Reimbursement Review

Fecal Microbiota (Rebyota)

Sponsor: Ferring Canada Inc.

Therapeutic area: Clostridioides difficile infection, prevention

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

CDI = Clostridioides difficile infection; NOC = Notice of Compliance.

Introduction

Clostridioides difficile infection (CDI) is a spore-forming, toxin-producing, Gram-positive anaerobe that colonizes the gut, frequently in association with antibiotic therapy.¹ Its hallmark symptom is profuse watery diarrhea (≥ 3 loose stools in 24 hours), although severity ranges from mild diarrhea to fulminant colitis with systemic toxicity and shock.² CDI is a leading cause of health care–associated diarrhea, contributing to significant morbidity and mortality.³ Recurrent CDI (rCDI) occurs when symptoms return, often 2 to 8 weeks after treatment, and affects up to 25% of patients within 30 days.¹ Diagnosis is based on clinical presentation and stool testing.⁴ CDI has a significant impact on health-related quality of life (HRQoL), and affects physical, mental, social, and professional functioning.⁵ Patients report symptoms like fatigue; weight loss; abdominal pain; and frequent, urgent bathroom use; alongside psychological distress, which includes anxiety, depression, and social isolation.⁶

Based on prevalence estimates from Levy et al.,⁷ the projected number of CDI cases in Canada in 2024 was approximately 47,000. In 2021, health care–associated CDI (i.e., CDI that has been acquired in a health care facility) rates were 3.54 infections per 10,000 patient days in Canada.^8,9 CDI severity increases with age, as seen in a 2002 Quebec outbreak in which infection rates were 10 times higher in patients aged 65 years or older than in younger patients. CDI is associated with a substantial increase in the risk of mortality, with reported 30-day, all-cause mortality rates that range from 6.1% in Germany to 11.4% in the US.^10-15 In Canada, the mortality rate within 30 days of a CDI diagnosis in 2021 was 2.3 per 100 cases.⁸

The Health Canada–approved indication for fecal microbiota (Rebyota) is for the prevention of a recurrence of CDI in adults after antibiotic treatment for rCDI, which is in line with the sponsor’s reimbursement request. Of note, the sponsor requests reimbursement to prevent rCDI as early as the first recurrence. The recommended dose of fecal microbiota (Rebyota) is 1 single dose of 150 mL microbiota suspension administered by rectal administration. Additional treatment may be administered in the event of CDI recurrence.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of the fecal microbiota (Rebyota) 150 mL rectal suspension for the prevention of a recurrence of CDI in adults after antibiotic treatment for rCDI.

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups that responded to the Canada's Drug Agency (CDA-AMC) call for input and from clinical experts consulted for the purpose of this review.

Patient Input

Patient input was submitted by the Gastrointestinal Society, the Peggy Lillis Foundation, and the Canadian Digestive Health Foundation for this review, with data gathered from patient questionnaires, interviews, social media posts, emails, and personal stories. The total number of patients who contributed to the input was not reported. According to the input, CDI is a debilitating condition characterized primarily by severe diarrhea, often accompanied by symptoms like dehydration, fever, abdominal pain, and fatigue. It can lead to life-threatening complications, including recurrent infections, sepsis, and, in extreme cases, the need for colon removal. Certain populations, such as those aged 65 years or older or individuals on prolonged antibiotics, are at higher risk. The input noted that with the chronic nature and high recurrence rate, the impact of CDI extends beyond physical symptoms, profoundly affecting patients’ mental health, with feelings of shame, anxiety, and even post-traumatic stress disorder. The condition disrupts daily life, requiring isolation to prevent transmission and placing significant burdens on patients and caregivers, and their ability to work or socialize.

The patient input stated that current treatments for CDI include antibiotics like vancomycin, metronidazole, and fidaxomicin. However, metronidazole has limited effectiveness for patients with severe CDI and has significant side effects. Despite the availability of these drugs, they can destabilize gut microbiota, contributing to the cycle of recurrence, according to the input. The input also stated that probiotics and prebiotics may be helpful in improving the balance of the microbiome, but current research has not yet provided evidence of their benefit in CDI management. As such, there is a need for treatments that adequately manage symptoms, are curative, and prevent CDI recurrence, the input noted.

Patients who had experience with the treatment under review reported significant benefits, citing ease of access, minimal side effects, and effective relief from rCDI. Many expressed the wish that it had been offered earlier in their treatment journey. Among the respondents who contributed to the input, fecal microbiota (Rebyota) was preferred over vancomycin because of its simpler administration — it is delivered once via enema or colonoscopy without the need for bowel preparation — and its ability to address microbiome dysbiosis, reducing vulnerability to future recurrences. Patients highlighted its simplicity and efficiency; the procedure takes about 30 minutes and causes only minor side effects, such as slight cramping.

Clinician Input

Input From Clinical Experts Consulted for This Review

The information in this section is based on input received from a panel of 3 clinical specialists consulted by CDA-AMC for the purpose of this review.

The clinical experts highlighted the need for accessible, effective, and well-tolerated therapies to prevent rCDI in patients who have a multirecurrent condition, despite appropriate antibiotic treatment, and in whose quality of life is substantially impacted by the condition. As such, the clinical experts recommended the use of fecal microbiota (Rebyota) in patients who have experienced at least 2 recurrences, at least 1 of which occurred despite a prolonged vancomycin taper or pulse regimen. In patients who experience a first recurrence, the condition may improve spontaneously. However, the natural disease trajectory becomes more complex in patients who have experienced at least 2 recurrences, and the risk of further recurrences becomes incrementally higher. Fecal microbiota (Rebyota) will likely be used in clinical practice in patients who have concomitant inflammatory bowel disease (IBD) or immunocompromising conditions, despite the fact that these patients have been underrepresented in fecal microbiota (Rebyota) studies, according to the clinical experts.

Fecal microbiota (Rebyota) is very similar to the product that is being administered through conventional fecal microbiota transplant (FMT), the clinical experts noted. However, fecal microbiota (Rebyota) relies on a single administration, whereas FMT programs routinely offer repeated doses over 1 week. The clinical experts indicated that although FMT is effective at preventing rCDI, it is not readily available to many patients in Canada. Issues surrounding limited access to FMT include the lack of public or private funding, the infrastructures and level of expertise required to run an FMT program, and challenges related to the establishment and maintenance of stool banks for FMT. Fecal microbiota (Rebyota) would be regulated in terms of stability, reliability, and quality standards, and it is expected to remove the onus of managing stool banks from FMT providers. As such, the commercial version of fecal microbiota (Rebyota) could potentially increase access to treatment in Canada, which the clinical experts viewed as an acceptable trade-off, despite the single administration. In addition, the clinical experts made the CDA-AMC clinical review team aware of the possibility that conventional FMT programs could be shut down by Health Canada when a commercial product becomes available. Health Canada notified CDA-AMC that clinicians have been advised that, although fecal microbiota (Rebyota) has been authorized, it is not yet marketed. Therefore, no changes will be made to the current interim policy outlined in the guidance document Fecal Microbiota Therapy Used in the Treatment of Clostridioides difficile Infection Not Responsive to Conventional Therapies. Once fecal microbiota (Rebyota) becomes marketed, Health Canada will explore options for transitioning away from the interim policy, with further details to be provided in due course.

The experts indicated that the increased availability of fecal microbiota (Rebyota) may cause a shift in the current treatment paradigm, as long as health care systems can provide the funding, infrastructures, and resources related to administration of the product.

The clinical experts suggested that prescribing and treatment administration of fecal microbiota (Rebyota) should be limited to clinicians and health care teams with expertise in the management of patients with rCDI and, ideally, in providing FMT, which would optimize the selection of patients who may benefit the most from treatment with fecal microbiota (Rebyota). In addition, the experts emphasized that both fecal microbiota (Rebyota) and conventional FMT are not risk-free and require a thorough informed consent process, as is the standard of care (SOC) for any intervention. The clinical experts highlighted the importance of follow-up after fecal microbiota (Rebyota) administration. Experience from clinical practice suggests that symptoms at 1 month are most predictive of long-term prognosis. The experts do not expect that all patients will go back to their pre-CDI baseline bowel habits; the goal is to reduce symptoms to a reasonable level and achieve a better quality of life while avoiding chronic antibiotic use.

Clinician Group Input

One clinician group, the Canadian Antimicrobial Resistance Alliance, provided input for this review. The input stated that fecal microbiota (Rebyota) demonstrates efficacy and safety in patients with rCDI infection and offers a first-in-class live therapeutic option. The input noted that fecal microbiota (Rebyota) will improve antimicrobial stewardship because it reduces reliance on prolonged courses of vancomycin or fidaxomicin. The treatment under review would be most appropriate for patients who have experienced at least 2 CDI recurrences, particularly those in high-risk groups, such as hospitalized patients, older adults, patients with severe disease, and those with immunocompromised conditions, the input stated.

Drug Program Input

The drug programs provide input on each drug being reviewed through CDA-AMC reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. For this review, the drug plans provided questions pertaining mainly to considerations for the initiation and prescribing of therapy. These questions were addressed by the clinical experts consulted for this review, and their responses are provided in Table 3.

Clinical Evidence

Systematic Review

Description of Studies

The 1 study reviewed — the PUNCH CD3 study (n = 289) — was a phase III, multicentre, double-blind (DB), placebo-controlled, randomized trial designed to evaluate the efficacy and safety of fecal microbiota (Rebyota) in the prevention of recurrence of CDI in adult patients after antibiotic treatment for rCDI. Patients could enter the trial if they had at least 1 recurrence after a primary episode and had received at least 1 round of oral antibiotic therapy. Fecal microbiota (Rebyota) was administered as 1 single-dose enema.

The primary outcome was the recurrence of CDI over 8 weeks, which was defined as the presence of CDI diarrhea, with a stool test positive for the presence of C. difficile toxin in the 8 weeks after administration of the study enema. The primary efficacy analysis was performed using a Bayesian hierarchical model, which formally incorporated data on the treatment effect of fecal microbiota (Rebyota) from the randomized, placebo-controlled, phase IIb PUNCH CD2 study. To account for potential heterogeneity between populations in the 2 trials, a dynamic borrowing approach was used. This method allowed for data to be borrowed from the previous trial when response rates were similar.

A sustained clinical response at 6 months in patients who had previously achieved treatment success at 8 weeks was assessed as the secondary end point in the study. HRQoL was an exploratory outcome in the studies and was assessed using the C. difficile Health-Related Quality-of-Life Questionnaire (Cdiff32) Questionnaire, a validated, disease-specific assessment tool that indicates how a person is affected by CDI-related physical, mental, and social health concerns. The total and domain scores of the Cdiff32 Questionnaire range from 0 to 100, and lower scores denote a greater negative impact on quality of life. A minimal clinically important difference (MCID) of 10 points, using a distribution-based approach, has been suggested in the literature.

Efficacy Results

Response to Treatment at 8 Weeks

For the primary outcome, the mean success rate was 70.4% in the fecal microbiota (Rebyota) group and 58.1% in the placebo group. The between-group difference in mean success rate was 12.3% (95% credible interval [CrI, 1.4% to 23.3%), based on posterior estimates from the Bayesian hierarchical model.

The between-group difference for treatment success was 5.4% (95% confidence interval [CI], −9.4% to 20.2%; █████████) in patients who had no more than 3 prior CDI episodes (or 2 CDI recurrences) and 16.1% (95% CI; −5.4% to 37.7%; █████████) in patients who had more than 3 prior CDI episodes (or more than 2 CDI recurrences). In patients who received vancomycin alone, the between-group difference was 1.9% (95% CI; −20.3% to 24.0%; █████████) in patients who were treated for no more than 14 days and 12.8% (95% CI; −3.5% to 29.1%; █████████) in patients who were treated for more than 14 days.

Among patients who achieved treatment success at 8 weeks after treatment with fecal microbiota (Rebyota), the increase in the proportion of patients with a sustained clinical response at 6 months, compared to placebo, may not be clinically important, based on a between-group difference of 1.5% ████ ███ ████ ██ █████ █████████.

Health-Related Quality of Life

HRQoL was assessed as an exploratory outcome. HRQoL was not tested statistically and the results are considered to be supportive evidence. Results suggest that treatment with fecal microbiota (Rebyota) may result in little to no difference in the change from baseline in HRQoL, measured with the Cdiff32 Questionnaire, over 8 weeks, compared to placebo. The mean between-group difference in change from baseline at 8 weeks in Cdiff32 Questionnaire score was 5.71 ████ ███ █████ ██ ██████.

The sponsor provided an additional exploratory analysis of HRQoL data in patients who were deemed responders at 8 weeks. In both the main study population and the responder patients, the between-group differences reported in overall Cdiff32 Questionnaire scores crossed the null and were modest, especially relative to the large within-group improvements seen in both patients receiving fecal microbiota (Rebyota) and those receiving placebo. Although statistical significance was achieved for the mental domain summary in responder patients, these domain-level results are from exploratory analyses without multiplicity adjustment and from restricted responder subsets, increasing the risk of chance findings. In addition, limited details were provided for proper appraisal of the findings; this precluded formal assessments of the magnitude of effect and clinical relevance.

Stool Testing: Fecal Microbial Composition

Fecal sequencing analysis suggests that the microbiome composition of patients who experienced treatment success changed from baseline at all time points (P < 0.001 for within-group change from baseline using the generalized Wald test). The change in microbiome composition after treatment was characterized by an increase in Bacteroidia-class bacteria and Clostridia-class bacteria and a decrease in Gammaproteobacteria-class bacteria and Bacilli-class bacteria.

Health Care Resource Use

Hospitalizations and intensive care unit (ICU) admissions were reported as harms outcomes for patients who were randomized to active treatment with fecal microbiota (Rebyota), but ██ ██████ was reported for patients who were randomized to placebo. In the PUNCH CD3 study, a total of ██ patients in the fecal microbiota (Rebyota) group required hospitalization for rCDI during the 8-week follow-up after blinded treatment, as did ██ patients during the 8-week follow-up after open-label (OL) enema. A total of 2 patients in the fecal microbiota (Rebyota) group required ICU admission during the 8-week follow-up after blinded treatment. No patient experienced major complications of CDI after OL enema in this treatment group.

Harms Results

A relatively high proportion of patients receiving fecal microbiota (Rebyota) in the PUNCH CD3 study (70%) experienced at least 1 adverse event (AE), compared with 60% in the placebo group. AEs were numerically more frequent in patients who received 2 fecal microbiota (Rebyota) enemas █████ than in those who received only 1 fecal microbiota (Rebyota) enema ███. The most common treatment-emergent adverse events (TEAEs) were related to gastrointestinal disorders, and included diarrhea, abdominal pain, nausea, and abdominal distention.

Serious adverse events (SAEs) were relatively uncommon in patients receiving a fecal microbiota (Rebyota) enema (8%) or placebo (7%), but they were also numerically more frequent in patients who received 2 fecal microbiota (Rebyota) enemas ████ than in patients who received only 1 fecal microbiota (Rebyota) enema ████. Two deaths were reported during the trial in patients who received fecal microbiota (Rebyota), but they were not related to the study drug or the enema procedure, according to the sponsor. The sponsor reported no events of toxic megacolon or colonic perforation; however, 1 patient in the fecal microbiota (Rebyota) group experienced septic shock and underwent an emergency colectomy to deal with major complications of a new CDI.

Overall, the clinical experts indicated that the harms profile of fecal microbiota (Rebyota) did not raise any new safety signals or any particular safety concerns. As with most clinical trials, the study was not powered to detect infrequent AEs or designed to detect those with a lag time. The clinical experts indicated that there may be long-term, unintended effects related to the manipulation of a patient’s microbiome, such as the risk of developing a range of conditions over time; the impact of this is currently unknown.

Critical Appraisal

Although the randomization methods were appropriate for reducing the risk of bias in the randomization process, more patients in the fecal microbiota group than in the placebo group had experienced 2 or more CDI recurrences. This could have introduced a possible risk of bias of uncertain direction or magnitude, but it may have directionally favoured placebo.

Because patients who experienced treatment failure at 8 weeks could receive OL fecal microbiota (Rebyota), the interpretation of end points tested beyond 8 weeks is challenged by the fact that a proportion of patients in the placebo group received fecal microbiota (Rebyota).

There is uncertainty surrounding the interpretation of the findings. Because no MCID was reported in the literature as a threshold for treatment success, the presence of an important effect was informed by the clinical experts consulted for this review. The point estimate (12.3%) suggests the presence of a clinically important effect; however, the lower bound of the CrI (1.4%) is consistent with a trivial effect that would not be considered clinically important for patients. On the Cdiff32 Questionnaire, the magnitude of the findings was not considered clinically meaningful by the clinical experts consulted for this review. The MCID of 10 points estimated in the literature used a distribution-based approach, so it may not fully reflect a change that is important for patients. Further, the MCID was suggested for within-group changes, rather than for between-group differences. In addition, there is a risk of bias because of missing outcome data at 6 months; relatively few patients in both groups were available for HRQoL assessments, and missing data were imputed using the last observation carried forward (LOCF), which relies on assumptions about the trajectory of the end point that may not be plausible.

A sustained clinical response at 6 months was measured in patients with a response at 8 weeks; there is a risk of bias in the measurement of this end point, as it is unclear whether prognostic balance would be maintained in this subpopulation.

Input from clinical experts suggested that findings from the PUNCH CD3 study may be generalizable to patients considered, overall, to be at lower risk for CDI recurrences than patients typically seen in clinical practice, who would have the greatest unmet need and be the best candidates to receive fecal microbiota (Rebyota). This was based on the low number of patients with previous CDI recurrences in the trial, as well as the exclusion of patients with relevant comorbidities. In addition, it is uncertain whether patients previously received an appropriate antibiotic regimen for the treatment of the qualifying CDI episode. The trial could not inform on the effectiveness and safety of fecal microbiota (Rebyota) relative to other currently used therapies for rCDI, such as conventional FMT.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence for outcomes considered most relevant to expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^16,17

In accordance with the GRADE approach, evidence from the PUNCH CD3 study started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The selection of outcomes for GRADE was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• treatment success rate

• sustained clinical response among patients who previously achieved treatment success

• HRQoL (Cdiff32 Questionnaire)

• SAEs.

Table 2 presents the GRADE summary of findings for fecal microbiota (Rebyota) versus placebo.

Table 2: Summary of Findings for Fecal Microbiota (Rebyota) vs. Placebo for Patients With Recurrent CDI

CDI = Clostridium difficile infection; Cdiff32 = C. difficile Health-Related Quality of Life; CI = confidence interval; CrI = credible interval; HRQoL = health-related quality of life; NA = not applicable; NR = not reported; RCT = randomized controlled trial; SAE = serious adverse event; SD = standard deviation; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aTreatment success: Rated down 1 level for imprecision. The presence of an important effect was informed by the clinical expert consulted for this review. The point estimate (12.3%) suggests the presence of a clinically important effect; however, the lower bound of the CrI (1.4%) is consistent with an effect that would not be considered clinically important for patients.

^bSustained clinical response: Rated down 1 level for imprecision. The presence of an important effect was informed by the clinical experts consulted for this review. The point estimate (1.5%) suggests a trivial effect, which would not be considered clinically important for patients; however, the lower bound ███████ and upper bound ███████ of the CrI could be consistent with either a clinically important decrease or increase, respectively, in sustained clinical response.

Rated down 1 level for study limitation. There likely was a loss of prognosis balance in the subpopulation of patients analyzed, as it consisted of patients who previously achieved treatment success at 8 weeks.

^cHRQoL: Rated down 1 level for imprecision. The Cdiff32 Questionnaire was assessed as an exploratory outcome. Change from baseline in Cdiff32 Questionnaire score was not tested statistically in the trial, and should be considered to be supportive evidence. Although the point estimate for the between-group difference suggests little to no clinically important difference, based on a suggested MCID of 10 points, the upper bound of the 95% CI suggests the possibility of a clinically important difference between fecal microbiota (Rebyota) and placebo. The MCID of 10 points suggested in the literature for this instrument is, however, uncertain, because it was estimated using a distribution-based approach. Because distribution-based methods rely on the statistical properties of the data, they may not always reflect clinically meaningful changes from the perspectives of patients. This MCID was also estimated for within-group changes, rather than between-group differences.

^dHRQoL: Rated down 1 level for serious imprecision. Although the point estimate for the between-group difference suggests little to no clinically important difference, based on a suggested MCID of 10 points, the lower bound of the 95% CI suggests a clinically important detriment with fecal microbiota (Rebyota) compared to placebo. The MCID of 10 points suggested in the literature for this instrument is uncertain, as it was estimated using a distribution-based approach. Because distribution-based methods rely on statistical properties of the data, they may not always reflect clinically meaningful changes from the perspectives of patients. In addition, this MCID was estimated for within-group changes, rather than between-group differences.

Rated down 2 levels for very serious study limitations. Few patients completed the 6-month assessments. The last observation carried forward was used to impute missing outcome data, but this approach relies on assumptions about the missing data that are unlikely to be realistic. Further, some patients in the placebo group had received open-label fecal microbiota (Rebyota). The Cdiff32 Questionnaire was assessed as an exploratory outcome. Statistical testing for the Cdiff32 Questionnaire was not adjusted for multiplicity in the trial and should be considered to be supportive evidence.

^eHarms: Rated down 1 level for imprecision because the between-group effect estimate was based on few events, and rated down 1 level for study limitation because some patients in the placebo group received active treatment with open-label fecal microbiota (Rebyota).

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor for this review.

Indirect Comparisons

No indirect treatment comparison were submitted by the sponsor for this review. According to the sponsor, there are no comparators to fecal microbiota (Rebyota) in Canada for the preventive treatment of rCDI after antibiotic treatment for rCDI. In clinical practice, treatment options include long-term vancomycin administered in a taper or pulse regimen and conventional FMT.

Studies Addressing Gaps in the Evidence From the Systematic Review

PUNCH CD2 Study

Description of Study

The PUNCH CD2 study (N = 133) was a phase II, prospective, multicentre, DB, randomized, placebo-controlled trial designed to assess the efficacy and safety of fecal microbiota (Rebyota) for rCDI and to establish a treatment regimen for subsequent confirmation in the PUNCH CD3 study. The PUNCH CD2 study included adults (aged ≥ 18 years) with rCDI who had experienced at least 2 CDI recurrences that required at least 2 rounds of SOC oral antibiotic therapy or who had 2 severe CDI episodes that resulted in hospitalization. Of the 150 patients enrolled, 133 were randomized into 1 of 3 groups: group A (N = 45), group B (N = 44), and group C (N = 44). Patients were randomized in a 1:1:1 ratio to receive 2 fecal microbiota (Rebyota) enemas (group A), 2 doses of placebo (group B), or 1 dose of fecal microbiota (Rebyota) followed by 1 dose of placebo (group C). Doses were administered 7 days apart. If patients experienced a CDI recurrence in the 8 weeks after treatment, they could opt for either SOC treatment or a second OL fecal microbiota (Rebyota) course. This report primarily focuses on group B and group C, which align with Health Canada’s proposed recommended 1-dose fecal microbiota (Rebyota) regimen.

Efficacy and Harms Results

Efficacy results in the intention-to-treat (ITT) population showed that 8 weeks after treatment completion, treatment success rates were 43.2% (19 of 44 patients) in group B and 56.8% (25 of 44 patients) in group C, for a difference of 13.6% (95% CI, █████ ██ █████; P = 0.201). The 25th percentile for time to recurrence, estimated using the Kaplan-Meier method, was 8.0 days in both group B (95% CI, ██ ██ ████) and group C (95% CI, ██ ██ ████). The combined treatment success rate (defined as no C. difficile–associated diarrhea and no need for re-treatment or fecal transplant by day 56 after the last study enema) of all patients in the OL portion was █████ ███████. Additionally, HRQoL was assessed using the 36-Item Short Form Survey (SF-36). Baseline values were comparable between groups, and both treatment groups showed a numerical increase in mean scores for all SF-36 components from baseline to week 8. Between-group differences were not reported. Safety was assessed up to 24 months after treatment. TEAEs occurred in 86.4% of group B and 78.6% of group C. For TEAEs, anemia, nausea, flatulence, hematochezia, pyrexia, pneumonia, falls, and dyspnea were more frequent in group C than in group B. SAEs were reported in 36.4% and 35.7% of patients in group B and group C, respectively, but none were considered to be related to treatment, according to the sponsor. Deaths occurred in ████ (group B) and █████ (group C) of patients, primarily related to pre-existing conditions.

Critical Appraisal

The PUNCH CD2 study provided additional data on CDI recurrence, HRQoL (SF-36), and long-term safety up to 24 months. The primary efficacy analysis (ITT) did not reject the null hypothesis, and secondary comparisons proceeded without alpha adjustment, increasing the risk of false positives in the secondary analysis results. Because of the small sample sizes across groups, there is an increased risk that prognostic balance was not achieved (as evidenced by imbalances across groups by sex and prior hospitalization for CDI). As such, it is possible that the observed effects were either overestimated or underestimated. The study is limited by the lack of placebo control beyond 8 weeks of treatment; as such, results beyond 8 weeks are confounded by OL fecal microbiota (Rebyota) use in the placebo group. In the analysis of SF-36 scores, there is a risk of bias because of missing outcome data. Data were missing for up to 30% of patients across groups at 8 weeks. These data were imputed using the LOCF, a single-imputation method that relies on the assumption that HRQoL remains constant over time after the last available assessment, which is likely not reasonable. Immunocompromised patients were excluded from the PUNCH CD2 study, raising concerns about pathogen transmission. Most patients in the trial (89.8%) used vancomycin, which aligns with clinical practice; fidaxomicin is rarely used to treat rCDI in Canada.

PUNCH CD3 OLS Study

Description of Study

The PUNCH CD3 OLS study (N = 698) was a phase III, prospective, multicentre, OL, single-arm study. The objective of the study was to evaluate the safety, tolerability, and effectiveness of fecal microbiota (Rebyota) as single and repeat administrations in a broader population of patients than in previous trials, which had excluded patients with conditions such as Crohn disease, ulcerative colitis, IBD, irritable bowel syndrome (IBS), and immunodeficiency.

