ANTIMICROBIAL RESISTANCE
The fall of COVID-19 and the rise of antimicrobial resistance
With evidence of antimicrobial resistance increasing, can innovation incentives drive pharma to fight back? Donald McNab and Mark Schuster of Marks & Clerk explore.
At the time of writing, the nations of the UK are in the process of abandoning or at least easing, the legal restrictions introduced during the COVID-19 pandemic. So, it appears that this crisis is reaching—if not an end—the end of the beginning. For the past two years, the pandemic has dominated the public scientific conversation, with enormous amounts of public and private resources being directed to its resolution.
But has the COVID-19 emergency distracted us from a well-established, but no less serious, medical threat? Described variously as “an overlooked pandemic” (E Pelfrene, R Botgros and M Cavaleri, “Antimicrobial Resistance & Infection Control”, 2021) and a “forgotten plight” (R Laxminarayan, The Lancet, 2022), is it now time to turn more attention and resource to the rise of antimicrobial resistance (AMR)?
Antimicrobials, such as antibiotics, are used to treat infections by disease-causing microorganisms. AMR describes the ability of microorganisms to withstand exposure to such antimicrobials, making treatments less effective or, at worst, ineffective.
As with escape mutants in the context of COVID-19, exposure to antimicrobials imposes a selection pressure on microorganisms, which enables resistance mechanisms to develop over time. Misuse and overuse of antimicrobials can accelerate these processes, increasing the prevalence of resistant strains; this is driving the global growth of AMR.
As resistance proliferates, diseases that became easily treatable following the development of antibiotics in the early 20th century could once again become life-threatening. It is already estimated that 700,000 global deaths per year are attributable to AMR, with the figure expected to increase to 10 million per year by 2050.
Rather than just distracting us from the emergence of AMR, there is also concern that COVID-19 may have exacerbated the problem. These concerns stem from the widespread administration of antibiotics to patients admitted to hospital with the disease, especially in the early stages of the pandemic.
”With few candidate treatments reaching the approval stage, many pharmaceutical players do not view investment into antimicrobials as a profitable proposition.”
Donald McNab
Mark Schuster
This was done with a view to pre-empting secondary infections, and in the belief that some antibiotics—such as hydroxychloroquine—might be an effective treatment against the primary infection (SARS-CoV-2) itself. It is feared that this potential overuse of antimicrobials may have accelerated the development of AMR in these settings (Russell, et al, The Lancet Microbe, 2021; J Hsu, BMJ, 2020).
Tackling AMR
AMR has not caught us by surprise: Alexander Fleming, the discoverer of penicillin, warned of the future risk of resistance after his receipt of the Nobel Prize in 1945. But what can we do now to turn the tide against this rapidly escalating crisis?
Measures that fall under the umbrella of “antimicrobial stewardship” aim to promote judicious use and prescription of antimicrobials. By reducing the exposure of microorganisms to these medicines, the hope is to slow the development of resistance mechanisms and prolong the efficacy of our existing antimicrobial arsenal.
Similarly, improvements to global hygiene and sanitation levels are a key component of international efforts, with the aim of reducing the spread of infections and thus the need to administer antimicrobial treatments in the first place.
Avoiding overuse or misuse of antimicrobials and promoting cleanliness will not be enough on their own. As microorganisms develop resistance mechanisms against our current stock of antimicrobials, there is a pressing need to develop new agents, acting by novel mechanisms, which can bypass existing resistance.
Yet, in the World Health Organization’s most recent annual analysis of the antibacterial development pipeline, it was found that only two of the 11 new antibiotics approved between 2017 and 2020 did not belong to a class of antibiotics for which resistance mechanisms are already well-established. Pharmaceutical innovation undoubtedly has a large role to play in tackling AMR.
