Dear All (and with thanks to Kevin for co-authoring),
In a clear and compelling policy paper, a dozen of the DRIVE-AB alumni have proposed a concept for a pan-EU/EEA Pull Incentive. To follow the plot, here are the key points as a refresh:
- To date, the only strong, active Pull model is the UK NHS project that is moving from a test of a delinked model for 2 antibiotics to expanded implementation
- See the 11 July 2023 newsletter (“UK To Expand NHS Subscription Pilot!”) for more details.
- Also outside the EU, we have the ongoing efforts to pass the PASTEUR Act in the United States as well as similar early-stage projects in Canada and Japan.
- In the EU, the strongest call to date for broad action was the Council Recommendation on stepping up EU actions to combat antimicrobial resistance (AMR) in a One Health approach approved during the Swedish Presidency in June 2023:
- “Contribute to the design and governance of a Union multi-country pull incentive scheme in order to improve innovation, the development of new antimicrobials and access to existing and new antimicrobials where Member States can participate on a voluntary basis.
- “Such scheme could e.g. take the form of revenue guarantee, market entry rewards combined with revenue guarantee, lump-sum market entry rewards or milestone payments and may be financed at EU level, national level or co-financed, as appropriate.”
- See the 1 Jul 2023 newsletter entitled “EU Council Recommendation Adopted! But What Does It Mean?” for additional details.
- It is worth mentioning that in May 2023 the European Commission also included a “temporary mechanism consisting of transferable data exclusivity vouchers, for the development of novel antimicrobials to be granted and used under strict conditions” in its proposal for a revision of the existing general pharmaceutical legislation:
- See the 5 May 2023 newsletter (“European Commission: Proposed Pull Incentives”) for additional details.
- Since then, the creation of transferable data exclusivity vouchers has been removed from the text of the revision of the pharma legislation by the Rapporteur of the European Parliament. ·
- (5 Dec 2023 post-newsletter clarification: I’ve learned from the combined comments of Deepali Patel, Arjon van Hengel, and Damiano de Felice that the previous paragraphs may have misled some readers to conclude that the TEV is not any longer a part of the negotiations within the European Parliament and among EU institutions. To clarify, the removal of the TEV (transferrable exclusivity voucher) concept from the draft legislation by the Rapporteur is only a proposal at this point. Importantly, the conversation is still in flux as amendments both with and without the voucher language have been submitted. Going forward, the varied viewpoints on the draft legislation will be discussed and brought for a vote in the coming months, potentially next spring. Fingers crossed that the urgency of the situation and the need for pragmatic progress will win the day – we need action NOW to ensure the pipeline is sustained!)
- The next steps will be negotiations between the European Commission, the European Parliament, and the EU/EAA Member States, with a fast-approaching deadline of new elections for the European Parliament in June 2024 which could further delay any legislative approval.
- Aside: If you need a broader review of Pull incentive discussions to date, the 5 Nov 2023 newsletter entitled “Pulling For Pandemic Preparedness” would be a good place to start.
OK … so with that background in our heads, we come to the DRIVE-AB Policy brief entitled “Pan-EU/EEA Pull Incentive for Antimicrobial Innovation and Access.” Released at the end of November 2023, the policy brief speaks directly to the EC’s proposal to create a voluntary scheme to reward innovation and its authorship features the leading academic thinkers from the DRIVE-AB project itself (for clarity, this translates to Kevin having been involved but not John).
The core concept of the proposal is very similar to PASTEUR in that it proposes a revenue guarantee based on the value of the new drug, operating within the values and constraints of the EU/EEA. Member States would buy the new agent in their usual way but each Member State that opted in will annually pay the innovator the difference between its financing commitment amount and actual consumption (i.e., unit sales), coordinated through HERA..
Here is the executive summary:
The incentive: A pan-EU/EEA flexible revenue guarantee led by HERA with sufficient financial resources is the most promising and feasible incentive to stimulate innovation of and secure access to antimicrobial agents that meet public health and clinical needs.
- The incentive can be used to stimulate innovation of high-value new antimicrobial agents as well as to secure access to both new and priority generic antimicrobial agents. Aside: See newsletter text below for a discussion of how value is defined.
- Member States participate on a voluntary basis according to a predetermined financing commitment.
- Each participating Member State uses its normal processes for pricing, procurement, and reimbursement.