Efficacy Results

Of 676 patients in the primary efficacy analysis, 499 patients (73.8%) achieved treatment success in the 8 weeks after the first dose of fecal microbiota (Rebyota), which was defined the absence of CDI diarrhea during the 8 weeks after the first dose. Similar treatment success rates were observed for most demographic subgroups, including sex, race, ethnic group, site geography, number of prior CDI episodes, and Cdiff32 Questionnaire score; however, the treatment effect appeared to be of smaller magnitude in patients aged 65 years and older.

A total of 151 patients experienced a recurrence of CDI after the first dose and, of these, 121 patients received a second dose of fecal microbiota (Rebyota). Treatment success was then achieved in 67 (55.4%) of those patients.

Among patients who completed the 6-month follow-up, the sustained clinical response rate of fecal microbiota (Rebyota) among patients who previously achieved treatment success was 91.0%.

The mean (standard deviation [SD]) change from screening to 6 months in the Cdiff32 Questionnaire scores was █████ █████████

Harms Results

Of the 697 patients included in the safety population, ███ ███████ patients reported AEs after fecal microbiota (Rebyota) administration. These were mostly mild (20.4%) to moderate ███████ in severity, and the most frequently reported AEs included gastrointestinal disorders and infections.

Critical Appraisal

The single-arm nature of the PUNCH CD3 OLS does not allow for causal conclusions to be drawn regarding the efficacy and safety of fecal microbiota (Rebyota). Having knowledge of the treatment received can introduce bias in the assessment of subjective outcomes. Although the selection criteria allowed for a broader population, the number of patients with Crohn disease, ulcerative colitis, IBD, IBS, or immunodeficiency enrolled in the study was small. Therefore, the generalizability of the findings to patients who have these coexisting comorbidities remains uncertain.

Feuerstadt et al. Study

A retrospective study by Feuerstadt et al. (2023)¹⁹ (N = 94) assessed the effectiveness and safety of fecal microbiota (Rebyota) in adults with rCDI using broad eligibility criteria to reflect real-world conditions, including those with comorbidities such as IBS, IBD, or immunodeficiency. The study enrolled patients in 5 study sites in the US from 2015 to 2019. Patients could receive up to 4 fecal microbiota (Rebyota) enemas (2 treatment courses of 2 doses each), per physician discretion. No lab confirmation of CDI was required, there were no exclusion criteria, and data were retrospectively collected via chart review. The mean age of the patients was 59.8 years, 44.7% were 65 years or older, and 72.3% were female.

Sixty-six of the 94 (70.2%) patients in the full analysis set (FAS) achieved treatment success (defined as no CDI recurrence in the 8 weeks after the final treatment dose for the qualifying event) at week 8, 58 (87.9%) of whom maintained a sustained clinical response for 6 months after treatment. TEAEs occurred in 40 of 64 patients (62.5%) in the primary safety set (PSS), 17.2% of which were deemed to be product-related by the investigators and 4.7% of which were deemed to be procedure-related. Common TEAEs in the PSS included abdominal pain (14.1%), diarrhea (14.1%), and urinary tract infection (10.9%). SAEs occurred in 12.5% of patients; the 1 death (1.6%), due to multiorgan failure, was unrelated to treatment, according to the investigators.

The study included broad eligibility criteria but the noncomparative nature of its design does not allow for causal conclusions to be drawn regarding the efficacy and harms of fecal microbiota (Rebyota). Subjective outcome reporting may be biased and dosing could have exceeded Health Canada’s 1-dose recommendation.

Lee et al. Study

The summary by Lee et al. included pooled safety data from 5 prospective studies, incorporating 3 phase II studies (the PUNCH CD, PUNCH CD2, and PUNCH OL studies) and 2 phase III studies (the PUNCH CD3 and PUNCH CD3 OLS studies). These studies evaluated the cumulative safety of fecal microbiota (Rebyota) using standardized manufacturing practices and evolving pathogen screening to ensure safety.

All 5 trials enrolled adults aged at least 18 years with rCDI who had received antibiotics for their CDI episode before study treatment. Dosing regimens varied, with patients receiving either a single or 2 doses of fecal microbiota (Rebyota) and/or placebo, administered 7 ± 2 days apart. Four trials allowed OL treatment if CDI recurrence was confirmed in the 8 weeks after the initial course. The full population comprised 978 patients who received at least 1 dose of fecal microbiota (Rebyota) and 83 patients who received only placebo. At baseline, the pooled trial data showed that a higher proportion of patients in the fecal microbiota (Rebyota) group were 65 years or older than in the placebo group (48.2% versus 37.3%). Additionally, more patients in the fecal microbiota (Rebyota) group (78.0%), the placebo plus fecal microbiota (Rebyota) group (83.3%), and the fecal microbiota (Rebyota) plus OL fecal microbiota (Rebyota) group (79.6%) had experienced 3 or more CDI episodes before trial entry than those in the placebo group (68.7%).

The primary outcome measured the number of patients who experienced TEAEs related to fecal microbiota (Rebyota) and/or to the administration procedure; TEAEs were defined as AEs occurring on or after the day of treatment. The most common TEAEs were gastrointestinal disorders, and most were mild or moderate in severity. Serious TEAEs were similar in the placebo (60.2%) and fecal microbiota (Rebyota) 1-dose (66.4%) groups, but higher in blinded or any fecal microbiota (Rebyota) groups (68.8%). Eighteen deaths were reported, all in patients who received fecal microbiota (Rebyota); however, none were considered to be related to the treatment.

Limitations included heterogeneity in study protocols, varied dosing regimens, and differences in patient populations, which affected internal validity. OL treatments could introduce bias in the reporting of subjective AEs. Pooling data from multiple trials may obscure specific interactions or effects, impacting safety outcome interpretations.

Khanna et al. Study

The sponsor provided additional data from a retrospective cohort study by Khanna et al. (2025).²⁰ In this study of 196 adults in the US with rCDI who received fecal microbiota (Rebyota) between July 2023 and August 2024, the overall treatment success rate at 8 weeks was 83%. In the overall population, most patients (n = 136) had at least 3 prior CDI recurrences. Success rates were consistent across subgroups of patients categorized by the number of prior recurrences. The study, however, had important limitations. Baseline patient characteristics were limited; no detailed information was provided on the exact number of prior CDI episodes, comorbidities, or the antibiotic regimen used (other than product name), preventing assessment of the impact of the characteristics on outcomes. The analyses did not adjust for confounding factors, lacked a control arm, and could have been subject to selection bias because of its nonrandomized design. Differences in health care access and the predominance of treatment administration in infusion centres in the southern and western US may further limit the generalizability of the findings. As such, the results should be considered to be supportive evidence.

Conclusions

In patients with rCDI, findings of moderate certainty from the PUNCH CD3 study suggest that treatment with fecal microbiota (Rebyota) likely results in a clinically important increase in the treatment success rate over 8 weeks compared to placebo. Findings were obtained in a population of patients who were, however, at a lower risk of experiencing CDI recurrences than those who have the greatest unmet need and who would benefit the most from treatment with fecal microbiota (Rebyota), according to the clinical experts. This population in need would include patients who experienced at least 2 recurrences despite an appropriate antibiotic treatment that consisted of a vancomycin taper or pulse regimen. Findings from supplementary, prespecified subgroup analyses created uncertainty as to whether the overall effect can be generalized to patients with fewer than 2 recurrences or who received vancomycin for 14 days or less. Although the generalizability of the study population to patients who would be candidates for fecal microbiota (Rebyota) in clinical practice is uncertain, it appears plausible that the benefits of treatment could be maintained in a population at higher risk of recurrence. Most patients who previously achieved treatment success at 8 weeks with either fecal microbiota (Rebyota) or placebo were able to maintain a sustained clinical response at 6 months; therefore, fecal microbiota (Rebyota) may be no more beneficial for maintaining response over time than placebo. Based on results from exploratory analyses, fecal microbiota (Rebyota) may result in little to no difference in HRQoL, measured with the Cdiff32 Questionnaire, over 8 weeks compared to placebo. HRQoL results at 6 months were too uncertain to draw a definite conclusion. In addition, the evidence was insufficient to draw any conclusions about the effect of fecal microbiota (Rebyota) relative to placebo on hospitalizations or ICU admissions.

A relatively high proportion of patients in the PUNCH CD3 study experienced AEs, most notably relating to gastrointestinal disorders. AEs were numerically more frequent in patients who received 2 doses of fecal microbiota (Rebyota) than in patients who received only 1 fecal microbiota (Rebyota) enema, and were also numerically more frequent than in patients who received placebo. However, fecal microbiota (Rebyota) appeared to be well tolerated, with relatively few SAEs. The clinical experts noted that although treatment with fecal microbiota (Rebyota) is not without risks, the overall harms profile did not raise any particular safety signals. However, the long-term, unintended effects of manipulating a patient’s microbiome are currently unknown.

The trial could not inform on the effectiveness and safety of fecal microbiota (Rebyota) relative to other currently used therapies for rCDI, such as conventional, multidose FMT. Whether patients in the 2 groups previously received an appropriate antibiotic regimen of vancomycin taper or pulse for the treatment of the qualifying CDI episode is unknown. The relevance of using placebo as a comparator is therefore uncertain, as the CDI treatment in the study was not consistent with recommendations from the Canadian guidelines or with the treatment that patients would receive in clinical practice. Four additional studies were assessed in the fecal microbiota (Rebyota) review, but could not inform on important gaps in the evidence.

The clinical experts indicated that although effective, FMT is an intervention with limited access and, therefore, it is not readily available to many patients in Canada. A commercial, regulated stool-derived product such as fecal microbiota (Rebyota) can potentially increase access to treatment, which was viewed by the clinical experts as an appropriate trade-off to its single administration. The experts indicated that fecal microbiota (Rebyota) may, therefore, cause a shift in the current treatment paradigm, as long as the health care systems can provide the infrastructures and resources to address prescribing considerations and administration of the product.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of the rectal administration of fecal microbiota (Rebyota), 150 mL, in the prevention of CDI recurrence in adult patients after antibiotic treatment for rCDI.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

CDI is a spore-forming, toxin-producing, and Gram-positive anaerobic bacterium that typically colonizes the human intestinal tract after the normal gut flora has been disrupted, frequently in association with antibiotic therapy.¹ Profuse watery diarrhea, characterized by 3 or more loose stools in 24 hours, is the hallmark symptom of CDI.² However, patients can experience a range of symptoms, from mild diarrhea to severe disease or fulminant colitis, which includes significant systemic toxic effects and shock.² CDI is a leading infectious cause of health care–associated diarrhea and a major cause of morbidity and mortality among hospitalized patients.³ Recurrent СDІ is characterized by the return of symptoms, often 2 to 8 weeks after they have resolved with appropriate treatment. Up to 25% of patients experience recurrent CDΙ in the 30 days after treatment.¹ The diagnosis of CDI relies on clinical presentation and is confirmed with stool testing.⁴

CDI has a significant impact on patients' HRQoL, affecting physical, mental, social, and professional functioning both during infection and after infection resolution.⁵ Patients have reported symptoms such as disturbed sleep, fatigue, weight loss, appetite loss, abdominal pain, and frequent, urgent bathroom use, along with unpleasant odours. Beyond these physical effects, CDI and the fear of recurrence can have a profound mental impact, with patients experiencing anxiety, depression, isolation, stress, anger, and embarrassment related to the loss of bowel control.⁶

In Canada, health care–associated CDI rates (CDI that has been acquired in a health care facility) were 3.54 infections per 10,000 patient days in 2021.^8,9 CDI is also a concern in community settings, with approximately 25% of CDI cases being community-acquired, but this rate is potentially underestimated in the literature.^6,21-27 Using the estimates from the study by Levy et al.,⁷ the sponsor estimates that the prevalence of CDI in Canada in 2024 was approximately 47,000 cases. CDI frequency and severity increase with age, as demonstrated by a 2002 Quebec outbreak in which the rate of CDI among patients aged 65 years or older was 10 times higher than that observed in younger patients.²⁸ CDI significantly increases the risk of mortality, with 30-day all-cause mortality rates ranging from 6.1% to 11.4% across various countries.^10-15 In Canada, the Canadian Antimicrobial Resistance Surveillance System monitors attributable mortality using surveillance data from select hospitals. The overall mortality rate in the 30 days after diagnosis in 2021 was 2.3 per 100 cases.⁸

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

The clinical experts indicated that most patients with a first CDI episode will respond to antibiotic treatment with vancomycin or fidaxomicin, and noted that rCDI will occur in approximately 15% of patients. Patients who experience a first recurrence may have their condition improve spontaneously after treatment with oral vancomycin or fidaxomicin. However, the natural disease trajectory becomes more complex in patients who have experienced at least 2 recurrences, and the risk of experiencing further recurrences becomes incrementally higher. According to the Association of Medical Microbiology and Infectious Disease Canadian guidelines,²⁷ a 10-day to 14-day vancomycin regimen is considered the treatment of choice for a first recurrence of CDI, whereas a prolonged vancomycin taper or pulse regimen (in which the dose is gradually decreased [tapered] and/or given intermittently [pulse]) is recommended for the treatment of a second recurrence of CDI.²⁷ Although antibiotic therapy is targeted at the infection itself, it also negatively impacts the gut microbiome. Therefore, the Association of Medical Microbiology and Infectious Disease guidelines²⁷ recommend FMT as a treatment option for subsequent recurrences after a vancomycin taper. FMT is expected to address the underlying disease process by repopulating and restoring the composition and diversity of the gut microbiome.

The main goal of treatment is to achieve a complete and sustained clinical response. Not all patients are expected to return to their pre-CDI baseline bowel habits, according to the clinical experts; the goal is to reduce symptoms to a reasonable level and achieve a better quality of life. Measures can be taken to reduce the risk of subsequent CDI, including avoiding unnecessary antibiotics, reducing immunosuppression when relevant, and preventing reinfection from ambient spores in the home environment.

Drug Under Review

The mechanism of action for fecal microbiota (Rebyota) is believed to involve repopulation and restoration of the composition and diversity of the gut microbiome to suppress C. difficile outgrowth and CDI recurrence.²⁹ The Health Canada–approved indication is for the prevention of recurrence of CDI in adults after antibiotic treatment for rCDI that is in line with the sponsor’s reimbursement request. Of note, the sponsor requests reimbursement to prevent rCDI as early as the first recurrence.

The recommended dose of fecal microbiota (Rebyota) is 1 single dose of 150 mL of microbiota suspension by rectal administration. Additional treatment may be administered in the event of a CDI recurrence.²⁹ It is recommended that the treatment be administered from 24 hours to approximately 72 hours after the last dose of antibiotics. It should not be administered during antibiotic treatment for CDI. Patients should not take any oral antibiotic therapy for up to 8 weeks after administration of fecal microbiota (Rebyota) unless directed by their physician.²⁹

FMT is the only preventive option for rCDI after antibiotic treatment; however, it is not an approved treatment by Health Canada. Health Canada issued interim guidance for FMT that classified it as a biologic drug.³⁰ Its use across Canada is highly heterogenous, with limited access, and it requires significant time from specialists.³¹

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

Patient input was submitted by the Gastrointestinal Society, the Peggy Lillis Foundation, and the Canadian Digestive Health Foundation for this review. Input from the Gastrointestinal Society was gathered mainly from patient questionnaires and interviews, whereas input from the Peggy Lillis Foundation and Canadian Digestive Health Foundation was collected via emails from patients, social media posts, and personal patient stories. The total number of patients who contributed to the input was not reported. According to the input, CDI is a debilitating condition characterized primarily by severe diarrhea, and often accompanied by symptoms like dehydration, fever, abdominal pain, and fatigue. It can lead to life-threatening complications, including recurrent infections, sepsis, and, in extreme cases, the need for colon removal. Certain patients, such as those aged 65 years or older or individuals on prolonged antibiotics, are at higher risk. The input noted that with the chronic nature and high recurrence rate of CDI, the impact extends beyond physical symptoms, profoundly affecting patients’ mental health, with feelings of shame, anxiety, and even post-traumatic stress disorder. The condition disrupts daily life, requiring isolation to prevent transmission and placing significant burdens on patients, caregivers, and their ability to work or socialize.

The patient input stated that current treatments for CDI include antibiotics like vancomycin, metronidazole, and fidaxomicin. However, metronidazole has limited effectiveness for severe cases and has significant side effects. Despite the availability of drugs, the input noted that such treatments can destabilize gut microbiota, contributing to the cycle of recurrence. The input stated that probiotics and prebiotics may be helpful in improving the balance of the microbiome, but current research has not yet provided evidence of their benefit in CDI management. As such, the input noted, there is a need for treatments that adequately manage symptoms, are curative, and prevent CDI recurrence.

Patients who had experience with the treatment under review reported significant benefits, citing ease of access, minimal side effects, and effective relief from rCDI. Many wish it were offered earlier in their treatment journey. Among the respondents, fecal microbiota (Rebyota) was preferred over vancomycin because of its simpler administration — it is delivered once via enema or colonoscopy without the need for bowel preparation — and its ability to address microbiome dysbiosis, reducing vulnerability to future recurrences. Patients highlighted its simplicity and efficiency, with the procedure taking about 30 minutes and causing only minor side effects, such as slight cramping.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). In addition, as part of the review of fecal microbiota (Rebyota), a panel of 3 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating situations in which there are gaps in the evidence that could be addressed through the collection of additional data, promote the early identification of potential implementation challenges, gain further insight into the clinical management of patients living with a condition, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). A summary of this panel discussion follows.

Unmet Needs

The clinical experts indicated that most patients with a first CDI episode will respond to antibiotic treatment with vancomycin or fidaxomicin, and noted that rCDI will occur in approximately 15% to 20% of patients after a first CDI episode. According to the literature, however, up to 25% of patients may experience rCDI after antibiotic treatment, and after the second recurrence, the risk of recurrence increases substantially, to up to 50%.²⁷ Indeed, the clinical experts confirmed that patients who experience a first recurrence may have their condition improve spontaneously after treatment with vancomycin or fidaxomicin; however, the natural disease trajectory becomes more complex in patients who have experienced at least 2 recurrences, and the risk of experiencing further recurrences and more severe disease becomes incrementally higher.

The clinical experts indicated that in clinical practice, FMT is considered effective at preventing rCDI in patients who have experienced at least 2 recurrences; however, FMT is not readily available to many patients in Canada. Issues surrounding limited access to FMT are multifactorial, according to the clinical experts. The lack of public or private funding for FMT programs has resulted in a heavy dependence on physicians and research grants. Additionally, the establishment and maintenance of an FMT program requires significant infrastructure and specialized expertise. Finally, there are challenges in setting up and sustaining stool banks for FMT, as criteria to become a stool donor are strict and donors are usually volunteers, which makes them difficult to retain. In addition, the clinical experts made the CDA-AMC clinical review team aware of the possibility that conventional FMT programs could be shut down by Health Canada when a commercial product (i.e., fecal microbiota [Rebyota]) becomes available. Health Canada notified CDA-AMC that clinicians were advised that, although fecal microbiota (Rebyota) has been authorized, it is not yet marketed. Therefore, no changes will be made to the current interim policy outlined in the guidance document: Fecal Microbiota Therapy Used in the Treatment of Clostridioides difficile Infection Not Responsive to Conventional Therapies. Once fecal microbiota (Rebyota) becomes marketed, Health Canada will explore options for transitioning away from the interim policy, with further details to be provided in due course.

Therefore, the clinical experts highlighted the need for accessible, effective, and well-tolerated therapies to prevent rCDI, especially in patients who have experienced at least 2 recurrences despite appropriate antibiotic treatment. Patients with the greatest unmet needs are those who have a multirecurrent condition with a high risk of further recurrences, those who are not able to stop an antibiotic taper or pulse regimen, and those who have a substantially impacted quality of life from the condition.

Place in Therapy

The clinical experts recommended the use of fecal microbiota (Rebyota) in patients who have experienced at least 2 recurrences despite appropriate antibiotic treatment, as is the case for FMT, because the natural trajectory becomes more severe at this stage of the disease.

The clinical experts highlighted the need for patients to first receive an appropriate antibiotic regimen for the treatment of rCDI, namely vancomycin administered in a taper or pulse regimen over several weeks. A prolonged vancomycin taper or pulse regimen is considered the treatment of choice for a second rCDI²⁷ and should be used before the initiation of treatment with fecal microbiota (Rebyota), according to the experts. Although antibiotic therapy is targeted at the acute, active infection, it also negatively impacts the gut microbiome. Fecal microbiota (Rebyota) is expected to address the underlying disease process by repopulating and restoring the composition and diversity of the gut microbiome.

According to the clinical experts, fecal microbiota (Rebyota) is similar to the product that is being administered through conventional FMT. However, an important difference between fecal microbiota (Rebyota) and conventional FMT resides in the number of doses administered per treatment. Whereas fecal microbiota (Rebyota) relies on a single administration as the total regimen for preventing each rCDI, FMT may routinely offer repeated doses over 1 week. With such multidose regimens, experience from clinical practice and data from the literature suggests that FMT may achieve clinical response rates of up to more than 90%.²⁷ Therefore, the clinical experts showed concern regarding the potential lower magnitude of effect with fecal microbiota (Rebyota), as they felt that its single administration may lead to less successful outcomes than a series of doses upfront. In addition, conventional FMT offers flexibility in the mode of administration, as delivery can be delivered by enema, oral capsules, or, in some cases, colonoscopy. There is currently no specific guidance for dosing frequency, volume, or mode of delivery for conventional FMT; protocols vary in FMT clinics across Canada.

However, the main advantages that were noted with fecal microbiota (Rebyota) included the fact that the product administered would be regulated in terms of stability, reliability, and high-quality standards, and that it is expected to remove the onus of managing stool banks from FMT providers. As such, a commercial version of fecal microbiota (Rebyota) can potentially increase access to treatment in Canada. Accessibility to FMT is a major issue, according to the clinical experts, who viewed the use of the single-administration, commercially manufactured enema to be an acceptable trade-off. In addition, as previously mentioned, there is a possibility that conventional FMT programs may be shut down when a commercial product becomes available. Therefore, the experts indicated that fecal microbiota (Rebyota) may cause a shift in the current treatment paradigm through increased availability, provided that health care systems can provide the necessary funding, infrastructure, and resources required for product administration and that there are no interruptions in the supply chain.

Patient Population

Patients who would be suited for treatment with fecal microbiota (Rebyota) are those who have experienced at least 2 recurrences despite having tried an appropriate antibiotic treatment with a prolonged vancomycin taper or pulse regimen. Patients should have typical presentations of multiple episodes of rCDI, have no other gastrointestinal issues, and should be able to retain and have no contraindication to enema infusions. The clinical experts emphasized the importance of ensuring that patients are stable and do not have evidence of ongoing, active inflammation of the bowel when they receive a fecal microbiota (Rebyota) enema.

The clinical experts indicated that they would use fecal microbiota (Rebyota) in patients who have concomitant IBD, a population that was underrepresented in the fecal microbiota (Rebyota) studies. The presence of concomitant IBD poses a challenge because of the vicious cycle of dysbiosis related to IBD and the inability to decrease the inflammatory response to CDI to the desired level. In addition, FMT may trigger IBD flare in some patients. Cautions should also be used when providing fecal microbiota (Rebyota) to patients with severe immunocompromising disease, but the clinical experts did not consider this to be a contraindication. Patients who cannot receive an enema because of anatomic issues should not receive fecal microbiota (Rebyota) and should be referred to a conventional FMT program that uses orally administered capsules.

Assessing the Response to Treatment

The clinical experts indicated that response to treatment is entirely based on clinical assessment, which focuses on self-reported resolution or diminution of symptoms to a level that is acceptable for patients to maintain their quality of life.

Stool testing is not routinely performed or recommended after CDI treatment, as most patients with rCDI remain colonized by C. difficile after recovering. Similarly, the experts indicated that there would be no role for testing stools for C. difficile after fecal microbiota (Rebyota), unless a recurrence is suspected.

The clinical experts highlighted the importance of follow-up after fecal microbiota (Rebyota) administration. Experience from clinical practice suggests that symptoms at 1 month are most predictive of long-term prognosis. The experts expect that not all patients will revert to their pre-CDI baseline bowel habits; the goal is to reduce symptoms to a reasonable level and achieve a better quality of life.

Per the Health Canada indication, a second dose of fecal microbiota (Rebyota) is only recommended in the case of a recurrence. Most recurrences would typically be expected to occur 4 weeks to 8 weeks after treatment. If a recurrence occurs, patients should receive a new antibiotic course of vancomycin, using a taper or pulse regimen, to get immediate symptom relief and reduce active inflammation before any additional administration of fecal microbiota (Rebyota) or FMT is considered. In the context of a conventional FMT program, the clinical experts indicated that after a recurrence, they would not consider administering a second round of single-dose FMT using the same mode of administration. The experts would consider repeating FMT either with a more aggressive treatment approach (e.g., multiple doses) or with a different route of administration (e.g., capsules or colonoscopy) after the vancomycin taper or pulse regimen. This would, however, not apply to fecal microbiota (Rebyota) because the recommended dosage is a single-dose enema.

Prescribing Considerations

The clinical experts suggested that prescribing and treatment administration of fecal microbiota (Rebyota) should be limited to clinicians and health care teams with expertise in the management of patients with rCDI and, ideally, in providing FMT. The experts emphasized the need to optimize the selection of patients who may benefit the most from treatment with fecal microbiota (Rebyota). For example, the experts noted that there can be many issues with diagnosis, specifically, overdiagnosis of rCDI in patients who are colonized with C. difficile and have other conditions that cause diarrhea. In addition, the experts emphasized that both fecal microbiota (Rebyota) and FMT are not risk-free and require a thorough informed consent process. Therefore, providers should be well aware of the risks and alternatives when discussing treatment options with patients. The risks associated with the interventions can include the following.

• Acute procedure-related risks: Although enemas are generally gentle procedures, they carry a low risk of perforation related to the introduction of a catheter, especially if the bowel wall is already weakened because of inflammation. This can be minimized by not performing FMT on patients who have evidence of ongoing, active inflammation of the colon. There is also a risk of translocation of bacteria and other microbes into the bloodstream during the procedure, which has the potential of causing bacteremia, particularly in patients with severe immunodeficiency and medically complex conditions.

