The Crisis in Antibiotic Research and Development

It’s impossible to understate the importance of antibiotics. They’ve made many once fatal bacterial infections easily treatable, and procedures such as chemotherapy, organ transplants and surgery much safer. They became essential to medicine as the ubiquitously used miracle drugs. With increased use of antibiotics, antibiotic-resistant microbes are on the rise. Antibiotic resistance has always been a challenge in treating bacterial infections since penicillin transformed the medical world.

Resistance mainly arises either from genetic mutation on genes targeted by antibiotics, or by acquiring resistance genes encoded on transferrable plasmids – independent rings of DNA that replicate on their own. As bacteria are exposed to a selective pressure of which bacteria that can resist the effects of antibiotics would survive and multiply, and thus leading to the spread of resistant strains. There is a need for new classes of antibiotics to help fight bacterial infections.

Alexander Fleming, one of the recipients of the Nobel Prize for penicillin, warned about antibiotic resistance as early as 1945, saying “The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism.”

However, there has been no new classes of antibiotics development since the 1980s. Although, according to World Health Organisation (WHO)’s report on antimicrobial development pipeline, there are currently 40-50 chemicals being tested for their potential as a novel class of antibiotics, pharmaceuticals still face financial and power struggles in developing new antibiotics.

Money and Power

From discovering a chemical, to testing its clinical potential, and to passing regulations and being sold in the market, developing new antibiotics can take up to 10-15 years and cost over $1 billion. This process is time-consuming and expensive because of the nature of antibiotics research and regulations.

After identifying a potential chemical, its harmfulness to the human body has to be assessed. It is difficult to identify chemicals that can kill or inhibit growth of bacteria, and at the same time remain harmless to human beings. In addition, after passing the pre-clinical research stage, clinical trials often consist of three stages and involves a large number of test subjects. It can take years and is expensive for a drug to pass clinical trials.

As a result, only big pharmaceutical companies such as GlaxoSmithKline, Novartis, AstraZeneca, Merck and Pfizer have the financial resources to fund antibiotics R&D projects. Having only a few big pharmaceutical companies developing antibiotics creates an oligopoly. As oligopolies reduce competition, there is no motivation for pharmaceuticals to refine their products in order to outcompete their rivals. Consequently, pharmaceuticals have a lower incentive to produce good antibiotics. Oligopolies also reduce consumer choice, raise the barrier of entry for new companies and cause loss of economic welfare.

Not only are clinical trials expensive, antibiotics provide little revenue for pharmaceutical companies. Compared to long-term drugs for treating chronic diseases, antibiotics are short-term drugs which patients do not purchase regularly, hence providing less revenue for pharmaceuticals. Additionally, WHO guidelines state that new antibiotics are used as a last resort to avoid development of drug resistance. This greatly reduces the incentive for the healthcare sector to purchase newly developed antibiotics, further decreasing revenue for pharmaceuticals.

After passing clinical trials, new antibiotics have to be registered with a drug regulator to obtain a license. At this stage, researchers must prove that the new antibiotics is more effective than existing antibiotics, making it hard for pharmaceuticals to obtain a market share. After registering with a drug regulator such as the FDA, “data exclusivity” can be granted (the chemical formula of the drug is kept exclusive to the company that developed it) for a maximum of 5 years. This further disincentivises raising revenue for pharmaceuticals.

What have been done to improve the situation?

To tackle the problem of the lack of antibiotics R&D projects, governments around the globe have implemented several schemes.

One example looks to shorten the drug approval pipeline. In June 2018, the FDA simplified the drug-approval pipeline by approving the new rapid antibacterial approval pathway (LPAD) for treating life-threatening infections for limited population of patients with unmet needs. This means that the FDA may approve treatments with insufficient clinical data to conclude a benefit-risk profile in the general population including patients with less serious diseases.

The treatment may be harmful to the broader population but may be effective for patients with serious disease without better alternatives. Three months after these reforms, Arikayce was approved for treating lung disease caused by the Mycobacterium avium complex. LPAD drastically shortened the drug development process from 10-15 years to 3 months, though with greater uncertainty in the efficacy and safety of the treatment.

Another approach at the FDA has involved approving an extension of the 5 year “data exclusivity” under the Generating Antibiotic Incentives Now (GAIN) component of the FDA Safety and Innovation Act in 2012, allowing pharmaceuticals to have a longer period of monopoly for the antibiotic they developed. The logic is that companies will earn more revenue, incentivising them to fund more R&D projects.

The NHS are one of many organisations instigating reforms to tackle the antibiotics R&D crisis (photo credit: User:FrancisTyers~commonswiki)

On the other hand, the UK NHS will be piloting a subscription style payment model for antibiotics to incentivise antibiotics R&D. Before this payment model, individual hospitals purchase antibiotics from pharmaceuticals only when needed, leading to an unstable source of revenue for pharmaceuticals.

With the subscription style payment model, the government will pay pharmaceuticals upfront for NHS access to antibiotics that are useful for treating antibiotic-resistant infections developed by that pharmaceutical. This tackles the problem of healthcare sector not purchasing new antibiotics and provides incentives for pharmaceuticals to invest in antibiotics R&D projects.

Another idea is to look for alternatives to antibiotics. For example, more pharmaceuticals are focusing on the role of microbiome in combating infections and there are pre-clinical trials on engineered bacteria to help fight against Clostridium difficile infection in the gut, although the project is still at its early stages.

Phage therapy is another alternative. Phages are viruses that infect bacteria and replicate within the bacteria. Eventually, the bacteria are lysed (broken down) and phages are released for a second infection cycle. Currently there are approved phage therapies for fighting bacterial infections such as Escherichia coli, Salmonella enterica and Pseudomonas aeruginosa but bacterial resistance to phages has been reported and immunogenicity is a major health concern for phage therapies.

These recent scientific advances show the power researchers have to tackle the global crisis of antibiotics resistance; they should not be hindered by socioeconomic factors. Governments around the globe must prioritise drug development for antibiotic-resistant infections to improve the livelihood of the citizens.

Christy Hoi Ching Cheung is currently studying an MRes in Biomedical Research at Imperial College

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