ReviewVolume 2, No. 1

Ensuring Safer and More Effective Regulation of Fecal Microbial Transplantation (FMT): A Renewed Understanding

Arsalan Ahmed

McGill University Faculty of Law
Citation:Ahmed A. Ensuring Safer and More Effective Regulation of Fecal Microbial Transplantation (FMT): A Renewed Understanding. Col Med Rev. 2018 December 29; 2(1).


This paper examines fecal microbiota transplant (FMT) and the problems it encompasses for the Food and Drug Administration (FDA) in defining it as a biologic drug. As of 2017, the regulatory climate around FMT remains grey. It is unclear whether FMT should be classified as a chemical pharmaceutical, a biologic drug, a device, or an entirely new kind of therapy. Per a 2015 FDA publication, the FDA intended to classify FMT as a drug. Under this framework, FMT would undergo the Investigational New Drug (IND) approval, and possibly, a biologic drug approval process. However, since the FDA’s initial indication, concerned and vocal physicians from across the country successfully petitioned that discretion be used when enforcing regulation surrounding FMT.

A succinct and conclusive decision has yet to be made. Some scholars have used this grace period as an opportunity to petition to the FDA to consider a non-IND, non-regulatory pathway for FMT. Others have supported the IND/drug-driven regulatory process. Contrary to other authors, this paper recognizes the benefits of using an IND process and classifying fecal matter used for FMT (or classifying FMT for short) as a biologic drug. A “biologic” or “biologic drug,” is a compound that may be manufactured in or extracted from biological sources, distinct from a “chemical pharmaceutical”; The terms “biologic”, “drug”, and “biologic drug” are used interchangeably in this paper. A few concerns around Do-It-Yourself (D-I-Y) FMT kits and a future for bio-similars in the FMT market remain.

Background and Context

C. Diff Infection: A Growing Concern

A healthy human body contains a diverse ecosystem of necessary (good) bacteria in its gastrointestinal (GI) tract.1 Fecal Microbiota Transplantation (FMT) is a procedure that involves taking stool from a healthy person and transferring it into a person suffering from Clostridium difficile infection (CDI), a disease characterized by reduced amounts of the necessary GI bacteria. According to a fact sheet by the Public Health Agency of Canada, CDI is caused a bacterium of the same name, Clostridium difficile (C. diff) which causes mild to severe diarrhea and inflames the colon. Most cases of C. diff occur in patients who are taking certain antibiotics in high doses or over a prolonged period of time. Antibiotics can destroy the normal bacteria found in the gut, creating an opportunity for C. diff to grow; the bacteria invade the colon and produce toxins as they reproduce. 2 They can damage the bowel, cause diarrhea, or lead to life-threatening inflammation of the colon. 3 Patients can either experience incident CDI, which may progress to severe CDI, or experience recurring CDI (rCDI). The C. diff problem is broad in scope; in most industrialized countries, C. diff is the most frequent cause of infectious diarrhea in hospitals and long-term care facilities. CDI is a serious diarrheal illness associated with substantial morbidity and mortality, affecting about half a million people in the United States alone.4 CDI kills 14,000 patients in the U.S. each year.5 Fecal transplantation is most commonly used today as a treatment for CDI when standard treatment therapies have failed.6 During the past decade, the clinical profile of CDI has worsened; there are an increased number of cases, greater morbidity, and an increased incidence of complications requiring surgical intervention.7

What is FMT and Why Does It Matter

The goal of any effective CDI treatment is to reinstate good bacteria that have been killed or suppressed due to C. diff overpopulation in the colon.8 Commonly used existing therapies to CDI are chemical antibiotics, such as vancomycin.  However, recurrence after vancomycin treatment is a common concern, and most recurrent C. diff episodes are the same bacterial strain. 9 Other research and increased clinical adoption supports the use of fidaxomicin, which was shown to be associated with a significantly lower rate of recurrence of CDI

Recently, however, research suggests that FMT offers a more sustainable alternative to antibiotics.10 It is a new kind of treatment for CDI patients. Beyond offering an alternative to traditional antibiotic therapies, FMT is more effective. The first randomized control trial (RCT) evaluating FMT was conducted in 2013. 95% of patients who underwent FMT for recurrent C. diff were effectively cured. 81% were cured after the first application.11 Vancomycin, for comparison amongst recurring CDI patients (rCDI), achieved a 31% recovery rate for those who took the antibiotic by mouth alone, or 23% post-enema.12 FMT has a low re-use rate, while vancomycin has a re-use rate of 25-30%.13

In essence, FMT taps into novel research findings supporting the impact and benefit of “good” gut bacteria. The human GI tract contains thousands of different bacteria and other microorganisms which are essential to maintaining health. Heavy antibiotic use can disrupt these bacteria and allow disease-causing bacteria such as C. diff to flourish.14 In a healthy gut community, C. diff is out-competed by many different bacterial species. However, antibiotic treatment disrupts this ecosystem by killing those protective bacteria.  C. diff forms spores that are resistant to antibiotics. No longer outcompeted, this pathogen establishes itself in the gut and produces toxins that leave patients suffering from severe diarrhea, abdominal pain, and often fever. With an infusion of bacteria from a healthy donor’s stool, the C. diff is again out-competed.