• Risks related to donor stools: There is a risk of transmission of various infections from the stool donor to the receiving patient. The clinical experts indicated that stool donor recruitment in FMT programs is performed under strict criteria. Laboratory and questionnaire screenings occur regularly to ensure that donors are healthy and to test for different pathogens. However, no donor screening program can eliminate the risk of all infections, including emerging infectious diseases that may not yet be discovered.

• Long-term, unintended effects of manipulating the gut microbiota: The clinical experts indicated that there is hypothesis-generating evidence surrounding the role of the intestinal microbiome in human health in general. Changing a patient’s microbiome may affect the risk of developing a range of conditions over time, the impact of which is currently unknown.

Fecal microbiota (Rebyota) could be administered in an outpatient or inpatient setting, according to the clinical experts.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

One clinician group, the Canadian Antimicrobial Resistance Alliance, provided input for this review. In the opinion of the clinician group, fecal microbiota (Rebyota) demonstrates efficacy and safety in patients with rCDI infection, offering a first-in-class live therapeutic option. The input noted that fecal microbiota (Rebyota) will improve antimicrobial stewardship. In the opinion of the clinician group, it reduces reliance on prolonged courses of vancomycin or fidaxomicin. The input stated that the treatment under review would be most appropriate for patients who have experienced at least 2 CDI recurrences, particularly for high-risk groups such as hospitalized patients, older adults, and patients with severe disease or immunocompromised conditions.

Drug Program Input

The drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by for this review are summarized in Table 3.

Table 3: Summary of Drug Plan Input and Clinical Expert Response

CDI = Clostridium difficile infection; FMT = fecal microbiota transplant; PSP = Patient Support Program; rCDI = recurrent C. difficile infection; RCT = randomized controlled trial.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of rectally administered fecal microbiota (Rebyota), 150 mL, in the prevention of CDI recurrence in adult patients after antibiotic treatment for rCDI. The focus will be placed on comparing fecal microbiota (Rebyota) to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of fecal microbiota (Rebyota) is presented in 4 sections, with a CDA-AMC critical appraisal of the evidence included at the end of each section. The first section, the Systematic Review, includes pivotal studies and RCTs that were selected in accordance with the sponsor’s systematic review protocol. CDA-AMC assessment of the certainty of the evidence in this first section, using the GRADE approach, follows the critical appraisal of the evidence. No long-term extension study or indirect evidence was submitted by the sponsor. The last section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

Clinical evidence from the following is included in the review and appraised in this document:

• 1 pivotal study or RCT identified in the systematic review

• 3 additional studies addressing gaps in the evidence.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Description of the Study

One study was identified and included in the systematic review. The PUNCH CD3 study was a phase III, multicentre, DB, placebo-controlled, randomized trial designed to evaluate the efficacy and safety of fecal microbiota (Rebyota) in the prevention of recurrences of CDI in adult patients after antibiotic treatment for rCDI. The primary outcome was the recurrence of CDI in the 8 weeks after treatment. The primary efficacy analysis was performed using a Bayesian hierarchical model, which formally incorporated data on the treatment effect of fecal microbiota (Rebyota) from the prior randomized, placebo-controlled, phase IIb PUNCH CD2 study.

At the time of enrolment, patients were to receive antibiotic treatment for rCDI, chosen at the discretion of the investigator. A 24-hour to 72-hour washout period was required at the end of antibiotic treatment, before administration of the study drug. Patients were then randomized in a 2:1 ratio to receive a single dose of either fecal microbiota (Rebyota) or placebo enema at the beginning of the 8-week DB treatment phase. Randomization was performed using an interactive response technology and was stratified by the antibiotic therapy used at screening (vancomycin alone, vancomycin in combination, fidaxomicin, or other). Patients, investigators, and study-site personnel were blinded to the randomization assignment.

Two interim analyses were performed by an independent statistical analysis committee. The trial was to be stopped early for success at either of the interim analyses if the posterior probability of superiority exceeded 0.99943, based on a Pocock group sequential design that controlled the type I error rate, without borrowing, at 0.00125 (1-sided).

After the primary outcome assessment at 8 weeks, patients who had a CDI recurrence could receive an additional OL fecal microbiota (Rebyota) enema. Follow-up continued for a total of 6 months.

The characteristics of the included study are summarized in Table 4.

Table 4: Details of the Study Included in the Systematic Review

AE = adverse event; ATLAS = age, temperature, leucocytes, albumin, systemic antibiotics; CDI = Clostridium difficile infection; Cdiff32 = C. difficile Health-Related Quality of Life; DB = double-blind; IBD = inflammatory bowel disease; IBS = irritable bowel syndrome; ICU = intensive care unit; IP = investigative product; rCDI = recurrent C. difficile infection; TEAE = treatment-emergent adverse event; VRE = vancomycin-resistant enterococci.

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The PUNCH CD3 study design is illustrated in Figure 1.

Figure 1: PUNCH CD3 Study Design

CDI = Clostridium difficile infection; RBX2660 = fecal microbiota (Rebyota).

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the figure are from the sponsor’s Summary of Clinical Evidence.

Populations

Inclusion and Exclusion Criteria

Patients aged 18 years and older were eligible for the PUNCH CD3 trial if they had a documented recurrence of CDI, which was defined in the trial as at least 1 recurrence after a primary episode (with at least 1 round of SOC oral antibiotic therapy) or at least 2 episodes of severe CDI resulting in hospitalization in the previous year. Participants had to have received a positive stool test for the presence of toxigenic C. difficile in the previous 30 days, and had to be taking or to have just been prescribed antibiotics to control CDI-related diarrhea at the time of enrolment.

Patients were excluded from the trial if they had a known history of refractory CDI or experienced continued CDI diarrhea despite appropriate antibiotic treatment. The receipt of prior FMT, CDI vaccine, or monoclonal antibodies was prohibited, as was the use of an antibiotic for a condition other than CDI. Other key exclusion criteria included a wide range of comorbidities — such as IBD (e.g., ulcerative colitis, Crohn disease, or microscopic colitis), IBS, celiac disease, short gut syndrome or motility disorders, current colostomy, recent intra-abdominal surgery, chronic diarrhea or diarrhea caused by something other than CDI — or a compromised immune system (e.g., HIV infection, inherited or primary immune disorder, or immunodeficiency or immunosuppression due to a medical condition or medication). Finally, the concomitant use of systemic steroids exceeding 20 mg of prednisone or prednisone-equivalent a day was not permitted.

Interventions

Patients received either a single-dose fecal microbiota (Rebyota) enema or a matching-administration placebo enema. Both study treatments were administered by a qualified and trained health care professional.

Nondietary probiotics, as well as oral vancomycin, metronidazole, fidaxomicin, rifaximin, nitazoxanide, and IV immunoglobulin, were not allowed during the 8-week DB assessment, unless they were newly prescribed by a treating investigator during the course of the study as a result of rCDI diagnosis.

All patients who had a treatment failure at 8 weeks were eligible to receive an OL dose of fecal microbiota (Rebyota). Treatment failure was defined as the presence of CDI diarrhea in patients with a positive stool test for the presence of a C. difficile toxin in the 8 weeks after administration of a study enema.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 5, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence, any outcomes identified as important to this review by the clinical experts consulted for this review, and input from patient and clinician groups and public drug plans. Using the same considerations, CDA-AMC selected end points that were considered to be most relevant to expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. Recurrence of CDI (treatment success), loss of sustained clinical response, HRQoL (measured using the Cdiff32 Questionnaire), and SAEs were assessed using GRADE. Fecal microbial composition and ICU admissions were included as supportive evidence but were not assessed using GRADE.

Table 5: Outcomes Summarized From the Study Included in the Systematic Review

CDI = Clostridium difficile infection; Cdiff32 = C. difficile Health-Related Quality of Life; HRQoL = health-related quality of life; ICU = intensive care unit.

^aOutcomes included in the GRADE assessment.

^bStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchal testing).

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Clinical Response

Recurrence of CDI: The primary outcome in the PUNCH CD3 study was the recurrence of CDI within 8 weeks. Recurrence of CDI in the study was synonymous with treatment failure, which was defined as the presence of CDI diarrhea, with a positive stool test for the presence of a C. difficile toxin in the 8 weeks after administration of a study enema.

Patients were followed for recurrence via study follow-up visits at 1 week, 4 weeks, and 8 weeks (± 3 days) and via phone assessments at week 2, week 3, and week 6 (± 3 days) after the administration of a study enema. Recurrences could also be identified during unscheduled visits.

Sustained clinical response: A sustained clinical response in patients who previously achieved treatment success was the secondary outcome in the PUNCH CD3 study. The outcome was defined as the absence of CDI diarrhea for 8 weeks after administration of a study enema, which was also labelled a treatment success for the presenting CDI recurrence, in addition to having no new CDI episodes through 6 months.

Patients were followed for recurrence via phone assessment at 6 months (± 14 days). Recurrences could also be identified via unscheduled visits.

Health-Related Quality of Life

Cdiff32 Questionnaire: HRQoL was assessed in the PUNCH CD3 study using the Cdiff32 Questionnaire, a disease-specific HRQoL assessment tool that includes domains related to physical, mental, and social health.^38,39 The self-administered questionnaire comprises 32 items; patients provided responses to each question on a 5-point Likert scale, which indicated how that patient was affected by CDI-related concerns in the previous 7 days. Total and domain scores on the Cdiff32 Questionnaire range from 0 (worst score) to 100 (best score), and responses to the questions are aggregated and rescaled so that lower scores denote a greater negative impact on quality of life. An MCID of 10 points using a distribution-based approach has been suggested in the literature.⁴⁰ The MCID was estimated for within-group changes, rather than between-group differences. The measurement properties of the Cdiff32 Questionnaire are summarized in Table 7. The recall period of this questionnaire was not reported.

Patients completed the Cdiff32 Questionnaire at screening, and 1 week (± 3 days), 4 weeks (± 3 days), 8 weeks (± 3 days), 3 months (± 14 days), and 6 months (± 14 days) after administration of a study enema.

Fecal Microbiota (Rebyota) Composition

Stool samples were collected by patients at home in prelabelled containers to assess changes in fecal microbial composition 4 weeks, 8 weeks, 3 months, and 6 months after blinded study treatment.

Harms

The safety analysis included AEs, SAEs, AEs leading to study discontinuation, and mortality. In addition, the number of ICU admissions through 8 weeks was reported as a safety outcome. AEs of special interest included septic shock, toxic megacolon, colonic perforation, and emergency colectomy.

Patients were followed for harms outcomes via study follow-up visits at 1 week (± 3 days), 4 weeks (± 3 days), and 8 weeks (± 3 days) after the administration of a study enema and via phone assessments at 2 weeks (± 3 days), 3 weeks (± 3 days), 6 weeks (± 3 days), 3 months (± 14 days) and 6 months (± 14 days). Recurrences could also be identified during enema administration and unscheduled visits.

Table 6: Summary of Outcome Measure and Its Measurement Properties

CDI = Clostridium difficile infection; Cdiff32 = C. difficile Health-Related Quality of Life; EQ-5D-5L = 5-Level EQ-5D; HRQoL = health-related quality of life; MCID = minimal clinically important difference; MID = minimal important difference; rCDI = recurrent C. difficile infection; SD = standard deviation; SF-36 = 36-Item Short Form Health Survey; vs. = versus.

Statistical Analysis

A summary of the statistical analyses is presented in Table 7.

Sample Size and Power Calculation

The sample size calculation used a Pocock spending function, taking into account 2 interim analyses for futility, and assumed a treatment success rate of 69% for fecal microbiota (Rebyota) and 47% for placebo. Based on these considerations, a sample size of 240 patients, randomized in a 2:1 ratio to fecal microbiota (Rebyota) or placebo, was determined to provide sufficient statistical power (> 90%, nominal 2.5% type I error rate) to detect a statistically significant effect in the primary end point of CDI recurrence at 8 weeks at either of the 2 interim analyses or at the end-of-trial analysis. Up to an additional 30 patients were enrolled to allow for a 10% loss-to-follow-up rate, for a total of approximately 270 patients.

Statistical Test or Model: Bayesian Borrowing

The primary efficacy analysis of CDI recurrence at 8 weeks was performed using a Bayesian hierarchical model, which formally incorporated data on the treatment effect of fecal microbiota (Rebyota) from the prior randomized, placebo-controlled, phase IIb PUNCH CD2 study. The protocol-specified decision rule was to declare study success if the posterior probability of superiority exceeded 0.99943 at the first 2 interim analyses and exceeded 0.9993275 at the final analysis. This threshold was selected to control the type I error rate, without borrowing at a 1-sided 0.00125 alpha, accounting for multiple interim analyses.¹⁸ Additionally, superiority was also evaluated using a lower threshold, set at 0.97706 in the Statistical Analysis Plan, which corresponded to a less demanding 1-sided alpha of 0.025.¹⁸ The final secondary threshold used was adjusted to 0.9750338 to reflect the actual number of patients and events observed in the trial.¹⁸ This is the relevant threshold used for the treatment comparison. The sponsor reported that this approach was taken in agreement with the FDA during recruitment to the phase III PUNCH CD3 trial, and is consistent with the FDA’s guidance on Complex Innovative Trial Designs for Drugs and Biological Products.⁴¹

Details regarding the PUNCH CD2 study can be found in the previous section on Clinical Evidence, which includes additional studies considered to address important gaps in the systematic review evidence. As the PUNCH CD3 study was not originally designed to use a Bayesian hierarchical model to dynamically borrow information from the PUNCH CD2 study, some differences between the protocols for the 2 trials existed. To account for potential heterogeneity between the populations in the 2 trials, a dynamic borrowing approach was used, which aimed to ensure that an appropriate amount of data was borrowed from the PUNCH CD2 study. The dynamic aspect of the borrowing meant that the more similar the response rates were between the 2 trials, the more previous data were borrowed. Differences between the 2 protocols included the following.

• Differences in populations: Patients enrolled in the PUNCH CD2 study had to have experienced at least 2 recurrences of CDI, whereas patients in the PUNCH CD3 study had to have experienced at least 1 recurrence, according to the inclusion criteria for the respective trials.

• Differences in the intervention received and follow-up duration: The PUNCH CD2 study investigated a dosing regimen in which 2 doses were administered 1 week apart, with a follow-up period from the first dose of 9 weeks instead of 8 weeks.

• Differences in the analysis populations: The planned primary analysis for the PUNCH CD2 study was based on the ITT population, which included all randomized patients, regardless of whether they completed their assigned study treatment. In the PUNCH CD3 study, however, the primary analysis was based on the modified intention-to-treat (mITT) population, which included only randomized patients who successfully received blinded treatment and excluded patients who discontinued the study before the primary efficacy end point assessment of treatment success at 8 weeks (if the reason for exit was not related to CDI symptoms).

In the final Bayesian hierarchical analysis of the primary end point, the sponsor addressed these differences by borrowing data from only the 1-dose fecal microbiota (Rebyota) group and the placebo group in the PUNCH CD2 study, as this was the dosing scheme used in the PUNCH CD3 study and is the recommended dose in the proposed indication. The mITT analysis population was used in the Bayesian hierarchical model, and the PUNCH CD3 study definition of the analysis population was applied to the PUNCH CD2 study efficacy data. In addition, the follow-up period in the PUNCH CD2 study was restricted to 8 weeks from the first dose.

Sensitivity Analyses

Analysis population in the Bayesian hierarchical analysis: Sensitivity analyses of the primary end point were performed using alternate analysis populations. The primary efficacy analysis was repeated using the ITT and per protocol (PP) populations; the ITT analysis served as the conservative analysis, as it considered that all patients who exited either study before the 8-week efficacy assessment experienced treatment failures, regardless of treatment failure documentation.

Additional sensitivity analyses of the primary end point were performed using different analysis populations from the PUNCH CD2 study, which included the ITT population and a population of 1 patient who was exposed to fecal microbiota (Rebyota) but did not receive the full enema, to assess the sensitivity of the results to the borrowing of historical data from the previous PUNCH CD2 study.

Testing of the primary end point without Bayesian borrowing: The primary efficacy analysis was repeated without the borrowing of historical data from the PUNCH CD2 study using the mITT, ITT, and PP populations. In addition, alternate testing (i.e., Pearson’s chi-square test), using data only from the PUNCH CD3 study, was used to test the null hypothesis that the response rate in the treatment group is equal to that of the control group. Two-sided 95% CIs for the difference in response rate between arms were calculated using a normal distribution approximation. This sensitivity analysis was conducted using the mITT, ITT, and PP populations.

Additional assessments of the primary outcome using Kaplan-Meier estimates: An analysis of time to CDI recurrence after completion of the assigned blinded treatment was performed using the Kaplan-Meier procedure. The median duration was reported in days and weeks using the ITT, mITT, and PP populations. The Kaplan-Meier estimate of the median time in days and the associated 95% CI were presented for each treatment group. Between-group comparisons were performed using the stratified log-rank test, based on the stratification factor at randomization (antibiotic therapy used at screening). The corresponding hazard ratio of the treatment effect, along with the 95% CI, was calculated using a Cox proportional hazards model, with treatment and the stratification factor at randomization as explanatory variables. Time to CDI recurrence was defined as the number of days from enema administration to first assessment indicating CDI recurrence for patients who were deemed to have a treatment failure. All patients whose assessment of treatment failure was indeterminate or who discontinued the study for any reason before the assessment of efficacy were censored at the last assessment date at or before week 8. For the analysis of time to CDI recurrence within 8 weeks, all patients considered to have a treatment success were censored at the date of their 8-week assessment. For the analysis of time to CDI recurrence through 6 months, all patients considered to have achieved a sustained clinical response were censored at the date of their 6-month assessment.

Additional assessments of the primary outcome using multivariate logistic regression: Sensitivity of the primary efficacy end point was assessed in a multivariate logistic regression that adjusted for possible interactions of the following covariates with treatment group [wording from original source]: age (< 65 years, ≥ 65 years), sex (female, male), race group (white, nonwhite), ethnicity (Hispanic-Latino, not Hispanic-Latino), site geography (outside the US, Eastern US, Southern US, Northern US, Western US), randomization strata (i.e., antibiotic treatment received at the qualifying event), and number of previous episodes of CDI recurrence at baseline. This analysis was performed on all analysis populations that had at least 20 patients in each subgroup available for analysis.

Secondary End Points of the Studies and Multiple Testing Procedure

The secondary efficacy end point was a sustained clinical response throughout the remainder of the 6-month follow-up period. This end point aimed to evaluate whether patients without a recurrence of CDI 8 weeks after fecal microbiota (Rebyota) treatment remained disease-free after 6 months. A hierarchical, closed-testing procedure was used for the primary end point and for the secondary end point of loss of sustained clinical response at 6 months. As such, analysis of the secondary end point was to be performed only if statistical significance was demonstrated for the primary efficacy end point. A Pearson’s chi-square test was used to assess the null hypothesis that the response rate in the treatment group is equal to that of the control group. The secondary end point was tested at a 2-sided significance level of 0.05. Two-sided 95% CIs for the difference in response rate between arms were calculated using a normal distribution approximation. In addition, an analysis of time to CDI occurrence was preformed using the Kaplan-Meier procedure, where between-group comparisons were preformed using the log-rank test.

Data Imputation Methods

No imputations were used in the primary or secondary end point analyses. Patients exiting the study before the 8-week efficacy assessment were excluded from the analysis that used the mITT population (primary analysis population), and were considered to have experienced treatment failure, regardless of treatment failure documentation in the analysis using the ITT population (sensitivity analysis).

A LOCF analysis was used for evaluation of Cdiff32 Questionnaire scores.

Subgroup Analyses

Subgroup analyses were performed for the primary end point based on the following patient characteristics and baseline variables [wording from original source]:

• age (< 65 years, ≥ 65 years)

• sex (female, male)

• race group (white, nonwhite)

• ethnicity (Hispanic-Latino, not Hispanic-Latino)

• site geography (outside the US, Eastern US, Southern US, Northern US, and Western US)

• number of previous episodes of CDI recurrence at baseline

• vancomycin use duration for the qualifying CDI episode.

Subgroup efficacy analyses were prespecified and were performed using the Cochran-Mantel-Haenszel test for the mITT, ITT, and PP populations. Whether the comparability of the treatment arms was checked and whether multiplicity was taken into account were not reported.

Table 7: Statistical Analysis of Efficacy End Points

CDI = Clostridium difficile infection; Cdiff32 = C. difficile Health-Related Quality of Life; ITT = intention to treat; LOCF = last observation carried forward; PP = per protocol.

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Analysis Populations

The analysis populations in the PUNCH CD3 study are described in Table 8.

Table 8: Analysis Populations of the PUNCH CD3 Study

CDI = Clostridium difficile infection.

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

Of the 320 screened patients in the PUNCH CD3 study, 31 failed screening and 289 were randomized in the study. Historical data were borrowed from ██ patients who participated in the PUNCH CD2 study. A total of 41 patients in the fecal microbiota (Rebyota) group and 24 patients in the placebo group opted to receive an OL second study treatment with fecal microbiota (Rebyota) after a documented treatment failure at 8 weeks.

Overall, discontinuations and reasons for discontinuations appeared to be balanced between treatment groups. Details of patient disposition are presented in Table 9. Only a few patients who received DB study treatment discontinued before the 8-week primary efficacy assessment (3 patients in the fecal microbiota [Rebyota] group and no patients in the placebo group).

Table 9: Summary of Patient Disposition in the PUNCH CD3 Study

ITT = intention to treat; mITT = modified intention to treat; NR = not reported; PP = per protocol.

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

The baseline characteristics that are most relevant to this review or that may affect the interpretation of the study results are outlined in Table 10.

The mean (SD) age was ████ ███████ years in patients who received fecal microbiota (Rebyota) and ████ ███████ years in patients who received placebo, with patients ranging in age from ██ ██ ██ years. A total of ██ patients █████ in the fecal microbiota (Rebyota) group and ██ patients █████ in the placebo group were at least 65 years of age. There were more females █████ than males █████ in the study, and most █████ patients were classified as white. The majority of patients in the study █████ received vancomycin alone to treat the qualifying CDI episode. The mean (SD) duration of the qualifying CDI episode was ████ ███████ days in the fecal microbiota (Rebyota) group and ████ ███████ days in the placebo group.

Overall, most baseline characteristics appeared to be balanced between treatment groups in the PUNCH CD3 study; however, there was imbalance between groups in the total number of previous CDI episodes, which was identified as a relevant prognosis factor by the clinical experts. In the PUNCH CD3 study, patients who received fecal microbiota (Rebyota) appeared to have more severe conditions, based on the number of previous CDI episodes (███ of these patients had experienced 2 episodes and ███ had experienced more than 3 episodes) than patients who received placebo (███ of these patients had experienced 2 episodes and ███ had experienced more than 3 episodes).

Table 10: Summary of Baseline Characteristics in the PUNCH CD3 Study ████

ATLAS = age, temperature, leucocytes, albumin, systemic antibiotics; CDI = Clostridium difficile infection; Cdiff32 = C. difficile Health-Related Quality of Life; DB = double blind; EIA = enzyme immunoassay; GDH = glutamate dehydrogenase; LAMP = loop-mediated isothermal amplification; PCR = polymerase chain reaction; SD = standard deviation.

Note: Racial categories used in the table are as reported in the original source and may not align with Canada's Drug Agency inclusive language guidelines.

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

Exposure to study treatment is outlined in Table 11. Data were reported for the safety population (i.e., patients in whom any blinded treatment was attempted or completed).

Of the 267 patients in the safety population who received blinded study treatment successfully in the blinded phase of the study, 180 patients received fecal microbiota (Rebyota) and 87 patients received placebo. In addition, 41 patients (22.8%) in the fecal microbiota (Rebyota) group and 24 patients (27.6%) in the placebo group who were deemed to experience treatment failure during the DB period, based on the 8-week efficacy assessment, opted to receive a second enema during the OL phase (and all of these patients received fecal microbiota [Rebyota]).

Table 11: Summary of Patient Exposure in the PUNCH CD3 Study (Safety Population)

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Efficacy

Detailed efficacy results are presented in Table 12 for the primary outcome and in Table 13 for the secondary and exploratory outcomes.

Treatment Response After 8 Weeks

Primary Analysis

The mean success rate after 8 weeks was 70.4% in patients in the fecal microbiota (Rebyota) group and 58.1% in patients in the placebo group, based on posterior estimates from the Bayesian hierarchical model in the mITT population. This primary analysis in the study resulted in a between-group difference of 12.3% (95% CrI, 1.4% to 23.3%). The magnitude of the findings was considered to be clinically meaningful by the clinical experts consulted for this review, based on the point estimate. The posterior probability of superiority was 0.986354, which exceeded the secondary threshold of 0.9750338 that controlled the type I error rate at a 1-sided level of 0.025. This indicates a 98.6% probability of statistical superiority of fecal microbiota (Rebyota), compared to placebo, at a 2-sided alpha level of 0.05.

Sensitivity Analyses

Alternate analysis populations: Sensitivity analyses of the primary outcome, based on alternate analysis populations, yielded consistent results, aligned with those from the main analysis, with a between-group difference of 12.5% (95% CrI, 1.6% to 23.3%) in the ITT population and of 13.7% (95% CrI, 2.4% to 25.1%) in the PP population.

Analysis without Bayesian borrowing: In the sensitivity analysis without Bayesian borrowing, the mean success rate after 8 weeks was 71.2% in patients in the fecal microbiota (Rebyota) group and 62.4% in patients in the placebo group, yielding a between-group difference of 8.8% ████ ██ █████ █████ █████████ in the mITT population. Results obtained in the ITT and PP populations suggested consistent findings. Overall, results aligned with those from the main analysis, suggesting an effect bordering on clinically important, with imprecision related to the potential for little to no difference, based on the lower bound of the 95% CrI or CI.

