Arkkila, P.

Keller, Josbert J.

Standards Guidelines Initiative

Vehreschild, Maria J. G. T.

English

Helsingin yliopiston digitaalinen arkisto

Letter to the EditorStool for fecal microbiota transplantationshould be classified as a transplantproduct and not as a drugJosbert J Keller1,2, Maria JGT Vehreschild3, Christian L Hvas4,Simon MD Jørgensen4 , Jouzas Kupciskas5, Alexander Link6, Chris JJ Mulder7,Simon D Goldenberg8, Ramesh Arasaradnam9 , Harry Sokol10,11,12,Antonio Gasbarrini13, Christoph Hoegenauer14, Elizabeth M Terveer15,2,Ed J Kuijper16,2 and Perttu Arkkila17; On behalf of the UEG working groupof the Standards and Guidelines initiative Stool banking for FMTFecal microbiota transplantation (FMT) or donor fecesinfusion is a therapy that aims to restore a perturbedgut microbiota composition and function. FMT iseﬀective for treatment of patients with (multiple) recur-rent Clostridioides diﬃcile infections1–3 and recom-mended by current guidelines.4–6 In the near future,FMT may also become an accepted treatment optionfor other intestinal or extra-intestinal diseases.7FMT is performed using suspensions made of donorstool from carefully selected and screened healthy indi-viduals.1,7 Donor screening is time consuming andcostly. Before the establishment of stool banks, phys-icians and patients had to ﬁnd their own donors. Thisresulted in uncontrolled application of FMT, and thelogistical challenge made physicians reluctant to oﬀerFMT to their patients. To overcome these problems,stool banks have been established.8,9 The mission ofthose stool banks is:(i) to produce ready-to-use donor feces suspensionsfor treatment of patients,(ii) to improve the quality and safety of FMT by cen-tralization and standardization,(iii) to increase the cost eﬀectiveness of FMT, and(iv) to facilitate research.Stool banks are built in concordance with the modelof blood banks and should follow quality standardsapplied to other transplantation products. Most stoolbanks are non-proﬁt institutions, operating at a local(institution-based), national or international level.Recently, a UEG-funded working group was initiatedto deﬁne quality standards for stool banking and FMT,which will result in further standardization of this newtreatment approach. The current costs to deliver aready-to-use stool suspension are E1050–1700 in1Department of Gastroenterology, Haaglanden Medical Center, The Hague,The Netherlands, and Leiden University Medical Center, Leiden, TheNetherlands2Netherlands Donor Feces Bank, Leiden University Medical Center3University of Cologne, Faculty of Medicine and University Hospital ofCologne, Department I of Internal Medicine, Center for IntegratedOncology Aachen Bonn Cologne Du¨sseldorf (CIO ABCD), German Centrefor Infection Research (DZIF), partner site Bonn – Cologne, Cologne,Germany; Department of Internal Medicine, Infectious Diseases, GoetheUniversity Frankfurt, Frankfurt am Main, Germany4Department of Hepatology and Gastroenterology, Aarhus UniversityHospital, Aarhus, Denmark5Department of Gastroenterology and Institute for Digestive Research,Lithuanian University of Health Sciences, Kaunas, Lithuania6Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany7Chris Mulder, Department of Gastroenterology, Free University MedicalCenter, Amsterdam, The Netherlands8Centre for Clinical Infection and Diagnostics Research (CIDR), King’sCollege London and Guy’s and St. Thomas’ NHS Foundation Trust,London, UK9Warwick Medical School, University of Warwick, Coventry, UK10Sorbonne Universite´, INSERM, Saint-Antoine Research Center (CRSA),Paris, France11French Group of Fecal Microbiota Transplantation (GFTF)12INRA, UMR1319 Micalis, AgroParisTech, Jouy-en-Josas, France13Gastroenterology Area, Fondazione Policlinico Universitario Gemelli,Universita` Cattolica del Sacro Cuore, Rome, Italy14Division of Gastroenterology and Hepatology, Department of InternalMedicine, Medical University of Graz, Graz, Austria15Department of Medical Microbiology and Netherlands Donor Feces Bank,Leiden University Medical Centre, Leiden, The Netherlands16Centre for Microbiota Analysis and Therapeutics, Department of MedicalMicrobiology, Leiden University Medical Centre, Leiden, The Netherlands17Helsinki University Hospital and Helsinki University, Helsinki, FinlandCorresponding author:Dr JJ Keller, Haaglanden Medical Center, Lijnbaan 32, 2596SR The Hague,The Netherlands.Email: j.keller@haaglandenmc.nlUnited European Gastroenterology Journal2019, Vol. 7(10) 1408–1410! Author(s) 2019Article reuse guidelines:sagepub.com/journals-permissionsDOI: 10.1177/2050640619887579journals.sagepub.com/home/uegEurope.9,10 