FormalPara Key Summary Points

Why carry out this study?

Clostridioides difficile infection (CDI) is an urgent public health threat in the USA and is associated with significant economic and clinical burden. Many patients with CDI experience high rates of CDI recurrence (rCDI)

Treatments for active CDI include oral antibiotics vancomycin or fidaxomicin. The purpose of this study is to evaluate the budget impact of REBYOTA™ (fecal microbiota, live-jslm [FMBL]) for the prevention of rCDI after receipt of oral antibiotic treatment

What was learned from this study?

FMBL introduction results in a cost-saving budget impact compared to no FMBL from a US third-party payer perspective (an average saving of $0.0039 on a per member per month basis over 3 years)

The higher initial drug costs associated with FMBL were fully offset by savings in medical costs through lowering recurrence and healthcare resource utilization

Introduction

Clostridioides difficile infection (CDI) represents an urgent health threat in the USA, as identified in the 2019 Antibiotic Resistance Threat Report by the Centers for Disease Control and Prevention [1]. CDI is caused by Clostridioides difficile, an anaerobic gram-positive, spore-forming, toxin-producing bacterium. Clostridioides difficile is most often found in health care facilities and is also found in the environment [2, 3]; it is transmissible through the fecal-oral route. CDI is the most commonly isolated pathogen of antibiotic- and healthcare-associated infection in the US [4]. Recurrent CDI (rCDI) is commonplace among patients with CDI.

Treatments for primary CDI and rCDI typically involve oral antibiotics vancomycin or fidaxomicin [5]. A 2021 real-world US claims study found that vancomycin was the most commonly used antibiotic for CDI and rCDI, with 55% of patients receiving vancomycin for their first recurrence, 56% for second recurrence, and 60% for third recurrence [6]. Despite current treatment options, patients with CDI experience high rates of rCDI. Up to 35% of patients with a primary CDI episode experience recurrence(s), and up to 65% who develop rCDI go on to have more recurrences [7,8,9].

REBYOTA™ (fecal microbiota, live-jslm [FMBL]) is a rectally administered suspension and is the first microbiota-based live biotherapeutic for the prevention of rCDI following antibiotic treatment for rCDI recently approved by the US Food and Drug Administration (FDA) [10]. Given the novelty of FMBL, a careful evaluation of the economic implications is needed. This study estimated the budget impact of FMBL from a US third-party payer perspective.

Methods

Model Overview

The model assessed the budget impact of FMBL during the first 3 years following the approval and introduction of FMBL for preventing rCDI. The budget impact was estimated by comparing the total budget with FMBL (a market basket of FMBL and standard of care [SOC]) to without FMBL (SOC only). One course of FMBL in the scenario with FMBL was considered. SOC for the prevention of rCDI, proxied by the placebo arm of the FMBL phase 3 clinical trial (PUNCH CD3, NCT03244644) [10], was defined as no treatment to prevent recurrence following antibiotic treatment for rCDI (i.e., rCDI diarrhea being under control). Model outputs included estimates of budget impact of FMBL and the total cost per year without FMBL and with FMBL, from the overall US health plan perspective, on a per member per month (PMPM) basis, and on a per treated member per month (PTMPM) basis. PTMPM cost was calculated as the total costs divided by the total number of patients treated with either FMBL or SOC. The drug cost with FMBL was calculated as the drug costs of FMBL per course multiplied by the number of patients received FMBL per market share of FMBL in respective years and then divided by the total number of patients treated with either FMBL or SOC. The average budget impact on a PMPM and on a PTMPM and the total budget impact on a plan level over 3 years were estimated.

A decision-tree model was used to estimate the total costs with and without FMBL as a treatment for preventing rCDI (see Fig. 1). There were three decision points: initial treatment choice, 8-week response status, and 6-month response status. Per the endpoints in the PUNCH CD3 trial, patients could have an initial 8-week treatment success, defined as the absence of CDI diarrhea within 8 weeks of administration of FMBL or treatment failure [10]. After the 8-week period, patients could have sustained clinical response, defined as treatment success of the presenting CDI recurrence and no more CDI episodes for > 8 weeks through 6 months after administration of FMBL, or could experience more CDI episodes within this time period. Patients would continue the same response status for the remaining 6 months through the end of the year. The clinical inputs that informed response status at 8 weeks and 6 months are presented in Table 1.