Time-to-event analysis: In the comparison of fecal microbiota (Rebyota) with placebo for time to CDI recurrence, the hazard ratio was ████ ████ ██ █████ █████ ████████ █████████ in the mITT population. Results for time to CDI recurrence through 8 weeks are presented as Kaplan-Meier curves in Figure 2. ███████ ████████ ██ ███ ███ ███ ██ ███████████ █████████ ██████████ ████████.

Subgroup Analyses

Subgroup analyses identified by the clinical experts that are particularly relevant in the context of rCDI included number of prior CDI episodes (≤ 3 episodes; > 3 episodes) and vancomycin use duration for qualifying CDI episode in patients who received vancomycin alone (≤ 14 days; > 14 days). The between-group difference for treatment success was 5.4% (95% CI, −9.4% to 20.2%; ████████) in patients who had experienced 3 or fewer CDI episodes and 16.1% (95% CI, −5.4% to 37.7%; ████████) in patients who had experienced more than 3 CDI episodes. In patients who received vancomycin alone, the between-group difference was 1.9% (95% CI, −20.3% to 24.0%; ████████) in patients who were treated for 14 or fewer days and 12.8% (95% CI, −3.5% to 29.1%; ████████) in patients who were treated for more than 14 days.

The results of the subgroup analyses were, overall, aligned with those from the main analysis in terms of direction. The magnitude of effect appeared to be greater in patients who had experienced more than 3 CDI episodes and in those who received treatment with vancomycin for more than 14 days; however, the number of patients in each subgroup was small and, therefore, the CIs crossed the null.

Response to OL Fecal Microbiota (Rebyota) Enema

Fecal microbiota (Rebyota) group: Of the 41 patients in the fecal microbiota (Rebyota) group who were deemed to have experienced treatment failure at the primary efficacy assessment at 8 weeks and went on to receive a second, OL enema of fecal microbiota (Rebyota), 22 patients achieved treatment success 8 weeks after the second enema, resulting in a treatment success rate of 53.7%.

Placebo group: Of the 24 patients in the placebo group who were deemed to have experienced treatment failure at the primary efficacy assessment at 8 weeks and went on to receive an OL enema of fecal microbiota (Rebyota), 15 patients achieved treatment success 8 weeks after the second enema, resulting in a treatment success rate of 62.5%.

Sustained Clinical Response After 6 Months

In the mITT population, 116 of 126 patients (92.1%) in the fecal microbiota (Rebyota) group who achieved previous treatment success maintained a sustained clinical response after 6 months, compared with 48 of 53 patients (90.6%) in the placebo group. This resulted in a between-group difference of 1.5% ████ ██ █████ █████ █████████. Results obtained in the ITT and PP populations suggested consistent findings. The magnitude of the between-group difference based on the point estimate was not considered clinically meaningful by the clinical experts consulted for this review.

HRQoL (Cdiff32 Questionnaire)

In the mITT population, nearly all patients in the fecal microbiota (Rebyota) and placebo groups, respectively, provided baseline ██████ ███ ██████ and 8-week ██████ ███ ██████ assessments. At 6 months, assessments were available for a respective █████ and █████ of patients. The mean (SD) change from baseline through 8 weeks in Cdiff32 Questionnaire score was █████ ████████ in patients in the fecal microbiota (Rebyota) group and █████ ████████ in patients in the placebo group, yielding a between-group difference of ████ ████ ██ ██████ ██████. The mean (SD) change from baseline through 6 months was █████ ████████ in patients in the fecal microbiota (Rebyota) group and █████ ████████ in patients in the placebo group, yielding a between-group difference of ████ ███████ ██████. The magnitude of the findings was not considered clinically meaningful by the clinical experts consulted for this review.

The sponsor provided an additional exploratory analysis of HRQoL data for patients who were deemed to be responders at 8 weeks. ██ ████ ███ ████ █████ ██████████ ███ ███ █████████ █████████ ███ █████████████ ███████████ ████████ ██ ███████ ███████ ██████ ███████ ███ ████ ███ ████ ███████ ██████████ ████████ ██ ███ █████ ████████████ ███ ██████████ █████████ ██ █████████ ███████ ███████ ████ ████████ ███ ██████ ███████████ ███ ██████ ██████████ ██ ███ █████████ ██ ██████ ███ ████████ █████████ ██ ███ █████████

Stool Testing (Fecal Microbial Composition)

Fecal sequencing analysis suggested that the microbiome composition of patients experiencing treatment success changed from baseline over all time points (P < 0.001 for within-group change from baseline using the generalized Wald test). Results are presented in Figure 3. The change in microbiome composition after treatment was characterized by an increase in Bacteroidia-class and Clostridia-class bacteria and a decrease in Gammaproteobacteria-class and Bacilli-class bacteria.

Health Care Resource Use

Hospitalizations and ICU Admissions

Both hospitalizations and ICU admissions were reported as harms outcomes in the PUNCH CD3 study. Results are described for patients who were ██████████ ██ ██████ █████████ ████ █████ ██████████ ██████████ ████████ ██ ██████ ███ ████████ ███ ████████ ███ ████ ██████████ ██ ████████

█████ ██ █ ████████ ██ ███ █████ ██████████ █████████ █████ ████████ ████████████████ ███ ██ ████ ██████ ██████ █████████ ██ ███████ ██████████ ███ █ ████████ ██████ ██████ █████████ ██ ██ ██████ ██ ████ █████████ ██████

A total of 2 patients in the fecal microbiota group (Rebyota) required ICU admission during the 8-week follow-up of blinded treatment. Of these, 1 patient experienced septic shock as a major complication of new CDI and underwent emergency colectomy, and another patient was admitted to the ICU because of the severity of a new CDI event. No patient experienced major complications of CDI after OL enema in this treatment group.

Table 12: Summary of Key Efficacy Results in the PUNCH CD3 Study — Primary Outcome (mITT Population)

CDI = Clostridium difficile infection; CI = confidence interval; CrI = credible interval; ITT = intention to treat; mITT = modified intention to treat; PP = per protocol; SD = standard deviation.

^aThe threshold used to evaluate the estimated posterior probability of superiority was 0.9750338.

^bP values are obtained from Pearson’s chi-square test.

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 13: Summary of Key Efficacy Results in the PUNCH CD3 Study — Secondary and Exploratory Outcomes (mITT Population)

Cdiff32 = Clostridium difficile Health-Related Quality of Life; CI = confidence interval; ITT = intention to treat; mITT = modified intention to treat; PP = per protocol; SD = standard deviation.

^aP values are obtained from Pearson’s chi-square test.

^bStatistical testing for the secondary end point was controlled for multiple comparisons.

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Figure 2: Kaplan-Meier Curve of ████ ███████████ [Redacted]

CDI = Clostridium difficile infection; mITT = modified intention to treat.

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸

Figure 3: Fecal Microbiota (Rebyota) Composition

IP = investigational product; RBX2660 = fecal microbiota Rebyota.

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸

Harms

Data for harms outcomes included in the review are presented in Table 14 and in Table 15.

Adverse Events

In the PUNCH CD3 study, 70.0% of 180 patients in the fecal microbiota (Rebyota) group and 59.8% of 87 patients in the placebo group experienced at least 1 AE.

Because patients in the study could receive up to 2 fecal microbiota (Rebyota) enemas, AEs were also reported according to the number of fecal microbiota (Rebyota) enemas received. This allowed for the description of potential additional harms in patients who received 2 fecal microbiota (Rebyota) enemas. In patients randomized to placebo who received no fecal microbiota (Rebyota) enema, 36 of 63 patients (57.1%) experienced at least 1 AE. In patients who were randomized to fecal microbiota (Rebyota), 94 of 139 patients (67.6%) who received only 1 blinded fecal microbiota (Rebyota) enema experienced at least 1 AE, as did 32 of 41 patients (78.0%) who received 1 blinded plus 1 OL fecal microbiota (Rebyota) enemas.

The most common TEAEs in the study included diarrhea, abdominal pain, nausea, and abdominal distension.

Serious Adverse Events

A total of 8.3% of patients in the fecal microbiota (Rebyota) group and 6.9% of patients in the placebo group experienced at least 1 SAE.

In patients randomized to placebo who received no fecal microbiota (Rebyota) enema, ██ ██ ████████ ██████ experienced at least 1 SAE. In patients who were randomized to fecal microbiota (Rebyota), ██ ███ ████████ ██████ who received only 1 blinded fecal microbiota (Rebyota) enema experienced at least 1 SAE, as did ██ ██ ████████ ████ ██ who received 1 blinded plus 1 OL fecal microbiota (Rebyota) enema.

The most common treatment-emergent SAEs in the study were not reported.

Withdrawals Due to Adverse Events

███ ████████ ██ ███ █████ ██████████ █████████ █████ ████████████ ███ █████ ███ ██ ████ ███ ██████ ███ ██████████ ██ ████ █████ ███ ████████. No patient in the placebo group withdrew from the study due to AEs.

Mortality

Of the 2 deaths were reported in the study, both were in patients in the fecal microbiota (Rebyota) group. The causes of death were reported as multimorbidity and cardiorespiratory arrest related to pre-existing conditions. None of the events were reported as being related to the study drug or enema procedure, according to the investigators.

Notable Harms

AEs of special interest in the study included septic shock, toxic megacolon, colonic perforation, and emergency colectomy. One patient in the fecal microbiota (Rebyota) group experienced septic shock as a major complication of new CDI and underwent emergency colectomy. The sponsor reported no events of toxic megacolon or colonic perforation. No event of bacteremia, considered a notable harm by the clinical experts consulted for this review, was reported during the study.

Table 14: Summary of Harms Results in the PUNCH CD3 Study (Safety Population)

rCDI = recurrent Clostridium difficile infection.

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 15: Most Commonly Reported Harms Results in the PUNCH CD3 Study (Safety Population)

OL = open label.

Source: Clinical Trial Report for PUNCH CD3 study.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

Study Design

Patients were allocated to treatment groups using appropriate methodology (i.e., an interactive response technology), and randomization was stratified by a relevant and clinically important potential prognostic factor (i.e., antibiotic therapy used at screening).

Patient Population

Overall, most baseline characteristics appeared to be balanced between treatment groups in the PUNCH CD3 study; however, there was an imbalance between groups in the total number of previous CDI episodes (more patients in the fecal microbiota (Rebyota) group than in the placebo group had > 3 prior episodes). This was identified as a relevant prognostic factor by the clinical experts; patients who have fewer recurrences may have their condition improve spontaneously, whereas the natural disease trajectory becomes more severe in patients who have experienced at least 2 recurrences. In the PUNCH CD3 study, patients who received fecal microbiota (Rebyota) appeared to have more severe conditions, based on the number of previous CDI episodes, than patients who received placebo. The direction of the bias is uncertain, although it may have favoured placebo.

Interventions

All patients who experienced treatment failure at 8 weeks were eligible to receive an OL dose of fecal microbiota (Rebyota). This is not expected to affect the assessment of outcomes at 8 weeks; however, it limits the interpretation of outcomes assessed at time points beyond 8 weeks (i.e., sustained clinical response, HRQoL, fecal microbial composition, and health care resource use, all of which were assessed at 6 months). Because a proportion of patients in each treatment group will have received active treatment with fecal microbiota (Rebyota), the direction of the bias would most likely be toward the null.

The relevant concomitant medications reported were not expected to have a clinically meaningful impact on disease course or on treatment response, according to the clinical experts.

Outcome Measures

HRQoL was assessed as an exploratory outcome using the Cdiff32 Questionnaire, which is a validated, disease-specific instrument that is, however, not routinely used in clinical practice. Patient-reported assessment of diarrhea and its impact on HRQoL may be viewed as somewhat subjective, as interpretation of bowel movement habits and diarrhea may be different from 1 individual to another. This could result in a risk of bias; a proportion of patients received OL fecal microbiota (Rebyota) and, thus, were aware of the treatment that they had received, which could have influenced their responses. The MCID of 10 points suggested in the literature for this instrument is uncertain, as it was estimated using a distribution-based approach (half SD approach). Because distribution-based methods rely on statistical properties of the data, they may not always reflect clinically meaningful changes from the perspective of patients. Thus, an anchor-based approach would have been preferred. In addition, this MCID was intended to inform a within-group change; therefore, the appropriateness of applying the same threshold to a between-group difference is unclear.

Statistical Analysis

In the primary efficacy analysis performed using a Bayesian hierarchical model, the posterior probability of superiority exceeded the final secondary threshold, but not the primary, protocol-specified threshold.

No sensitivity analysis of the Bayesian hierarchical approach was performed focusing specifically on the impact of the priors that were used from the PUNCH CD2 study. The best practice in a Bayesian analysis setting would be to rerun the Bayesian model with alternative priors to test the impact on the results. This may be evaluated to a degree in the frequentist sensitivity analysis; however, interpretation of the findings is limited by the fact that several additional factors that differ between a frequentist and Bayesian approach may also potentially explain some of the differences. Results from the frequentist sensitivity analysis, which used no data from the PUNCH CD2 study, were, overall, aligned with those from the Bayesian analysis. Although the results from the frequentist analysis were not statistically significant, estimates from both the Bayesian approach and the frequentist approach appear to suggest an effect bordering on clinically important, with imprecision related to the potential for little to no difference, based on the lower bound of the 95% CrI or CI.

The PUNCH CD3 study used a hierarchical, closed-testing procedure to control the overall type I error rate for the primary end point and for the secondary end point of loss of sustained clinical response at 6 months.

Prespecified subgroup analyses included the number of previous episodes of CDI recurrence at baseline and the duration of vancomycin use for the qualifying CDI episode, which were considered to be particularly relevant to the management of rCDI by the clinical experts. Whether multiplicity was taken into account was not reported. In addition, the subgroups were small, effects were imprecise, and there were no tests for subgroup by treatment interactions. Although the point estimate for the between-group difference appears larger in patients who had more than 3 prior CDI episodes and in those who received treatment with vancomycin for more than 14 days, the 95% CIs for the estimated effects in each group overlap as a result of imprecision. As such, credible conclusions about effect modification cannot be made, and findings from subgroup analyses should be viewed as supplementary.

No imputations were used in the primary or secondary end point analyses. Patients exiting the study before the 8-week efficacy assessment were excluded from the analysis that used the mITT population (primary analysis population), and were considered to have experienced treatment failure regardless of treatment failure documentation in the analysis using the ITT population (sensitivity analysis). Because results using the ITT population were aligned with those of the main analysis using the mITT population, the risk of bias related to missing outcome data for these end points can be considered low. However, an LOCF analysis was used for the evaluation of the Cdiff32 Questionnaire scores. This is not the approach of choice for HRQoL, as this imputation method hinges on the assumption that patients’ HRQoL will remain stable from the time of their last available assessment, which may not be realistic. No information was provided by the sponsor to justify this assumption. As such, there is risk of bias related to missing outcome data for this end point. In addition, the HRQoL analysis population at 6 months had substantial attrition, introducing uncertainty and precluding a definite conclusion.

As with most clinical trials, the studies were not powered to detect infrequent AEs or those with a lag time.

External Validity

Population

Patients with a wide range of comorbidities were excluded from the trial, including IBD (e.g., ulcerative colitis, Crohn disease, or microscopic colitis), IBS, celiac disease, short gut syndrome or motility disorders, chronic diarrhea, and a compromised immune system (e.g., HIV infection, inherited or primary immune disorders, or immunodeficiency or immunosuppression due to a medical condition or medication). Patients were also excluded from the trial if they had a known history of refractory CDI or experienced continued CDI diarrhea despite appropriate antibiotic treatment. Therefore, findings from the PUNCH CD3 study may not be generalizable to these patients. However, the clinical experts noted that fecal microbiota (Rebyota) is likely to be given to patients who have these concomitant conditions in clinical practice, in alignment with the Health Canada indication, despite the fact that the balance between the benefits and risks may differ and the fact that the effectiveness of the intervention has not been studied in these subpopulations.

The Health Canada indication is aligned with the trial and does not require a specific number of recurrences to be eligible to receive fecal microbiota (Rebyota). The clinical experts, however, indicated that patients included in the trial could be considered, overall, to be at a lower risk for CDI recurrences than patients typically seen in clinical practice, who would have the greatest unmet need and be the best candidates to receive fecal microbiota (Rebyota). One of the main reasons identified for this was the inclusion of patients who had only 1 recurrence of a CDI, who accounted for 29.5% of patients in the fecal microbiota (Rebyota) group and 38.5% of patients in the placebo group. Patients who experience a first recurrence may have their condition improve spontaneously and maintain a sustained response. However, the natural disease trajectory becomes more severe in patients who have experienced at least 2 recurrences, and the risk of experiencing further recurrences becomes incrementally higher.

The clinical experts emphasized that fecal microbiota (Rebyota) should be reserved for patients who experienced at least 2 recurrences and who had an unprovoked relapse after a vancomycin taper or pulse regimen. In the PUNCH CD3 study, although the majority of patients received vancomycin for the treatment of the qualifying episode, no details on the specific regimen used were provided (e.g., whether patients received a prolonged taper or pulse treatment). Therefore, it is uncertain whether the population from the study is consistent in that regard with patients who would be candidates to receive fecal microbiota (Rebyota) in clinical practice.

Intervention and Comparator

The administration of fecal microbiota (Rebyota) in the trial was consistent with the Health Canada recommended dosage (i.e., 1 single-dose enema administered 24 hours to 72 hours after the last dose of antibiotics, with a possible additional treatment in the event of a CDI recurrence).

Because the PUNCH CD3 study included a placebo control group, there is no direct evidence comparing fecal microbiota (Rebyota) to other currently used therapies for rCDI, such as a prolonged vancomycin taper or pulse regimen or conventional FMT. This absence restricts the ability of the trial to inform on the effectiveness and safety assessments relative to other treatment options available.

According to the clinical experts, fecal microbiota (Rebyota) can be considered very similar to the product that is being administered through conventional FMT, in that it is a prepared stool-derived product. However, an important difference between fecal microbiota (Rebyota) and FMT resides in the number of doses administered per treatment. Fecal microbiota (Rebyota) is indicated as a single administration. However, the administration regimen in FMT programs may routinely consist of a series of enemas over a 1-week period. With such regimens, experience from clinical practice and data from the literature suggests, FMT may achieve clinical response rates of up to more than 90%.²⁷ In addition, the clinical experts mentioned that in the case of a recurrence, they would consider repeating FMT either with a more aggressive treatment approach or using a different route of administration (e.g., capsules or colonoscopy) after a course of taper or pulse vancomycin. Therefore, the administration regimen in the trial was not representative of the way stool-derived products are currently being used in clinical practice with conventional FMT, according to the experts. There are currently no specific guidance for dosing frequency, volume, or mode of delivery for conventional FMT; protocols vary in FMT clinics across Canada.

The PUNCH CD3 study specified that study treatment was to be administered in the 21 days after the screening visit, which, according to the clinical experts, seemed too short to allow for settling of the acute inflammation in the gut after a CDI episode. Active inflammation in the gut could impede the uptake of the microbiota in the enema, which could have impacted the results in both groups. In clinical practice, clinicians would wait for a longer period of time, sometimes up to 6 weeks or more, before proceeding with administration of the stool-derived enemas in conventional FMT programs.

Outcomes

The primary outcome in the PUNCH CD3 study was the recurrence of CDI within 8 weeks, which was considered appropriate to assess the efficacy of fecal microbiota (Rebyota), according to the clinical experts. The experts considered this to be representative of routine clinical practice in Canada, which focuses on self-reported resolution or a diminution of symptoms to a level that is acceptable for patients to maintain their quality of life. This was also consistent with patient and clinician input, all of which highlighted the importance of preventing CDI recurrences and adequately managing symptoms to improve HRQoL.

Follow-Up

The follow-up duration of 8 weeks for assessment of the primary outcome was considered appropriate by the clinical experts. In clinical practice, symptoms at 1 month are considered the most predictive of long-term prognosis. As such, the experts felt that an 8-week time point would capture most relapses. Nevertheless, although treatment is likely to last in the long-term, evidence beyond the follow-up duration of the studies is limited. The clinical experts indicated that there may be long-term, unintended effects of manipulating a patient’s microbiome, such as affecting the risk of developing a range of conditions over time, the impact of which is currently unknown.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to expert committee deliberations, and a final certainty rating was determined, as outlined by the GRADE Working Group.^16,17

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word likely for evidence of moderate certainty (e.g., X intervention likely results in Y outcome).

• Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We use the word may for evidence of low certainty (e.g., X intervention may result in Y outcome).

• Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of the effect. We describe evidence of very low certainty as very uncertain.

In accordance with the GRADE approach, evidence from the PUNCH CD3 study started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for fecal microbiota (Rebyota) and placebo. The target of the certainty of evidence assessment was the presence or absence of an important effect, based on thresholds identified in the literature. In the absence of such thresholds, the presence or absence of an important effect was informed by the clinical experts consulted for this review.

Long-Term Extension Studies

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

No long-term extension studies were submitted by the sponsor.

Indirect Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

No indirect evidence was submitted by the sponsor or reviewed by the CDA-AMC team.

The sponsor deemed that there were no comparators to fecal microbiota (Rebyota) in Canada for the preventive treatment of rCDI after antibiotic treatment for rCDI.

The appropriateness of this assumption is limited by the fact that patients who experience rCDI in clinical practice would not be left untreated, according to the clinical experts consulted for this review. Most notably, treatment options include long-term vancomycin administered in a taper or pulse regimen, as well as FMT. The CDA-AMC review team acknowledged that the use of FMT is generally restricted to trial settings in Canada; however, Health Canada has exempted the use of FMT to treat patients with CDI who are not responsive to conventional therapies from this restricted use. In addition, there is evidence in the literature pertaining to the effectiveness of various FMT programs,²⁷ although these are not directly funded by CDA-AMC participating drug plans.

As a result, the efficacy and safety of fecal microbiota (Rebyota) compared with any other therapies used in clinical practice to prevent rCDI is unknown.

Studies Addressing Gaps in the Systematic Review Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

An overview of the studies addressing gaps in the systematic review evidence submitted by the sponsor, including a summary of key results, is provided in Table 16.

Table 16: Summary of Gaps in the Systematic Review Evidence

CDI = Clostridium difficile infection; IBD = inflammatory bowel disease; IBS = irritable bowel syndrome; mITT = modified intention to treat; OL = open-label; SAE = serious adverse event; SF-36 = 36-Item Short Form Health Survey; TEAE = treatment-emergent adverse event; vs. = versus.

Sources: Clinical Trial Reports for PUNCH CD3 OLS and PUNCH CD2 studies and Feuerstadt et al. (2023).^19,43,44 Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁴⁵

PUNCH CD2 Study

Description of Study

The PUNCH CD2 study was conducted to assess the efficacy and safety of fecal microbiota (Rebyota) and to establish a treatment regimen of fecal microbiota (Rebyota) for subsequent confirmation in the PUNCH CD3 study. The PUNCH CD2 study was a phase II, prospective, multicentre, DB, randomized, placebo-controlled trial and has been summarized to provide evidence on additional efficacy outcomes (i.e., quality of life, assessed with the SF-36, and time to recurrence of CDI), as well as long-term safety outcomes (i.e., follow-up of 24 months for SAEs).

Populations

As in the pivotal trial, the PUNCH CD2 study included adult patients aged 18 years or older with rCDI. The PUNCH CD2 study included patients with more rCDI episodes than the PUNCH CD3 study, which required patients to have had 2 recurrences of CDI and at least 2 rounds of SOC oral antibiotic therapy or at least 2 severe CDI episodes resulting in hospitalization. Overall, both studies included similar inclusion and exclusion criteria, so the study populations were similar, as shown in Table 4.

Interventions

Adult patients with rCDI were randomized in a 1:1:1 ratio to receive a treatment course consisting of 2 doses of fecal microbiota (Rebyota) (group A), 2 doses of placebo (group B), or 1 dose of fecal microbiota (Rebyota) followed by 1 dose of placebo (group C). Randomization was stratified by antibiotic therapy used at screening. After antibiotic therapy for the qualifying CDI episode and a 24-hour to 48-hour antibiotic washout period, patients received blinded treatment. In each treatment group, doses were administered 7 ± 2 days apart. If a patient experienced a confirmed CDI recurrence in the 8 weeks after administration of the first course of treatment, they could choose to receive either SOC treatment or a second OL treatment course of fecal microbiota (Rebyota) of up to 2 doses, administered 7 ± 2 days apart.

Antibiotic therapy before the OL treatment course was at the investigator’s discretion, and was followed by a 24-hour to 48-hour antibiotic washout period, if taken. If a patient received OL fecal microbiota (Rebyota), follow-up requirements restarted from the last OL fecal microbiota (Rebyota) dose, in alignment with the same schedule as required for the blinded part of the trial.

To reflect the Health Canada recommended administration of 1 dose of fecal microbiota (Rebyota), this report will focus on the results of group B and group C in the PUNCH CD2 trial.

Outcomes

In the PUNCH CD2 study, both efficacy and safety were assessed during in-person site visits for symptoms 1 week, 4 weeks, and 8 weeks after the last assigned enema and during weekly (week 2, week 3, week 5, week 6, and week 7) and monthly (month 3, month 6, month 12, and month 24) phone calls; as well, patient diaries were reviewed at baseline and week 1. If a patient received treatment during the OL phase of the study, follow-up visits, phone calls, and completion of a new posttreatment patient diary occurred, in alignment with the same schedule as in the blinded phase.

Treatment Success

Treatment success was defined as the absence of C. difficile–associated diarrhea without the need for re-treatment with C. difficile anti-infective therapy or fecal transplant 56 days after administration of the last assigned study enema. Because the PUNCH CD2 study used a dosing regimen of 2 doses given 1 week apart, the follow-up period after the first dose was effectively 9 weeks. Furthermore, in the PUNCH CD2 study, treatment failure consisted of 4 criteria:

• The presence of CDI diarrhea, with or without other CDI symptoms, occurring less than 8 weeks after administration of the last assigned trial dose

• A positive stool test for C. difficile

• The need for re-treatment for CDI

• No other cause for CDI symptoms had been determined.