Fecal transplant involves transferring the necessary microorganisms from a healthy donor into a patient with C. diff infection. Transplanted “good” donor bacteria then begin to grow in the patient’s colon and prevent C. diff from overgrowing again. This implantation procedure is typically done during a colonoscopy, but other methods of administering FMT, which have been successful in limited settings and select patient cases, include transplant via fecal enemas, nasogastric transposition into the upper gastrointestinal (GI) tract, or administration as an oral pill.15

In general, eligibility for FMT is often restricted to (1) patients who have had at least three C. diff recurrences and have failed at least one tapering course of the antibiotic vancomycin,16 the current preferred treatment drug, and (2) patients who have experienced two more severe episodes of C. diff infection with admission to an intensive care unit. At this time, FMT is not actively performed on patients with irritable bowel syndrome (IBS), but is in clinical trial.17 Research on the topic continues to grow. One study which conducted a data scrub using EMBASE found six conference abstracts, one case report, one letter to the editor, and one clinical review on a total of 48 IBS patients. Treatment found an overall improvement in 58% of IBS cases. However, the study team concluded the data was too limited to make a statement on FMT for IBS, and a recommendation for a standardized RCT was made.18  This posits a concern for patients seeking treatment for IBS.

For patients who use FMT, it is recommended that the donor is someone in good health who has not taken any antibiotics for at least 90 days. Most patients choose an immediate family member, although the donor does not necessarily have to be related to the recipient. The latter option has opened up the opportunity for stool banks to become more prevalent in the United States. OpenBiome, for example, is a non-profit organization in Massachusetts that actively seeks healthy volunteer donors to provide life-saving treatment for people with C. diff infection. As a reimbursement for their commitment, donors are paid $40 per donation of stool.19 Donors who wish to contribute to the stool bank go through at least two rounds of rigorous screens that involve blood and stool tests. They must drop off donations several days a week for at least 60 days. In addition to working as a non-profit stool bank for public use, OpenBiome contributes to larger scholarship regarding FMT regulation and effectiveness through its partnerships with 800 hospitals across the country. The emergence of stool banking can be a stepping stone towards increased national adoption of FMT and other stool treatment research.20

However, although FMT is a powerful tool for treating C. diff infection, there are also important risks. It is well-recognized that stool is a complex living mixture of bacteria and other organisms.21 While stool donors can be carefully screened for known infectious agents, there is always a risk that the tests might fail to detect a pathogen. There are also procedural risks associated with receiving an FMT by colonoscopy or other methods of administration. These factors can be an additional frustration for regulators, but have also been recognized as a pathway for regulation. In other words, instead of allowing for the patenting and market exclusivity of specific formulations of stool, regulators could attempt to initiate and maintain industry standards on stool and FMT’s clinical use by regulating the way it is handled and determining who has the authority and responsibility to make sure the supply is safely extracted, transported, stored, and delivered for clinical use.22

In addition to natural concerns about the content of transplanted stool, increasing attention to its effectiveness has brought up another issue: “Do-It-Yourself (DIY)” FMT users. As one concerned citizens website “advises” to its readers: “e-Patients please note that stool banks will not sell fecal microbiota to patients directly and that in the US your doctor can only use FMT to treat C. diff that does not respond to multiple courses of antibiotics.  Unfortunately, that excludes many seriously ill patients who want to try FMT under medical guidance, for other conditions…. So if you do at home, we constantly urge DIY patients to test their donors, and most are finding a way to do this.” 23 Oftentimes, donors will use fecal samples from family members to lower the risk of an autoimmune attack and will insert the stool slurry into one’s own colon by pushing it through with water through an enema. Given intense demand and inherent safety concerns with stool transplant and FMT, DIY FMT application is a major concern for regulators.

Understanding Regulation

FDA Authority and Involvement

In a 2015 publication, the FDA signalled that it wished to classify FMT as a biologic drug.  This decision to view FMT as a drug that would need to undergo theInvestigational New Drug (IND) approval process has been problematic for a number of scholars. The later decision by the FDA to exercise discretion when enforcing IND regulation for FMT under certain conditions has opened the conversation to different kinds of regulatory pathways.

FMT administered to treat C. diff infection meets the definition of a biological product, as defined in section 351(i) of the PHS Act (42 U.S.C. 262(i)), as it is a regulated article applicable to the prevention, treatment, or cure of a disease or condition of human beings. Section 351 of the Public Health Service (PHS) Act defines a biological product as a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.” FDA regulations and policies have established that biological products include blood-derived products, vaccines, in vivo diagnostic allergenic products, immunoglobulin products, products containing cells or microorganisms, and most protein products.  Biological products subject to the PHS Act also meet the definition of a drug under the Federal Food, Drug and Cosmetic Act (FD&C Act).24 However, fecal matter for FMT also meets the definition of a chemical pharmaceutical within the meaning of section 201(g) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(g)),25 in that it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or is intended to affect the structure or any function of the body of man.

