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Fecal Microbiome Transplants: Growing Success Requires New Ethics And Clear Regulation

INTRODUCTION

Fecal Microbiome Transplants

Events taking place in the gut are known to play an important role health and disease, in terms of determining the development of metabolic diseases as well as other illnesses, centered on the pathophysiology of gastrointestinal inflammatory diseases. This is in terms of the balance and composition of the intestinal microbiota (1). In addition, the existence of bidirectional communication between the gut and the brain has been shown to influence both behavior and cognitive function (2). For these reasons, there is an interest in the gut microbiome and the composition of the gut microbiota. It is also of interest that an imbalance of certain pathogens can be off-set by tilting the balance towards beneficial bacteria. This imbalance is referred to as dysbiosis. This imbalance could be due to the gain or loss of community members or changes in relative abundance of microbes (3).

For these reasons, fecal bacteriotherapy or fecal microbiome transplants (4), have been attracting considerable interest from the medical profession and, perhaps inevitably, the pharmaceutical industry. This brings with it questions of regulation – is the product a tissue product or a biologic drug? – and questions of ethics (5). Just as Richard Titmuss did in relation to blood and blood products (6), an emerging new therapy needs to be brought under an ethical framework as soon as is practicable and based on a framework that preserves the public good.

The objective of fecal microbiome transplants is to establish a healthy balance of microbiota within the gut microbiome through the supply beneficial microorganisms. This is accomplished by ‘transplanting’ a donation of fecal matter from a healthy individual, diluted, strained and introduced into another individual. This occurs either by transfusion or in pill form. For the general process, the donor is first tested to make sure that s/he is healthy and has a good balance of both good and bad bacteria in her or his colon. Donors (who can be family members or unrelated) should be screened for enteric bacterial pathogens, viruses and parasites. For this assessment, donor feces should be taken and diluted with water, saline or another liquid such as milk or yogurt, and subsequently strained to remove large particles.  Then the fecal matter is transferred to the person being transplanted through a series of enemas. This involves using a suspension that is introduced into the recipient's gut via a nasogastric tube, nasoduodenal tube, rectal enema or via the biopsy channel of a colonoscope. Recipients may receive a bowel lavage before transplantation, in order to reduce the microbial load in the intestines. Unlike a heart, liver, or kidney transplant there is very little fear of rejection and the patient does not need to take immune-suppressing drugs for the rest of their life.

The procedure has reported success in the treatment of patients with Clostridium difficile infections, especially when the use of antibiotics has not been successful (7) (and sometimes antibiotics upset the balance of bacteria in the allowing C. difficile to multiply more than normal and become a bowel infection). The emerging body of literature further demonstrates that the procedure has been effective in treating diseases such as colitis and other inflammatory bowel diseases. Researchers have also applied fecal material to combat the effects of vancomycin-resistant Enterococcus faecium and multi-drug resistant Klebsiella pneumonia (8). There are other investigational lines that are assessing different areas of medical inquiry. For example, studies into children with autism and moderate to severe gastrointestinal problems suggests that, following the fecal therapy, positive changes (assessed via the Childhood Autism Rating Scale) have been observed following eight weeks of fecal bacteriotherapy treatment (9). Other areas of clinical trial investigation extend to Crohn's disease and ulcerative colitis (chronic inflammatory bowel diseases).

There is also a connection to obesity and the metabolic disease connected with the condition. Studies suggest that people with a high diversity of bacteria in their feces tended to carry lower levels of visceral fat. In contrast, those with a narrower range of bacteria, tended to carry more fat. Visceral fat refers to the body fat stored in the abdominal cavity, in close proximity to important internal organs. Higher levels of fat in this area have been connected with a greater chance of developing metabolic diseases, including cardiovascular disease and diabetes.

SIDE-EFFECTS AND INFECTION RISKS

Despite reported successes, mostly in animal models, the transplants remain an investigational therapy and there is considerable divergence of thought as to the level of risk and the degree of regulation required (10), both within and between nations. This divergence rests on how the therapy is to be classified (for example, should it fall under tissue regulations?) and with understanding the level of risk, in terms of unintended contamination being passed from donor to patient or with the recipient developing unintended metabolic effects (11). Other side-effects include: Burping, cramps, tummy pain, diarrhea, infections of the stomach, symptomatic choledocholithiasis, bowel and the tissue lining the inside of the abdomen (12, 13). There is also a chance that the therapy is unsuccessful or that the patient relapses (in terms of the original problem recurring) (14).

REGULATORY VARIANCES

Based on the above reasons, a warning note issued by the U.S. Food and Drug Administration (FDA) highlighted a lack of control around screening for other pathogens (15). This warning has been written as to so avoid the transfer high levels of a different pathogen into a patient in addition to the pathogen that is intended to be treated.

Earlier (and current) FDA guidance enables the therapy to be undertaken at the discretion of a medical doctor (16). Here the primary activity that the medical establishment is required to undertake is for the lead physician to seek informed consent from the individual set to receive the treatment and ensure that the patient is aware that fecal therapy products  remain investigational and that an informed discussion is held with the patient as to the potential risks.

