Antimicrobial resistance (AMR) is a looming public health crisis impacting every country globally with a disproportionate impact on lives and livelihood in low and middle-income countries. A recent report from the Global Research on AntiMicrobial resistance (GRAM) project found that in 2019, an estimated 4.95 million people suffered from at least one drug-resistant infection and AMR directly caused 1.27 million deaths.
AMR is one of India’s major public health problems, directly contributing to about 30% of deaths due to neonatal sepsis across India. These are due to multidrug-resistant (MDR) hospital-acquired infections in many cases. Over 30% of the COVID-19 deaths in India could be attributed to our failure to treat the secondary bacterial infections caused by MDR pathogens with the appropriate antibiotics.
Irrational antibiotic use by the medical community, the general public and the farmers generate drug-resistant superbugs. Inadequate infection control measures in the hospitals and the sanitation issues in the community result in the dissemination of these superbugs. Currently, there is no reliable and rapid point of care diagnostics that can guide the clinician with the right choice of antibiotic to be used. and spare indiscriminate use when not required.
To tackle the AMR crisis, we need robust investment in research and development of new antibiotics, rapid and affordable diagnostics, strengthening infection control and prevention practices, formulating and implementing antibiotic stewardship programmes across the country and ensuring equitable access to life-saving antibiotics. In addition, curbing the increasing trends in antimicrobial use across various sectors requires an integrated One Health approach that focuses on the four spheres: humans, animals, food, and the environment. One such immediate intervention is a welcome move by the Government of India to pass legislation banning the use of streptomycin and tetracycline in agriculture and the growth promotional use of colistin in poultry farming.
With India’s reputation as the pharmacy of the global South, with numerous global compliant manufacturing plants, it’s time to expand our focus and investment in early R&D of life-saving antibiotics. We have the intellectual firepower and critical talent pool. However, we need robust investment from Government and private sector in specialised training coupled with an investment mindset that can fund and sustain drug discovery and development.
Dry antibiotic pipeline
During the last decade, the success rate from Phase 1 to FDA approval for new antibacterial drugs was found to be 16.3% in comparison to the overall industry average of 7.9%. Despite this higher success rate, antibiotic development suffers from a lack of investment and quick market uptake of newly approved products. Several companies that have successfully taken novel antibiotics from discovery to approval have filed for bankruptcy due to the broken market dynamics. The exit of big pharma from antibiotic development coupled with a lack of investment from venture capitalists and the paucity of enabling regulatory and policy solutions to support the commercial viability of antibacterial agents has pushed AMR into a global health crisis.
Though no one questions the unmet need for antibiotics, a comparison of COVID-19 and oncology drugs provides a stark example of how lopsided is the clinical pipeline for new antibiotics. In 2020-21, there were 260 COVID-19 antivirals in clinical development, and for drugs to treat breast cancer alone, the number was 158. In contrast, the number of new antibacterial agents in clinical development was single digits.
Why is the market for antibiotics broken and the drug pipeline ultra thin? Unlike most new drugs, post-approval, new antibiotics are used sparingly (antibiotic stewardship practices) and reserved mainly for cases in which older antibiotics are ineffective. This strategy is essential to preserve the longevity of a new antibacterial agent and delay the emergence of drug-resistant bacteria. In addition, the reimbursement mechanisms in several countries discourage hospitals from using an expensive novel broad-spectrum antibacterial agent when a cheaper generic option is available. These unique challenges in the current treatment guidelines and archaic reimbursement models contribute to commercial failure and restricted or lack of access for patients in dire need of these live-saving agents.
Most major pharma companies have exited the AMR space because of the low return on investment (ROI). Surprisingly, around 80% of the antibiotics currently in the clinical pipeline are developed by small biotech companies.
To reverse this trend, we need immediate solutions and sustainable mechanisms in the long term.
The push-pull model
Small companies are getting early-stage funding from public-private partnerships like CARB-X (the Combating Antibiotic Resistance Bacteria Biopharmaceutical Accelerator), which has provided more than $360 million in funding for 92 antibacterial projects over the past five years. This funding is an example of the push model that has catalysed the creation of a robust pipeline of projects in early discovery.
The pull vector may come from the “Pioneering Antimicrobial Subscriptions to End Upsurging Resistance” (PASTEUR) Act, if and when the U.S. government passes it. This Act will incentivise antibiotic developers with substantial upfront funding for new antibiotics that win regulatory approval. Companies that develop critically needed antibiotics for drug-resistant infections would receive a federal government contract ranging from $750 million to $3 billion spread over ten years.
To incentivise the creation of new treatments, the U.S. Congress enacted the Generating Antibiotic Incentives Now Act (GAIN Act) of 2012, which provides benefits to manufacturers of Qualified Infectious Disease Products (QIDPs) including five years of additional non-patent exclusivity. However, inclusion of molecules irrespective of the potential to treat drug resistant infections diluted the benefits of the GAIN Act.
Another promising initiative is delinking the value of antibiotics from sales volume. The U.K. is set to launch the world’s first “subscription” scheme for antibiotics. This initiative will pay anti-infective manufacturers a flat rate for making new drugs available to the National Health Services (NHS). This is a guaranteed scheme regardless of how much or how little these new drugs are used in treatment.
In addition, the recent creation of the AMR Action Fund with a mandate to invest more than $1 billion to address the current funding gaps in the development of new antibiotics will give a boost to late-stage molecules in clinical development.
(Abdul Ghafur is Coordinator, Chennai Declaration on AMR and Consultant in Infectious Diseases, Apollo Cancer Institute, Chennai. Anand Anandkumar is CEO, Bugworks, Bengaluru.)