As a biological product, FMT administered to treat C. diff infection is subject to the licensing requirements set forth in section 351 of the PHS Act (42 U.S.C. 262). It is, however, exempt from these licensing requirements when administered pursuant to an IND application and in compliance with the IND regulations set forth in 21 CFR Part 312.26 Sachs and Edelstein (2015) note that biological products may be regulated as chemical pharmaceuticals through FD&C or as biologic drugs under the PHS Act, or both. 27 Here, the FDA has chosen to define fecal matter used in FMT as a biologic drug. Thus, traditionally, all uses of FMT would require an IND and patients who wanted to be treated with FMT for recurrent C. diff would need to participate in a clinical trial to do so.28

However,  FMT regulation is currently in a grey zone. In essence, it is viewed as a quasi-biologic drug, but the FDA has relaxed enforcement of the IND to ensure that patients not responding to standard therapies can access FMT, and so that stool banks can operate within this window.29 30 31 An industry guidance document from the FDA published in 2013 allowed physicians to administer FMT to patients with CDI where standard therapies have failed – provided that the treating physician obtains adequate informed consent from the patient or his or her legally authorized representative for the use of FMT products.32 The intent was to provide a “last resort” approach to patients while the FDA and the medical community could better understand this new treatment.

In Spring 2016, however, the FDA took a pivot towards increasing regulation, citing concerns for safety and a need to properly regulating FMT as a biologic drug.33 The FDA published a draft guidance outlining how it intended to regulate FMT.34 The FDA said it would continue to use enforcement discretion, no IND required, but added two conditions. The first condition stipulated that FMT product may not originate from stool banks. This implicates stool banks like OpenBiome, whose purpose is to screen and test donors to expand the FMT pool. Second, the stool donor and stool must be qualified by screening and testing performed under the direction of the licensed health care provider. This means hospitals would have to develop their own banks and have licensed providers supervise screening for their patients.35 As of August 2018, however, the 2016 changes proposed in the draft guidance have not been realized. FMT is defined as a biologic drug, but discretion is still practiced when enforcing regulation of its use. Physicians can perform FMT on patients who are not responsive to standard therapy without filing an IND. FMT can only be used for rCDI or severe C. diff without an IND – other applications of FMT require an IND. Stool bank use is encouraged.36

A final decision on FMT’s regulatory fate has not yet been made. Strong arguments have been presented in a 2015 work by Sachs and Edelstein to consider an alternative model to regulation in lieu of defining FMT as a biologic drug.37 This publication argues for framing FMT as a biologic drug requiring an IND process, with a goal of understanding why the FDA might choose to regulate FMT as a biologic drug with the IND requirement, and what the potential benefits might be of such regulation.


Biologics Pose a Difficulty for Regulation – Background

Most chemical pharmaceuticals, the bulk of drugs approved by the FDA, consist of a predetermined formulation of substances with a known structure. Biologics, however, are complex mixtures that are much more difficult to identify or characterize. Biologics are also increasingly sensitive to microbial contamination, requiring high levels of oversight on the manufacturing process and production.38 Biologic drugs and their biosimilars have been approved in recent years, but they are often accompanied by an increased scrutiny over their manufacturing processes. Subtle manufacturing process changes can also have major impact on the biologic produced.39 For example, culturing bacteria on a certain media may result in substitutions in the resulting protein. A typical manufacturing process for a chemical drug might contain forty to fifty critical tests, whereas a biologic may undergo two hundred to two hundred and fifty quality control tests.40

Biological products, like other drugs, are used for the treatment, prevention or cure of disease in humans. In contrast to chemically synthesized small molecular weight drugs, which have a well-defined structure and can be thoroughly characterized, biological products are generally derived from living material: human, animal, or microorganism. They are complex in structure, and thus are usually not fully characterized. The challenges of regulating biologics is a very difficult task, requiring many more considerations than a typical chemical pharmaceutical. Classifying stool as a biologic product makes more sense because of its irreplicable structure and heterogeneous components.

Both the FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) have regulatory responsibility for therapeutic biological products, including premarket review and oversight.41 Following initial laboratory and animal testing that show that investigational use in humans is reasonably safe, biological products can be studied in clinical trials in humans under an IND in accordance with the regulations set forth in Part 312 of the Code of Federal Regulations section of the United States Federal Food, Drug, and Cosmetic Act (FD&C).42 If the data generated by the studies demonstrate that the product is safe and effective for its intended use, the data are submitted as part of a marketing application.  Whereas a new drug application (NDA) is used for drugs subject to the drug approval provisions of the FDC Act, a biologics license application (BLA) is required for biological products subject to licensure under the PHS Act.43 Issuance of a biologics license is a determination that the product, the manufacturing process, and the manufacturing facilities meet applicable requirements to ensure the continued safety, purity and potency of the product.

Amongst biologics, fecal matter is unique. The microbial contents of human stool vary across individuals and over time.44 Currently, no process has yet been identified to recognize or isolate the fecal matter’s active components to provide a consistent product between batches, making it difficult to regulate traditionally.45 Instead, there is a greatly selective and lengthy screening process in place to ensure safety.

