. Both speakers also noted the value of trial networks and the willingness to use data obtained globally. Aside: This idea is not limited to rare pathogens and might be a way to facilitate some types of development.
7. As an aside (and we did not cover this during the fireside chat), you can get further deep background on developing for rare pathogens by reviewing (i) the materials from the 18-19 Jul 2016 workshop entitled “Facilitating Antibacterial Drug Development for Patients with Unmet Need and Developing Antibacterial Drugs that Target a Single Species” (link), (ii) the subsequent 13 Apr 2017 meeting of the FDA Antimicrobial Drugs Advisory Committee on “Developing Antibacterial Therapies Targeting a Single Bacterial Species” (link), (iii) an IDSA-sponsored white paper in JID on this topic by Boucher et al. (link), and (iv) an editorial commentary by George Drusano (link).

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Finally, we have these themes on challenges of running trials in the era of COVID;

1. FDA’s most current COVID-related guidance is here.
2. EMA’s most current COVID-related guidance is here.
3. Both speakers emphasized the need to maintain GCP, the need at times for creative solutions to ensure data quality and reliability (in particular, issues with specimen handling), and the willingness of the agencies to discuss issues with Sponsors.

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Thanks to Sumati and Marco for a great conversation and I look forward to more of same in the future!

All best wishes, –jr

PS: They deserve and will get their own newsletter later this week (I hope), but while we’re discussing regulatory topics I’d like to mention birefly a pair of papers by Bai et al. that address the concern that sequential non-inferiority studies might lead to approval of agents with reduced efficacy via biocreep. In brief, the authors looked for biocreep, found it to be rare, and conclude (as with previous reviews) that use of the best current treatment as the control reduces the risk of biocreep:

1. Bai, A. D., et al. (2020). “Novel antibiotics may be non-inferior, but are they becoming less effective? A systematic review.” Antimicrob Agents Chemother. (link).
2. Bai, A. D., et al. (2020). “Methodological and reporting quality of non-inferiority randomized controlled trials comparing antibiotic therapies: a systematic review.” Clin Infect Dis. (link).

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.