- The reward is based upon the antimicrobial agent’s value, with higher rewards for innovative agents with demonstrated evidence of treating the World Health Organization’s priority pathogens.
Visually, the concept looks like this:
Intriguing features of the plan that emerge as you read the details are:
- EMA will categorize each new agent into a value tier (see below our signatures for details.
- For new agents, these are High, Medium, Low, and No Reward.
- Priority generics are their own tier
- Member States opt in/out on a per drug basis.
- The hope is that all 30 EU/EEA Member States would opt in.
- The total annual reward for any given agent from all 30 Member States taken together would be
- High: €120m/year (€1.2 over 10 years)
- This approximates the value estimate from Outterson K: Estimating The Appropriate Size Of Global Pull Incentives For Antibacterial Medicines. Health Affairs 40:11, 1758-1765, 2021.
- Medium: €80m/year (€800m over 10 years):
- This is a mid-point estimate of needed share based upon Outterson 2021 and a 2023 analysis by HERA.
- Low: €15m/year (€150m over 10 years)
- This is a value from the Swedish efforts to define a suitable amount to ensure access to new antimicrobials
- Priority Generic: €3-30m/year
- This value is a range due to limited data
- High: €120m/year (€1.2 over 10 years)
- To manage orders and product flows, each participating Member State uses its normal processes for pricing, procurement, and reimbursement.
- These will determine the participating Member State’s annual consumption, i.e., unit sales.
- At the end of the contract year, each Member State will pay the innovator the difference between its financing commitment amount and actual consumption (i.e., unit sales).
- To stimulate innovation and ensure access, the revenue guarantee is always expected to be larger than actual revenues from consumption.
- The process includes further requirements for
- Prompt access for Member States (including the ability to use product labeled for another Member State)
- Offering an opportunity to license or distribute at a low unit price in low- and middle-income countries
- Stewardship by Member States
Fascinating and a great start! There will of course be debate on the precise details, but the principles are sound and aligned with prior work. It is especially noteworthy that (i) the proposed values across the tiers are in the needed global range and (ii) that the brief anticipates concerns raised by work to date around issues that arise if normal procurement processes are altered.
Fingers crossed for steady progression of this conversation and with 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
Value Tiers that would be designed by EMA (excerpted from Table 1 of the policy brief)
- High
- Activity against at least one WHO “critical” priority pathogen, or activity against multiple “high” or “medium” WHO priority pathogens
- Considered innovative (see definition below)
- Provides meaningful clinical evidence of the agent’s ability to meet clinical needs (see definition below)
- Medium
- Activity against one “high” or “medium” pathogens included in the WHO priority pathogen List
- Considered innovative (see definition below)
- Provides meaningful clinical evidence of the agent’s ability to meet clinical needs (see definition below)
- Low
- Activity against susceptible Pathogens
- Provides meaningful clinical evidence of the agent’s ability to meet clinical needs (see definition below)
- No Reward
- Undifferentiated, noninnovative antimicrobials
- Priority Generic
- Proposed by Member State as an important generic antimicrobial at risk of either shortages (due to e.g., fragile supply chains) or deregistration (due to e.g., low profitability), including child formulations
Definitions
- “Innovative means that the antimicrobial agent according to EMA’s judgement provides evidence of an absence or low level of cross-resistance and at least one of the three WHO innovation criteria: new chemical class, new target, or new method of action.
- “Agents will be considered innovative so long as, at the time of regulatory approval of the first-to-market, the similar agent has commenced a clinical trial.
- “For non-traditional agents (of which there are many in the preclinical pipeline), EMA must use its own discretion to assess if innovativeness has been achieved. New types of evidence may be required.”
- Editorial comment: We (Kevin & John) could quibble with the precise wording of the definition of “innovative” here, but the important thing is to set clear targets through a transparent and scientific process. While the standards in the policy brief are underdeveloped, they are a useful placeholder for the eventual targets. For an example of this process, see the UK public consultation (11 Jul 2023 newsletter) for their proposed new evaluation standards, which are a significant improvement upon the original version back when the UK pilot was first floated.
- “Meaningful Clinical Evidence means that available data demonstrates that the medicinal product is effective against WHO priority pathogens, based on meaningful in vitro data and based on the results of at least one clinical study, and demonstrate that no or only limited therapy options or possibilities of prophylaxis are available.”
