1. Introduction
]. Clinical response to antibiotic treatment of CDI is 80% in the primary episode [
] and rapidly falls to only 30–40% in recurrent disease [
]. Faecal Microbiota Transplant (FMT) is highly successful for the treatment of recurrent CDI with significantly improved efficacy rates compared to antibiotic therapy [
,
]. It has also been used for the treatment of severe CDI [
]. The National Institute for Healthcare and Excellence recommend FMT for the treatment of recurrent CDI, in patients failing to respond to antibiotics and other treatments [
].
]. In the USA and Canada, FMT is considered a biologic drug, while in Europe, without a formal position from the European Medicines Agency, a mixture of regulatory frameworks exist [
]. As a medicinal product under regulation by the Medicines and Healthcare products Regulatory Agency (MHRA), FMT can be prescribed and produced locally by a medical practitioner for a named patient under a pharmacy exemption. However production and supply to a third party, via a stool bank, requires a Specials licence.
]. Both European and UK FMT guidelines for good clinical practice and standardisation have been published [
,
- Mullish B.H.
- Quraishi M.N.
- Segal J.P.
- McCune V.L.
- Baxter M.
- Marsden G.L.
- et al.
,
], and there have been commentaries describing the practical and logistical requirements for stool bank operation [
,
], however there is little guidance regarding the specific methodology compliant with the production of a safe and quality assured medicinal product.
We have worked with the HTA and then the MRHA to create a licenced FMT service, using a banked supply of FMT for the treatment of CDI within the National Health Service (NHS). We present outcome data for the first 124 patients treated under HTA approval and present the methodology framework which supported MHRA licencing. Our licenced service is currently supplying FMT to the population of England free of charge under an NHS innovation tariff. The production framework presented will be of value to practitioners in other countries wanting to establish a regulated service for the treatment of CDI and other conditions.
4. Discussion
,
,
]. Administration in our cohort was predominantly via the upper gastrointestinal (GI) route, however one patient received FMT by colonoscopy. A specific administration procedure was available to clinicians, but protocol deviation may have occurred in this real world setting, possibly introducing centre specific bias. Meta-analysis comparing FMT administration routes, have observed a trend toward higher efficacy rates with lower GI compared to upper GI administration, but this often does not reach statistical significance [
,
]. The low numbers of lower GI administration precluded analysis here. This series included both fresh FMT and frozen FMT, reflecting the development of the service over time. Similarly to that previously reported [
,
], we observed no significant difference in FMT outcome between these groups, although the study was not powered to assess such differences and fresh FMT comprised only 25% of cases (31/124). Frozen supply was found to be advantageous over fresh FMT on the basis of logistics, turnaround time and minimising the donor screening window, factors which have also been highlighted by others [
,
].
,
,
], the overall numbers are small and this report presents one of the largest refractory case series to date, particularly in the primary and secondary episode of infection. The use of FMT in refractory CDI is complicated by the absence of accepted standard definitions. In some published studies recurrent and refractory are used interchangeably or poorly defined [
,
,
]. It has been defined as CDI not responding to conventional therapy without specific symptom duration thresholds [
]. Others have defined it as ongoing diarrhoea despite at least five days of oral vancomycin 125 mg given six hourly [
]. In this series the clinical response to FMT, measured at day seven, was higher in recurrent CDI compared to refractory cases (91·0% vs. 73·0%, p = 0·007), however at day 90 no difference was observed in outcome between these groups. A recent meta-analysis found lower cure rates in studies which included both recurrent and refractory patients, compared to studies including only recurrent cases (weighted pooled rate 63.9% vs. 79%; P
], particularly in complicated or refractory cases [
].
Only microbiologically confirmed and clinically symptomatic patients were offered FMT, this approach aimed to avoid using FMT in asymptomatic C. difficile carriers. Those who were negative for C. difficile toxin in stool by EIA but positive for toxigenic C. difficile by PCR may have been more likely to have alternative reasons for ongoing diarrhoea, which could have limited our findings; however these patients were being treated clinically as CDI cases at the time of request for FMT. By definition the refractory group had failed to respond to antibiotics for CDI, which may increase the possibility of other contributing causes of diarrhoea in these cases, particularly as the incidence of resistance to vancomycin and fidaxomicin in C. difficile is thought to be low.
