Why a UK clinical trial could lead the way for antimicrobial resistance efforts

Dr Peter Jackson, executive director of the AMR Centre explains why a new clinical trial taking place in the UK could represent a major step forward in the fight against antimicrobial resistance (AMR).

The way the coronavirus has affected our way of life and threatened global economic stability serves as an immediate reminder that when it comes to infectious diseases, it is impossible to understate the importance of preparedness.

While the AMR Centre’s focus, antimicrobial resistance (AMR), does not have the immediacy of the coronavirus viral pandemic, the ever-rising levels of drug-resistant bacterial infections around the world mean it is imperative we do everything we can to get ahead of the curve on AMR.  Failing to do so, as charted by the UK government’s AMR review led by Jim O’Neill, would reverse decades of advances in treating infectious disease with antibiotics that now no longer work.  No new, effective antibiotics would potentially lead to AMR claiming more lives than cancer, and would make even routine operations life threatening. 

Antibiotic resistance is increasing to extraordinary levels throughout the world, with new resistance mechanisms constantly emerging, and damaging our ability to treat common infectious diseases such as pneumonia, tuberculosis, sepsis and gonorrhoea. All of these infections are becoming much more difficult – and in some instances impossible - to treat as the number of antibiotics that can provide adequate treatment grows smaller.   

The antibiotic market problem is this: we need new drugs to treat rising levels of drug-resistant microbes, but we also need to hold them back for only essential use to prevent further development of resistance to the new treatments.

In response to the challenge, governments around the world are now considering how to incentivise and accelerate the supply of new treatments for critically-ill patients. These include so-called PUSH incentives – grants to life-science companies to encourage early-stage research and development, and market PULL mechanisms to reward developers for bringing innovative and effective treatments through clinical trials to make them available for patients.

In the UK, the NHS is collaborating with the National Institute for Health and Care Excellence (NICE) on a world-leading project under which NHS England will evaluate and procure two AMR drugs on a trial basis. This will effectively ‘de-link’ the valuation and reward payments made to the developer from the volume of medicine used. If successful, this could provide sufficient income revenue to act as a PULL incentive to encourage more investment in antibiotic R&D.

In order to do this, NICE will implement new measures of value for new AMR drugs that fully reflect the healthcare and societal value of these new products, rather than simply compare net health benefits of new antibiotics with cheaper and older generic ones. These new metrics have been developed into a revised HTA framework specific to antimicrobials that will be real-world tested in the trial.

The project is part of the UK government’s five-year, multi-agency action plan that includes improved stewardship to minimise the chances of resistant strains emerging. This is the latest step towards the government’s broader 20-year vision, and includes the targets to halve health associated Gram-negative blood stream infections and further reduce antimicrobial use by 15% by 2024. 

The procurement project has recently gone live for consultation with a wide range of stakeholders, and a Project Advisory Group has been formed, which held its first meeting in April to support the team through the trial. 

In recent weeks, the project team has published the proposed evaluation and reward metrics for consultation. Under the proposals, the project will select two new AMR drugs, one recently introduced to the UK market, and a second to be launched before January 2021. The two AMR drugs will be selected based upon a proposed scoring system across five key categories. The selected drugs will then progress into the new AMR Health Technology Assessment (HTA) analysis to establish the value to NHS England before moving to contract with the developers.

The proposed scoring mechanism will see projects score highly for novelty, utility, unmet need and relevance to the UK setting, in addition to requiring high standards of supply chain security, antimicrobial stewardship and post-approval surveillance.

The underlying aim of the UK trial is effectively to remove the link between volume of drug sold and payment received by the pharma company. Instead, a negotiated payment will be for qualifying products regardless of how much or how little the drug is used.

The draft procurement papers propose for each drug a maximum payment of £10m per year for an initial three year period, extendable up to 10 years, i.e. a total maximum payment of £100m from the UK system.

The project team has calculated that the UK’s share is between 3% and 3.5% of the total G20 healthcare market, so if scaled up pro rata across major markets, this could be an international reward of up to £3.3 billion ($4.0 billion) for each successful product brought to market.

Clearly this needs the support of other countries around the world, and the NICE/NHS England trial is sending an important signal to other governments to encourage similar schemes to be implemented.  

It should be remembered that this is a trial, and that any PULL incentive scheme will need to take into account the results of the trial and wider international progress on reimbursement reform.

We are clearly operating in unprecedented circumstances but from the initial consultation, this trial is widely seen as a major step forward in reform of the AMR market, and the commitment to drive this essential development forward during the Covid-19 crisis is to be commended.