And one more thing: As a reward for having read to this point in the newsletter, you also learn about a new episode in our long-running collection of discussions of Movies to Discover Antibiotics By. The new episode considers The English, a fabulous mini-series in which the desire for revenge is generated by an infection. Check it out!
Current funding opportunities (most current list is here)
- BARDA’s long-running BAA (Broad Agency Announcement) for medical countermeasures (MCMs) for chemical, biological, radiological, and nuclear (CBRN) threats, pandemic influenza, and emerging infectious diseases is now BAA-23-100-SOL-00004 and offers support for both antibacterial and antifungal agents (as well as antivirals, antitoxins, diagnostics, and more). Note especially these Areas of Interest: Area 3.1 (MDR Bacteria and Biothreat Pathogens), Area 3.2 (MDR Fungal Infections), and Area 7.2 (Antibiotic Resistance Diagnostics for Priority Bacterial Pathogens). Although prior BAAs used a rolling cycle of 4 deadlines/year, the updated BAA released 26 Sep 2023 has a 5-year application period that ends 25 Sep 2028 and is open to applicants regardless of location: BARDA seeks the best science from anywhere in the world! See also this newsletter for further comments on the BAA and its areas of interest.
- FDA have released a BAA covering a wide variety of regulatory topics. See this newsletter for general details; also note in particular an RFP for work on urine-specific breakpoints for uUTI. Early concept papers are due 6 Nov 2023; full proposals are due 19 Feb 2024.
- PACE (Pathways to Antimicrobial Clinical Efficacy), a £30 million initiative supporting early-stage innovation, has been created by jointly by Innovate UK, LifeArc, and Medicines Discovery Catapult (MDC). An initial round of up to £10 million in grant funding is available to support up to 12 projects focused on developing new treatments for the most threatening microbes and resistance mechanisms. Applications are welcomed from any part of the world for projects expected to last up to two years and with total funding of up to £1 million per project. Expressions of interest are invited by 24 November, and an informational webinar was held on 31 October 2023.
- ARPA-H have an Open BAA that is accepting applications through 14 March 2024. It is quite wide-ranging in its scope and definitely includes AMR-related projects. See this newsletter for discussion of the BAA and an AMR project that it now supports.
- HERA Invest was launched August 2023 with €100 million to support innovative EU-based SMEs in the early and late phases of clinical trials. Part of the InvestEU program supporting sustainable investment, innovation, and job creation in Europe, HERA Invest is open for application to companies developing medical countermeasures that address one of the following cross-border health threats: (i) Pathogens with pandemic or epidemic potential, (ii) Chemical, biological, radiological and nuclear (CBRN) threats originating from accidental or deliberate release, and (iii) Antimicrobial resistance (AMR). Non-dilutive venture loans covering up to 50% of investment costs are available. Applications are accepted on a rolling basis; go here for all the details.
- The ENABLE-2 consortium has announced a call to support hit-to-lead compound development by researchers at publicly-funded European universities. The call is focused on molecules with the potential to be direct-acting therapies for one or more of the following priority pathogens: ESBL-producing/carbapenem-resistant Enterobacteriaceae (E. coli, K. pneumoniae), P. aeruginosa, A. baumannii, methicillin-resistant S. aureus, or vancomycin-resistant E. faecium. The Call is open continuously, applications are reviewed at intervals, and funding is non-dilutive. Expressions of interest received before 30 Sep 2023 would be considered in November 2023. Applications received after this date will be evaluated in the spring of 2024 (date to be decided). Go to https://www.ilk.uu.se/enable2/apply/ for further details.
- The AMR Action Fund is now open to proposals for funding of Phase 2 / Phase 3 antibacterial therapeutics. Per its charter, the fund prioritizes investment in treatments that address a pathogen prioritized by the WHO, the CDC and/or other public health entities that: (i) are novel (e.g., absence of known cross-resistance, novel targets, new chemical classes, or new mechanisms of action); and/or (ii) have significant differentiated clinical utility (e.g., differentiated innovation that provides clinical value versus standard of care to prescribers and patients, such as safety/tolerability, oral formulation, different spectrum of activity); and (iii) reduce patient mortality. It is also expected that such agents would have the potential to strongly address the likely requirements for delinked Pull incentives such as the UK (NHS England) subscription pilot and the PASTEUR Act in the US. Submit queries to contact@amractionfund.com.