There is a clear benefit in fostering greater innovation in the antimicrobial development pipeline. However, there are notable commercial barriers to such innovation. As with the development of any pharmaceutical intervention, R&D pathways can be long and expensive. Innovators, and their backers, require assurance that investment in the R&D process will, or at least may, be rewarded with profit.
With few candidate treatments reaching the approval stage, many pharmaceutical players do not view investment into antimicrobials as a profitable proposition.
Incentivising innovation through IP
Intellectual property rights, in particular patent rights, have long provided a commercial incentive for innovation in the pharmaceutical industry. Policymakers have therefore turned to the patent system for solutions as to how pharmaceutical innovation against AMR can be increased.
A report from the UK (the House of Commons Health and Social Care Select Committee), for example, recommended that changes to patent law should form part of a response to what it described as the “pharmaceutical market failure” for antimicrobial medicines.
Patents provide an inventor with a time-limited monopoly over an invention, such as a new antimicrobial treatment. This period of market exclusivity provides an opportunity to recoup R&D development costs before competing generics companies enter the market, lowering the market rate and eroding profits.
One solution which has been proposed to incentivise innovation against AMR is the introduction of extensions to the normal maximum 20-year terms, and thus monopolies, of patents for antimicrobial innovations (P Batista, D Byrski, M Lamping and R Romandini, “International Review of Intellectual Property and Competition Law”, 2019).
In theory, an extended period of exclusivity creates a longer window during which R&D costs can be recovered, and profits made. A similar scheme has already been introduced in the US through the Generating Antibiotic Incentives Now (GAIN) Act, which grants an additional five-year period of non-patent, regulatory exclusivity to qualifying antimicrobial drugs.
But an extended monopoly period may not be a sufficient incentive for innovation on its own. Even within a period of exclusivity, the likelihood of making adequate profits from antimicrobials can still be limited. Three particular barriers are in evidence.
”A fascinating alternative policy proposal has been raised, in the form of a transferable exclusivity extension.”
First, regulatory restrictions, which aim to keep new antimicrobial drugs as treatments “of last resort”, limit potential sales volumes. Second, treatment courses for antimicrobials are typically short, reducing sales per patient. Third, mechanisms of AMR can lead to a new treatment becoming ineffective even before the patent term concludes, eliminating future sales. The sale of antimicrobials, therefore, remains less lucrative than that of drugs targeted at non-communicable, so-called “lifestyle diseases”.
In view of these additional barriers, a fascinating alternative policy proposal has been raised, in the form of a transferable exclusivity extension. Under this proposal, rather than extending the patent term for the antimicrobial innovation itself, a qualifying antimicrobial innovation would entitle an inventor to a transferable extension “voucher”.
This voucher could then be used to extend the term of another patent in the inventor’s portfolio. The voucher could, for example, be redeemed against a patent for a potentially more lucrative drug, perhaps one targeted at a lifestyle disease.
The voucher could also be sold to another party. This proposal appears to have gained some traction, at least in the US, with pharmaceuticals giant Pfizer among those having supported the idea, and a formal proposal having been brought before the US House of Representatives in 2018 (B Rome and A Kesselheim, “Clinical Infectious Diseases”, 2019).
Outlook
It is said that necessity is the mother of invention. With that mindset having been adopted from the onset of the COVID-19 pandemic two years ago, it is remarkable how concerted scientific and pharmaceutical innovation has now delivered us past the worst of the crisis. It is time for AMR to be viewed through a similar prism. If it is, we are confident that similar innovation will also provide solutions to the growing threat of AMR; and it needs to.
We look forward to seeing how the development of IP policy proposals can continue to incentivise this innovation in the future, and even more so to the inventions and therapies that will result from this.
Donald McNab is a principal associate at Marks & Clerk. He can be contacted at: dmcnab@marks-clerk.com
Mark Schuster is a trainee patent attorney at Marks & Clerk. He can be contacted at: mschuster@marks-clerk.com
Images, from top: Shutterstock / angellodeco, Jarun Ontakrai