There are also commercial initiatives,11which may aim for much higher prices.Driven by the needs of patients, stool banks haveemerged as new entities in a landscape without existingregulatory boundaries. This lack of guidance andNational or European legislation may become a seriousthreat to providing the treatment for severely ill patients.This is also illustrated by the recent safety alert in the USabout the transmission of multi-drug resistant organ-isms through FMT,12 which underlines the need forstandardization, quality assurance, and a regulatoryframework supporting the activities of stool banks.Legislation requires classiﬁcation of stool as a productto treat patients.We strongly believe that stool should beconsidered a transplant product, or be regarded equiva-lent in status to blood products used for transplantationor transfusion purposes. The EU Tissue and CellsDirective (2004/23/EC) is best suited to guide FMT.Currently, this Directive does not cover FMT becausethe mechanism of action is not mediated by human cells.An adjustment to align this directive with the new realityof fecal transplantation is thus urgently needed. Only inthe case of modiﬁcation to the donated feces, other thanthose necessary for the conservation of the microbialcommunity, does the product made of the donatedfeces become comparable to a drug and is best coveredwithin the European directive for medicinal productsintended for human use (2001/83/EC).Unfortunately, the misclassiﬁcation of donor fecessuspensions as a drug or pharmaceutical product,although diﬃcult to imagine, is still one of the possibleoutcomes of the current discussion about classiﬁcation.Currently, stool has already been classiﬁed as a drug incountries such as France, Germany, and the UnitedKingdom. Recently, companies have formed the‘‘Pharmabiotic Research Institute’’ in Europe and the‘‘Microbiome Therapeutics Innovation Group(MTIG)’’ in the US. The mission of those groups is‘‘to improve market access,’’ and to ‘‘enhance the regu-latory, investment, and commercial environment formicrobiome therapeutic drug product development.’’Both groups have published statements about the clas-siﬁcation of FMT as a drug.13,14 MTIG actively collab-orates with the Food and Drug Administration for theevaluation of safety parameters related to microbiota-based therapeutic products. Concern has been raised bythe MTIG that the existence and accessibility of mater-ial from stool banks limits enrollment into clinical trialsfor microbiome therapeutics. This illustrates how com-panies are active to inﬂuence the current discussionabout classiﬁcation and regulation of FMT. In fact,this discussion has already been troubled by commer-cial interest in the US some years ago.15In this regard, it is important to mention the overallmajor disadvantages of classiﬁcation as a drug, whichwill result in time-consuming and costly registrationprocesses, and a sharp and unjustiﬁed rise in costs.Most importantly, this will negatively impact availabil-ity and innovation, obstructing, for example, the futuredevelopment of single-donor individualized solutionsdue to the requirements for standardization of activesubstances. We postulate that stool treatment deﬁnedas drug treatment is counterproductive. Stool is not astandardized product that is produced in a factory, buta highly diverse and donor-speciﬁc substance of humanorigin (SoHO) delivered by healthy, usually unpaid,volunteer donors. Therefore, stool suspensions requiresuitable guidance of quality and safety measures com-parable to guidance of other SoHO (blood, tissues, cellsand organs) within the EU.If government authorities seek aﬀordable and qual-ity-assured FMT, a supportive regulatory framework,in combination with appropriate funding or reimburse-ment, is required for stool banks. This will not onlyguarantee broad access and safety of FMT, but alsoenable the future innovation of this new treatmentstrategy targeting the gut microbiota. If eventuallyfuture research results in the replacement of FMT bystandardized mixtures of bacteria (or another yet undis-covered stool extract that could theoretically underlythe clinical eﬀects of FMT), these should indeed beregulated as a drug or pharmaceutical product.AcknowledgmentThe UEG working group of the Standards and Guidelinesinitiative Stool banking for FMT were MJGT Vehreschild,A Gasbarrini, O Gridnyev, F Me´graud, PK Kump,R Nakov, SD Goldenberg, R Satokari, S Tkatch,M Sanguinetti, H Sokol, G Cammarota, A Dorofeev,JJ Keller, C Hoegenauer, O Gubska, G Ianiro, E Mattila,RE Ooijevaar, R Arasaradnam, SK Sarin, A Sood,L Putignani, L Alric, P