Antimicrobial Resistance: Key Policy Updates

The purpose of this article is to summarise the status and recent changes in policy related to antimicrobial resistance (AMR). The article focusses on the updates related to the United Nations General Assembly political declaration of September 2024. The article also summarises the current and evolving policy landscape for incentivising pharmaceutical R&D in Europe.

Antimicrobial resistance (AMR) is a global health priority. AMR occurs when bacteria, viruses, fungi and parasites no longer respond to antimicrobial medicines. Drug resistance means antimicrobial medicines become ineffective and infections become difficult or impossible to treat. This increases the risk of disease spread, severe illness, disability and death. It also impacts the ability to perform life-saving procedures including cancer chemotherapy, caesarean sections, and routine procedures (e.g. hip replacement).

Tackling AMR has been subject to a range of political commitments at the recent United Nations General Assembly High-level meeting on AMR in September 2024. Furthermore, regional policy makers are actively considering how to incentivise pharmaceutical R&D. This article focuses on possible incentives in the European Region.

Antimicrobial Resistance – A Global Urgent Health Threat

The global threat of antimicrobial resistance has led to the need to tackle AMR as a health priority.  Global Leaders approved a political declaration at the United Nations General Assembly High-level Meeting on Antimicrobial Resistance in September 2024. As well as the human cost, the financial scale of the problem was re-emphasised. Concerning estimates that globally AMR could result in US$1 trillion of additional healthcare costs per year by 2050, US$1 trillion to 3.4 trillion of gross domestic product (GDP) losses per year by 2030, and that treating drug-resistant bacterial infections alone could cost US$412 billion annually were reported.

Call to Action

The declaration commits to targets and actions, including reducing the ~4.95 million human deaths associated with bacterial AMR annually by 10% by 2030.

One-Health Approach

The declaration recognises the need to address AMR through a One Health Approach which is an integrated strategy balancing the health of humans, animals and ecosystems aiming to prevent, detect and respond to global public health threats including antimicrobial resistance.

Commitments to Research and Development and Innovation

With regards to research and development (R&D) and innovation, the declaration notes that the R&D pipeline for vaccines, diagnostics, therapeutics (including antimicrobials and alternatives to the use of antimicrobials, especially antibiotics) is insufficient.  It further notes that affordability and equitable access to new antimicrobial treatments should be a global priority.

Commitments include exploring, encouraging and promoting innovative incentives and financing mechanisms for R&D to address AMR. This includes “push-pull incentives”. It is important to ensure that the R&D focus is needs-driven. Additionally, equitable access mechanisms should be considered (particularly in developing countries).

The declaration recognises the benefit of public-private partnerships in the development and access to therapeutics. There is a commitment to build a stronger and transparent partnership between public and private sectors, and the academic and scientific community. The important role of the private sector in R&D is recognised. A commitment is also made to continue to support voluntary initiatives and incentive mechanisms which separate the cost of investment from the return.

R&D models need to change to tackle AMR

It is recognised that current R&D is insufficiently incentivised.  Problems arise with volume-driven drug reimbursement models coupled with a drive for prudent use. This makes for unsustainable returns.

Push Incentives

These are government or regulatory interventions which support R&D by directly lowering the costs of development.  Push incentives implemented include early stage financing for R&D targeting the WHO Priority Pathogen List, such as the Combating Antibiotic-Resistant Bacteria Fund (CARB-X), the Global Antibiotic Research and Development Partnership (GARDP) and the Antimicrobial Resistance Action Fund (AMR Action fund).

Push incentives alone are insufficient to incentivise R&D. Simulation of these types of push funding incentives demonstrate that they can be complemented by pull incentives.

Pull Incentives

These aim to improve the commercial viability of development by reducing the risk of low revenues. These strategies are needed alongside enhanced funding push incentives. Policymakers need to consider innovative incentives.  Some pull incentives being considered are as follows:

Transferable Data Exclusivity Vouchers (EU potential pull incentive)

The reform of the EU pharmaceutical legislation is ongoing.  In April 2023 a revision proposal was submitted by the European Commission. A regulatory pull incentive of Transferable data exclusivity vouchers (TEVs) is outlined in the draft regulation and draft directive.

TEVs are planned to promote the development of “priority antimicrobials”. A priority antimicrobial must show a significant clinical benefit with respect to AMR (considering the WHO priority pathogens list). Figure 1 below depicts the proposed eligibility criteria for the voucher.

Figure 1: Proposed eligibility criteria of a priority antimicrobial for the transferable data exclusivity voucher (TEV).

Regulatory Data Protection (RDP)

An additional year of regulatory data protection (RDP) would be granted to the developer of a ‘priority antimicrobial’ via the TEV. RDP refers to the period for which another applicant cannot refer to the data submitted by the original developer for a marketing authorisation application.

The developer could use the TEV for a product in their own portfolio to extend the RDP period. Alternatively, the TEV could be sold to another marketing authorisation holder. Strict conditions would accompany the granting, use and sale of the vouchers. Developers would need to demonstrate the capacity to supply the antimicrobial to meet the expected needs of the EU market. They would also be expected to provide information on all direct financial support received for R&D of the priority antimicrobial. This information would be made public.