Fig. 1
figure 1

Model structure diagram. CDI Clostridioides difficile infection, FMBL fecal microbiota, live-jslm, SOC standard of care

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Table 1 Clinical and cost inputs
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Target Population

Calculation of the target population used an incidence-based approach to estimate the total number of patients in the plan, assuming a 1,000,000-person population size, eligible to be treated with FMBL for rCDI prevention within the year. Patients who have at least one recurrence after a primary episode of CDI and have completed at least one round of oral antibiotic therapy would be eligible [10].

It was further assumed that 25.3% of the total plan population had Medicare coverage, with a CDI incidence of 627.7 per 100,000 patients, while the remaining 74.7% had commercial coverage, with a CDI incidence of 97.8 per 100,000 patients [7]. The relative percentages of Medicare and commercial coverage were based on health insurance coverage information collected in the Current Population Survey Annual Social and Economic Supplement released by US Census Bureau from the general US population. This model assumed that the distribution would be similar for the rCDI population [11]. The primary CDI recurrence rate was 20.2%, and the subsequent recurrence rate was 65.0% [7, 12, 13] (Table 2).

Table 2 Model population
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The main analysis included all patients who had ≥ 1 rCDI episode. The treatment effect of FMBL in reducing rCDI was also demonstrated as early as the first recurrence. Therefore, a subgroup analysis of patients who had their first recurrence was conducted to assess the economic implications of an early treatment with FMBL.

Market Shares

The assumption on market shares of FMBL and SOC is presented in Fig. 2 for 3 years based on data from market research. Specifically, the market shares were assumed to be 5% FMBL and 95% SOC in year 1, 15% FMBL and 85% SOC in year 2, and 20% FMBL and 80% SOC in year 3 under the scenario with FMBL. Under the scenario without FMBL, the market share is 100% SOC.

Fig. 2
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Market share for the scenario with FMBL market entry over 3 years. FMBL fecal microbiota, live-jslm

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Cost Inputs

The base case model considered drug costs for the initial treatment with FMBL and rCDI-related medical costs; subsequent treatment costs were not considered in the base case model (Table 1). The drug costs of the initial antibiotic treatment were not considered because all patients (including patients who received FMBL or SOC) would have completed the initial antibiotic treatment before entering the model and drug costs of the antibiotic treatment before the model entry were assumed to be the same.

All costs were estimated in or inflated to 2022 US dollars (USD) using the Personal Consumption Expenditure (PCE) Index for health care services from the US Bureau of Economic Analysis [14]. The price of FMBL was set at $9000. The FMBL administration cost was based on the 2022 Centers for Medicare and Medicaid Services (CMS) physician fee schedule [15]. In a sensitivity analysis considering subsequent antibiotic treatment (a composite of oral vancomycin taper-pulse and fidaxomicin), the drug cost of subsequent antibiotic treatment was estimated to be $2342 per treatment regimen based on the average wholesale acquisition cost (WAC) prices for oral antibiotics taken from IBM Micromedex Red Book® and dosing schedules taken from the Infectious Diseases Society of America (IDSA) 2021 guidelines [10, 16] (Appendix Table 5).

Healthcare resource utilization (HRU) directly attributable to rCDI was included as medical cost. Annual rates of rCDI-related HRU were extracted from Rodrigues et al. 2017 [17] as it provided recent real-world data of rCDI-related HRU among patients with rCDI. Other publications reporting all-cause HRU were not applicable for this study because the model considered rCDI-related HRU. rCDI-related HRU included hospitalizations, intensive care unit (ICU), post-acute care (defined as a stay in a skilled nursing facility, inpatient rehabilitation facility, or long-term acute care hospital or services provided by a home health agency), colectomy, ileostomy reversal, stool tests, outpatient visits, emergency department (ED) visits, and terminal care. A one-time terminal care cost was applied upon death, and it was assumed that death occurred at the end of the year. Unit costs for each rCDI-related HRU category were obtained from the literature [12, 17,18,19,20], the Optum360 National Fee Analyzer [21], and the Healthcare Cost and Utilization Project (HCUP) [22]. Total annual rCDI-related medical costs were estimated at $77,861.23 per patient as the sum of the unit costs multiplied by the annual HRU rates across care settings. Costs of adverse events (AEs) were not considered in our study given their minimal, if any, impact on the model results. The proportions of patients experiencing moderate and severe AEs were similar between the FMBL and SOC treatment arms, although patients experiencing a higher incidence of mild gastrointestinal events in the FMBL vs. SOC arm.