Regulatory Options and Reasons for IND Approval

A number of regulatory options outside of classifying FMT as a drug through the FD&C have been suggested to help classify FMT. It is important to understand the motivations and the risks of each alternative to better understand why an IND process would prove valuable for FMT. Sachs and Edelstein, in particular, identified two categories of similar biologics that FMT could fit into: blood or cord blood/tissue.46


Blood and fecal microbiota both evoke safety concerns involving transmissible disease. Blood is currently regulated under PHS to ensure a safe supply and set protocols for extensive testing as biologic products under the PHS Act. This regulatory system is largely focused on ensuring the safety of the blood supply and setting a testing protocol prior to transfusion.47 If FMT was to be classified similar to that of a blood product, it would fall under a completely unique set of regulations. Since 1973, the FDA has progressively strengthened safeguards over blood to better monitor the US blood supply and protect patients from unsuitable blood and blood products.48 The PHS Act explicitly mentions blood as a biologic. However, the FDA has established an entirely separate regulatory system for monitoring its handling and safe supply.49 As blood production cannot be easily scaled up, Sachs and Edelstein note, it is viewed more as a commodity than a therapeutic instrument, where licenses for storing and distributing blood are granted to anyone meeting the requirements.50 Under these licenses, the storage, screening, and distribution of blood products does not require an IND. The impact of a blood-regulation scheme does not end there. As of now, stool banks like Openbiome work within an unregulated field. To ensure quality and public confidence, they use very rigorous screening protocols to ensure their samples are reliable.51 The explicit lack of clinical RCTs demands this kind of carefulness; we remain unsure if such strict screening protocols are necessary.

For blood, this setup made sense. By 1973, the importance of a safe and adequate national blood supply was well recognized.52 The IND process is more important for novel applications. It necessitates the use of clinical trials and furthers scientific research. Sachs and Edelstein argue that we could choose to regulate fecal matter for FMT as we regulate blood because of its substantive properties: it’s a raw, natural material.53

However, making this connection comes at the cost of ignoring an important distinction. Unlike the recognized importance of blood in 1973, not much is known about the therapeutic value of fecal matter or the microbiome. A regulatory scheme similar to blood would prioritize accessibility and greatly favor the use of banks, but it comes at the cost of innovation. An IND, required for most biologic drugs, is a source of competitive advantage. It requires companies to conduct human clinical trials, but then allows them to receive a marketing application with an exclusivity period.54 This incentive is what propels the field forward. In an area where stool samples could be bottlenecked by unnecessarily rigorous screening, RCTs, undertaken by drug companies competing for a drug patent and market exclusivity, can give us clues on how to be more efficient. Not only that, offering a competitive advantage to companies who want to invest in and enter the FMT market spurs innovation and interest not only to FMT but other ancillary disease treatment models involving the microbiome.55

The question is this: do we want to stop innovation now and focus on stool bank accessibility by waiving the IND process without truly understanding the field, which we could better do under the requirements for an IND process?  INDs aid the field by providing a reliable way to conduct RCTs and build confidence in the value of a therapy. Moreover, INDs are a stepping stone towards market exclusivity. If we resort to a a blood-regulation scheme or a “banking-focused” model, it would disincentivize innovation for what could be an important therapeutic instrument, as companies would not be able to guarantee market exclusivity over their product. FMT is a relatively novel introduction, but its applications and wider ties to the microbiome remain unexplored.

This is not to say the IND process is perfect. Successful completion of an RCT under an IND is a stepping stone towards market exclusivity – the exclusive right to sell a drug on the market.56 If classified as a drug, any successfully-approved FMTs would be protected under both the Orphan Drug Act,57 which awards seven years of market exclusivity, and the Biologics Price Competition and Innovation Act58, which provides data exclusivity and prevents biosimilars from entering the market for twelve years. Sachs and Edelstein argued that overly-broad licensing agreements could shut down existing stool banks,59 likening the gravity of the situation to that of colchicine – a drug whose manufacturer was given market exclusivity over indications that were previously treated off-label with generics.60Theoretically, a manufacturer holding an FMT patent could limit how widely they license their product, but this would restrict economic growth potential over a relatively rare disease. Manufacturers could raise costs so prohibitively high that patients could not receive the product. Competition induced by the FDA’s IND protocol will be key in its success, as private manufacturers strive to demonstrate that their product and their process have greater value over existing non-profit or community stool-banks, which already have a recognized low cost for FMT. Excessive raises would likely be put under great public scrutiny.