Some patients were considered to have experienced treatment failure by the study investigator because of a suspected CDI recurrence, despite not meeting all 4 criteria. These patients were classified as having an indeterminate response and were considered to have experienced treatment failure for efficacy analyses. Additionally, some patients were classified as experiencing treatment failure and offered OL treatment after only 1 blinded study treatment. These instances were recorded as protocol deviations, but the patients were still considered to have experienced treatment failure in the efficacy analysis.

Time to CDI Recurrence

Time to CDI recurrence was defined as the number of days from the second enema administration to the first assessment indicating recurrence for patients who met the criteria for failed treatment defined for the primary efficacy end point.

Quality of Life

The SF-36 scale was used to identify changes to quality of life after study treatment. The scale assesses 8 health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. Each item is scored from 0 to 100, with a higher score indicating a more favourable health state. Results were reported for the physical component and mental component summary scores.

Harms

Data related to AEs and SAEs were systematically collected during in-office visits and during phone calls after the last enema for up to 24 months.

Statistical Analysis

To demonstrate 80% treatment success with 2 doses of fecal microbiota (Rebyota) versus 40% with placebo, and to evaluate 1 dose of fecal microbiota (Rebyota) and 1 dose of placebo, 105 patients were required (to provide power of 90% at a type I error of 0.05). An additional 12 patients were enrolled to account for a 10% dropout rate, totalling 117 patients (39 per group). After protocol changes and the addition of antibiotic use as a stratification factor, the randomization schedule was updated, bringing the total to 132 patients (44 per group).

The primary efficacy analysis of group A versus group B and the first 2 secondary efficacy analyses of group C versus group B and group A versus group C were completed on the ITT, mITT, and PP populations (defined in a manner similar to that used in the PUNCH CD3 trial, with ITT being the primary analysis). A hierarchal testing method was used to assess treatment success. Comparisons followed a closed hierarchical testing method at a 2-sided alpha of 0.05. If group A and group B differed significantly, group C was compared to group B and, if significant, group A was compared to group C. However, the null hypothesis was not rejected for the primary efficacy analysis, and the proposed comparison of group C to group B commenced without alpha level adjustment. Patients who did not complete treatment or discontinued before 8 weeks after administration of the last dose were considered to have experienced treatment failure.

Time to CDI recurrence was analyzed using the Kaplan-Meier method, with median duration reported in days (and weeks) for both the ITT and PP populations. Estimates were provided for each scheduled CDI recurrence assessment time point (weekly up to week 8). Group comparisons between group B and group C were conducted using the log-rank test.

For SF-36 end points, changes from baseline were summarized using descriptive statistics by treatment arms using the ITT population. LOCF was used to impute missing postbaseline data.

Results

Patient Disposition

A total of 150 patients were enrolled into the PUNCH CD2 trial, with 133 patients randomized into group A (N = 45), group B (N = 44), and group C (N = 44) (Table 17). Of these, ██ ███████ in group B and ██ ███████ in group C entered the OL period after week 8. A total of ███████ patients in group B and ██ ███████ patients in group C discontinued the study for various reasons, including death █████ ██ ██████, other reasons █████ ██ █████, patient withdrawal █████ ██ █████, loss to follow-up █████ ██ ███████ or investigator withdrawal ███ ██ █████.

Table 17: Patient Disposition in the PUNCH CD2 Study

ITT = intention to treat; mITT = modified intention to treat; PP = per protocol.

Sources: Clinical Trial Report for PUNCH CD2 study.⁴³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁴⁵

Baseline Characteristics

The demographic characteristics were mostly balanced across treatment groups and were in line with those of patients in the PUNCH CD3 study, as shown in Table 9. Most patients in group B and group C were female (68.2% and 57.1%, respectively), white (█████ and 95.2%, respectively), and used vancomycin at screening (90.9% and █████, respectively). Compared with the PUNCH CD3 study, ████ ████████ ██ █████ ███ ███ ████ ████████████ ███ ████ ███ ███ ██████████ ██ ██████████ ███ ██████████ ██████ ██████ ██████ ██ █████ █ ███████ ██ █ ██ ███████ ███████ █ ███████ ██████████ ██ ████████ ██ █████ ███ ███ █████ ███ ███ ███████████ █ ██ ████ ███████████ ██ ████ ██ ████ ███████████ ███ ███ ████████ ██ █████ ████

Exposure to Study Treatments

All patients in group B (100%; n = 44) and all but 1 patient in group C (███████) received at least 1 enema during the blinded treatment portion of the trial. A total of ██ ███████ patients in group B and ██ ███████ patients in group C received their second blinded dose. During the OL portion, ██ ██ ██ enrolled ███████ patients originally in group B and ██ of ██ ███████ patients originally in group C received 2 fecal microbiota (Rebyota) enemas; the remaining patients received 1 enema.

Efficacy

A summary of efficacy results can be found in Table 18.

Treatment Success

In the ITT population, the treatment success rate 8 weeks after completion of the study treatment was 43.2% (19 of 44 patients) for group B and 56.8% (25 of 44 patients) for group C, with a difference of 13.6% (95% CI, ████ ██ ████; P = 0.201). During the OL phase, the treatment success rate among patients originally randomized to group B and group C was █████ ███ ██ ██ █████████ and █████ ██ ██ ██ █████████, respectively. The combined treatment success of all patients in the OL portion was █████ ███ ██ ██ █████████.

Time to CDI Recurrence

In the ITT population, the time at which ███ of the patients had a recurrence was ███ days in both group B (███ ███ █ ██ ██) and group C (███ ███ █ ██ ██).

Quality of Life

At baseline, all patients in group B and 95% of those in group C completed SF-36 assessments. At week 8, assessments were available for 70% and 73% of patients in group B and group C, respectively. Overall, both group B and group C showed an increase in mean scores for all SF-36 components from baseline to week 8. Between-group differences in the change from baseline were not reported.

Table 18: Summary of Efficacy Outcomes in the PUNCH CD2 Study

CDI = Clostridium difficile infection; CI = confidence interval; ITT = intention to treat; mITT = modified intention to treat; NE = not estimable; PP = per protocol; SD = standard deviation; SF-36 = 36-Item Short Form Health Survey.

Note: Treatment success in the PUNCH CD2 study was defined as the absence of C. difficile–associated diarrhea without the need for re-treatment with C. difficile anti-infective therapy or fecal transplant 56 days after administration of the last assigned study enema. Patients in group B received 1 dose of fecal microbiota (Rebyota) followed by 1 dose of placebo; patients in group C received 2 doses of placebo.

^aDifference in the percentage of treatment success between the treatment groups 8 weeks after treatment completion.

^bTwo-sided 95% CI using normal approximation for the difference in percentages between treatments.

^cThe P value from Pearson's chi-square test is for the difference between the treatment groups with respect to percentage of treatment successes. Indeterminate response was treated as a failure for the purpose of analysis.

^dThe null hypothesis was not rejected for the primary analysis and statistical comparisons continued without adjustment for multiple comparisons.

^eTime to CDI recurrence is the number of days from the second enema administration to the first assessment indicating recurrence. Patients who did not complete the assigned study treatment were censored at day 0. Patients who discontinued before 56 days after treatment completion were censored at the date of discontinuation. Patients whose treatment was considered a success were censored at day 56.

Source: Clinical Trial Report for PUNCH CD2 study.⁴³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁴⁵

Harms

In the PUNCH CD2 study, 86.4% of patients in group B and 78.6% in group C reported TEAEs during both the blinded and OL periods. From the start of the blinded phase through to 24 months after the last study enema or until OL treatment, █████ of group B and █████ of group C reported TEAEs. Of the most common TEAEs reported during this period (with at least 5% of patients in either arm), the following events were reported more frequently in group C than group B: ██████ █████ ███ ██████ ████████████ █████ ███ ██████ ██████ █████ ███ ██████ ██████████ █████ ███ ██████ ████████████ █████ ███ ██████ ███████ ██████ ███ ██████ █████████ █████ ███ ██████ ████ █████ ███ ██████ ███ ███████ █████ ███ █████. Overall, █████ of group B and █████ of group C reported SAEs, none of which were deemed by the investigators to be related to the treatment. ███ ███████ ██████ ██ █████ █ ███ ████████████ upon CDI recurrence within 8 weeks of blinded treatment and there were no ICU admissions. ████ ██████ ██████ occurred in group B and ███████ in group C, with most attributed to pre-existing conditions, and none were considered by the investigator to be related to the treatment under review or the enema procedure.

Critical Appraisal

The PUNCH CD2 study provided additional data on CDI recurrence, HRQoL assessed by the SF-36, as well as long-term safety data through the OL period, up to 24 months. Although the randomization methods appeared to be appropriate for limiting risk of bias in the randomization process, the small sample sizes in the study groups increased the risk that prognostic balance was not achieved (evidenced by imbalances in groups by sex and prior hospitalization for CDI). As such, it is possible that the observed effects were either overestimated or underestimated. The null hypothesis of the primary outcome of treatment success between group A and group B was not rejected in the primary efficacy analysis population (ITT), and the proposed secondary comparisons commenced without alpha level adjustment, violating the closed hierarchical testing method. In fact, continued testing without adjustments led to an increased risk of false positives in subsequent comparisons, such as for the primary end point in the PP population. The study is limited by the lack of placebo control beyond 8 weeks of treatment; results beyond 8 weeks are confounded by the use of OL fecal microbiota (Rebyota) in the placebo group. In the analysis of SF-36 scores, there is a risk of bias because of missing outcome data. Data were missing for up to ███ of patients across groups at 8 weeks. These data were imputed using the LOCF, a single-imputation method that relies on the assumption that HRQoL remained constant over time after the last available assessment, which is likely not reasonable. In terms of generalizability, patients with immunodeficiency, IBD, IBS, or celiac disease were excluded from the trial, which may raise concerns regarding the potential for pathogen transmission in such patient populations. A large majority of patients ███████ were using vancomycin at screening, which aligns with clinical practice, the clinical experts explained, because fidaxomicin is not commonly used to treat rCDI in Canada. As in the PUNCH CD3 study, the lack of comparative data limited the trial's ability to provide insight into the effectiveness and safety of fecal microbiota (Rebyota) compared to other available treatment options. In the PUNCH CD2 study, patients were required to have at least 2 recurrences of CDI in the trial; as such, the study population reflects that which the clinical experts indicated would be treated with fecal microbiota (Rebyota) in clinical practice.

PUNCH CD3 OLS Study

Description of Study

The PUNCH CD3 OLS study was a phase III, prospective, multicentre, OL, single-arm study. The objective of the study was to evaluate the safety, tolerability, and effectiveness of fecal microbiota (Rebyota) as single and repeat administrations in a population of patients with conditions that were excluded from previous trials. Specifically, this trial included patients with conditions such as IBS, IBD, and immunodeficiency.⁴⁴

Populations

Key inclusion criteria included:

• age 18 years or older.

• medical record documentation of either

  • a current diagnosis or history of rCDI, determined by the treating physician, or

  • at least 2 previous episodes of severe CDI resulting in hospitalization

• currently taking or newly prescribed antibiotics to control CDI-related diarrhea at the time of enrolment

• agreement not to take oral vancomycin, metronidazole, fidaxomicin, rifaximin, nitazoxanide, bezlotoxumab, or IV immunoglobulin before the 8-week follow-up assessment, unless newly prescribed by a treating investigator during the course of the trial as a result of rCDI diagnosis.

Key exclusion criteria included:

• a known history of refractory CDI

• continued CDI diarrhea despite receiving a course of antibiotics prescribed for CDI treatment

• receipt of systemic antibiotic therapy for a condition other than CDI

• prior participation in a clinical trial in which fecal microbiota (Rebyota) was received

• FMT in the previous 6 months

• FMT with an associated SAE related to the FMT product or procedure

• receipt of the CDI monoclonal antibody bezlotoxumab in the year before trial enrolment

• disease symptoms (diarrhea) caused by a confirmed intestinal pathogen other than C. difficile.

Interventions

At the time of enrolment in the PUNCH CD3 OLS study, patients were on active antibiotic treatment or had been prescribed antibiotics to control rCDI symptoms. Therefore, patients who had already completed a prescribed course of antibiotics to treat rCDI could not be considered for enrolment unless they had another recurrence requiring antibiotics.

Patients were treated with OL fecal microbiota (Rebyota), which was administered as a single dose. Trial treatment was completed in the 24 hours to 72 hours after completion of antibiotic treatment (i.e., antibiotic washout). Patients were eligible to receive a second dose of fecal microbiota (Rebyota) if the first dose was deemed to have failed. The use of antibiotics before the second dose was at the discretion of the investigator. If antibiotics were prescribed to control symptoms, the antibiotics were to be discontinued 24 hours to 72 hours before the administration of fecal microbiota (Rebyota).

Outcomes

The primary objective was to evaluate the safety and tolerability of fecal microbiota (Rebyota) in patients with rCDI. The primary safety end point was the number of patients with a TEAE related to treatment and/or to the administration procedure.

Other safety end points included the number of AEs per patient; the timing of attributable TEAEs; the duration of TEAEs; the relatedness of TEAEs; the severity of TEAEs; the causality of TEAEs to fecal microbiota (Rebyota), the administration procedure, C. difficile, or a prior condition; and number of each of the major complications of CDI reported up to 8 weeks after treatment.

Assessment of the secondary objectives included the following efficacy end points:

• recurrence of CDI up to 8 weeks after treatment

• loss of a sustained clinical response up to 6 months after treatment

• change from baseline in Cdiff32 Questionnaire score up to 8 weeks and up to 6 months after treatment.

Statistical Analysis

For continuous variables, descriptive statistics were generated. For discrete and/or categorical variables, the number and percentage of nonmissing patients were generated. Descriptive statistics were provided for all patients.

Assessment of the primary safety end point was performed on all patients exposed to fecal microbiota (Rebyota) (safety population), and included descriptive statistics. The safety population was used to summarize all AE data, unless otherwise specified. Safety data were summarized separately, using the same approach, for the first dose and, if applicable, the second dose.

Assessment of secondary efficacy objectives for the analysis of treatment success included descriptive statistics and was performed on the mITT population, defined as all enrolled patients who successfully received treatment, but excluding patients in whom treatment was attempted but not completed and patients who died, withdrew consent, or discontinued the trial before the 8-week efficacy end point evaluation, if the reason for exit was not related to CDI symptoms. To assess the sensitivity of the end points, efficacy analyses were repeated using the ITT population (i.e., all enrolled patients, excluding those who failed screening) and the PP population (i.e., patients who successfully received treatment and were analyzed according to the treatment they received, excluding patients with documented deviations from the inclusion or exclusion criteria and/or patients who exited the study before the 8-week efficacy evaluation, if the reason for exit was not related to CDI symptoms).

Results

Patient Disposition

Patient disposition in the PUNCH CD3 OLS study is summarized in Table 19. A total of 793 patients were screened, of whom 698 were enrolled and 697 were treated. Nine percent (n = 63) of treated patients discontinued the study, mostly because of loss to follow-up or withdrawal by the patient.

Table 19: Patient Disposition in the PUNCH CD3 OLS Study

ITT = intention to treat; mITT = modified intention to treat; PP = per protocol.

Source: Clinical Trial Report for PUNCH CD3-OLS study.⁴⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

Baseline characteristics of patients in the PUNCH CD3 OLS study are summarized in Table 20. The median age was ████ years (range, ██ ██ ██); 69.9% of patients were female; 93.8% of patients were white; 73.0% of patients had at least 3 prior CDI episodes; 84.6% of patients had received vancomycin to treat the CDI; 10.6% of patients had ulcerative colitis, Crohn disease, or IBD; and 20.2% of patients had immunocompromising conditions.

Table 20: Baseline Characteristics in the PUNCH CD3 OLS Study

CDI = Clostridioides difficile infection; EIA = enzyme immunoassay; GDH = glutamate dehydrogenase; ITT = intention to treat; PCR = polymerase chain reaction; SD = standard deviation.

^aNumber of CDI episodes recorded was incomplete for 4 participants.

^bEnrolling tests could be used in combination.

^cCategory other for enrolling diagnostic tests included medical record documentation of toxin A and toxin B and loop-mediated isothermal amplification (LAMP).

^dStandardized Medical Dictionary for Regulatory Activities (MedDRA) query of malignant tumours.

^eOther medical history includes the preferred terms of end stage renal disease, renal failure, asplenia, HIV, and HIV infection; the high-level term of hemoglobinopathies congenital; and the high-level group term of immunodeficiency syndromes.

^fImmunocompromising medications included corticosteroids and systemic immunosuppressive medications.

Source: Clinical Trial Report for PUNCH CD3-OLS study.⁴⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

Of the 697 patients in the safety population, all 697 (100%) patients successfully received 1 dose of fecal microbiota (Rebyota). An additional 121 patients successfully received a second dose, for a total of 818 doses administered during the trial.

Efficacy

Treatment Success

Treatment success was defined as the absence of CDI diarrhea in the 8 weeks after completion of the first dose. Of the 676 patients in the primary efficacy analysis population (mITT), 499 (73.8%) patients were reported to have treatment success in the 8 weeks after the first dose of fecal microbiota (Rebyota) (Table 21). Similar treatment success rates were observed for most demographic subgroups, including sex, race, ethnic group, site geography, number of prior CDI episodes, and Cdiff32 Questionnaire score; however, the treatment effect appeared to be of a smaller magnitude in patients aged65 years and older.

Table 21: Treatment Success in the 8 Weeks After the First Treatment in the PUNCH CD3 OLS Study

ITT = intention to treat; mITT = modified intention to treat; PP = per protocol.

Notes: Percentage is calculated using the number of patients in the column as the denominator.

The treatment outcomes were based on Endpoint Adjudication Committee determination.

Treatment success is defined as the absence of CDI diarrhea up to 8 weeks after completion of the first dose. Treatment failure is defined as the presence of CDI diarrhea in the 8 weeks after administration of a dose, which includes a positive stool test for C. difficile (determined by the central laboratory). If neither of the definitions was met, the treatment outcome was considered indeterminate.

Source: Clinical Trial Report for PUNCH CD3-OLS study.⁴⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

In the mITT population, a total of 121 patients experienced a recurrence of CDI after the first dose and received a second dose. Of those 121 patients, 67 patients (55.4%) achieved treatment success (Table 22).

Table 22: Treatment Success in the 8 Weeks After the Second Treatment in the PUNCH CD3 OLS Study

ITT = intention to treat; mITT = modified intention to treat.

Notes: Percentage is calculated using the number of patients who received 2 doses of fecal microbiota (Rebyota) as the denominator.

Treatment success is defined as absence of CDI diarrhea up to 8 weeks after completion of the second dose.

The treatment outcomes are based on the investigator's determination.

Source: Clinical Trial Report for PUNCH CD3-OLS study.⁴⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Sustained Clinical Response

Among patients who completed the 6-month follow-up, the sustained clinical response rate of fecal microbiota (Rebyota) among patients who previously achieved treatment success was 91.0% (Table 23).

Table 23: Sustained Clinical Response Rate up to 6 Months After the First Dose in the PUNCH CD3 OLS Study

ITT = intention to treat; mITT = modified intention to treat; PP = per protocol.

Note: Percentage is calculated using the number of patients with treatment success in the 8 weeks after the first treatment dose as the denominator.

^aSustained clinical response is defined as treatment success for the presenting CDI recurrence, with no new CDI episodes for more than 8 weeks after completion of the first dose during the 6 months of follow-up.

Source: Clinical Trial Report for PUNCH CD3-OLS study.⁴⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

HRQoL (Cdiff32 Questionnaire Score)

The mean (SD) change from screening to postdose assessment in Cdiff32 Questionnaire scores, ██████████████████████████ ███████████████ (Table 24).

Table 24: Summary of Cdiff32 Questionnaire Scores by Visit After the First Dose in the PUNCH CD3 OLS Study

Cdiff32 = Clostridioides difficile infection Health-Related Quality of Life; mITT = modified intention to treat; SD = standard deviation.

^aN is the number of patients with both screening and postdose measurements.

Source: Clinical Trial Report for PUNCH CD3-OLS study.⁴⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Harms

A total of 697 patients were included in the safety population. Of these, ██████████ patients reported TEAEs after fecal microbiota (Rebyota) administration. TEAEs were ██████████████████████████████████ in severity and related to pre-existing conditions and/or CDI (█████████████ respectively) (Table 25 and Table 26).

Table 25: Summary of Harms in the PUNCH CD3 OLS Study (Safety Population)

TEAE = treatment-emergent adverse events.

Notes: Percentage is calculated using the number of patients in the column heading as the denominator.

TEAEs are defined as any adverse events occurring on or after the first dose.

^aBoth patients and events are by maximum severity per patient.

Source: Clinical Trial Report for PUNCH CD3-OLS study.⁴⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 26: Details of Harms in the PUNCH CD3 OLS Study (Safety Population)

MedDRA = Medical Dictionary for Regulatory Activities; TEAE = treatment-emergent adverse events.

Notes: Percentage is calculated using the number of patients in the column heading as the denominator.

TEAEs are defined as any adverse events occurring on or after the first dose.

TEAEs counted in the second treatment period are reported with an onset date on or after the date of the second dose during the 8-week time frame.

Source: Clinical Trial Report for PUNCH CD3-OLS study.⁴⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

The single-arm nature of the PUNCH CD3 OLS study does not allow for causal conclusions to be drawn regarding the efficacy or safety of fecal microbiota (Rebyota). Given the absence of a randomized comparator, it is not possible to determine the extent to which the observed responses can be attributed to fecal microbiota (Rebyota) or to the natural history of disease. A patient’s awareness of the treatment received can introduce bias in outcomes such as HRQoL and subjective harms outcomes. Although the selection criteria allowed for a broader population, the number of patients with Crohn disease, ulcerative colitis, IBD, and immunodeficiency was small. Therefore, the generalizability of the findings to patients who have these coexisting comorbidities is uncertain.

Feuerstadt et al. Study

A retrospective study by Feuerstadt et al. (2023)¹⁹ assessed the efficacy and safety of fecal microbiota (Rebyota) administered to adult patients with rCDI, using broad eligibility criteria to reflect real-world conditions. The study provides evidence on the effectiveness and safety of fecal microbiota (Rebyota) in patients with common rCDI comorbidities, such as IBS, IBD, and immunodeficiency.

Populations

The study enrolled adult patients with rCDI who received fecal microbiota (Rebyota) across 5 study sites in the US from November 2015 to September 2019. Eligibility was determined by the treating physician, in accordance with guidance from the FDA enforcement discretion policy⁴⁶ to include patients with CDI that is unresponsive to standard therapies. A C. difficile lab diagnosis was not required, and there were no exclusion criteria. The treating physician decided on whether to administer 1 or 2 doses of fecal microbiota (Rebyota) before the intervention. Patients with rCDI after the first dose could receive a second dose. The maximum number of doses per patient was 4 (2 treatment courses of 2 doses each).

Outcomes

The primary end point was the number of patients with TEAEs, defined as AEs that occurred after treatment with fecal microbiota (Rebyota). Other safety end points included TEAEs of special interest, the relatedness and severity of TEAEs, and the onset or worsening of chronic conditions. Secondary objectives assessed the efficacy of fecal microbiota (Rebyota) in preventing rCDI in the 8 weeks after treatment and the sustained response up to 6 months. Treatment success was defined as the absence of CDI recurrence in the 8 weeks after administration of fecal microbiota (Rebyota). Sustained clinical response was defined as no documented on-study CDI event in the 6 months after the final dose of fecal microbiota (Rebyota) administered for the qualifying CDI event.

Statistical Analysis

Patient data were retrospectively captured by site staff chart review and recorded using an electronic database using a prespecified protocol. The FAS (N = 94) comprised all enrolled patients that met the eligibility criteria. The PSS (N = 64) included patients who were naive to fecal microbiota (Rebyota) treatment and who had continuous medical records for 6 months after treatment administration.

Results

In the FAS, the mean age was 59.8 years (SD = 20.3 years), 44.7% of patients were aged 65 years or older, and 72.3% were female. A total of 47.9% of patients had a comorbid condition, with the most common including gastroesophageal reflux disease (47.9%), IBS (17.0%), diverticulitis (14.9%), and gastritis (11.7%).

In the FAS, 66 of 94 patients (70.2%) achieved treatment success at week 8 after their first fecal microbiota (Rebyota) treatment, with 74.4% and 66.7% of patients who received 1 or 2 doses, respectively, experiencing treatment success at week 8. Of the 66 patients who experienced treatment success at week 8, 58 (87.9%) showed a sustained clinical response for 6 months after treatment. In the PSS, 53 of 64 patients (82.8%) experienced treatment success, of whom 47 (88.7%) demonstrated a sustained clinical response at 6 months.

In the PSS, 40 of 64 patients (62.5%) experienced any TEAE, 17.2% of which were deemed to be related to fecal microbiota (Rebyota) and 4.7% of which were deemed related to the procedure, according to the investigators. The most common TEAEs included abdominal pain (14.1%), diarrhea (14.1%), and urinary tract infection (10.9%). A total of 12.5% of patients experienced an SAE, and 1 patient (1.6%) died during the study analysis period from multiorgan failure; none of these events were deemed to be related to the treatment or procedure, according to the investigators.

Critical Appraisal

The retrospective analysis evaluated a patient population with broad eligibility criteria, which included patients with various comorbidities and immunocompromising conditions. As only a publication was provided for this retrospective study, the review team was unable to perform a thorough evaluation of the methods and the reporting of the analyses. The reporting of harms and subjective measures (such as symptoms) may be biased by patient knowledge of the treatment received. The noncomparative nature of the study design does not allow for causal conclusions to be drawn regarding the efficacy and harms of fecal microbiota (Rebyota). Patients were eligible to receive up to 4 doses of fecal microbiota (Rebyota) over the course of 2 treatments, which is more than the Health Canada recommendation of 1 dose of fecal microbiota (Rebyota). As such, the results may not be generalizable to the Health Canada recommended dose.

Lee et al. Study

Description of Study

The summary by Lee et al.⁴² included pooled safety data from 5 prospective studies of patients exposed to at least 1 study treatment, including 3 phase II studies (the PUNCH CD, PUNCH CD2, and PUNCH CD3 OLS studies), and 2 phase III studies (the PUNCH CD3 study and an interim data cut of the PUNCH CD3-OLS study). These studies evaluated the cumulative safety of fecal microbiota (Rebyota) using standardized manufacturing practices and evolving pathogen screening to ensure safety.

