Faecal microbiota transplant for recurrent Clostridioides difficile infection

The randomised controlled trial (RCT) evidence showed that faecal microbiota transplant (FMT) after pretreatment antibiotics was significantly better at resolving a recurrent Clostridioides difficile infection than vancomycin in 4 RCTs, and better than fidaxomicin in 1 RCT. Only 1 RCT found no statistical difference in the efficacy of FMT compared with antibiotics. The committee acknowledged that there are limitations to the evidence base. However, it considered that, because there is an unmet need in this population, FMT is likely to be an effective alternative to continued antibiotic use. It also acknowledged that FMT is already being used in the NHS for recurrent C. difficile infections and is recommended in NICE's guideline on antimicrobial prescribing for C. difficile infection. Therefore, the committee agreed that FMT should be recommended to treat a recurrent episode of C. difficile infection if people have had 2 or more previous episodes.

The external assessment centre (EAC) did not identify any in-scope RCTs comparing FMT with antibiotics for refractory C. difficile infections. The clinical experts said that there is no consensus on the definition of refractory C. difficile infection, meaning that there is less available evidence. The committee acknowledged that FMT could benefit this population, but there was too much uncertainty about the definition of a refractory infection to make a recommendation in this population.

The clinical evidence presented showed that FMT given via enema is likely to be less effective than the other administration routes evaluated. However, the included studies were not designed to compare FMT administration routes with each other. Clinical experts said that FMT is usually done by NGT or colonoscopy, depending on patient preference and suitability of the procedure. They said that enema would only be an option for people who could not have FMT via other routes, and would be based on discussions with the patient. They said that the challenge of administering FMT via enema is around the FMT sample being retained for long enough for the treatment to be successful. The EAC's economic model showed that FMT via enema was less likely to be a cost saving route of FMT administration and could be cost incurring in some instances, as discussed in section 4.10. The committee concluded that, although enema may be a less effective route of administration, it could be available as an option for the minority of people who cannot have FMT by another route.

The EAC did not identify any RCTs comparing FMT given in oral capsules with antibiotics in people who have had 2 or more previous episodes of C. difficile infection. As a result, no evidence was presented for the clinical efficacy of oral capsules. However, the EAC did identify 2 studies for its economic evaluation (1 RCT and 1 systematic review and meta-analysis), which showed that oral capsules were comparable to FMT via colonoscopy. It also said there are 2 ongoing RCTs comparing the oral capsules with antibiotic treatment. Clinical experts said that, if oral capsules were more widely available, they would be preferred because of safety and patient acceptability, especially because newer capsules containing lyophilised FMT material can be given in fewer pills than older versions. The committee acknowledged that, although the comparative evidence presented was limited, oral capsules are a promising option for FMT treatment.

The British Society of Gastroenterology and Healthcare Infection Society guidelines say that donor screening should be done for all potential stool donors. This includes a questionnaire and personal interview, to establish risk factors for transmissible diseases and factors that could affect the gut microbiome. Blood and stool screening for transmissible disease must also be done. Clinical experts said that only a small proportion of donors pass screening, and they are generally young and healthy adults. The committee acknowledged that there is still a risk of disease transmission because screening tests are not 100% sensitive. However, it acknowledged that the strict donor screen programme currently used makes FMT relatively safe. The committee also acknowledged that there is a lack of long-term safety data on FMT treatment and thought that a registry to collect this information would be appropriate. It also recognised that NICE's interventional procedures guidance on FMT for recurrent C. difficile infection has reviewed the safety of FMT and concluded that there is adequate evidence to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.

Patient experts said that recurrent C. difficile infections reduce quality of life. Pain and diarrhoea mean people can need help with day to day living and may not be able to work, so lose income. Diarrhoea can also affect people's dignity, especially when it leads to incontinence or when the person is in a hospital or nursing home. The patient experts said patients and clinicians need to be made more aware that FMT is a treatment option for recurrent C. difficile infection. The committee also acknowledged there should be shared decision making with people with the condition, to help them understand their treatment options and the role of FMT in the treatment pathway.

The committee acknowledged that FMT may not be appropriate for some people with an anaphylactic food allergy. It also recognised that the diet and alcohol consumption of potential donors may be a barrier to having FMT for people from some faith groups or people with dietary preferences. The clinical experts said they had not experienced problems relating to religious beliefs but acknowledged that this is a valid consideration. The committee also acknowledged that there are some people who FMT treatment may not be appropriate for, or who will need treating with additional caution, such as people who are immunosuppressed or immunocompromised and people who are pregnant.

The base case showed that FMT is likely to be cost saving by at least £3,300 per person, compared with antibiotics. The committee acknowledged that the clinical evidence was very heterogeneous. But the cost savings were robust enough to recommend FMT for recurrent C. difficile infections for people who have had 2 or more previous episodes.

After feedback from clinical experts, the EAC updated the original base case to amend 4 assumptions. This is because clinical experts said that a short course of antibiotics is used before most FMT treatments and that the length of stay for treatment with FMT or antibiotics is likely to be short. They also said that not everyone in the antibiotic group would need hospitalisation for treatment. The unit cost in the EAC's original base case also did not take into account additional costs associated with sample transportation and of maintaining a Medicines and Healthcare products Regulatory Agency (MHRA) licence. The amended base case includes:

• the unit cost of FMT being £1,300 per 50 ml (£2,600 for 150 ml)

• a 1‑day hospital stay for all groups

• pretreatment with antibiotics for all FMT rounds

• 25% of people having antibiotic treatment being treated in the community (calculated as the cost of 2 GP appointments and a microbiology stool test, in addition to the antibiotics).

Almost all routes of FMT remained cost saving against all 3 comparators considered, with cost savings ranging from £769 (FMT via colonoscopy compared with VTP) to £8,297 (FMT via oral capsule compared with vancomycin). The exception was FMT via enema, which was cost incurring compared with VTP by £1,287 per person. Threshold analysis found that FMT remained cost saving compared with VTP until the unit cost of FMT is approximately £1,650 to £4,620 (FMT via colonoscopy and oral capsules, respectively). For FMT via enema compared with VTP, the unit cost would have to be reduced to £640 for FMT to be cost neutral. The EAC also did a threshold analysis of the proportion treated in hospital in the comparator arm, in which FMT was compared with VTP. FMT remained cost saving until the proportion treated in hospital was between 14% and 92% (FMT via oral capsule and enema, respectively). The committee concluded that FMT was highly likely to be cost saving even when the cost changes are taken into account.

The committee recognised that there is not much data on the long-term outcomes of FMT treatment and encouraged establishing a registry to collect them. This would help identify long-term adverse events and reduce uncertainty in the economic modelling. The committee also acknowledged that more RCT evidence comparing capsulised FMT with antibiotic treatment would improve the evidence base for this treatment.