5 challenges that governments need to address in resolving the stagnation in antibiotic development

2022-09-29

We are now well into a third decade of failure and standstill in developing new antibiotics. Meanwhile resistance to all of our existing antibiotics continues to develop across the world and antibiotic resistance was the cause of 1.2 million deaths in 2019, more than for HIV/AIDS and malaria. The traditional market-based financing model for research and development of new antibiotics continues to fail. The reason for the lack of innovation is often presented as a matter of insufficient profitability for the pharmaceutical industry. However, there are significant scientific challenges that remain unresolved, which contributed to large pharmaceutical companies abandoning the field over the past decades.

To address the problem of antibiotic resistance, it is clear that new antibiotics must be developed. A renewed and public health needs-driven overall approach in research and innovation is needed. This will require governments to start doing things differently and to take an “end-to-end approach” that considers the entire chain of actors, investments and regulatory measures, implicated in developing and bringing novel antibiotics to patients – from discovery to access. The problem of antibiotic resistance must be seen as a global development issue and therefore tackled through systematic global collaborations.

A new approach should be guided by the following end goals

• That effective antibiotics are affordable and accessible to everyone in need.
• That antibiotics are managed in a way that preserves their therapeutic effectiveness and thereby slows down the development of resistance.
• That antibiotic production from a robust, reliable and environmentally sound supply chain is able to satisfy global demand.

In 2021, ReAct Europe launched the report:“Ensuring sustainable access to effective antibiotics for everyone, everywhere – How to address the global crisis in antibiotic Research and Development” .The report takes an end-to-end approach to antibiotic development and identifies five key challenges that must be solved in order to achieve sustainable access for all, and charts out options for governmental action in response to each of them.

We here present a summary of these challenges, and the high-level recommendations on how to address them.

Challenge 1: Setting research priorities that address the most significant and unmet global health needs

The first challenge has to do with priority setting and the importance of addressing the most significant and unmet global health needs. Antibiotic Research and Development and the funding for it is largely a national endeavor and this means that Research & Development funding is mainly shaped by national interests and medical priorities of the countries that are funding it.

This results in a fragmented Research & Development landscape where pathogens that are prevalent in low- and middle-income countries are largely left under-prioritized, and pathogens of biggest global concern, are not actually sufficiently addressed.

Currently, looking at the most recent antibacterial pipeline analysis from the WHO, only about a third of the compounds in clinical development are actually targeting the pathogens that are listed on the WHO global Priority Pathogens List (PPL). Additionally, only a fraction of the compounds that are in clinical development are considered to be innovative. Funders of Research & Development have not yet implemented a sufficiently coordinated approach to cover global priorities.

Challenge number 2: Overcoming the barriers of the early discovery and research phases

The second challenge relates to the problem of lack of innovation. A problem that is often overlooked is that big unresolved scientific challenges continue to hamper Research & Development of new antibiotics. Traditionally antibacterial drugs have been estimated to have a tenfold lower yield in the discovery stage compared to other drug classes. Many of the scientific challenges leading to these higher failure rates such as penetration, efflux and managing toxicity, still remain unresolved.

Furthermore, the withdrawal of most multinational pharmaceutical companies from the antibacterial space over the last 20 years has also led to both finance and expertise disappearing from the field.

Today small biotech companies and academics have filled some of the gaps of the early stages of clinical development. But they often lack expertise in later stages of clinical development. These smaller companies and academics seeking expand into clinical stages of Research & Development would need to cross the so called “valley of death”, which means moving a compound from basic into clinical research. This is proving very difficult because public funding for such translational research is limited, and securing venture capital is almost impossible unless there is an indication that a larger company will eventually acquire the compound.

Some biotech companies have in recent years partnered with not-for-profit product development partnerships such as the Global Antibiotic Research and Development Partnership (GARDP) as an alternative way forward.

Challenge 3: Financing late-stage clinical Research & Development without relying on price and sales volumes of the end-product

The traditional market-based financing model for pharmaceutical Research & Development relies on charging high prices and pursuing high sales volumes in profitable markets until the patent or other monopolies expire. Such model is not appropriate neither from the perspective of minimizing use, nor for ensuring affordable access. It has also clearly failed to incentivize development of new antibiotics.

If we want to achieve sustainable access to effective antibiotics, misaligned incentives to oversell antibiotics need to be removed. This is why “delinkage” has emerged as a promising model, whereby the cost of Research & Development is separated from high prices and sales volumes. A delinked model can pay for Research & Development costs and remove the need to charge high prices or the maximizing of sales volumes. Implementing delinkage for antibiotics would mean providing increased public funding to pay upfront for pre-clinical and clinical development.

Challenge 4: Ensuring sustainable production quality, procurement and registration of novel antibiotics

Shortages of antibiotics are a chronic problem for many countries, which can lead to limited treatment options for patients, and be a driver of resistance. Once a novel antibiotic has been brought through clinical development, there are still several problems with the current approach to production, registration, and supply of antibiotics. All of these problems need to be addressed in order to avoid shortages, to improve poor production practices, to address problems with sub-standard or low-quality drugs, and also to improve global registration of antibiotics.

However, our current tools and systems that are available to control and manage new antibiotics are not fit to address these comprehensively. Patents only provide limited means of control. Actions at national level to control these problems can only take us some of the way and they are only pieces in a larger global puzzle. We need a different way to address these issues that go beyond the durability and fragmentation constraints.

Challenge 5: Ensuring sustainable access to new antibiotics in countries

New antibiotics need to be introduced in countries and health systems in a way that avoids current practices of overuse, misuse, and massive problems with lack of access to essential drugs, water and sanitation. This is a major challenge that has not received enough attention so far. If we introduce new antibiotics to systems that are not able to preserve them, resistance will develop too fast.

To ensure that the time and resources we have been spending on new antibiotics will not be in vain, the holes in the bucket must be closed.

Rather than a narrow discussion about incentives to promote drug development, the discussions about antibiotic Research & Development need to be broadened to also consider how to manage these drugs in a far better way in the longer term.

Governments are ultimately those responsible and accountable for the introduction and distribution of new antibiotics in a manner that ensures responsible use, equitable affordable access, and minimize resistance development.

High level recommendations

Most of the problems related to antibiotics development are transnational and even global in their nature. Addressing these will be more successful if governments can collaborate and work together through a system of rules-based global governance to introduce common rules and priorities, and focus on what is needed for global public health. This does not mean that national action is not needed.

However, a commonly defined playbook is needed to ensure that individual action by governments can become much more coordinated and, as a result, become more effective.

More specifically, governments should come together to:

• Adopt the ambition to ensuring sustainable access to effective antibiotics for all, and start to steer public action with much more intent.
• Establish a global Research & Development coordination entity with stable and sufficient funding and appropriate mandate and expertise to effectively coordinate antibiotic Research & Development, under for example the WHO.
• Increase early-stage funding for antibiotic R&D and increase transparency of R&D costs and agreements.
• Establish a new global Research & Development financing model that delivers affordable antibiotics and removes misaligned incentives to oversell (full delinkage).
• Reinvigorate negotiations of rules-based governance for Research & Development, access and stewardship. This should include a mechanism for pooled/centralized procurement and global mechanism for pooling of intellectual property (IP).
• Develop a taskforce for introduction of new antibiotics with broad country representation, and ensure that input is also sourced widely, including from civil society.
• Strengthening health systems and provide financing options for low- and-middle income countries to do this.