Population

All trials enrolled adults aged at least 18 years with rCDI who had received antibiotics for their CDI episode before study treatment. Dosing regimens varied among trials, with patients receiving either a single dose or 2 doses of fecal microbiota (Rebyota) and/or placebo, administered 7 ± 2 days apart. Four trials allowed OL treatment with fecal microbiota (Rebyota) if a CDI recurrence was confirmed during the 8 weeks after the initial treatment course. The full summary population comprised 978 patients who received at least 1 dose of fecal microbiota (Rebyota) and 83 patients who received only placebo. At baseline, the pooled trial data showed that a higher proportion of patients in the fecal microbiota (Rebyota) group were aged 65 years or older than in the placebo group (48.2% versus 37.3%). Additionally, more patients in the fecal microbiota (Rebyota) group (78.0%), the placebo plus fecal microbiota (Rebyota) group (83.3%), and the fecal microbiota (Rebyota) plus OL fecal microbiota (Rebyota) group (79.6%) had experienced 3 or more CDI episodes before trial entry than in the placebo group (68.7%).

Outcomes

The primary outcome was the number of patients who experienced a TEAE related to fecal microbiota (Rebyota) and/or the administration procedure that occurred on or after the day of treatment. Additional safety objectives included the number of AEs per patient, the occurrence of TEAEs of special interest (per the study definition), the relation between TEAEs and the treatment, the severity of TEAEs, and the onset of new chronic conditions or the worsening of existing conditions after treatment.

Results

The most common TEAEs across all treatment groups and courses were in the gastrointestinal disorders system organ class, and included diarrhea, abdominal pain, and nausea. Most of the events were mild or moderate in severity. Serious TEAEs were similar in the placebo (60.2%) and fecal microbiota (Rebyota) 1-dose (66.4%) groups, but higher in the blinded or any fecal microbiota (Rebyota) groups (68.8%). The majority of serious TEAEs were unrelated to fecal microbiota (Rebyota) treatment. A total of 18 deaths were reported in the clinical trials, all in patients who received fecal microbiota (Rebyota), although none were considered to be related to the treatment.

Critical Appraisal

Evidence from the pooled safety data suggests acceptable tolerability of fecal microbiota (Rebyota) in a diverse cohort of patients from 5 prospective trials, although a small proportion received placebo only (N = 83). The long-term harms data from these trials are consistent, with gastrointestinal disorders being the most common TEAE. However, it is important to note that the pooled data were not designed to assess the safety of fecal microbiota (Rebyota) in a statistically rigorous manner. Limitations include potential heterogeneity in the study protocols, variations in dosing regimens, and differences in patient populations that may have affected the internal validity of the safety results. Furthermore, the OL treatment allowed in some trials could introduce bias, particularly in the reporting of subjective AEs if participants believed the treatment was beneficial. Additionally, the pooling of data from multiple trials may obscure specific interactions or effects evident in individual studies, impacting the overall interpretation of safety outcomes.

Khanna et al. Study

The sponsor provided additional data from a retrospective cohort study by Khanna et al. (2025).²⁰ In this study of 196 adults in the US with rCDI who received fecal microbiota (Rebyota) between July 2023 and August 2024, the overall treatment success rate at 8 weeks was 83%. In the overall population, most patients (n = 136) had experienced at least 3 prior CDI recurrences. Success rates were consistent in the subgroups of the number of prior recurrences. The study, however, had important limitations. Baseline patient characteristics were limited, with no detailed information on the exact number of prior CDI episodes, comorbidities, or the antibiotic regimen used other than the product name, preventing the assessment of their impact on outcomes. The analyses did not adjust for confounding factors, lacked a control arm, and may have been subject to selection bias because of the nonrandomized study design. Differences in health care access and the predominance of treatment in infusion centres in the southern and western US may further limit the generalizability of the findings. As such, the results should be considered to be supportive evidence.

Discussion

Summary of Available Evidence

One study was identified in systematic review: the PUNCH CD3 study (n = 289), which was a phase III, multicentre, DB, placebo-controlled, randomized trial designed to evaluate the efficacy and safety of fecal microbiota (Rebyota) in preventing recurrences of CDI in adult patients after antibiotic treatment for rCDI. The primary outcome was the recurrence of CDI at 8 weeks.

Input from clinical experts suggested that findings from the PUNCH CD3 trial may be generalizable to patients considered, overall, to be at a lower risk for CDI recurrences than patients typically seen in clinical practice who would have the greatest unmet need and be the best candidates to receive fecal microbiota (Rebyota). This was based on the low number of previous CDI recurrences in the trial, as well as on the exclusion of patients with relevant comorbidities. In addition, it is unknown whether patients in both groups previously received an appropriate antibiotic regimen of vancomycin taper or pulse for the treatment of the qualifying CDI episode. The relevance of using placebo as a comparator is, therefore, uncertain, as the CDI treatment in the study was not consistent with recommendations from the Canadian guidelines or with the treatment that patients would receive in clinical practice.

Additional studies assessed in the fecal microbiota (Rebyota) review to address important gaps in the evidence included the following:

• The PUNCH CD2 study (N = 133) is a phase II, prospective, multicentre, DB, randomized, placebo-controlled trial that assessed the efficacy and safety of fecal microbiota (Rebyota) in adult patients aged 18 years or older with rCDI. Patients were randomized into 1 of 3 groups after a course of antibiotics: 2 doses of fecal microbiota (Rebyota) (group A); 2 doses of placebo (group B); or 1 dose of each (group C). The study focused on treatment success (no CDI recurrence in the 8 weeks after treatment), time to CDI recurrence, quality-of-life changes measured with the SF-36 scale, and long-term safety outcomes (with follow-up for AEs up to 24 months).

• The PUNCH CD3 OLS study (N = 698) was a phase III, prospective, multicentre, OL, single-arm study. The objective of the study was to evaluate the safety, tolerability, and effectiveness of fecal microbiota (Rebyota) as single and repeat administrations in a population of patients with conditions that were excluded from previous trials, such as Crohn disease, ulcerative colitis, IBD, IBS, and immunodeficiency.

• Feuerstadt et al. (2023)¹⁹ (N = 94) conducted a retrospective study on the efficacy and safety of fecal microbiota (Rebyota) in adult patients with rCDI, using broad eligibility criteria to mirror real-world conditions. The study assessed the effectiveness and safety of fecal microbiota (Rebyota) in patients with comorbidities like IBS, IBD, and immunodeficiency.

• Lee et al.⁴² assessed pooled safety data from 5 prospective studies of patients exposed to at least 1 study treatment, including 3 phase II studies (the PUNCH CD, PUNCH CD2, and PUNCH CD3 OLS studies) and 2 phase III studies (the PUNCH CD3 study and an interim data cut of the PUNCH CD3-OLS study).

Interpretation of Results

Efficacy

CDI is a spore-forming, toxin-producing, Gram-positive anaerobe that colonizes the gut,¹ causing profuse, watery diarrhea. Severity can reach fulminant colitis with systemic toxicity and shock² and, as such, CDI contributes to significant morbidity and mortality.³ Based on prevalence estimates, the projected number of CDI cases in Canada in 2024 was approximately 47,000.⁷ With symptoms such as fatigue, weight loss, abdominal pain, frequent urgent bathroom use, and psychological distress, CDI significantly impacts HRQoL.⁵ Up to 25% of patients may experience rCDI after antibiotic treatment, and the risk of recurrence increases substantially, to up to 50%, after the second recurrence.²⁷ Indeed, the natural disease trajectory becomes more complex in patients who have experienced at least 2 recurrences, after which the risk of experiencing further recurrences becomes incrementally higher. Therefore, there is a need for accessible, effective, and well-tolerated therapies to prevent rCDI in patients who have a multirecurrent condition despite appropriate antibiotic treatment and whose condition has a substantial impact on quality of life.

The primary outcome in the PUNCH CD3 study was treatment response after 8 weeks. Results suggest that a higher proportion of patients is likely to achieve treatment success at 8 weeks after fecal microbiota (Rebyota) than after placebo. The between-group difference in the mean success rate was 12.3% (95% CrI, 1.4% to 23.3%) over 8 weeks. No MCID was reported in the literature as a threshold for treatment success or for between-group differences, so the presence of an important effect was informed by the clinical experts consulted for this review. The point estimate suggests the presence of a clinically important effect; however, the lower bound of the CrI is consistent with a trivial effect, which would not be considered clinically important for patients.

The clinical experts noted that patients included in the trial were likely to be at a lower risk for CDI recurrence than patients typically seen in clinical practice who would have the greatest unmet need and be the best candidates to receive fecal microbiota (Rebyota). One of the reasons for this is the inclusion of patients who had only 1 recurrence of CDI, who accounted for █████ of patients in the fecal microbiota (Rebyota) group and █████ of patients in the placebo group. Patients who experience a first recurrence may have their condition improve spontaneously and may maintain a sustained response without active treatment. However, the natural disease trajectory becomes more severe in patients who have experienced at least 2 recurrences, and the risk of experiencing further recurrences becomes incrementally higher. Therefore, the clinical experts emphasized that fecal microbiota (Rebyota) should be reserved for patients who have experienced at least 2 recurrences and who have had a relapse after a vancomycin taper or pulse regimen. Results of the prespecified subgroup analyses of treatment response were mostly consistent with the main analysis; however, for patients who experienced 2 or fewer recurrences and who were treated with vancomycin for 14 days or less, the results suggested less benefit with fecal microbiota (Rebyota). Although credible effect modification could not be inferred from these analyses, the results raise uncertainty about whether the magnitude of benefit observed in the PUNCH CD3 study can be generalized to these groups of patients. However, it appears plausible, based on experience in clinical practice and supplementary findings from the PUNCH CD3 study, that the benefits of treatment would be maintained in a population of patients who have a more severe condition. In the PUNCH CD3 study, although the majority of patients received vancomycin for the treatment of the qualifying episode, no detail was reported regarding the specific regimen used (e.g., whether patients received a prolonged taper or pulse vancomycin treatment, per recommendations from the Canadian guidelines). Short courses of antibiotics, even up to 21 days (as the trial’s protocol required), are unlikely to be sufficient to manage multiple episodes of rCDI, according to the clinical experts. The relevance of using placebo as a comparator is, therefore, uncertain, as the CDI treatment in the study was not consistent with the treatment that patients would receive in clinical practice. Thus, the generalizability of the results from patients in the study population to patients who would be candidate to receive fecal microbiota (Rebyota) in clinical practice is uncertain.

The primary analysis was based on posterior estimates from the Bayesian hierarchical model in the mITT population. The posterior probability of superiority exceeded the final secondary threshold, but not the primary, protocol-specified threshold. Sensitivity analyses of the primary outcome based on alternate analysis populations yielded consistent results. Findings from a frequentist sensitivity analysis without Bayesian borrowing were, overall, consistent and suggest that results from the Bayesian approach are likely driven by the informative priors used based on the phase II PUNCH CD2 trial.

There was no clinically important difference between fecal microbiota (Rebyota) and placebo in sustained clinical response at 6 months among patients who previously achieved treatment success at 8 weeks. In addition, the evidence was insufficient to draw any conclusions about the effect of fecal microbiota (Rebyota) relative to placebo on hospitalizations and ICU admissions.

HRQoL was assessed as an exploratory outcome using the Cdiff32 Questionnaire. The study was not designed to test for differences in HRQoL, and findings should be interpreted with this consideration. The results did not suggest HRQoL benefits with fecal microbiota (Rebyota). The between-group difference in the change from baseline in HRQoL was less than the suggested MCID of 10 points. There was uncertainty because of imprecision and the literature-based MCID, which was estimated using a distribution-based approach. As such, it is unclear whether the estimated MCID would reflect a clinically meaningful change from the perspectives of patients. This MCID was also estimated for within-group changes, rather than between-group differences. The evidence for change from baseline HRQoL at 6 months was very uncertain, owing to imprecision and an important risk of bias due to missing outcome data. In addition, some patients in the placebo group had also received active treatment with OL fecal microbiota (Rebyota).

Fecal sequencing analysis suggests that the microbiome composition of patients experiencing treatment success changed from baseline over all time points. The change in microbiome composition after treatment was characterized by an increase in Bacteroidia-class and Clostridia-class bacteria and a decrease in Gammaproteobacteria-class and Bacilli-class bacteria.

Additional studies were assessed in the fecal microbiota (Rebyota) review to address important gaps in the evidence. In the PUNCH CD2 study, efficacy results of treatment success at 8 weeks and median time to CDI recurrence between treatment group B versus treatment group C align with the results of the PUNCH CD3 study. However, the primary outcome's null hypothesis between group A and group B was not rejected. In the PUNCH CD3 OLS single-arm study, efficacy results suggested a treatment success at 8 weeks that aligns with the results of the PUNCH CD3 study. In the absence of a randomized comparator, however, it is not possible to draw causal conclusions regarding the efficacy of fecal microbiota (Rebyota) from this study. In addition, the number of patients with Crohn disease, ulcerative colitis, IBD, IBS, and immunodeficiency enrolled in the study was small; thus, the generalizability of the findings to patients who have these coexisting comorbidities remains uncertain. Feuerstadt et al. (2023)¹⁹ showed that a similar proportion of real-world patients, including those with comorbidities (IBS, IBD, immunodeficiency) achieved treatment success at week 8 after fecal microbiota (Rebyota) treatment; however, the design of this study did not allow for causal conclusions to be drawn regarding the efficacy of fecal microbiota (Rebyota), and patients could receive up to 4 doses of fecal microbiota (Rebyota) — 2 courses of 2 doses each — which exceeds Health Canada’s 1-dose recommendation and could, therefore, lead to an overestimation of treatment response.

Because the PUNCH CD3 study included a placebo control group, there is no direct evidence to inform the effectiveness and safety of fecal microbiota (Rebyota) relative to other currently used therapies for the prevention of rCDI, particularly FMT, in patients who have received an appropriate antibiotic regimen of prolonged vancomycin taper or pulse. In addition, no indirect evidence was submitted. The absence of comparative evidence, especially against conventional, multidose FMT, was considered a limitation, as experience from clinical practice and data from the literature suggest that FMT may achieve clinical response rates of up to more than 90%.²⁷ As a result, however, the comparative efficacy and safety of fecal microbiota (Rebyota) is unknown. It is worth noting, however, that the RCTs investigating FMT are heterogeneous; many studies included small patient numbers, and trials varied by inclusion and exclusion criteria, donor type, mode of delivery, number of doses, length of follow-up, and volume per dose. The response rates ranged from 44% up to more than 90%, and it appears that patients may require multiple FMTs to achieve a clinical response rate of more than 80%.²⁷

Harms

More than two-thirds of patients receiving fecal microbiota (Rebyota) experienced at least 1 AE during the PUNCH CD3 study. AEs were numerically more frequent in patients who received 2 doses of fecal microbiota (Rebyota) than in patients who received only 1 fecal microbiota (Rebyota) dose. The most common TEAEs were related to gastrointestinal disorders (i.e., diarrhea, abdominal pain, nausea, and abdominal distention).

SAEs were relatively uncommon, but were also numerically more frequent in patients who received 2 doses of fecal microbiota (Rebyota) than in patients who received only 1 fecal microbiota (Rebyota) dose. The 2 deaths reported during the trial were in patients who received fecal microbiota (Rebyota), but were not related to the study drug or enema procedure, according to the sponsor. One patient in the fecal microbiota (Rebyota) group experienced septic shock as a major complication of new CDI and underwent emergency colectomy. The sponsor reported no events of toxic megacolon or colonic perforation. Findings from the phase II, placebo-controlled PUNCH CD2 study, as well as from the single-arm PUNCH CD3 OLS study, were consistent with those from the pivotal trial. However, because of the absence of a randomized comparator, the PUNCH CD3 OLS study did not allow for causal conclusions to be drawn regarding the safety of fecal microbiota (Rebyota).

Overall, the clinical experts indicated that the harms profile of fecal microbiota (Rebyota) did not raise any new safety signals or any particular safety concern. As with most clinical trials, the study was not powered to detect infrequent AEs or those with a lag time. The clinical experts indicated that there may be long-term, unintended effects of manipulating a patient’s microbiome, such as affecting the risk of developing a range of conditions over time, the impact of which is currently unknown. In addition, the experts emphasized that fecal microbiota (Rebyota) is not risk-free and, therefore, shared decision-making is required so that patients are informed about the balance of potential benefits and risks before they decide whether to proceed with fecal microbiota (Rebyota) treatment.

Other Considerations

The clinical experts highlighted the need for accessible, effective, and well-tolerated therapies to prevent rCDI. Patients with the greatest unmet needs are those who have a severe, multirecurrent condition; those who are not able to stop an antibiotic taper or pulse regimen; and those in whom the condition has a substantial impact on quality of life.

The clinical experts indicated that in clinical practice, FMT is effective in these patients at preventing rCDI; however, FMT is not readily available to many patients in Canada. Issues currently surrounding the limited access to FMT, according to the clinical experts, include the lack of public or private funding for FMT (which leaves FMT programs heavily dependant on physicians and research grants); the infrastructures and level of expertise that are required to create and administer an FMT program; and the challenges involved in establishing and maintaining stool banks for FMT (criteria to become a stool donor are strict and donors are essentially volunteering, which makes them difficult to retain).

In addition, the clinical experts made the CDA-AMC clinical review team aware of the possibility that conventional FMT programs could be shut down by Health Canada when a commercial product, (i.e., fecal microbiota [Rebyota]) becomes available. Health Canada notified CDA-AMC that clinicians were advised that, although fecal microbiota (Rebyota) has been authorized, it is not yet marketed. Therefore, no changes will be made to the current interim policy outlined in the guidance document: Fecal Microbiota Therapy Used in the Treatment of Clostridioides difficile Infection Not Responsive to Conventional Therapies. Once fecal microbiota (Rebyota) becomes marketed, Health Canada will explore options for transitioning away from the interim policy, with further details to be provided in due course.

According to the clinical experts, fecal microbiota (Rebyota) can be considered very similar to the product that is being administered through conventional FMT. However, whereas fecal microbiota (Rebyota) relies on a single administration, FMT programs may routinely offer repeated doses over 1 week. A commercial, regulated, stool-derived product such as fecal microbiota (Rebyota) can potentially increase access to treatment, which was viewed by the clinical experts as an acceptable trade-off to its single administration. The experts indicated that fecal microbiota (Rebyota) may, therefore, cause a shift in the current treatment paradigm, provided that health care systems can offer the necessary funding, infrastructures, and resources for product administration and that there are no interruptions in the supply chain.

Conclusion

In patients with rCDI, moderate-certainty findings from the PUNCH CD3 study suggest that treatment with fecal microbiota (Rebyota) likely results in a clinically important increase in the treatment success rate over 8 weeks, compared to placebo. Findings were obtained in a population that was, however, at a lower risk for CDI recurrences than patients who have the greatest unmet need and would benefit the most from treatment with fecal microbiota (Rebyota), according to the clinical experts. This population at need would include patients who have experienced at least 2 recurrences despite an appropriate antibiotic treatment consisting of a vancomycin taper or pulse regimen. Findings from supplementary, prespecified subgroup analyses raise uncertainty as to whether the overall effect can be generalized to patients who have experienced fewer than 2 recurrences or who have received vancomycin for 14 days or less. Although the generalizability of results from patients in the study population to patients who would be candidates to receive fecal microbiota (Rebyota) in clinical practice is uncertain, it appears plausible that the benefits of treatment could be maintained in a population of patients who have a higher risk of recurrence. Most patients who previously achieved treatment success at 8 weeks with either fecal microbiota (Rebyota) or placebo were able to maintain a sustained clinical response at 6 months; therefore, there may be no added benefit with fecal microbiota (Rebyota) for maintaining response over time compared to placebo. Based on results from exploratory analyses, fecal microbiota (Rebyota) may result in little to no difference in HRQoL, measured with the Cdiff32 Questionnaire, over 8 weeks compared to placebo. HRQoL results at 6 months were too uncertain to draw a definite conclusion. In addition, the evidence was insufficient to draw any conclusions about the effect of fecal microbiota (Rebyota) relative to placebo on hospitalizations and ICU admissions.

A relatively high proportion of patients in the PUNCH CD3 study experienced AEs, most notably related to gastrointestinal disorders. AEs were numerically more frequent in patients who received 2 doses of fecal microbiota (Rebyota) than in patients who received only 1 fecal microbiota (Rebyota) dose and in patients who received placebo. However, fecal microbiota (Rebyota) appeared to be well tolerated, with relatively few SAEs. The clinical experts noted that although treatment with fecal microbiota (Rebyota) is not without risks, the overall harms profile did not raise any particular safety signals. However, the long-term, unintended effects of manipulating a patient’s microbiome are currently unknown.

The trial could not inform on the effectiveness and safety of fecal microbiota (Rebyota) relative to other currently used therapies for rCDI, such as conventional, multidose FMT. Whether patients in the 2 groups previously received an appropriate antibiotic regimen of vancomycin taper or pulse for the treatment of the qualifying CDI episode is unknown. The relevance of using placebo as a comparator is therefore uncertain, as the CDI treatment in the study was not consistent with recommendations from the Canadian guidelines or with the treatment that patients would receive in clinical practice. Four additional studies were assessed in the fecal microbiota (Rebyota) review, but could not inform on important gaps in the evidence.

The clinical experts indicated that although effective, FMT is an intervention with limited access and, therefore, it is not readily available to many patients in Canada. A commercial, regulated, stool-derived product such as fecal microbiota (Rebyota) can potentially increase access to treatment, which was viewed by the clinical experts as an appropriate trade-off to its single administration. The experts indicated that fecal microbiota (Rebyota) may, therefore, cause a shift in the current treatment paradigm, as long as health care systems can provide the infrastructures and resources related to prescribing considerations and administration of the product.

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Appendix 1: Detailed Outcome Data

Please note that this appendix has not been copy-edited.

Additional post hoc survival analyses conducted on PUNCH-CD2 data were used to inform the pharmacoeconomic model, the results of which are described below.

PUNCH CD2 ITT Survival Analysis

As noted in Table 27, in a post hoc survival analysis in the ITT population, ████████ ███████████ █████████ ████ ████ ██ ██████ █ ███ ██ ███████ █████ █ ████ ███ █████ █████ ██ █████ █ ████ █ ████████ ███████████ ████ ████████ For Arm A, ███ █████ █████ ████████ ██ █████ ██ ████ █ ██████ ███ ██ ██ █████████ █████████ ██ █ ████████ ███████████ ████████ By month 12, ███ ██████████ █████ ████████ ███ ██ ███ █████████ ██ █████████ ███████ ██ █ ████████ ███████████ ██ █████████ █████████ ██████ ██████ █ ███████ ███████ ██ █████ ██ █████ ███████████ ███ ████████ ██████████████

Table 27: Post Hoc Survival Analysis (ITT Population)

CI = confidence interval; ITT = intention to treat; SE = standard error.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁴⁵

mITT and SP Survival Analysis

In the modified intended to treat (mITT) and safety population (SP) designs, ███ ████ ██████████ ████████ ██ ██ ███ ███ ██████ ████ ████████ ███ ████ ███████ ████████ ██ ████ ████████

PP Survival Analysis

As show in Table 28, in the per protocol design, ████████ ███████████ █████████ ████ ████ ██ █████ ██ ████ █████ █████████ ██ █████ █ ███ █████ ███ █████ █ ███ █ ████ ███ ██████ █████ ██ █████ ██ ███ █████ ██ ████████████.

Table 28: Post Hoc Survival Analysis (PP Population)

CI = confidence interval; PP = per protocol; SE = standard error.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁴⁵

In the PUNCH-CD2 study, long-term follow-up data were collected via monthly phone assessments (months 3, 6, 12, and 24), which may not fully capture changes in patients’ health status between assessments. This could have led to an underreporting of events in the survival analysis. A large proportion of patients discontinued the study (█████████████ ███ ██ █████ ██ █████ ████ ██ █████████. This can introduce bias, as patients who withdrew may have been in worse health, which could artificially inflate the survival probability. The combination of high dropout rates, potential underreporting of events, and censoring bias limits the reliability of the results of the survival analysis.

Pharmacoeconomic Review

Abbreviations

Executive Summary

The executive summary comprises 2 tables (Table 1 and Table 2) and a conclusion.

Table 1: Submitted for Review

CDI = Clostridioides difficile infection; NOC = Notice of Compliance.

Table 2: Summary of the Economic Evaluation

CDA-AMC = Canada's Drug Agency; CDI = Clostridioides difficile infection; FMT = fecal microbiota transplant; ICER = incremental cost-effectiveness ratio; LY = life-year; QALY = quality-adjusted life-year; rCDI = recurrent C. difficile infection; vs. = versus; WTP = willingness to pay.

Conclusions

Evidence from the PUNCH CD3 trial suggests that fecal microbiota (Rebyota) likely leads to a clinically important improvement in treatment success rate over 8 weeks compared to placebo for the prevention of the recurrence of Clostridioides difficile infection (CDI) in adults after antibiotic treatment for recurrent CDI (rCDI). According to the Canada's Drug Agency (CDA-AMC) Clinical Review Report, most patients who previously achieved treatment success at 8 weeks with either fecal microbiota (Rebyota) or placebo were able to maintain a sustained clinical response at 6 months; therefore, there may be no added benefit with fecal microbiota (Rebyota) on this outcome compared to placebo. Based on results from exploratory analyses, fecal microbiota (Rebyota) may result in little to no difference in health-related quality of life (HRQoL) over 8 weeks compared to placebo, and HRQoL results at 6 months were too uncertain to draw a definite conclusion. In addition, the evidence was insufficient to draw any conclusions on the effect of fecal microbiota (Rebyota) relative to placebo on hospitalizations or intensive care unit (ICU) admissions. The trial could not inform on the effectiveness or safety of fecal microbiota (Rebyota) relative to other currently used therapies for rCDI, such as conventional, multidose fecal microbiota transplant (FMT), nor did the sponsor submit indirect evidence to supplement the gap in comparative evidence. Whether patients in the 2 groups previously received an appropriate antibiotic regimen of vancomycin taper-pulse for the treatment of the qualifying CDI episode is unknown. The relevance of using placebo as a comparator is, therefore, uncertain, as the CDI treatment in the study was not consistent with recommendations from the Canadian guidelines or with the treatment that patients would receive in clinical practice.