Within the European Union, it is acknowledged there are technical and logistical issues in establishing such a non-standardized treatment into the clinical practice with safety and proper governance (as assessed under the European Advanced Therapy Medicinal Products regulation). Regulation does not (yet) fall under the Human Tissue Directive 2004/23/EC, although the material should be regarded as a biologic as it contains colonocytes (as set out in a guidance document) (17). The approach is based on evidence-based recommendations for each proposed practical implementation of the therapy, under the control of each individual member state. However, it is possible that stool banks will become embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application. This would mean the Directive would address how voluntarily donated material (i.e. feces) should be collected, handled and used. However, as discussed below this outcome is not certain.

In order to assess the suitability of therapy, one model being used within Europe is the GRADE system. The GRADE system (Grades of Recommendation Assessment, Development and Evaluation) is a method to grade the strength of evidence (high/moderate/low/very low) and strength of recommendation (strong/weak) (18), in relation to fecal transplants.

Outside of the European Union (as of 2021)  the UK guidance is provided by the National Institute for Health and Care Excellence (NICE). In Australia, while there is some national guidance (see below), hospitals and health services are regulated by State or Territory Governments, and hence the registration and licensing requirements will vary between the states and territories. The Australian guidance attempts to push the application, outside of clinical trials, to come under pharmaceutical standards and under Good Manufacturing Practice (GMP) regulations.

TISSUE PREPARATION OR PHARMACEUTICAL PRODUCT?

The argument that fecal transplantation is a tissue rather than a drug product is based on the substance containing human cells (fecal material is classed as ‘combined substance’) and the argument that fecal microbiota transplantation resembles an organ transplantation, and this should be accompanied by corresponding screening standards (19).

The barrier to a unified set of guidances under tissue directives is where countries instead elect to class fecal therapy as a drug product, based on the need to carry out modifications necessary for conservation and administration of the end ‘product’. Between European nations, as an example, there is no consensus with France and Belgium taking different policy positions; and likewise there is no sign of a clear direction merging from the U.S. FDA (although there are signs of the definition gravitating towards that of a pharmaceutical products) (20). The driver for classification as a drug comes from the pharmaceutical sector. While this may enhance the commercial environment for the drug product development, it will also lead to a more time-consuming and costly registration processes, higher-end costs to the hospital, patenting, more limited availability, and perhaps fewer innovations. Moreover, pharmaceutical product classification would provide exclusivity to the sector and restrict patients’ access to the therapy outside of drug company-sponsored trials.

What Should Regulations Stipulate?

That there is need for regulation is unquestionable, otherwise this paves the way for unethical commercialization of human material. But what would such regulation look like? Questions that require addressing, drawing on some set out by the Australian Government (21) and added to by the author, include:

  • Donor selection – what risk criteria should be assessed for donor suitability?
  • Donor testing – what testing should be considered for donor suitability?
  • Stool testing – what testing should be applied to ensure pathogenic agents are minimized?
    • SOPs, guidelines, reference manuals, reporting forms and procedural protocols will be required and these should be updated continuously.
    • Ensuring personnel are trained.
  • Building in safety
    • How can processes which may critically affect the quality or the safety of donated material be identified?
    • How can precautionary measures be in-built?
      • This will include describing responsible personnel, SOPs, logging and referencing manuals.
  • Is identification of microorganisms required? 
  • Manufacturing considerations – what controls are required to prevent contamination?
  • What is required to identify and quantitate the active component (potency) to ensure product consistency?
  • Distribution
    • All activities related to the preparation and distribution of donated material must be tracked and traced.
  • Inspection
    • Auditing by national authorities should be part of the quality management. Audits should make sure that data are entered and maintained properly, and also evaluate the operations and quality assurance system.
  • Transparency
    • A registry of activity should be in place to ensure that the facility undertaking the fecal therapy is able to collect and report data on the patients treated with the preparations it distributes.
    • All adverse reactions should be reported. The facility should communicate data related to performance, outcome and safety to national health authorities. Such reporting should be based upon International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) harmonized tripartite guidelines (22).
    • Annual reporting should extend to the number of patients, the treatment modalities used (colonoscopy, enema, gastric or duodenal tube, gastroscopy, capsules, etc.), plus data pertaining safety and the therapeutic outcome of treatment.
    • Data between facilities should be entered into a national and, ideally, international registry, to be available for all researchers and public policy makers to access.

In putting forward the argument for regulation, it should be noted that donated material is diverse, and the process of obtaining human material and the precautionary measures needed are not covered by current drug legislation. Collected material poses similar risks as other medicines currently regulated as biologicals, including the risk of infectious disease transmission. Risks are of particular concern if the material is banked, where a single batch can be administered to multiple patients, or pooled, where material from more than one donor may be mixed prior to use. 

The ethical question is with which type of legislation – human tissue or pharmaceutical? The answer to this will depend upon how society wishes to use and market the substance – free at the point of use or a low cost, or a fully commercial, patented product in the hands of major companies? The social and ethical juncture is here and the questions this bring forth require resolving.