- INCATE (Incubator for Antibacterial Therapies in Europe) is an early-stage funding vehicle supporting innovation vs. drug-resistant bacterial infections. The fund provides advice, community, and non-dilutive funding (€10k in Stage I and up to €250k in Stage II) to support early-stage ventures in creating the evidence and building the team needed to get next-level funding. Details and contacts on their website (https://www.incate.net/).
- These things aren’t sources of funds but would help you develop funding applications
- AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
- The Global AMR R&D Hub’s dynamic dashboard (link) summarizes the global clinical development pipeline, incentives for AMR R&D, and investors/investments in AMR R&D.
- Diagnostic developers would find valuable guidance in this 6-part series on in vitro diagnostic (IVD) development. Sponsored by CARB-X, C-CAMP, and FIND, it pulls together real-life insights into a succinct set of tutorials.
- In addition to the lists provided by the Global AMR R&D Hub, you might also be interested in my most current lists of R&D incentives (link) and priority pathogens (link).
Upcoming meetings of interest to the AMR community (most current list is here):
- General note: Virtual meetings are easy to attend, but regular attendance at in-person events is the key to networking and deeper insight. My personal favorites for such in-person meetings are marked below as PERSONAL FAVORITE and are the BEAM Alliance’s AMR Conference (March, Europe), ECCMID (April, Europe), the ASM-ESCMID Developer’s meeting (September, alternates sides of the Atlantic), and ID Week (October, USA). Of particular value for developers are the AMR Conference and the ASM-ESCMID conference. Hope to see you there!
- 12 Dec 2023 (virtual, 1-2.15p ET): Duke-Margolis presents the third and final installment of their webinar series for policymakers combating AMR with a webinar entitled “Improving Regulatory Practices to Sustain Antibiotic Innovation.” The webinar will feature perspectives from experts affiliated with the FDA, Industry, GARDP, CARB-X, and the Center for Global Development. HIGHLY RECOMMENDED! Go here to register; prior webinars occurred on 9 May 2023 on the Need for New Antibiotics, and on 29 Aug 2023 on Preparedness for AMR Threats (also see their related October 2023 report on Preparedness and Post-Market Incentives for Novel Antibiotics).
- 24 Jan 2024 (online, 9a-1p London): Webinar entitled “Priorities and next steps for tackling antimicrobial resistance in the UK”, sponsored by the Westminster Health Forum. Featured speakers include Dame Sally Davies and the focus is on the UK’s 20-year vision and 5-year action plan for AMR. Go here for details and to register.
- 6-7 Feb 2024 (online): Antimicrobial Chemotherapy Conference. This is an annual, free of charge conference that is co-organized by GARDP and the British Society for Antimicrobial Chemotherapy (BSAC). Details to follow — for now, just mark your calendar.
- [NEW] 8 Feb 2024 (in person, Liverpool, UK, 8.30a – 4p): 2024 BioInfect Conference. A full-day AMR conference that includes a keynote from Lord Jim O’Neill (Chairman of the UK AMR Review). Go here for details and to register.
- 6-7 Mar 2024 (Basel, 6-7 Mar 2024): Sponsored by the BEAM Alliance, the AMR Conference is now in its 8th year and is consistently an excellent meeting for developers. You can’t register yet but you can mark your calendar and signup for notifications about the meeting. PERSONAL FAVORITE.
- 17-22 Mar 2024 (Ventura Beach, CA, in person): Gordon Research Conference (GRC) entitled “New Antibacterial Discovery and Development” with a 16-17 Mar 2024 pre-conference Gordon Research Seminar (GRS) for young doctoral and post-doctoral researchers. An intensive residential meeting, GRCs are highly recommended for networking and deep research insights. Apply here for the GRC and here for the GRS.
- 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. PERSONAL FAVORITE.
- 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.
- 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. Go here for the meeting’s general website. You can’t register (yet) for the 2024 event, but you can mark your calendar. PERSONAL FAVORITE.
- 16-24 Oct 2023 (Los Angeles, USA): IDWeek 2024, the annual meeting of the Infectious Diseases Society of America. Limited details as yet on line, watch https://idweek.org/ for updates. PERSONAL FAVORITE.an