CDA-AMC undertook reanalyses to address several key limitations in the sponsors submission, including the assumption that a sustained response does not change after 6 months; the application of more appropriate rates for death and colectomy occurring in the rCDI health state; the alignment of antibiotic distributions for no preventive therapy with what patients received in the PUNCH CD3 trial; the addition of administration costs for fecal microbiota (Rebyota); and the application of more appropriate assumptions to estimate productivity losses. Results from the CDA-AMC base case suggest that the incremental cost-effectiveness ratio (ICER) for fecal microbiota (Rebyota) versus no preventive therapy is $203,679 per quality-adjusted life-year (QALY) gained (incremental costs = $6,328; incremental QALYs = 0.03) for the health care payer perspective and $136,782 per QALY gained (incremental costs = $4,547; incremental QALYs = 0.03) for the societal perspectives. At the sponsor’s submitted price, fecal microbiota (Rebyota) would require price reductions of 53% or 32%, (from $9,125 per dose to $4,289 or $6,205 per dose) to be considered cost-effective at a willingness-to-pay (WTP) threshold of $50,000 per QALY gained for the public health care payer and societal perspectives, respectively.

The CDA-AMC base case maintained some benefit for fecal microbiota (Rebyota) that has not been clinically proven, including maintained differences in sustained response between fecal microbiota (Rebyota) and no preventive therapy and impacts on rCDI-related mortality and colectomy. In a scenario in which there is no difference in sustained response after 6 months between fecal microbiota (Rebyota) and no preventive therapy, the ICER for fecal microbiota (Rebyota) versus no preventive therapy increased to $476,035 per QALY gained and $407,736 per QALY gained in the health care payer and societal perspectives, respectively. This could be clinically plausible, given the CDA-AMC Clinical Review Report conclusion that there may be no added benefit with fecal microbiota (Rebyota) compared to placebo in terms of sustained response at 6 months among patients who achieved treatment success at 8 weeks. Additionally, in a scenario in which the mortality and colectomy benefit associated with fecal microbiota (Rebyota) was removed, which is consistent with the clinical evidence provided in the PUNCH CD3 trial, the ICER for fecal microbiota (Rebyota) versus no preventive therapy increased to $212,188 per QALY gained and $158,901 per QALY gained in the health care payer and societal perspectives, respectively. Therefore, the CDA-AMC base case may represent an optimistic reimbursement context, should these longer-term benefits associated with fecal microbiota (Rebyota) not be realized.

CDA-AMC was unable to address uncertainty related to the homogenous rCDI health state, which was more representative of an acute recurrence of CDI than the spectrum of rCDI symptoms and severity that patients with rCDI may experience. Because it is likely that rCDI is less severe in the overall patient population, such patients will incur fewer costs (both health care and indirect) than modelled by the sponsor, the CDA-AMC base case is likely conservative in terms of overall cost-effectiveness of fecal microbiota (Rebyota).

As well, CDA-AMC was unable to address the lack of comparative efficacy between fecal microbiota (Rebyota) and FMT. Given that there are no available cost estimates for FMT, there is insufficient evidence for a price premium for fecal microbiota (Rebyota) over FMT.

Input Relevant to the Economic Review

This section is a summary of the feedback received from the patient groups, clinician groups, and drug plans that participated in the CDA-AMC review process.

Patient input was provided by 3 groups: the Gastrointestinal Society, the Peggy Lillis Foundation, and the Canadian Digestive Health Foundation. Input was gathered through questionnaires, interviews, and email testimonials of patients and caregivers (119 patients and 48 caregivers living in Canada), with participants indicating the significant mental, physical, psychological, and life-threatening impacts of CDI. Patients reported the use of antibiotics, such as vancomycin, fidaxomicin, and metronidazole, to treat and cure CDI. Although these treatments were noted by patients to aid in the resolution of symptoms, they were also noted to possibly have a negative impact the gut microbiome. Participants also indicated that CDI can become recurrent, at which point treatment access becomes imperative, because treatment options are limited to a vancomycin taper-pulse regimen and FMT. The patient groups indicated that treatments that can provide stabilization of the microbiome and the desired alleviation of symptoms and improvement in quality of life. Patient experience with fecal microbiota (Rebyota) indicated improved rates of treatment success (i.e., prevention of rCDI) with minimal side effects.

No clinician input was received for this review.

The drug plans expressed concerns about the use of placebo as a comparator in the PUNCH CD3 trial, the use of no preventive therapy as the comparator in the pharmacoeconomic evaluation (rather than long-term oral vancomycin), the variability in coverage of current antibiotic treatments, the expected place in therapy of fecal microbiota (Rebyota), and the misalignment of the sponsor’s pharmacoeconomic evaluation with current clinical practice guidelines (i.e., the 2018 Association of Medical Microbiology and Infectious Disease guidelines, and, specifically, the use of FMT for patients after the second recurrence and antibiotic dosing). The plans expressed implementation concerns regarding the use of fecal microbiota (Rebyota) in rural settings related to limited health care resources, including the clinician time and expertise required for enema administration. The drug plans also had questions regarding the provision of additional doses of fecal microbiota (Rebyota) upon CDI recurrence. Additionally, the plans noted that the provision of fecal microbiota (Rebyota) for the first recurrence of CDI may have a substantial budget impact.

Several of these concerns were addressed in the sponsor’s model:

• Quality of life was incorporated in the sponsor’s model using EQ-5D values sourced from literature.

• Prevention of rCDI was the primary outcome incorporated into the model.

CDA-AMC addressed some of these concerns as follows:

• Administration cost was considered.

• A scenario analysis was included to consider a second dose of fecal microbiota (Rebyota) upon recurrence.

CDA-AMC was unable to address the following concerns raised in the patient and drug program input:

• The use of placebo as a comparator could not be addressed.

Economic Review

Economic Evaluation

Summary of the Sponsor’s Economic Evaluation

Overview

The sponsor submitted a cost-utility analysis that compared fecal microbiota (Rebyota) to no preventive therapy for the prevention of recurrence of CDI in adults after antibiotic treatment for rCDI.¹ The modelled population was consistent with the PUNCH CD3, PUNCH CD2, and PUNCH open-label clinical trials and was aligned with the Health Canada indication.

Fecal microbiota (Rebyota) is available in a 150 mL liquid suspension containing microbiota created from healthy human stool.² The recommended dose of fecal microbiota (Rebyota) is 1 single dose of 150 mL microbiota suspension rectally administered 24 hours to 72 hours after the last dose of antibiotics.² At the submitted price of $9,125 per 150 mL liquid suspension, the sponsor estimated total fecal microbiota (Rebyota) treatment costs to be $9,125 per patient.¹ Patients were treated with fecal microbiota (Rebyota) after antibiotics (94% received vancomycin 125 mg 4 times daily for 2 weeks¹ and 6% received fidaxomicin 200 mg twice daily for 10 days)^3,4 or antibiotics and no preventive therapy (69% received a vancomycin taper-pulse regimen, 25% received vancomycin 125 mg 4 times daily for 2 weeks,¹ and 7% received fidaxomicin 200 mg twice daily for 10 days).⁵

The clinical outcomes of interest were QALYs and life-years (LYs) over a 5-year time horizon.⁶ A discount rate of 1.5% was applied to both costs and outcomes.⁷ Two base-case perspectives were presented: 1 from the perspective of the publicly funded health care payer and 1 from the societal perspective.⁶ The societal perspective included indirect costs related to patient productivity losses and transportation costs.⁶

Model Structure

The sponsor submitted a Markov model with an 8-week cycle length that consisted of 5 health states (i.e., rCDI, absence of CDI after rCDI, ileostomy, ileostomy reversal, and death) and 1 colectomy tunnel state (i.e., rCDI to colectomy to ileostomy) (Figure 1).⁶ All patients enter the model in the rCDI health state and, after 1 round of antibiotic treatment, they either received 1 dose of fecal microbiota (Rebyota) or no preventive therapy.⁶ Upon receiving treatment, patients who experience treatment success at 8 weeks, defined as the absence of CDI, could transition to the absence-of-CDI-after-rCDI health state.⁶ Patients who do not experience treatment success could remain in the rCDI health state and receive subsequent treatment with antibiotics.⁶ After subsequent antibiotic treatment, patients could either experience subsequent treatment success and transition to the absence-of-CDI-after-rCDI health state or they could continue to not experience treatment success and remain in the rCDI health state.⁶ From the rCDI health state, patients could require colectomy and transition to the colectomy health state or they could die. Patients who enter the colectomy tunnel state will remain there for 1 cycle and transition to the ileostomy health state or the death health state.⁶ Patients who transition to the ileostomy health state can transition to the ileostomy-reversal health state, remain in the ileostomy health state, or die.⁶ Patients who transition to the absence-of-CDI-after-rCDI health state could experience sustained response, characterized by the absence of CDI, and remain in the absence-of-CDI-after-rCDI health state. Patients who do not experience a sustained response could transition to the rCDI state or die.⁶

Model Inputs

The baseline characteristics used to inform the model were based on the safety population of the double-blind, randomized, placebo-controlled, phase III PUNCH CD3 clinical trial (69.1% of participants were female and mean age was 60.1 years).⁸

The primary measure of efficacy that informed the transition from rCDI to the absence-of-CDI-after-rCDI health state was the probability of treatment success at 8 weeks in the PUNCH CD3 trial, defined as the absence of CDI at 8 weeks.⁸ Primary results from the PUNCH CD3 trial reported that 70.4% and 58.1% of patients in the fecal microbiota (Rebyota) and placebo arms, respectively, achieved an absence of rCDI after 8 weeks.⁸ The probability of a sustained response, which was used to determine who remained in the absence-of-CDI-after-rCDI health state, and the probability of a transition back to the rCDI health state were derived from the secondary end points of the PUNCH CD3 trial and a post hoc analysis of the PUNCH CD open-label extension studies.^8,9 Of patients who experienced treatment success after 8 weeks with fecal microbiota (Rebyota) and no preventive therapy in the PUNCH CD3 trial, 92.1% and 90.6%, respectively, had a sustained response at 6 months.⁸ Sustained responses at 12 months and 24 months were estimated to be ████% and ████%, respectively, for fecal microbiota (Rebyota) and 88.2% and 81.9%, respectively, for placebo in a post hoc survival analysis of patients who achieved a primary response and a sustained response at 8 weeks and 6 months in the PUNCH CD2 trial.⁹ The transition probability of patients in the rCDI health state to the colectomy health state was informed by the literature.¹⁰ All patients who underwent a colectomy and did not die were assumed to undergo ileostomy. The transition from the ileostomy health state to the ileostomy-reversal health state was informed by the literature.¹¹

Background mortality was informed by all-cause mortality from Statistics Canada for all health states.^6,12 The rCDI and colectomy health states assumed an additional mortality risk based on the literature.⁶ Mortality for the rCDI health state was informed by a US retrospective comparative study, which showed that patients with CDI had a 10.9% higher annual all-cause mortality risk than people in the general population in 2010 to 2012.¹³ For the colectomy state, mortality was informed by a US retrospective study that evaluated the colectomy postoperative mortality rate.¹⁴

The sponsor assumed that utilities for the absence-of-CDI-after-rCDI and ileostomy-reversal health states would be equal to those in the general population (i.e., 0.842).^6,15 The utilities for all other health states (i.e., 0.420 for rCDI, 0.536 for colectomy, and 0.700 for ileostomy) were sourced from the literature.^15-17

From the public payer perspective, the sponsor included costs related to drug acquisition, medical care (i.e., health care resource use), and terminal care. Drug-acquisition costs for fecal microbiota (Rebyota) were based on the sponsor’s submitted price.¹ Antibiotic drug costs were obtained from the Ontario Drug Benefit Formulary (i.e., vancomycin)¹⁸ and the Ontario Exceptional Access Program (i.e., fidaxomicin).¹⁹ Medical costs included health care resource use (i.e., hospitalizations, sepsis-related hospitalizations, ICU stays, emergency department visits, general practitioner visits, specialists visits, nurse visits, and stool tests); the frequency of use was informed by multiple literature sources and sponsor-elicited clinician input.^20-22 Costs for health care resource use were informed by the Ontario Schedule of Benefits for Physician Services, the Canadian Institute of Health Information, the Ontario Nurse Collective Agreement, and the literature.^22-25 Surgery-related costs (i.e., colectomy and ileostomy) were informed by the literature, with ileostomy reversal assumed to be equivalent in cost to colectomy.^26,27 Terminal-care costs were informed by a Canadian comparative study that examined costs incurred over 6 months in a palliative care program in rural and urban areas.²⁸ All costs were reported in 2024 Canadian dollars and, when applicable, costs were inflated or discounted using the Bank of Canada’s inflation calculator.⁷

From the societal perspective, the sponsor additionally included indirect costs, which were associated with travel expenses and lost productivity hours for a patient, based on a human capital approach. Travel expenses were calculated for the number of general practitioner and specialist visits associated with each health state. The average travel distance was informed by the 2021 Canadian Digital Health Survey and an analysis that evaluated travel to and from gastroenterology appointments at a clinic in Ontario for general practitioner and specialist visits, respectively.^29,30 Total cost per trip was calculated using the aforementioned average distance, the prescribed rate per kilometre determined by the Canada Revenue Agency, and parking costs, which were informed by the University Health Network parking rates.^31,32 Productivity loss was calculated based on wages lost from the number of days absent from work. Lost wages were calculated from the average hourly wage in Canada for people 25 years and older, the average number of hours worked per day, and the employment rate for individuals 25 years and older, all informed by Statistics Canada.^33-35 The proportion and number of days patients with active and resolved rCDI who would be absent from work was informed by an observational, cross-sectional study in which patients with self-reported CDI in the US completed a quality-of-life survey.³⁶

Summary of the Sponsor’s Economic Evaluation Results

All analyses were run probabilistically (2,000 iterations for the base-case and scenario analyses). The deterministic and probabilistic results were similar; the probabilistic findings presented here.

Base-Case Results

From the publicly funded health care payer perspective, fecal microbiota (Rebyota) dominated no preventive therapy (fecal microbiota [Rebyota] was associated with an incremental QALY gain of 0.14 and a cost savings of $2,135) over the five-year time horizon (Table 3).⁶ Fecal microbiota (Rebyota) had a 87% probability of being cost-effective at a WTP threshold of $50,000 per QALY gained.

In the sponsor’s analysis conducted from the societal perspective, fecal microbiota (Rebyota) also dominated no preventive therapy (fecal microbiota [Rebyota] was associated with an incremental QALY gain of 0.14 and cost savings of $8,592) over the five-year time horizon (Table 3).⁶ Fecal microbiota (Rebyota) had a 91% probability of being cost-effective at a WTP threshold of $50,000 per QALY gained.

In both the health care payer and societal perspective, 33% of incremental QALYs gained were observed during the trial period. In both the health care payer and societal perspective, fecal microbiota (Rebyota) was associated with a 0.07 LY gain compared with no preventive therapy.

Full disaggregated results are presented in Table 10 in Appendix 3. Results were driven by drug-acquisition costs associated with fecal microbiota (Rebyota), which were entirely offset by medical costs associated with the management of CDI (Table 10). The key cost driver was medical costs, with the majority of those attributed to hospitalization costs in the rCDI health state. Medical costs associated with the rCDI health state contributed 85% of the medical cost savings associated with fecal microbiota (Rebyota). From the societal perspective, indirect costs also contributed to a large proportion (76%) of the cost savings associated with fecal microbiota (Rebyota) compared with no preventive therapy. From both the health care payer and societal perspectives, the incremental QALY benefits observed for fecal microbiota (Rebyota) were entirely driven by patients spending more time in the absence-of-CDI-after-rCDI health state (Table 10). Scatterplots in the sponsor’s base case indicated the uncertainty in the finding that fecal microbiota (Rebyota) is less costly than no preventive therapy; in 743 of 2,000 iterations in the public health care payer base case, fecal microbiota (Rebyota) was associated with incremental costs (Figure 2 in Appendix 3).

Table 3: Summary of the Sponsor’s Economic Evaluation Results (Probabilistic)

ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Source: Sponsor’s pharmacoeconomic submission.⁶

Sensitivity and Scenario Analyses Results

Scenario analyses conducted by the sponsor included subgroup analyses of patients younger than 65 years and 65 years or older, treatment of rCDI as early as the first recurrence, an additional dose of fecal microbiota (Rebyota) for patients who experience a recurrence, and alternative assumptions on discounting and mortality. All scenario analyses for the Canadian health care payer and societal perspectives had conclusions similar to the sponsor’s base case; that is, fecal microbiota (Rebyota) remained dominant or cost-effective compared to no preventive therapy.

CDA-AMC Appraisal of the Sponsor’s Economic Evaluation

CDA-AMC identified several key limitations to the sponsor’s analysis that have notable implications for the economic analysis.

• The comparative efficacy of fecal microbiota (Rebyota) is uncertain. In the sponsor’s model, the primary efficacy outcome (treatment success) was informed by the fecal microbiota (Rebyota) and placebo arms of the PUNCH CD3 trial, with the placebo arm representing the current standard of care (i.e., no preventive therapy after treatment of the recurrence with antibiotics).^6,37 According to the CDA-AMC Clinical Review Report, there was moderate certainty that treatment with fecal microbiota (Rebyota) would result in a clinically important increase in the treatment success rate over 8 weeks compared to placebo. The sponsor’s submitted base case attributed different antibiotic treatment distributions to the fecal microbiota (Rebyota) arm (94% received vancomycin 125 mg 4 times daily for 2 weeks¹ and 6% received fidaxomicin 200 mg twice daily for 10 days) and the no preventive therapy arm (69% received a vancomycin taper-pulse regimen, 25% received vancomycin 125 mg 4 times daily for 2 weeks,¹ and 7% received fidaxomicin 200 mg twice daily for 10 days), based on the antibiotic treatment observed in the PUNCH CD3 trial and sponsor-elicited clinical expert opinion, respectively.^3,8 As noted in the sponsor’s pharmacoeconomic report and the clinical group input received by CDA-AMC, and corroborated by clinical expert feedback obtained by CDA-AMC, a vancomycin taper-pulse regimen is commonly used for patients who experience 2 or more recurrences of CDI.³⁸ However, the CDA-AMC Clinical Review Report noted that it is unknown whether patients in both groups received an appropriate antibiotic regimen of vancomycin taper-pulse for the treatment of the qualifying CDI episode. Therefore, the relevance of using placebo as a comparator is uncertain, as the CDI treatment in the PUNCH CD3 trial was not consistent with recommendations from the Canadian guidelines or with the treatment that patients would receive in clinical practice.³⁸ Consequently, it is uncertain whether the efficacy of no preventive therapy in clinical practice is equivalent to the placebo arm of the PUNCH CD3 study.

• Additionally, in the sponsor’s model, if patients did not achieve treatment success after the first cycle, patients were assumed to receive subsequent antibiotic treatment upon recurrence.⁶ The efficacy of the subsequent antibiotic treatment was derived from a subgroup of patients who experienced 3 or more recurrences in the placebo arm of the PUNCH CD3 trial.³ However, in the model, the mix of subsequent antibiotic treatment was based on sponsor-elicited clinician opinion, rather than the PUNCH CD3 trial.⁵ Because the efficacy is derived from the PUNCH CD3 trial, it is inappropriate to attribute a different antibiotic treatment mix for costs.

• As well, conventional multidose FMT, which the clinical experts indicated is currently being used for the treatment of rCDI in Canada, was not included as a comparator in the sponsor’s submitted model.⁶ As noted in the CDA-AMC Clinical Review Report, no direct or indirect evidence was submitted to evaluate fecal microbiota (Rebyota) relative to other currently used therapies for the prevention of rCDI, including FMT. The lack of conventional FMT is a major limitation, as literature suggests that FMT can achieve clinical response rates of more than 90% (response rates range from 44% up to more than 90%, and it appears that patients may require multiple FMTs to achieve clinical response rates of more than 80%).³⁸

  • In its reanalysis, CDA-AMC revised the distribution of antibiotic treatment for the no preventive therapy arm to reflect the antibiotic treatment distribution in the PUNCH CD3 trial.³⁷ Similarly, the distribution of subsequent antibiotic treatment was changed to reflect that in the PUNCH CD3 trial.³⁷

  • CDA-AMC was unable to address the lack of FMT as a comparator in the model because of the gap in evidence. Similarly, CDA-AMC was unable to address limitations regarding whether the placebo arm represented the current standard of care.

• The long-term clinical efficacy of fecal microbiota (Rebyota) is uncertain. Long-term efficacy in the sponsor’s economic model was based on the proportion of patients who experienced a sustained response after treatment success at 6 months, 12 months, and 24 months.⁶ The sustained response at 6 months with fecal microbiota (Rebyota) and no preventive therapy was informed by the PUNCH CD3 trial (92.1% and 90.6%, respectively).⁸ The sustained response at 12 months and 24 months was informed by the sponsor’s survival analysis, which was based on a subgroup of patients who experienced treatment success in the PUNCH CD2 trial.³ Among the patients who were treated with 1 dose of fecal microbiota (Rebyota) in the PUNCH CD2 trial, there was only 1 observation of 1 recurrence at 6 months, which translated to a sustained response of ████%.³ The sustained response observed for fecal microbiota (Rebyota) at 6 months from the PUNCH CD2 trial was used as a proxy for the 12-month and 24-month sustained response in the sponsor’s base case.³ Patients treated with placebo in the PUNCH CD2 trial were observed to experience recurrences at both the 12-month and 24-month time points, which translated to sustained responses of 88.2% and 81.9%, respectively.³ This approach to estimating long-term efficacy is inappropriate, as the efficacy values incorporated were from different patient populations; the patients enrolled in the PUNCH CD2 trial were not the same as the patients enrolled in the PUNCH CD3 trial. This is highlighted by the lack of face validity in the approach, as the sustained response at 6 months in the PUNCH CD2 trial, based on the sponsor’s survival analysis, was higher than the sustained response at 6 months in the PUNCH CD3 trial. According to clinical expert feedback received by CDA-AMC for this review, there is no reason why the sustained response would be higher at 12 months and 24 months for fecal microbiota (Rebyota).

• According to the CDA-AMC Clinical Review Report, the sponsor’s post hoc survival analysis has several methodological limitations, including a lack of reporting on the number of patients who were censored at various follow-up times, and limitations stemming from the small sample size and very few events. Finally, according to the CDA-AMC Clinical Review Report, no conclusions can be drawn regarding the sustained response beyond 6 months, and the conclusion regarding this outcome at 6 months in patients who achieved previous treatment success at 8 weeks was that there was no clinically important difference between fecal microbiota (Rebyota) and placebo. Therefore, there may be no added benefit with fecal microbiota (Rebyota) in terms of sustained response at 6 months.

  • In its reanalysis, CDA-AMC assumed that, after 6 months, the probability of recurrence would not change.

  • Additionally, in alignment with the conclusion of the Clinical Review Report, there may be no added sustained response benefit for fecal microbiota (Rebyota) compared to no preventive therapy at 6 months. CDA-AMC conducted a scenario analysis in which the sustained response for fecal microbiota (Rebyota) and no preventive therapy were the same at 6 months and beyond.

• Model structure does not reflect clinical expectations. In the sponsor’s pharmacoeconomic model, patients with rCDI can remain in the rCDI health state or transition to 1 of the following health states: absence of CDI after rCDI, colectomy, or death.⁶ This model structure assumes that all patients with rCDI who do not experience treatment success, surgery, or death will have a similar experience. Clinical expert feedback obtained by CDA-AMC indicated that patients with rCDI are not homogenous and may experience a different severity of symptoms and different impacts of CDI. For example, some patients may not revert to their pre-CDI baseline of bowel habits, whereas chronic vancomycin suppression therapy can mitigate symptoms associated with an episode of CDI in other patients. As well, some patients may experience different severities of CDI, from mild diarrhea to fulminant colitis with systemic toxicity and stock.³⁹ Although patients will have different experiences during and after the occurrence of an rCDI episode, the sponsor’s model does not account for heterogeneity within the rCDI health state. The implications of heterogeneity in health states have been well documented in the literature.⁴⁰ The heterogeneity of the rCDI health state has implications for costs and quality of life associated with the health state, as outlined in subsequent limitations.

  • CDA-AMC was unable to address the homogenous nature of the rCDI health state in the sponsor’s model. Because patients who are treated with fecal microbiota (Rebyota) spend less time in the rCDI health state than those treated with no preventive therapy, if the rCDI health state is reflective of a poorer quality of life and higher costs than the average patient with rCDI, this approach will favour fecal microbiota (Rebyota).

• Utilities do not meet face validity and are associated with uncertainty. Because of limitations in the sponsor’s model structure stemming from heterogeneity in the rCDI health state (refer to previous model structure limitation), the utility value assigned to the rCDI health state is likely not reflective of all patients in that state. The utility value of the rCDI health state was informed by a retrospective study conducted in the UK with an observation period of 2012 to 2014, in which the EQ-5D estimate of 64 patients with rCDI and 64 patients with a first CDI episode who were hospitalized was reported to be 0.42 ± 0.29.¹⁶ According to clinical expert feedback, corroborated by the sponsor’s pharmacoeconomic report, not all patients with rCDI will be hospitalized and they will have different experiences with severity of disease and the potential application of chronic vancomycin suppression therapy. Thus, the assumption that all patients in the rCDI health state will experience a utility value similar to that in patients who are hospitalized with rCDI does not meet face validity. If the utility estimate of the rCDI health state is underestimated compared to the true utility experienced by patients with rCDI, there would be fewer incremental QALYs for fecal microbiota (Rebyota), as these patients would spend less time in the rCDI health state than those who received no preventive therapy.

