I never thought I’d someday write the sentence, “I really enjoyed that FDA meeting.” But here I am doing just that.
The topic of the meeting — regulatory implications of an emerging class of medicines to promote health by modulating the teeming microbial ecosystems that live inside each of us — may not sound like much fun, but for those of us in the field it was both enjoyable and enlightening.
The workshop, co-hosted by the National Institutes of Health, drew a packed house, filling a large conference room and two overflow rooms with clinicians, patient advocates, and industry representatives. The discussion was lively. It also provided a call to action to microbiome drug developers. The field is an exciting but wild frontier of biotechnology, and it is clear from the day’s proceedings that it needs rigorous regulatory oversight from the Food and Drug Administration.
Why do I call the field a wild frontier? For one thing, it’s moving incredibly fast. Five years ago, when the FDA first convened a microbiome workshop, the cutting edge of clinical research in this area involved using fecal transplants to seed “good” microbes into the digestive systems of sick patients to help them fight off infections.
We’ve come a long way since then.
Fecal transplants, which are inherently variable mixtures of undefined microbial composition, are no longer the only way to deliver health-promoting microbes to people who need them. Advances in basic science are positioning researchers to use more rigorous and systematic approaches to harnessing the power of the microbiome.
The company I lead, Vedanta Biosciences in Cambridge, Mass., and others are working to develop drugs that consist of carefully defined consortia of bacteria that have been shown to work together to fight off pathogens or to stimulate immune responses via the gut.
There will likely be many approaches to doing this. At Vedanta, we select strains of bacteria to include into possible drugs from a collection of tens of thousands of pure single-strain cultures. Once we have identified the strains we believe will work best together, we grow them separately in growth chambers called fermentors — no fecal donations needed. After extracting the bacteria from their fermentors, we freeze-dry them into stable powders, mix the powdered strains together, and pack the mixture into capsules.
Swallowing such a capsule releases the assemblage of helpful bacteria into the gut, where they are awakened from hibernation. As they colonize the gut and begin fitting in with the existing microbial ecosystem, they can help remodel the patient’s microbiome, creating a more resilient ecosystem better able to fight infections. The right mixtures can also manipulate the immune system in the intestine, either to tone it down (to help those with inflammatory bowel diseases or food allergies) or to rev it up (to help potentiate cancer immunotherapies and vaccines).
These living drugs are a new type of medicine, one consisting of different types of microbes rather than a single purified chemical compound. But the industry intends to make them every bit as standardized and purified as a capsule or tablet you’d pull from a package you get from your neighborhood pharmacist.
Several startups and large pharmaceutical companies are doing important work to advance microbiome-related treatments.
But there are still many questions, as the FDA workshop made clear. Here are three big ones: How can we ensure that the bacteria included in living drugs won’t contribute to the spread of antibiotic resistance or virulence genes? What are the appropriate assays to ensure the quality of a living drug that will be used in clinical studies and, hopefully, in treatments? Can we ensure the manufacturing process will create consistent products? The industry must answer these correctly before the FDA will approve living drugs.
Even this early in the process, there are some tensions around regulatory oversight in the microbiome field. At the FDA workshop, representatives of the dietary supplement industry and some researchers conducting clinical trials with over-the-counter probiotics questioned the need for filing investigational new drug applications for clinical studies evaluating probiotics.
It is not clear that requests for looser requirements will succeed. While probiotics as a class are viewed as generally safe in healthy adults, safety issues such as systemic infection and death have been reported in vulnerable populations, such as premature infants, adults with underlying medical problems, and those with weakened immune systems. In my view, that strongly suggests the FDA’s current level of oversight is appropriate.
There are also questions regarding how to regulate fecal transplants. The FDA made clear five years ago that it considers stool for medical uses to be a drug, and industry and academia have moved on with their clinical research accordingly. But some workshop participants would like looser regulation. They argued that stool used for medical applications should be regulated as a tissue not a drug, which would hold it to less rigorous standards than those applied to drugs.
I believe that the FDA-NIH workshop came at a good time. As FDA Commissioner Scott Gottlieb put it in a statement announcing the session, the agency has a vital role “in sorting through the science and the science fiction of this evolving field.”
I and my colleagues working on living drugs and other microbiome-related therapies look forward to seeing the FDA and NIH sort through the debates that flared during the workshop and will continue to develop a solid, science-based regulatory framework that will help us realize the promise of this bold new class of medicines and deliver safe, effective treatments to the people who need them.
Meanwhile, we’ll keep working on the science of living drugs. We’re excited to see where it will take us next.
Bernat Olle, Ph.D., is the chief executive officer at Vedanta Biosciences in Cambridge, Mass.