SUMMARY

If fecal bacteriotherapy is to transition to the status of a consistently produced and manufactured preparation, then a regulatory framework is needed. Whether this framework should fall under tissue guidance or as a pharmaceutical product is a matter to be resolved, from an ethical and scientific standpoint. Perhaps, the donation concept in relation to fecal microbiome therapy should be an altruistic endeavour and not something subject to competitive markets, matching the arguments used in the past for blood and tissue donation (23). What is essential is with safeguarding quality and this includes ensuring standardized microbiological quality control testing, both to assess the numbers and concentrations of beneficial bacteria that are required and in order to screen for the presence or absence of pathogens that might cause patient harm.

This can only be achieved through science based thinking and clear guidance, ideally guidance produced by regulators through international collaboration.

REFERENCES

  1. Mazzawi, T., Lied, G.A., Sangnes, D. A. et al (2018) The kinetics of gut microbial community composition in patients with irritable bowel syndrome following fecal microbiota transplantation, PLoS One, 14;13(11):e0194904
  2. Cryan JF, O'Riordan KJ, Cowan CSM, et al. (2019) The microbiota-gut-brain Axis. Physiol Rev. 2019;99(4):1877–2013
  3. Moos WH, Faller DV, Harpp DN, et al (2016) Microbiota and Neurological Disorders: A Gut Feeling, BioResearch Open Access. 5 (1): 137–145
  4. Aroniadis OC, Brandt LJ. (2013) Fecal microbiota transplantation: past, present and future. Current opinion in gastroenterology. 2013;29(1):79–84
  5. Sandle, T. (2020) Why an ethical code is needed for fecal microbiome therapy, Digital Journal, 28th December 2020, at: http://www.digitaljournal.com/tech-and-science/science/op-ed-why-an-ethi...
  6. Titmuss, R. (1970) The Gift Relationship: From Human Blood to Social Policy, New Press, ISBN 1-56584-403-3
  7. Dupont HL (2013) Diagnosis and management of Clostridium difficile infection. Clinical Gastroenterology and Hepatology. 11 (10): 1216–1223
  8. Caballero, S., Carter, R., Ke, X. et al (2015) Distinct but Spatially Overlapping Intestinal Niches for Vancomycin-Resistant Enterococcus faecium and Carbapenem-Resistant Klebsiella pneumoniae, PLOS Pathogens, https://doi.org/10.1371/journal.ppat.1005132
  9. Kang, D-W., Adams, J.B.,  Gregory, A. C. (2017) Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study, Microbiome, 5 (10): https://doi.org/10.1186/s40168-016-0225-7
  10. Smith MB, Kelly C, Alm EJ (2014) Policy: How to regulate faecal transplants, Nature. 506 (7488): 290–291
  11. Sandle, T. (2019) Multidrug Antimicrobial Resistance Testing and Fecal Transplant Therapy Risks, American Pharmaceutical Review, 22 (6): 116-118: https://www.americanpharmaceuticalreview.com/Featured-Articles/518551-Mu...
  12. van Nood E., Vrieze, A. et al. (2013) Duodenal infusion of donor feces for recurrent Clostridium difficile. New England Journal of Medicine 368 (5): 407415
  13. NICE (2014) Faecal microbiota transplant for recurrent Clostridium difficile infection, At: https://www.nice.org.uk/guidance/ipg485/ifp/chapter/Benefits-and-risks
  14. Sofi, A. A., Silverman, A. L. et al. (2013) Relationship of symptom duration and fecal bacteriotherapy in Clostridium difficile infection-pooled data analysis and a systematic review. Scandinavian Journal of Gastroenterology 48 (3): 266-273
  15. U.S. FDA Important Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms, at: https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologi...
  16. U.S. FDA Guidance for Industry Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies, at: https://www.fda.gov/media/86440/download
  17. HealthCare EDftQoM . Guide to the Quality and Safety of Tissues and Cells for Human Application, 4th ed. Strasbourg, France, European Directorate for the Qualtity of Healthcare & Medicines, https://www.edqm.eu/en/organs-tissues-and-cells-technical-guides
  18. Guyatt, GH, Oxman, AD, Vist, GE, et al. (2008) GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ, 336: 924–926.
  19. Cammarota G, Ioniro G, Bibbò S, Gasbarrini A. (2014) Gut microbiota modulation: probiotics, antibiotics or fecal microbiota transplantation? Intern Emerg Med. 9(4):365–73
  20. FDA Public hearing: Use of Fecal Microbiota for Transplantation (FMT) to Treat Clostridium difficile Infection Not Responsive to Standard Therapies, FDA, 4th November 2019. At: https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/u...
  21. TGA (2018) Regulation of Faecal Microbiota Transplants, Briefing Paper, Version 1.1, September 2018, Therapeutics Goods Association, at: https://consultations.health.gov.au/tga/05446878/user_uploads/regulation...
  22. International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) . Clinical safety data management: definitions and standards for expedited reporting , E2A. 1994. At: https://www.ema.europa.eu/en/documents/scientific-guideline/internationa...
  23. Boylan, A-M, Locock, L., Machin, L. (2018) From waste product to blood, brains and narratives: developing a pluralist sociology of contributions to health research, Sociology of Health & Illness, 41, 3: 585-600



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