In addition, the story of FMT is far from that of colchicine. Colchicine is a well-characterized chemical formulation; fecal matter is not. More likely than not, it may be in the manufacturer’s interest to capitalize more on the process of refining fecal matter rather than its components; screening for and recognizing suitable fecal matter is a slow, grueling process. Without clear regulation in place, the current FMT situation relies on extremely selective screening procedures to prevent mishaps. It can take several days to weeks to receive donor profiles before physicians are able to implement FMT.61 With increased delay, donors are at an increased risk of incurring a pathogen between screening and collection times.62

Current FMT operations also rely on only a handful of stool banks and ability to grow is limited by an already slow screening process. Though local successes are possible, such as OpenBiome and the State of Massachusetts,63 without a national interest in FMT, there is a recognizable risk that a great number of Americans with severe or rCDI will fail to receive an adequate fecal sample for FMT in time. The IND process is recommended because it allows for streamlining rules and regulations. It increases competition by recognizing FMT’s use as a therapeutic, promoting transparency on adequate FMT practice,64 and allows for greater expansion on a nationwide level. It also opens up a market for biologic biosimilars to reduce prices where applicable.65 With nationwide acceptance of FMT regulation, the United States also sets precedent for FMT development globally. This is an important show of leadership as the European Medicines Agency, China and Australia have yet to set an FMT protocol.66 67

Cord Blood and Other Tissues

A second approach has been proposed by Edelstein and Sachs. Instead of regulating FMT like a drug, the FDA could regulate it like cord blood.68 Cord blood may be used for both public purposes and private purposes (banking and use amongst close family members) without prior FDA approval, using instead a technique known as “informal rule-making”.69  This kind of regulation allows differentiated rules based on the end-user and the means of use. An analogous program to cord blood regulation for FMT would allow hospitals or registries to publicly bank and use stool samples. These samples could be used by hospitals in treating CDI. It would also allow private users to bank their own stool or access close family members’ stool samples for CDI. Such a method has been supported for maximizing access. Access issues are important to address because of the risks associated with a rising popularity of “Do-It-Yourself FMT kits” or “make-your-own FMT kit from homemade materials” on social media/ YouTube.70 The latter is most concerning. Even the strongest restrictions on FMT could not prevent private parties from collecting feces, diluting it, putting it through a sieve, and using an apparatus similar to that of a turkey baster to transplant it.

But differentiated regulation is fraught with difficulties. One of the rules surrounding such flexible regulation on cord blood was that uses had to be homologous. This means that use of cells must perform the same basic function (or functions) in the recipient as in the donor. 71 This poses a number of challenges when considering the inherent variability and difficulty in creating a consistent microflora profile from patient to patient. It seems unlikely that the definition or concept of homologous would remain intact if such an approach were applied to FMT. Blended regulation is also unfavorable because the impact of FMT is not entirely understood yet. Though successes have been shown in C. difficile treatment, one must ask whether C. diff treatment represents the best application of FMT. FMT may also work well in other diseases. If FDA laws were designed only around C. diff treatment, it may slow down the acceptance of a more robust regulatory framework for FMT. Broader laws will provide novel manufacturers a better understanding of the FDA’s stance on FMT and may encourage innovation in other areas of treatment using the microbiome.

This does not excuse the fact that off-label use (home-made FMT) is an issue. In designing an optimal policy, one must ask the question: what are such users motivated by? Is it the cost of receiving FMT at a hospital? Or is it because of the lack of verifiable, recognized stool banks or registries available to provide FMT? A potential course of action would be to create a national framework of stool banks that increases such access. This can best be done through a consolidated biologic with IND model.

Some Final Considerations on Regulation

As of today, the FDA is leaning towards defining fecal matter used in FMT as a biologic. However, it exercises discretion when  enforcing a critical component of the biologic approval process: the IND requirement. In 2013, the initial tradeoff was that having an IND may limit patient access to a a new FMT breakthrough treatment. However, 5 years later, we still find the FDA in a grey area. It pushes the idea of FMT being a  biologic drug but exercises enforcement discretion. Without the the requirement for IND there is a substantial risk to innovation at play, as completing the IND processes brings competitive advantage. Competitive advantages bring innovators, investors, and other vested interests into a new field. INDs are the stepping stone towards receiving market exclusivity, a valuable asset to any company risking an investment in a novel biologic. INDs also drive the academic field forward by bringing in dedicated funding to conduct valuable RCTs on humans in a novel area. For FMT today, the FDA has eased up on the IND process to aid physicians in giving FMT treatment to patients who need it. There is also a space available for stool banks to operate. Yet, we find that there are still significant gaps in knowledge when it comes to FMT effectiveness and the microbiome as a whole.  Recall the 2017 EMBASE data-scrub, which only found research on 48 patients who underwent FMT for IBS.72 There is a large need to further investigate the value of a novel treatment, and we must ask, is improving accessibility so early on limiting future innovation and interest when it comes to the larger potential of FMT? The answer is not a simple one to arrive at, but the benefit of the IND process is worth consideration. Yes, there is a clear need for better donor selection, quality control, and follow-up, but we lack the speed to rally vested interest of organizations or companies to conduct these RCTs and fortify our understanding of the field. Yes, IND can be lengthy and costly process, but remedies are available. To limit time, RCTs can go through expedited review if they demonstrate that FMT is a breakthrough therapy based on substantial evidence of efficacy.73 The question is: should we focus purely on the patients who can benefit from FMT for C. diff alone or should we incentivize more innovation in a field where the application of FMT for C. diff is only the starting point? INDs are the basis of innovation; there is a process and application that works. Now is the time to focus on conducting RCTs, limiting the screening time, and eventually extending research into other areas of the microbiome. Disincentivizing innovators from being able to enter a market and learn from an already-useful treatment is a precondition for lost opportunity.