• Additionally, the assumption that patients who experience treatment success return to baseline utility, compared to the general population, does not meet face validity. Clinical expert feedback obtained by CDA-AMC indicated that patients who experience treatment success may not return to their pre-CDI baseline bowel habits and may suffer from lingering mental health impacts, such as posttraumatic stress disorder, as noted in patient group input. If the utility value in the absence-of-CDI-after-rCDI health state is lower than assumed by the sponsor, this would result in fewer incremental QALYs for fecal microbiota (Rebyota), because patients who receive fecal microbiota (Rebyota) would spend more time in that state than those who receive no preventive therapy.

• The sponsor’s submitted model derived utility benefits based on the time spent in each health state and reported an incremental QALY benefit of 0.14, which represents approximately 2 quality-adjusted months gained over 5 years with fecal microbiota (Rebyota).⁶ HRQoL was reported in the PUNCH CD3 trial, based on C. difficile Health-Related Quality-of-Life (Cdiff32) Questionnaire scores.³⁷ As noted in the CDA-AMC Clinical Review Report, fecal microbiota (Rebyota) may result in little to no difference in HRQoL compared to placebo at 8 weeks, and results were too uncertain to draw any conclusions at 6 months.³⁷ Therefore, the incremental QALY benefit finding suggesting that fecal microbiota (Rebyota) will result in an improvement in quality of life is uncertain.

  • CDA-AMC was unable to address this limitation because of limitations in the sponsor’s model structure. If utilities were lower than assumed by the sponsor for the absence-of-CDI-after-rCDI health state and higher than assumed by the sponsor for the rCDI state, as expected based on clinical feedback received by CDA-AMC for this review, this would bias results in favour of fecal microbiota (Rebyota).

• Medical costs are associated with uncertainty and do not reflect clinical practice. Because of limitations in the sponsor’s model structure stemming from heterogeneity in the rCDI health state (refer to previous model structure limitation), the health care resource costs assigned to the rCDI health state are likely not reflective of all patients in that state. The sponsor relied on published literature and clinical expert opinion to assign and validate health care resource use for each acute case of recurrent CDI (i.e., the published literature cited by the sponsor estimates the proportion of patients that require health care resources when experiencing a recurrent episode of CDI).^20-22 As outlined previously, as the rCDI health state is heterogenous and includes people with an acute episode of recurrent CDI and those who are receiving chronic vancomycin suppression therapy to manage their chronic rCDI, the assumption that costs associated with an acute occurrence of an episode of recurrent CDI will be similar in all patients with rCDI is uncertain. According to clinical expert feedback, health care resource use during an acute episode can vary; some patients will only require a vancomycin taper-pulse regimen to achieve treatment success, whereas others may require surgery and an ICU stay to combat fulminant CDI and septic shock. This is in contrast to people in the general population with rCDI, as the costs associated with an acute episode of rCDI is drastically different than in patients whose disease is well controlled on chronic vancomycin suppression therapy (who would be expected to require minimal health care resource use to manage their rCDI). As well, according to the CDA-AMC Clinical Review Report, based on data from the PUNCH CD3 trial, there was insufficient evidence to draw any conclusions about the effect of fecal microbiota (Rebyota), relative to placebo, on hospitalizations and ICU admissions. As such, whether fecal microbiota (Rebyota) will lead to reductions in medical costs, and to what extent, is uncertain based on the available clinical evidence.

  • CDA-AMC was unable to address this limitation because of limitations in the sponsor’s model structure. The sponsor’s approach likely favours fecal microbiota (Rebyota); if rCDI health state costs were lower, patients receiving no preventive therapy would accrue fewer health state costs because those who receive no preventive therapy spend more time in the rCDI state than those who receive fecal microbiota (Rebyota).

• Some outcomes assumed by the sponsor were not reflective of the clinical trial evidence and did not align with clinical practice in Canada. The sponsor’s submitted model included an additional mortality risk associated with the rCDI and colectomy health states, along with background all-cause mortality, with the rates of additional mortality risk being sourced from the literature.^1,13,14 The rCDI health state mortality risk was based on a US study of the one-year all-cause probability of mortality attributed to patients with CDI compared to those without CDI.¹³ The study did not stratify the patient population by the number of recurrences previously experienced by the patient, but concluded that a 10.9% increased mortality risk exists for patients with CDI.¹³ The application of mortality due to rCDI is uncertain because mortality was not a clinical trial outcome in the PUNCH CD3 trial and there was no evidence from the PUNCH CD3 or PUNCH CD2 studies, or the PUNCH open-label extension study, that fecal microbiota (Rebyota) would generate a mortality benefit compared to no preventive therapy. More specifically, the 2 deaths reported over the trial’s duration in patients who received fecal microbiota (Rebyota) were not related to the study drug or the enema procedure, according to the sponsor; no deaths were observed in the placebo arm.^37,41,42 According to clinical expert feedback obtained by CDA-AMC for this review, rCDI should have almost no mortality, because people with rCDI will receive chronic vancomycin suppression therapy unless they experience delayed diagnosis and treatment. Although clinical expert feedback acknowledged that rCDI could result in a morality risk, the experts indicated that it is uncertain whether fecal microbiota (Rebyota) would result in a decrease in mortality risk because of the absence of evidence. As well, clinical expert feedback indicated that a 10.9% annual mortality risk is not representative of clinical practice in Canada, where expected mortality associated with rCDI is very low. In 2023, the Public Health Agency of Canada reported on CDI-attributable mortality, and estimated it to be between 1.2% to 2.6% between 2017 to 2021.⁴³ This was deemed by clinical experts to be more representative of rCDI mortality risk.

• In addition to mortality stemming from having rCDI, the sponsor’s model derived a 0.2 incremental LY gain for fecal microbiota (Rebyota) in surgical health states (i.e., colectomy, ileostomy, and ileostomy reversal), representing approximately 2 months gained with fecal microbiota (Rebyota) compared with no preventive therapy. As noted in the CDA-AMC Clinical Review Report, there was 1 reported colectomy in the fecal microbiota (Rebyota) arm of the PUNCH CD3 trial and no colectomy events in the placebo arm.³⁷ As such, there is no clinical evidence to support lower rates of colectomy with fecal microbiota (Rebyota). Further, there is no clinical evidence that fecal microbiota (Rebyota) would be associated with an incremental LY gain related to the prevention of colectomy.³⁷ Clinical expert feedback obtained by CDA-AMC indicated that fecal microbiota (Rebyota) could reduce the proportion of patients who will experience a subsequent recurrence, based on the difference in treatment success, and that it is clinically plausible that reductions in recurrence could result in fewer colectomies, as colectomy can be an rCDI complication. However, based on clinical expert feedback, the probability of colectomy in the sponsor’s model (7.3% annually) was higher than would be expected in clinical practice in Canada, as colectomies are very rare. A 2020 retrospective cohort study conducted in Ontario showed that the proportion of patients with community-onset and hospital-onset rCDI who required a colectomy was 0.4% and 1.3%, respectively.⁴⁴ Additionally, a 2017 population-based cohort study conducted in Ontario showed that the risk of colectomy for patients with community-onset rCDI was 0.6%.⁴⁵ Thus, the assumption that patients with rCDI in Canada would undergo a colectomy at a rate similar to patients in the US may not be applicable, based on clinical expert feedback and studies conducted in Canada.

• To estimate the mortality risk associated with colectomy, the sponsor used a US retrospective study of 30-day mortality in patients with CDI who underwent a colectomy (35.2%).¹⁴ This approach assumes that the rate of death during the 30 days after the procedure is constant for 8 weeks after the procedure, which may have limited face validity, as a Canadian study that showed a similar 30-day mortality rate (33%) had a median time to death of 8 days, and that patients who did not die were discharged after a mean of 24 days after colectomy.⁴⁶

  • In its reanalysis, CDA-AMC revised the annual mortality risk for the rCDI health state to the 2021 value for the Public Health Agency of Canada’s CDI-attributable mortality risk.⁴³ As well, to align with the care paradigm in Canada, CDA-AMC conducted a reanalysis in which the proportion of patients who transition from the rCDI to the colectomy health state is 0.7% annually, based on a weighted average of patients with community-onset and hospital-onset rCDI who required a colectomy.⁴⁴ In addition, CDA-AMC adjusted the 8-week mortality risk for the colectomy health state to reflect the 30-day mortality risk.^14,43

  • To explore the possibility that fecal microbiota (Rebyota) does not result in a mortality or colectomy benefit, which is consistent with findings from the PUNCH CD3 trial, CDA-AMC conducted a scenario analysis in which mortality risk and colectomy risk were both removed from the rCDI health state.

• Alternative dosing of fecal microbiota (Rebyota) was not included in the sponsor’s base case. The sponsor’s base case only evaluated the administration of 1 dose of fecal microbiota (Rebyota) upon recurrence of CDI (aligned with the product monograph).² Clinical expert feedback noted that, based on clinical experience with FMT, more than 1 dose of FMT may be administered per treatment course in FMT programs. Although the clinical experts acknowledged that a only single dose of fecal microbiota (Rebyota) is indicated per recurrence, if permitted or available, there may be cases in which multiple doses of fecal microbiota (Rebyota) per recurrence would be administered. Therefore, whether multiple doses of fecal microbiota (Rebyota) would be administered per treatment course, should this be permitted, is uncertain, especially because the PUNCH CD3 trial only investigated the administration of a single dose; however, 2 doses of fecal microbiota (Rebyota) were studied in 1 treatment arm of the PUNCH CD2 trial.

• Additionally, the sponsor’s base-case analysis did not evaluate the administration of further doses of fecal microbiota (Rebyota) upon subsequent recurrences, which is permitted, according to the fecal microbiota (Rebyota) product monograph.² However, the sponsor did submit a scenario analysis that explored the impact of using fecal microbiota (Rebyota) to treat subsequent recurrences after a patient has already received fecal microbiota (Rebyota) for a prior recurrence. According to clinical expert feedback received by CDA-AMC for this review, if patients with rCDI experience a relapse in symptoms after fecal microbiota (Rebyota) treatment, the subsequent use of fecal microbiota (Rebyota) would be considered.

  • To address uncertainty in the expected use of fecal microbiota (Rebyota), 2 scenario analyses were conducted: in the first, patients received 2 doses of fecal microbiota (Rebyota) for their first recurrence in the model (off-label dosing), with the assumption that the efficacy is equivalent to 1 dose of fecal microbiota (Rebyota) (in the absence of available evidence for 2 doses); and, in the second, patients were able to receive an additional treatment course of fecal microbiota (Rebyota) for their next recurrence, aligned with the sponsor’s submitted scenario analysis.

• The calculated productivity loss is likely inappropriate. To calculate productivity loss, the sponsor used a human capital approach that involved wage, employment, and loss of working hours due to illness.¹ The employment rate was derived from Statistics Canada and was for individuals 25 years and older.³⁵ This is inappropriate, as the cited employment rate of the general population 25 years and older of Canada is not expected to reflect the patient population of rCDI. In the PUNCH CD3 trial, the median age at baseline was 63 years, and 54.3% of patients were 65 years or older.³⁷ This is corroborated by published literature and by clinical expert feedback, which indicated that rCDI disproportionately affects patients 65 years and older.^10,37,38As such, the group of patients 25 years and older is not reflective of the expected patient population who will receive fecal microbiota (Rebyota).^6,34

• Additionally, the homogenous nature of the rCDI health state may introduce uncertainty to productivity loss, as the model assumes that wages and working time of the general population is reflective of that in patients with rCDI. This assumption may not be appropriate, as patients with rCDI can experience a range of severity, and the disease may be well controlled with vancomycin suppression therapy, which will impact the patient’s ability to work. The proportion of patients unable to work because of rCDI was informed by an observational, cross-sectional study of patients in the US with an active or previous CDI diagnosis, in which it was reported that 47.2% and 25.5% of patients with an active or previous CDI diagnosis, respectively, were unable to work.³⁶ The heterogenous nature of rCDI, as highlighted in the previous limitation, makes the likelihood that 47.2% of patients with rCDI would be unable to work uncertain, as the observational, cross-sectional study did not stratify patients by severity of disease. Although clinical expert feedback aligned with the proportion of patients with active CDI who are unable to work, it indicated that it is unreasonable to assume that patients with resolved CDI, in which their symptoms are under control, would be unable to work; however, given the possible post-CDI effects on bowel habits and mental health, the proportion of patients with resolved CDI who are unable to work may be plausible.

• The sponsor used the number of days away from work because of illness associated with the absence-of-CDI-after-rCDI and the rCDI health states to calculate the lost productivity. The sponsor’s cited evidence demonstrated that patients were unable to fulfill their professional responsibilities for a mean of 118.0 days and a median of 60.0 days during infection, and for a mean 310.0 days and a median of 62.5 days after CDI infection.³⁶ As such, the sponsor assumed that among patients who were off work, they would be off work for 56 days per 8-week cycle for both the rCDI and absence-of-CDI-after-rCDI health states, which represents every day for 8 weeks.³⁶ This is inappropriate, as most people do not work every day for 56 days straight. The average usual hours for people living in Canada in 2024 was 37.6 hours per week.⁴⁷ Given the sponsor’s estimate of 7.36 hours worked per day (informed by Statistics Canada³³), this translates to 5.1 days lost per week, or 40.9 days lost per 8-week cycle if patients were unable to work over an 8-week time period. Additionally, the studied population informing time off work may not be representative of the patient population that will receive fecal microbiota (Rebyota), as baseline characteristics indicated that ████% of patients were older than 50 years, ████% of patients were female, and the number of days unable to work was not stratified by the number of recurrences, so patients who experienced only 1 CDI episode could be included.

  • CDA-AMC revised the employment rate and accounted for retirees in its reanalysis by assuming that the proportion of patients 65 years and older (54.3%) from the PUNCH CD3 trial³⁷ was multiplied by the 65-years-and-older employment rate (14.4%) and the proportion of patients younger than 65 years (45.7%) from the PUNCH CD3 trial³⁷ was multiplied by the 25-years-and-older employment rate (62.4%), sourced from Statistics Canada in 2024,³⁵ to determine the proportion of patients with rCDI who are employed.

  • Additionally, CDA-AMC revised the number of days off per 8-week model cycle to 40.9 days (i.e., assuming a 5.1-day work week), based on the usual average hours worked by people in Canada.^33,47 To explore the impacts of productivity loss, CDA-AMC conducted a scenario analysis in which the proportion of patients with resolved rCDI who would be unable to work was revised to 0%.

• Administration costs were not considered in the model. The sponsor’s submitted model does not consider the administration costs for fecal microbiota (Rebyota). This assumption was deemed to be inappropriate, based on clinical expert feedback received for this review, which indicated that FMT involves the administration of an enema by a health care provider (physician or a nurse under physician supervision), nursing support, a private room with an attached washroom, housekeeping time, and personal protective equipment (gloves, gowns, and masks). As such, it is inappropriate to assume that the administration of fecal microbiota (Rebyota) will be $0.

• Additionally, the sponsor did not include transportation costs associated with the administration of fecal microbiota (Rebyota) in the societal perspective. This may be inappropriate, as patients in the model are expected to accrue transportation costs when visiting general practitioners and specialists, whereas transportation costs associated with fecal microbiota (Rebyota) were excluded, which will favour the fecal microbiota (Rebyota) arm.

  • In its reanalysis, CDA-AMC derived a cost for fecal microbiota (Rebyota) administration using a bottom-up approach, based on clinical expert feedback on administration costs (Table 14).

Additionally, the key assumptions outlined in Table 4 were made by the sponsor and have been appraised by CDA-AMC.

Table 4: Key Assumptions of the Submitted Economic Evaluation (Not Noted as Limitations to the Submission)

AE = adverse event; CDA-AMC = Canada's Drug Agency; ITT = intention to treat; rCDI = recurrent Clostridioides difficile infection.

CDA-AMC Reanalyses of the Economic Evaluation

Base-Case Results

The CDA-AMC base case was derived by making changes to model parameter values and assumptions, in consultation with clinical experts. CDA-AMC undertook reanalyses that addressed the limitations of the sponsor’s model, as summarized in Table 5. CDA-AMC was unable to address the following key limitations of the sponsor’s submitted model: the lack of FMT as a comparator; limitations regarding the placebo arm’s representativeness of the current standard of care; the homogenous nature of the rCDI health state; the lack of face validity of utility estimates; and the uncertainty associated with medical costs for rCDI.

Table 5: CDA-AMC Revisions to the Submitted Economic Evaluation

CDA-AMC = Canada's Drug Agency; rCDI = recurrent Clostridioides difficile infection.

The CDA-AMC base case from the public health care payer perspective estimated that fecal microbiota (Rebyota) was $6,328 more expensive and yielded 0.03 more QALYs than no preventive therapy (Table 6). Based on the CDA-AMC reanalysis, fecal microbiota (Rebyota) was associated with an ICER of $203,679 per QALY gained compared to no preventive therapy (Table 6). Fecal microbiota (Rebyota) had a 33% probability of being cost-effective at a WTP threshold of $50,000 per QALY gained. The stepped analysis is presented in Table 11.

From the societal perspective, the CDA-AMC base-case analysis estimated that fecal microbiota (Rebyota) was $4,547 more expensive and yielded 0.03 more QALYs than no preventive therapy (Table 6). Based on the CDA-AMC reanalysis, fecal microbiota (Rebyota) was associated with an ICER of $136,782 per QALY gained compared to no preventive therapy (Table 6). Fecal microbiota (Rebyota) had a 37% probability of being cost-effective at a WTP threshold of $50,000 per QALY gained. The stepped analysis is presented in Table 12.

For both public health care payer and societal perspectives, the CDA-AMC base-case results were similar, albeit the societal perspective ICER was lower, given the increased productivity from no preventive therapy. The key cost driver was treatment-acquisition costs, as they comprised 100% of the incremental costs attributed to fecal microbiota (Rebyota) (Table 13).

As in the sponsor’s base case, the incremental QALY gain in both perspectives was driven by patients spending more time in the absence-of-CDI-after rCDI health state when treated with fecal microbiota (Rebyota) compared to no preventive therapy (Table 13). In the CDA-AMC base case, the majority (70%) of the incremental QALY gains were observed within the trial period. Scatterplots of the CDA-AMC base-base results highlight the uncertainty associated with an incremental benefit of fecal microbiota (Rebyota) compared to no preventive therapy, because in 40% and 38% of the iterations in the public health care payer and societal perspectives, respectively, fecal microbiota (Rebyota) was associated with no benefit or with a QALY detriment compared to no preventive therapy (refer to Figure 3 and Figure 4).

Table 6: Summary of the CDA-AMC Economic Evaluation Results (Probabilistic)

CDA-AMC = Canada's Drug Agency; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Scenario Analysis Results

CDA-AMC undertook price-reduction analyses for the public health care payer and societal perspectives. In the CDA-AMC base case, to be considered cost-effective at a WTP threshold of $50,000 per QALY gained in the health care payer and societal perspectives, the price of fecal microbiota (Rebyota) would need to be reduced by 53%, corresponding to $4,288.75 per dose, or 32%, corresponding to $6,205.00 per dose, respectively (Table 7).

Table 7: CDA-AMC Price Reduction Analyses

CDA-AMC = Canada's Drug Agency; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

CDA-AMC conducted several scenario analyses on the CDA-AMC base case to explore the remaining sources of uncertainty (results are shown in Table 15). If subsequent doses of fecal microbiota (Rebyota) are permitted upon recurrence after fecal microbiota (Rebyota) treatment, which is aligned with product monograph dosing, the ICER is expected to increase to $257,843 and $256,069 per QALY gained for the health care payer and societal perspectives, respectively. If fecal microbiota (Rebyota) does not result in a benefit in terms of colectomy or mortality compared with no preventive therapy, then the ICER is also expected to increase (to $212,188 and $158,901 per QALY gained for the health care payer and societal perspectives, respectively). Finally, in a scenario that assumes that there is no difference in sustained response between fecal microbiota (Rebyota) and no preventive therapy after 6 months, in line with the CDA-AMC Clinical Review Report, the ICER increases to $476,035 and $407,736 per QALY gained in the health care payer and societal perspectives, respectively.

In the scenario in which people with resolved rCDI all return to work, the ICERs were lower than those in the CDA-AMC base case; however, the scenario analysis remained not cost-effective at a WTP of $50,000 per QALY gained.

Issues for Consideration

• Generalizability of the PUNCH CD3 trial results: As noted in the CDA-AMC Clinical Review Report, patients with some comorbidities (e.g., Crohn disease, ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome, and immunocompromised conditions) were excluded from the PUNCH CD3 trial.³⁷ Patients with comorbidities were permitted in the PUNCH open-label extension study,^37,42 but the proportion of such patients was small, limiting the generalizability of the findings and the certainty of evidence for patients with comorbid conditions.

• Storage of fecal microbiota (Rebyota): Fecal microbiota (Rebyota) must be stored in an ultracold freezer, at a temperature of −90°C to −60°C (–76ºF to –130ºF), or stored in the refrigerator at 2°C to 8°C (36°F to 46°F) for up to 5 days.² There may be implementation issues with storage because of these temperature requirements. Costs and considerations related to storage and implementation were not considered in the economic evaluation of either the sponsor or CDA-AMC.

• Availability of fidaxomicin: Public reimbursement of fidaxomicin is jurisdiction-dependent. Currently, British Columbia, Alberta, Saskatchewan, Ontario, New Brunswick, Nova Scotia, and Prince Edward Island provide public coverage of fidaxomicin through the Exceptional Access Program or the Special Access Program.^19,48-50 However, this is subject to change, as fidaxomicin is currently undergoing a CDA-AMC nonsponsored reimbursement review.⁵¹

• Confidential price for comparators: Analyses by the sponsor and the CDA-AMC are based on publicly available list prices for most comparators. Actual costs paid by public drug plans are unknown, and any potential confidential rebates are not reflected in the analyses.

Overall Conclusions

Evidence from the PUNCH CD3 trial suggests that fecal microbiota (Rebyota) likely leads to a clinically important improvement in the treatment success rate over 8 weeks, compared to placebo, for the prevention of the recurrence of CDI in adults after antibiotic treatment for rCDI. According to the CDA-AMC Clinical Review Report, most patients who achieved treatment success at 8 weeks with either fecal microbiota (Rebyota) or placebo were able to maintain a sustained clinical response at 6 months; therefore, there may be no added benefit with fecal microbiota (Rebyota) for this outcome, compared to placebo. Based on results from exploratory analyses, fecal microbiota (Rebyota) may result in little to no difference in HRQoL over 8 weeks, compared to placebo, and HRQoL results at 6 months were too uncertain to lead to a definite conclusion. In addition, the evidence was insufficient to conclude anything about the effect of fecal microbiota (Rebyota) relative to placebo on hospitalizations and ICU admissions. The trial could not inform on the effectiveness or safety of fecal microbiota (Rebyota) relative to other currently used therapies for rCDI, such as conventional, multidose FMT, nor did the sponsor submit indirect evidence to supplement the gap in the comparative evidence. Whether patients in the 2 groups previously received an appropriate antibiotic regimen of vancomycin taper-pulse for the treatment of the qualifying CDI episode is unknown. The relevance of using placebo as a comparator is, therefore, uncertain, as the CDI treatment in the study was not consistent with recommendations from the Canadian guidelines or with the treatment that patients would receive in clinical practice.

CDA-AMC undertook reanalyses to address several key limitations in the sponsors submission, including the assumption that a sustained response does not change after 6 months, the application of more appropriate rates for death and colectomy in the rCDI health state, the alignment of antibiotic distributions for no preventive therapy with those received in the PUNCH CD3 trial, the addition of administration costs for fecal microbiota (Rebyota), and the application of more appropriate assumptions to estimate productivity losses. Results from the CDA-AMC base case suggest that the ICER for fecal microbiota (Rebyota) versus no preventive therapy is $203,679 per QALY gained (incremental costs = $6,328; incremental QALYs = 0.03) for the health care payer perspective and $136,782 per QALY gained (incremental costs = $4,547; incremental QALYs = 0.03) for the societal perspectives. At the sponsor’s submitted price, fecal microbiota (Rebyota) would require price reductions of 53% or 32% (from $9,125 per dose to $4,289 or $6,205 per dose) to be considered cost-effective at a WTP threshold of $50,000 per QALY gained for the public health care payer and societal perspectives, respectively.

The CDA-AMC base case maintained some benefit for fecal microbiota (Rebyota) that has not been clinically proven, including maintained differences in sustained responses between fecal microbiota (Rebyota) and no preventive therapy and impacts on rCDI-related mortality and colectomy. In a scenario in which there is no difference in sustained response after 6 months between fecal microbiota (Rebyota) and no preventive therapy, the ICER for fecal microbiota (Rebyota) versus no preventive therapy increased to $476,035 and $407,736 per QALY gained in the health care payer and societal perspectives, respectively. This could be clinically plausible, given the conclusion in the CDA-AMC Clinical Review Report that there may be no added benefit with fecal microbiota (Rebyota), compared to placebo, in terms of sustained response at 6 months among patients who achieved treatment success at 8 weeks. Additionally, in a scenario in which the mortality and colectomy benefit associated with fecal microbiota (Rebyota) was removed, which is consistent with the clinical evidence provided in the PUNCH CD3 trial, the ICER for fecal microbiota (Rebyota) versus no preventive therapy increased to $212,188 and $158,901 per QALY gained in the health care payer and societal perspectives, respectively. Therefore, the CDA-AMC base case may represent an optimistic reimbursement context, should these longer-term benefits associated with fecal microbiota (Rebyota) not be realized.

CDA-AMC was unable to address the uncertainty related to the homogenous rCDI health state, which was more representative of an acute recurrence of CDI than the spectrum of rCDI symptoms and severities that patients with rCDI may experience. As its likely that the overall patient population with rCDI has less severe disease and will incur fewer costs (both health care and indirect) than modelled by the sponsor, the CDA-AMC base case is likely conservative in terms of the overall cost-effectiveness of fecal microbiota (Rebyota).

As well, CDA-AMC was unable to address the lack of comparative efficacy of fecal microbiota (Rebyota) and FMT. Given that there are no available cost estimates for FMT, there is insufficient evidence for a price premium for fecal microbiota (Rebyota) over FMT.

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