FDA Regulation in the Age of Superbugs

In a 2014 report, a committee formed to study antimicrobial resistance warned that superbugs would soon kill more people every year than cancer. These superbugs are the product of the bacterial resistance that forms to antibiotics, often due to overprescription. But while new technologies, like bacteriophage therapy, offer hope as we exhaust our antibiotic arsenal, the most daunting hurdles to combating superbugs are not technological but legal, with overregulation and a misguided FDA standing in our way.

This process of resistance, like natural selection, creates stronger and stronger strains of bacteria that survive antibiotic treatment. This leads common pathogens, which would cause you no real harm today, to one day evolve into a death sentence.

Today, the superbug problem looms over us, with the CDC claiming that antimicrobial resistance directly kills 1.27 million people per year, and 4.9 million indirectly. As those numbers continue to grow, it could kill an estimated 10 million annually before 2050. Recent estimates project lower death tolls by taking the right actions to contain resistance, but Covid-19 has only accelerated the problem. As the use of antibiotics increased during the pandemic, antimicrobial-resistant infections in America rose by 20%.

Current approaches by the CDC, WHO, and FDA to fight resistance involve restricting the use of antibiotics. But rather than limit access to our most powerful weapon against bacteria, a new technology called bacteriophages can eliminate superbugs and defeat resistance. 

Far from being a new innovation, bacteriophage therapy is a forgotten and re-emerging technology from the Soviet Union. While bacteriophages are about 3 billion years old, they were only discovered when biologist Felix d’Herelle began treating dysentery in World War I. After collecting stool samples from recovering patients, d’Herelle observed that bacteria were being wiped out by curious microscopic beings, which he correctly guessed were bacteria-eating viruses, later called bacteriophages.

The popularity of bacteriophages (commonly called phages) has come in waves, with any creeping excitement usually eclipsed by antibiotic breakthroughs. This is because, unlike phages, antibiotics are incredibly cheap to mass produce, simple to patent, and can be applied to a wide range of pathogens. 

But today, antibiotics and phages play a complementary role. The more bacteria evolve to defend against phages, the more they become vulnerable to antibiotics. Because of resource constraints in bacterial cells, phage resistance reduces antibiotic resistance, and vice versa, forcing bacteria to choose one or the other. Even a tiny dose of antibiotics alongside phages can give them a significant leg up in the evolutionary arms race against bacteria and prevent resistance through proper dosage.

The pairing of antibiotics and phages holds immense promise for combating superbugs, but regulatory obstacles are quickly becoming the bottleneck.

Regulation struggles with the specificity problem of bacteriophages, meaning that any particular phage variant will only be able to target a very specific variant of bacteria. For example, the bacteriophage P22 might be highly effective against some variants of Salmonella, but would be useless against, say, E. coli, N. gonorrhoeae, Staphylococcus, or even against slightly different strains of Salmonella itself. 

This means phage therapy often needs to be developed on an ad hoc basis for specific infections. Older bacteriophages need to be updated to remain effective against new generations of bacteria, which are constantly evolving in nature. This leads to bacteria evolving faster than phage therapy can be approved and implies that clinical trials for a specific phage are likely to be outdated once completed.

Because the FDA has not yet approved phage therapy, Americans can only receive it under “compassionate use” as a last resort if they are dying of an otherwise untreatable superbug. However, even under compassionate use, doctors still have to present each treatment to the FDA. These urgent treatments are filed as Investigational New Drugs and take a median of 171 days to approve. Meanwhile, foreign regulatory frameworks like those in the ex-Soviet Union allow the safe treatment of hundreds of patients every year with phage therapy.

The staggering delay is due to the FDA’s mandate to enforce the safety and efficacy of medication, which is difficult with evolving biological drugs like phages.

A large part of the FDA’s reluctance to embrace bacteriophages has to do with minimizing phage-resistant bacteria and the fear of worsening antimicrobial resistance. While creating more superbugs is understandably the last thing the FDA wants to do, inaction around bacteriophages is even riskier. The political repercussions of accidentally creating superbugs through an excessive use of phages would be far greater than avoiding the problem and blaming antibiotic overuse in poorer countries. 

Another important obstacle for phages is that FDA regulation is traditionally based on dosage, but bacteriophage dosages vary on a case-by-case basis and are affected by environmental factors, infection shape, burst size, etc. This underlines the importance of granting doctors more freedom to design individualized treatments and measure dosage on an ad hoc basis.

Because of the individualized nature of phage therapy, regulation will require some level of trust in doctors. The next step could be to loosen regulations, implementing a framework similar to compound pharmacies, which are free to develop ad hoc medicine for individuals so long as they respect safety guidelines around fabrication. Similar fabrication guidelines could provide the FDA with real-time oversight on potential antimicrobial resistance to phages and give doctors the freedom to treat their patients. This would ensure that patients, in consultation with their doctors, have every right to follow the therapy with the best odds of saving their lives.

A lack of FDA approval is throttling innovation in phage therapy, but as the issue of resistance continues to grow, we will one day be forced to act and deploy alternative weapons like bacteriophages. With proper FDA guidelines today, we will be better equipped tomorrow to deploy such weapons effectively, but this work needs to happen soon if we want to stay ahead of the coming superbug crisis.