Defining fecal matter for FMT as a biologic drug posits a number of novel complexities which will require redefining the FDA’s position on what a drug is. But the FDA is moving in the right direction. FMT has been correctly defined as a biologic drug, but, using discretion when enforcing the IND process is limiting interest in the field. The traditional drug approval process for FMT will allow for a certain level of control over processing, ensuring patient safety. INDs can also be influential in creating a national awareness of a useful medical procedure through more robust clinical trials. They can bring in new players beyond a few non-profit stool banks and they can improve overall transparency as the data collected through IND applications can aid in the assessment of risks and benefits associated with FMT in future applications. Treating FMT like blood would mean recognizing that the current recruitment and screening process used by a handful of non-profit stool banks are acceptable without creating an opportunity for competition. Treating FMT like that of cord-blood may mean creating a too-narrow regulatory framework based on a novel therapeutic solution which may not reflect the greater direction of the microbiome. There still remain a number of considerations when it comes to the use of off-label FMT (e.g. at home use). Even so, using a formal IND approval process for FMT will be necessary in setting the foundation for a regulatory framework focused on biologics and in a large part, the greater microbiome.


1 Round, June L., and Sarkis K. Mazmanian. “The gut microbiota shapes intestinal immune responses during health and disease.” Nature Reviews Immunology 9.5 (2009): 313.

2 Public Health Agency, Government of Canada. Fact Sheet – Clostridium difficile (C. difficile). Accessed December 7, 2018.

3 Mayo Clinic. C. difficile infection- Overview. Accessed August 27, 2018.

4 Louie, Thomas J., et al. “Fidaxomicin versus vancomycin for Clostridium difficile infection.” New England Journal of Medicine 364.5 (2011): 422-431.

5 Shields, Kelsey, Roger V. Araujo-Castillo, Thimmaiah G. Theethira, Carolyn D. Alonso, and Ciaran P. Kelly. “Recurrent Clostridium difficile infection: from colonization to cure.” Anaerobe 34 (2015): 59-73.

6 Mayo Clinic. C. difficile infection- Overview. Accessed August 27, 2018.

7 Louie, Thomas J., Mark A. Miller, Kathleen M. Mullane, Karl Weiss, Arnold Lentnek, Yoav Golan, Sherwood Gorbach, Pamela Sears, and Youe-Kong Shue. “Fidaxomicin versus vancomycin for Clostridium difficile infection.” New England Journal of Medicine 364, no. 5 (2011): 422-431.

8 Pamer, E. G. “Fecal microbiota transplantation: effectiveness, complexities, and lingering concerns.” Mucosal immunology 7, no. 2 (2014): 210-214.

9 Figueroa, Iris, et al. “Relapse versus reinfection: recurrent Clostridium difficile infection following treatment with fidaxomicin or vancomycin.” Clinical infectious diseases55.suppl_2 (2012): S104-S109.

10 Vincent, Caroline, and Amee R. Manges. “Antimicrobial use, human gut microbiota and Clostridium difficile colonization and infection.” Antibiotics 4, no. 3 (2015): 230-253.

11 Van Nood, Els, Anne Vrieze, Max Nieuwdorp, Susana Fuentes, Erwin G. Zoetendal, Willem M. de Vos, Caroline E. Visser et al. “Duodenal infusion of donor feces for recurrent Clostridium difficile.” New England Journal of Medicine 368, no. 5 (2013): 407-415.

12 Vyas, Dinesh, Apoorva Aekka, and Arpita Vyas. “Fecal transplant policy and legislation.” World Journal of Gastroenterology: WJG 21, no. 1 (2015): 6.

13 This does not necessarily discount the effectiveness of vancomycin in a clinical capacity. Other studies have shown that vancomycin is still comparatively an effective tool in preventing recurrence among severe incident C. diff  patients with an adjusted relative risk of recurrence at 0.79 in a study comparing vancomycin with metronidazole.

14 Schmidt, Michael A. Beyond antibiotics: Strategies for living in a world of emerging infections and antibiotic-resistant bacteria. North Atlantic Books, 2009.

15 Gough, Ethan, Henna Shaikh, and Amee R. Manges. “Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection.” Clinical infectious diseases 53.10 (2011): 994-1002.

16 Cohen, Stuart H., et al. “Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA).” Infection Control & Hospital Epidemiology 31.5 (2010): 431-455.

17 Holvoet, Tom, et al. “Assessment of faecal microbial transfer in irritable bowel syndrome with severe bloating.” Gut 66.5 (2017): 980-982.

18 Halkjær, Sofie Ingdam, et al. “Can fecal microbiota transplantation cure irritable bowel syndrome?.” World journal of gastroenterology 23.22 (2017): 4112.

19 Eric Nellis, M. D., et al. “Quality Assessment of the Efficacy and Cost-Effectiveness of Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection.” (2017).