,
]. Further to this FMT production is conducted in a dedicated clean non-sterile manufacturing room, which environmental monitoring has shown complies with grade D clean room recommended limits. This level of environmental review has not previously been commented on in international guidelines and is an evolving area for consideration. Control measures utilised to minimise the environmental contamination of the production facility are validated decontamination protocols, physical barriers (Tack-mats), limited personal access, the use of personal protective equipment (laboratory coats, hair nets and overshoes), and limiting material in the facility which supports microbial growth. The aim of the above GMP processes is to standardise and maintain the quality of FMT production as far as practically possible. However, the inherent variability in composition of human faeces between donors and within the same donor over time prevents true consistency and reproducibility control across FMT batches, as would be expected for the production of a drug-based medicinal product. In addition there is currently an absence of accepted profiling standards to quality assure donated faeces. Although it has been shown that higher bacterial diversity in donor faeces is associated with improved FMT clinical outcomes, the precise mechanisms of action of FMT are not fully understood, which limits the adoption of quality assurance testing during production. The selection of infectious agents screened for during FMT donor assessment varies between institutions [
] and until recently has not been expressly specified by regulating agencies, particularly those regulating FMT as a biological drug. However, a general consensus is emerging with the publication of guidelines for FMT production and use [
,
- Mullish B.H.
- Quraishi M.N.
- Segal J.P.
- McCune V.L.
- Baxter M.
- Marsden G.L.
- et al.
]. These guidelines recommend screening for multidrug resistant organisms (MDRO), in particular those producing Extended Spectrum β-lactamases (ESBL) and Carbapenemase producing Enterobacteriaceae (CPE), although other centre’s protocols do not always specify MDRO screening [
]. This topic has become relevant with the recent Food and Drug Administration (FDA) safety alert reporting two immunocompromised patients transplanted from the same donor who became colonised from the FMT with ESBL producing E. coli, with the death of one patient [
]. The FDA has mandated all holders of Investigational New Drug applications for FMT to not only test for ESBL and CPE, but also methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE). The diagnostic methods used to screen for MDROs and other pathogens should be validated and demonstrate acceptable sensitivity and specificity, to ensure the accuracy of donor testing. Although many guidelines specify the pathogens to screen for during donor selection, they often do not address which testing methodology to use. To maintain the quality of results, donor testing should be undertaken by accredited diagnostic laboratories following standard methods, such as those described in the UK Standards for Microbiological Investigation. In our own service, the donor screening algorithm continues to develop dynamically. For example to improve the diagnostic sensitivity of testing for enteric pathogens, culture methods will be replaced with Polymerase Chain Reaction (PCR) based tests. This will also enable the detection of pathogens not previously screened for such as all Shiga toxin producing E. coli (STEC) and rotavirus. The repertoire of screening tests for FMT to be given to immunocompromised patients has been discussed [
,
- Mullish B.H.
- Quraishi M.N.
- Segal J.P.
- McCune V.L.
- Baxter M.
- Marsden G.L.
- et al.
]. The groups concluded that caution should be exercised and the use of Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) negative donors should be considered for seronegative recipients, the role of other potential pathogens being considered on a case by case basis. This is an evolving area with a need for research, particularly with the potential use of FMT in patients post bone marrow transplantation.
,
]. Since the introduction of the revised regulatory position, FMT availability has been limited to intra-institution supply only. The systems described here now enable frozen FMT supply across institutions within a Specials licence, the first service of its kind in the UK. It is notable that encapsulation methods had been described for FMT administration and shown to be non-inferior to liquid FMT delivered via colonoscopy for the treatment of recurrent CDI [
]. The procedures and control measures that have been described here could be applicable to FMT banks preparing liquid or encapsulated FMT to medical product standards in other parts of the world.
]. A move towards FMT stool banks, where FMT is produced to GMP standards under a Specials licence will reduce costs through economy of scale and promote standardisation, safety and quality [
,
]. This approach will also widen access of treatment and reduce inequity of access in the NHS. However, to ensure the resilience of FMT services in the NHS steps need to be taken to develop a networked hub and spoke model of supply under appropriate licencing. Careful management of such a network would enable efficient use of resources across the NHS, while maintaining flexible and adaptable access to this life saving treatment. This will require further engagement with the MHRA to develop this unique regulatory framework appropriately.
Author contributionsVM, PH and MQ had full access to all of the study data and take full responsibility for data analysis. VM and PH were responsible for drafting the manuscript. MQ completed the statistical analysis. VM, SM, PH, TI, and CM planned and delivered the FMT service. CM, TI, MQ, DM, KB, GT and HS oversaw the clinical management of patients. VM, SM, DM, KB, GT, TI, MQ and HS contributed to the data collection. All authors critically revised the manuscript.