Arkkila, CL Hvas, SMD Jørgensen,EJ Kuijper, J Kupciskas, A Link, CJJ Mulder, HRTWilliams, A Goorhuis, HW Verspaget, EM Terveer, GLHold, H Tilg and CY Ponsioen.Declaration of conflicting interestsJ.J.K., E.M.T, and E.J.K. have received research fundingfrom Vedanta Biosciences. M.J.G.T.V. has received funding,speaker fees and/or consulting fees from 3M, Alb FilsKliniken GmbH, Astellas Pharma, bioMe´rieux, DaVolterra,Evonik, Ferring, Gilead Sciences, Glycom, Heel, MaaTPharma, MSD/Merck, Organobalance, Pﬁzer, RochePharma and Seres Therapeutics. S.D.G. has received researchfunding and/or consulting fees from Astellas, Enterobiotix,MSD, Pﬁzer, Shionogi and a grant from Shionogi. H.S. hasreceived research funding and/or consulting fees fromEnterome, Takeda, Abbvie, Roche, Amgen, BiomX,Danone, Ferring, BMS, Astellas, MSD, Novartis, TillotsPharma, Biose and Biocodex, and is co-founder of ExeliomBiosciences. C.H. has received research funding and/orKeller et al. 1409consulting fees from Seres Therapeutics, Astellas, MSD,Ferring. The other authors have nothing to disclose.FundingThe working group is supported by a UEG Standards andGuidelines Activity grant (2018).ORCID iDsSimon MD Jørgensen https://orcid.org/0000-0002-5135-7435Ramesh Arasaradnam https://orcid.org/0000-0002-2231-3062References1. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenalinfusion of donor feces for recurrent Clostridium difficile.N Engl J Med 2013; 368: 407–415.2. van Beurden YH, de Groot PF, van Nood E, et al.Complications, effectiveness, and long term follow-up offecal microbiota transfer by nasoduodenal tube for treat-ment of recurrent Clostridium difficile infection. UEG J2017; 5: 868–879.3. Ianiro G, Maida M, Burisch J, et al. Efficacy of differentfaecal microbiota transplantation protocols forClostridium difficile infection: A systematic review andmeta-analysis. UEG J 2018; 6: 1232–1244.4. Debast SB, Bauer MP, Kuijper EJ, et al. European Society ofClinical Microbiology and Infectious Diseases: Update of thetreatment guidance document for Clostridium difficile infec-tion. Clin Microbiol Infect 2014; 20(Suppl 2): 1–26.5. McDonald LC, Gerding DN, Johnson S, et al. Clinicalpractice guidelines for Clostridium difficile infection inadults and children: 2017 Update by the InfectiousDiseases Society of America (IDSA) and Society forHealthcare Epidemiology of America (SHEA). ClinInfect Dis 2018; 66: 987–994.6. Mullish BH, Quraishi MN, Segal JP, et al. The use offaecal microbiota transplant as treatment for recurrentor refractory Clostridium difficile infection and otherpotential indications: Joint British Society ofGastroenterology (BSG) and Healthcare InfectionSociety (HIS) guidelines. Gut 2018; 67: 1920–1941.7. Ooijevaar RE, Terveer EM, Verspaget HW, et al. Clinicalapplication and potential of fecal microbiota transplant-ation. Annu Rev Med 2019; 70: 335–351.8. Smith M, Kassam Z, Edelstein C, et al. OpenBiomeremains open to serve the medical community. NatBiotechnol 2014; 32: 867.9. Terveer EM, van Beurden YH, Goorhuis A, et al. Howto: Establish and run a stool bank. Clin Microbiol Infect2017; 23: 924–930.10. Dehlholm-Lambertsen E, Hall BK, Jorgensen SMD,et al. Cost savings following faecal microbiota transplant-ation for recurrent Clostridium difficile infection. TherapAdv Gastroenterol 2019; 12: 1756284819843002.11. Dubberke ER, Lee CH, Orenstein R, et al. Results froma randomized, placebo-controlled clinical trial of aRBX2660-A microbiota-based drug for the preventionof recurrent Clostridium difficile infection. Clin InfectDis 2018; 67: 1198–1204.12. Kuijper EJ, Allegretii J, Hawkey P, Sokol H, GoldenbergS, Ianiro G, Gasbarrini A, Kump P, Costello SP, Keller J,Vehreschild MJGT. A necessary discussion after trans-mission of multidrug-resistant organisms through faecalmicrobiota transplantations. Lancet Infect Dis 2019;19(11): 1161–1162. doi: 10.1016/S1473-3099(19)30545-6.13. https://microbiometig.org/statements (accessed 6 November2019).14. www.pharmabiotic.org/2019/05/20/imm-etg-a-new-eur-opean-initiative-for-intestinal-microbiome-medicinal-products (accessed 6 November 2019).15. Sachs RE and Edelstein CA. Ensuring the safe and effect-ive FDA regulation of fecal microbiota transplantation.J Law Biosci 2015; 2: 396–415.1410 United European Gastroenterology Journal 7(10)

Stool for fecal microbiota transplantation should be classified as a transplant product and not as a drug

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Stool for fecal microbiota transplantation should be classified as a transplant product and not as a drug

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