20 “OpenBiome partnering with Finch Therapeutics to enable FDA approval of a fecal transplant treatment for recurren C. difficile infection,” (2017), accessed October 31, 2018,

21] Sachs, Rachel E., and Carolyn A. Edelstein. “Ensuring the safe and effective FDA regulation of fecal microbiota transplantation.” Journal of Law and the Biosciences 2.2 (2015): 396-415.

22 Cernohorsky, Karel, et al. “A prospective, multi-center, randomized trial of fecal microbiota transplantation (FMT) delivered by capsule vs colonoscopy in the management of recurrent Clostridium difficile infection (CDI).”

23 “The Power of Poop.” (2016), Accessed April 23, 2018.

24 Kay, Jonathan. “Biosimilars: a regulatory perspective from America.” Arthritis research & therapy 13.3 (2011): 112.

25 Ross, Sharon. “Functional foods: the Food and Drug Administration perspective.” The American journal of clinical nutrition 71.6 (2000): 1735s-1738s.

26 Form, A. D. V. “21 CFR Part 50.”

27 Sachs, Rachel E., and Carolyn A. Edelstein. “Ensuring the safe and effective FDA regulation of fecal microbiota transplantation.” Journal of Law and the Biosciences 2, no. 2 (2015): 396-415.

28 Drew, Liam. “Microbiota: Reseeding the gut.” Nature 540, no. 7634 (2016): S109-S112.

29 Mark B. Smith, Colleen Kelly & Eric J. Alm, How to Regulate Faecal Transplants, 506 nature 290, 290 (2014).

30 Huss, John. “Fecal Transplant Bioethics: Beyond Chicken Little.” The American Journal of Bioethics 17, no. 5 (2017): 48-50.

31 “The FDA and National Institutes of Health subsequently convened a public workshop in May in order to address scientific and regulatory issues surrounding the use of FMT, and the decision was upheld. Shortly thereafter, the Infectious Diseases Society of America (IDSA) created another collaborative FMT workgroup that consisted of interested parties within the IDSA, Centers for Disease Control and Prevention, American Gastroenterological Association, and American College of Gastroenterology. Under the aegis of the IDSA, this workgroup petitioned the FDA to relax its enforcement, given the complexity of IND applications and its burden on physicians treating acutely ill patients. As a result of these efforts, in June the FDA announced its intention to exercise enforcement discretion regarding the required IND applications for use of FMT to treat individual cases of RCDI. In these cases, an IND is encouraged but not required.”

Source: Moore, Thomas, Andres Rodriguez, and Johan S. Bakken. “Fecal microbiota transplantation: a practical update for the infectious disease specialist.” Clinical infectious diseases 58, no. 4 (2013): 541-545.

32 Food and Drug Administration. “Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies.” Accessed December 7, 2018.

33 Browne, Alexander S., and Colleen R. Kelly. “Fecal Transplant in Inflammatory Bowel Disease.” Gastroenterology Clinics of North America (2017).

34 Federal Register.  “Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation To Treat Clostridium difficile Infection Not Responsive to Standard Therapies; Draft Guidance for Industry; Availability,” Accessed December 7, 2018.

35 Sachs, Rachel. “FDA Announces Draft Guidance That Would Limit Enforcement Discretion for FMT,” Accessed December 7, 2018.

36 Openbiome. “FDA Regulation of Fecal Microbiota for Transplantation.” Accessed December 7, 2018.

37 Sachs, Rachel E., and Carolyn A. Edelstein. “Ensuring the safe and effective FDA regulation of fecal microbiota transplantation.” Journal of Law and the Biosciences 2.2 (2015): 396-415.

38 Thomas Morrow and Linda Hull Felcone. “Defining the difference: what makes biologics unique.” Biotechnology healthcare 1, no. 4 (2004): 24.

39 Geigert, John. The challenge of CMC regulatory compliance for biopharmaceuticals and other biologics. Springer, 2013.

40 Geigert, John. The challenge of CMC regulatory compliance for biopharmaceuticals and other biologics. Springer, 2013.

41 Reichert, Janice M. “A guide to drug discovery: Trends in development and approval times for new therapeutics in the United States.” Nature Reviews Drug Discovery 2.9 (2003): 695.

42 Holbein, ME Blair. “Understanding FDA regulatory requirements for investigational new drug applications for sponsor-investigators.” Journal of investigative medicine 57.6 (2009): 688-694.

43 Thaul, Susan. “How FDA approves drugs and regulates their safety and effectiveness.” (2012).

44 Yatsunenko, Tanya, Federico E. Rey, Mark J. Manary, Indi Trehan, Maria Gloria Dominguez-Bello, Monica Contreras, Magda Magris et al. “Human gut microbiome viewed across age and geography.” Nature 486, no. 7402 (2012): 222-227.

45 Sachs, Rachel E., and Carolyn A. Edelstein. “Ensuring the safe and effective FDA regulation of fecal microbiota transplantation.” Journal of Law and the Biosciences 2, no. 2 (2015): 396-415.

46 Sachs, Rachel E., and Carolyn A. Edelstein. “Ensuring the safe and effective FDA regulation of fecal microbiota transplantation.” Journal of Law and the Biosciences 2, no. 2 (2015): 396-415.