A voucher could only be used once, within the first four years of the regulatory data protection (RDP) period and only if the product’s marketing authorisation has not been withdrawn. If transferred to another marketing authorisation holder, it could not be transferred further. The transfer value would be declared to the EMA and made public. It is proposed that a maximum of ten vouchers could be issued within a 15-year period, after which time the scheme would be reviewed.

Possible Changes  to the TEV incentive

In April 2024 the European Parliament adopted its position on first reading of the draft regulation and draft directive. The TEV incentive remains but its conditions are proposed to be tightened. The period of regulatory data protection would be between 6 to a maximum of 12 months dependent on the WHO priority pathogen list (critical vs high vs medium). Furthermore, the TEV would not be available to developers who benefited from market entry rewards and milestone payment schemes (discussed further below). The monetary value of the voucher would be paid to the authority, transferable to the developer in yearly instalments in order to ensure manufacturing capacity and supply of the antimicrobial for which the voucher was created. Of note, the European Council has not yet adopted its position on the reform of the EU pharmaceutical legislation. The TEV incentive is thus subject to further changes.

While TEV represent a new incentive in the EU, there is industry experience of similar incentives in other regions. An example would be the FDA priority review vouchers for tropical diseases.  This scheme aims to stimulate innovation in other disease areas.

Revised Procurement Mechanisms (EU potential pull incentives)

Several possible procurement mechanisms for access to new and existing antimicrobials that would guarantee revenue for antimicrobial marketing authorisation holders, regardless of sales volumes, were previously considered at the EU level. These were revenue guarantee, market entry rewards combined with revenue guarantee, lump-sum market entry rewards and milestone payments.

The EU pharmaceutical draft regulation, as modified by the European Parliament, currently proposes two schemes. Firstly, a milestone payment reward scheme which is complemented by a subscription model voluntary joint procurement scheme. These are proposed to try to ensure that a market exists for developers that delinks volumes sold from payment received.

Milestone payments

These are defined as an early-stage financial reward granted upon achieving certain R&D objectives prior to market approval, for example successful completion of phase one.  It is proposed that these are financed through resource matching by the commission. The awarding of milestone payments would be contingent on several legal commitments to the developer. This would include the use of payments to further develop the priority antimicrobial. The developer would also have to apply for marketing authorisation and to conduct AMR stewardship and access plans. Access plans are newly introduced in the modified draft directive. The developer would outline measures to promote and monitor the effectiveness of access, and outline plans to ensure marketing authorisations are received for key territories in a timely manner.

Subscription models

These consist of a series of financial payments to an antibiotic developer for successfully obtaining regulatory approval for an antibiotic that meets specific pre-defined criteria.  A voluntary joint procurement scheme, whereby member states request the commission to facilitate the procurement, is also proposed. The establishment of these models delinks the volume of antimicrobial sales from the reward received. When coupled with voluntary joint procurement, the schemes are proposed to help overcome market failures.

It is suggested that the joint procurement agreement would take the form of a multi-year subscription and there would be conditions associated. These would include a commitment to the supply, and a commitment to AMR stewardship. Commitments to the access plans and the Environmental Risk Assessment would also be required. Furthermore, the submission of a global access plan to supply third countries in critical need, including through development partners or voluntary licensing would be required.

As mentioned above, European Council has not yet adopted its position on the reform of the EU pharmaceutical legislation. These proposed pull incentives are thus subject to further changes.

Industry Feedback

Feedback from industry highlights that pull incentives must provide both predictability – by offering legal certainty that the incentive will be awarded once developed – and value – the incentive must be substantial enough to stimulate innovation.

Subscription Model Pricing (UK pull incentive)

The UK have developed a subscription model pricing for new antimicrobial agents, where the price is not linked to the sales volume. This has been dubbed the “Netflix” for antimicrobials.  Under this model, products which are active against pathogens on the WHO priority list will be eligible. Products will be assessed and placed within four contract value bands. Although the application process itself requires a significant data package and application timeline, the intention is that this is outweighed by the incentives awarded to the products with the highest clinical and societal value.

Industry Feedback

Feedback from industry considering  investor perspectives welcomed the establishment of a permanent subscription framework. This puts the UK at the forefront of a global movement to fix antibiotic market failure. It was highlighted though, that this UK pull incentive alone cannot solve the global underinvestment in new antibiotic development. Furthermore, there is a need to discuss and agree the level of pull incentives required as part of a wider collaboration. This would involve other regions including the EU and the US to unlock investments at the necessary scale.

Summary

The development of therapeutics to target the public health treat of AMR is currently not well incentivised. There is however a political will to incentivise research in this area.  The policy landscape is evolving as more policy makers move to action.  DLRC group is actively monitoring the AMR policy landscape.

Whether you want to navigate the requirements for new incentives or are planning your approach to regulators, our regulatory affairs experts at DLRC can help you to succeed. Contact us at hello@dlrcgroup.com to discover how.