The gut microbiota has gained renewed importance in the light of its functions and complex contributions to bodily health and metabolic order, stemming from both local and distant actions.
Disrupted gut microbiota can thus be held responsible for a number of chronic inflammatory gut disorders as well as other metabolic conditions including obesity, diabetes, and some neuropsychiatric illnesses.
In this setting, fecal microbiota transplant (FMT) has emerged as a highly promising new alternative intervention to restore normal gut microbiota and treat associated diseases. Available evidence shows undoubted efficacy in treating recurrent Clostridium difficile infection (RCDI) without recurrence.
Questions that remain to be answered are concerning its safety, best practices, and extent of approved applications. As interest in the procedure grows, especially in the light of its extra-intestinal uses, the need for regulation is also being brought into the spotlight.
Worldwide variation in FMT regulation
The regulation of FMT is quite diverse depending on the region it is being performed in. The Australian government does not yet consider it a drug, and it is not regulated as of now either there or in China as well as the EU. In Canada, it is regulated as a new biologic which must be used only as part of a clinical trial.
The USFDA has decided that FMT is a biological product and a drug. It is, therefore, subject to regulatory approval as an investigational new drug (IND) for which an application must be filed before each use. This process was designed for pharmaceutical products, and is therefore a cumbersome and time-consuming one. The follow-up is also a serious commitment in terms of time and administration. For this reason, FMT use under an IND would limit it to large firms with the commercial resources to go through this process and to fund clinical trials of sufficient power.
Is enforcement discretion the best route?
For this obvious limitation, concerned stakeholders under the umbrella of the Infectious Diseases Society of America (IDSA) argued for a more general availability of FMT including its use in critically ill patients, following which the FDA put it under the ‘enforcement discretion’ category for the single purpose of treating RCDI not amenable to standard treatment.
Patients who receive an FMT must give informed consent, understand that it is investigational, and be informed of the risks. All other uses still require an IND permit, as do clinical trials which use FMT for RCDI. This guideline continues to evolve, and is understood to be a temporary measure.
Advantages and disadvantages of regulation
The positive aspects of FDA regulation are the standardization of stool used in FMT, and the acquisition of safety and efficacy data. On the other hand, it is extremely difficult to standardize a natural substance which is highly variable in composition, and that can hardly be defined by strict scientific norms. Also, it can be administered by the patients themselves, which means that the normal period of exclusivity guaranteed following FDA approval of orphan drugs is unlikely to be enforceable.
Another area of concern is the way in which stool banks have emerged to take advantage of the growing demand. To regulate them, the FDA proposed that donors must be known to either the patient or the physician, and must conform to screening and testing norms under the supervision of the latter, with the intention of being used to treat the former.
This may severely limit the availability of stool to patients from unrelated volunteer donors, and make stool banks unviable. The cost savings associated with using stool banks include those that come by having many treatments using a single well-screened and prepared stool sample. This latter option would, however, be abolished in case a single stool provider is licensed, and would drive up prices.
It seems likely to some observers that the final model of regulatory oversight will be one which allows deserving candidates to benefit from the therapy while ensuring that screening standards are upheld. This may be by obtaining all FMT from a single provider who has a license, which may, however, drive up the costs significantly.
Secondly, the ease with which FMT can be performed at home may discourage patients from paying for it outside or going through a complicated process. This remedy may expose them to hidden safety risks from inadequate donor screening, patient follow-up, and transmission of undetected pathogens.
Yet another risk is that the usefulness of fecal therapy for other conditions which are probably linked to gut microbiota may not be discovered due to the cost factor, unless physicians can prescribe them off-label in these situations. On the other hand, such off-label use does not contribute to the body of knowledge regarding the efficacy of FMT for these indications, and may discourage the setting up of properly designed clinical trials to test it in such situations.
The best approach might be to issue strict and binding guidelines for stool collection and preparation, which includes donor selection by a narrowly defined set of criteria, establishment of rigorously enforced quality manufacturing facilities, and national registries that will help track patient and donor information over time. The aim of regulation is to achieve optimum access to FMT, maintain strict quality and safety norms, and acquire further data to establish and expand its use.