47 Food and Drug Administration, “Keeping Blood Transfusions Safe: FDA’s Multi-Layered Protections for Donated Blood,” Accessed December 10, 2017,

48 [48] Food and Drug Administration, “Blood and Blood Products,” Accessed December 11, 2018.

49 Dauer, Edward A., ed. Blood Banking and Regulation: Procedures, Problems, and Alternatives. National Academies Press, 1996.

50 Sachs, Rachel E., and Carolyn A. Edelstein. “Ensuring the safe and effective FDA regulation of fecal microbiota transplantation.” Journal of Law and the Biosciences 2.2 (2015): 396-415.

51 Openbiome. “Quality and Safety,” Accessed December 7, 2018.

52 Dauer, Edward A., ed. Blood Banking and Regulation: Procedures, Problems, and Alternatives. National Academies Press, 1996.

53 Sachs, Rachel E., and Carolyn A. Edelstein. “Ensuring the safe and effective FDA regulation of fecal microbiota transplantation.” Journal of Law and the Biosciences 2.2 (2015): 396-415.

54 Food and Drug Administration. “Investigational New Drug Application (IND)” Accessed December 4, 2018.

55 Hall, Andrew Brantley, Andrew C. Tolonen, and Ramnik J. Xavier. “Human genetic variation and the gut microbiome in disease.” Nature Reviews Genetics 18, no. 11 (2017): 690-699.

56 Sachs, Rachel E., and Carolyn A. Edelstein, 2015

57 Daniel, M. G., Pawlik, T. M., Fader, A. N., Esnaola, N. F., & Makary, M. A. (2016). The Orphan Drug Act: restoring the mission to rare diseases. American journal of clinical oncology39(2), 210-213.

58 Carver, Krista Hessler, Jeffrey Elikan, and Erika Lietzan. “An unofficial legislative history of the Biologics Price Competition and Innovation Act 2009.” Food & Drug LJ 65 (2010): 671.

59 Sachs, Rachel E., and Carolyn A. Edelstein, 2015

60 Riley, Margaret F., and Bernat Olle. “FDA’s pathway for regulation of FMT: not so fraught.” Journal of Law and the Biosciences 2, no. 3 (2015): 742.

61 Kassam, Zain, Christine H. Lee, Yuhong Yuan, and Richard H. Hunt. “Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis.” The American journal of gastroenterology 108, no. 4 (2013): 500-508.

62 Vyas, Dinesh, Apoorva Aekka, and Arpita Vyas. “Fecal transplant policy and legislation.” World Journal of Gastroenterology: WJG 21, no. 1 (2015): 6.

63 Smith, Mark, Zain Kassam, Carolyn Edelstein, James Burgess, and Eric Alm. “OpenBiome remains open to serve the medical community.” Nature biotechnology 32, no. 9 (2014): 867-867.

64 Hudson, Kathy L., Michael S. Lauer, and Francis S. Collins. “Toward a new era of trust and transparency in clinical trials.” Jama 316, no. 13 (2016): 1353-1354.

65 Kozlowski, Steven, Janet Woodcock, Karen Midthun, and Rachel Behrman Sherman. “Developing the nation’s biosimilars program.” New England Journal of Medicine 365, no. 5 (2011): 385-388.

66 van Nood, Els, Peter Speelman, Max Nieuwdorp, and Josbert Keller. “Fecal microbiota transplantation: facts and controversies.” Current opinion in gastroenterology 30, no. 1 (2014): 34-39.

67 Kelly, Colleen R., Stacy Kahn, Purna Kashyap, Loren Laine, David Rubin, Ashish Atreja, Thomas Moore, and Gary Wu. “Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms, and outlook.” Gastroenterology149, no. 1 (2015): 223-237.

68 “Cord blood stored for personal use, for use in first- or second-degree relatives, and that also meets other criteria in FDA’s regulations, does not require the agency’s approval before use.

Cord blood stored for use by a patient unrelated to the donor meets the legal definitions of both a “drug” and a “biological product.” Cord blood in this category must meet additional requirements and be licensed under a biologics license application, or be the subject of an investigational new drug application before use.”

Source: “Cord Blood: What You Need to Know,” Food and Drug Administration, accessed December 7, 2017,

69 Pedersen, William F. “Formal records and informal rulemaking.” The Yale Law Journal 85, no. 1 (1975): 38-88.

70 Swaminath, Arun. “The power of poop: patients getting ahead of their doctors using self-administered fecal transplants.” The American journal of gastroenterology 109, no. 5 (2014): 777.

71 Sensebe, L., M. Krampera, H. Schrezenmeier, P. Bourin, and R. Giordano. “Mesenchymal stem cells for clinical application.” Vox sanguinis 98, no. 2 (2010): 93-107.

72 Halkjær, Sofie Ingdam, et al. “Can fecal microbiota transplantation cure irritable bowel syndrome?.” World journal of gastroenterology 23.22 (2017): 4112.

73 Kesselheim, A. S., and J. J. Darrow. “FDA designations for therapeutics and their impact on drug development and regulatory review outcomes.” Clinical Pharmacology & Therapeutics 97, no. 1 (2015): 29-36.