Patients with treatment failure at 8 weeks were assumed to recur at the end of the first week based on the median time to recurrence reported in the PUNCH CD3 trial [10] and thus were assumed to incur rCDI-related medical cost for 51 weeks out of the total 52 weeks in the year annually (i.e., $76,363.90). Patients with treatment success at 8 weeks but having new CDI episodes within 6 months were assumed to have new CDI episodes at the end of 12 weeks based on the median time to recurrence reported in the PUNCH CD3 trial, and thus were assumed to incur rCDI-related medical cost for 40 weeks out of the total 52 weeks in the year annually (i.e., $59,893.25). Patients with treatment success at 8 weeks who did not have CDI episodes within 6 months were assumed to incur no rCDI-related medical costs.

In the subgroup of patients who had their first recurrence, data on treatment success were derived from an adjusted analysis of the PUNCH CD3 trial data. In a post hoc analysis of the modified intention-to-treat (mITT) population enrolled after one CDI recurrence (86/262 patients [32.8%]), FMBL demonstrated a 21% absolute risk reduction and a 52.5% relative risk reduction of recurrence compared to placebo by week 8. Treatment success was achieved by 81% of FMBL-treated patients compared to 60% of placebo-treated patients at week 8. This analysis adjusted for differences in known risk factors for recurrence, including age, gender, antibiotics use, and proton pump inhibitor (PPI) use, between the FMBL and placebo arms [23].

Sensitivity Analyses

One-way deterministic sensitivity analyses (DSAs) were conducted to examine varying inputs and assumptions one at a time (Fig. 3). Parameters such as efficacy, drug acquisition and administration costs, annual HRU, and unit costs were varied. Specifically, the 95% confidence interval of efficacy inputs and ± 25% of the cost inputs (in absence of data on variability) were used to inform the low and high values in the DSA. Scenario analyses included varying assumptions on the market uptake of FMBL and the inclusion of a second course of FMBL or oral antibiotics (composite treatment of 93% vancomycin taper-pulse and 7% fidaxomicin informed by antibiotics use at screening in the PUNCH CD3 trial) as subsequent treatment.

Fig. 3
figure 3

Tornado diagram based on DSAs/scenario analyses (PMPM) among patients with ≥ 1 rCDI1. 1The budget impact is presented in 2022 USD on a PMPM basis. CDI Clostridioides difficile infection, DSA deterministic sensitivity analyses, FMBL fecal microbiota, live-jslm, LOS length of stay, PMPM per member per month, rCDI recurrent C. difficile infection, SOC standard of care, YR year, USD US dollar

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s

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

Base Case Results

Model Population

The budget impact associated with one-course FMBL was modeled over 3 years using an incidence-based approach in a hypothetical plan population of 1,000,000 covered lives. Calculated using primary CDI and subsequent CDI recurrence rates, 468 of the 1,000,000 covered lives were estimated to have ≥ 1 rCDI episode. Among the 468 patients with ≥ 1 rCDI each year, the number of patients receiving FMBL increased from 23 in year 1 to 70 in year 2 and 94 in year 3 after FMBL introduction (Table 2). A total of 164 patients were estimated to have their first rCDI episode (i.e., no subsequent recurrences). Among the 164 (35%) patients at first rCDI each year, the number of patients receiving FMBL increased from 8 in year 1 to 25 in year 2 and 33 in year 3 after FMBL introduction (Table 2).

Budget Impact Among Patients with ≥ 1 rCDI

In the population with 468 patients with ≥ 1 rCDI, on a PMPM basis, the average total cost over 3 years was $1.3955 without FMBL versus $1.3916 with FMBL, corresponding to a cost saving of $0.0039 PMPM. The average drug costs over 3 years was $0 versus $0.0474 without versus with FMBL, respectively, corresponding to a drug cost difference of $0.0474 PMPM. The average medical costs over 3 years was $1.3955 versus $1.3442 without versus with FMBL, respectively, corresponding to medical cost savings of 0.0513 PMPM (Table 3).

Table 3 Budget impact results among patients with ≥ 1 rCDI (drug costs of initial antibiotic treatment before model entry were not included)
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On a PTMPM basis, the average total cost over 3 years was $2981.15 without FMBL versus $2972.85 with FMBL, corresponding to a cost saving of $8.30 PTMPM. The average drug costs over 3 years was $0 versus $101.26 without versus with FMBL, respectively, corresponding to a drug cost difference of $101.26 PTMPM. The average medical cost over 3 years was $2981.15 versus $2871.59 without versus with FMBL, respectively, corresponding to medical cost savings of 109.56 PTMPM (Table 3).

On a plan level, the total cost over 3 years was $50,236,719 without FMBL versus $50,096,855 with FMBL, corresponding to a cost saving of $139,865. The total drug cost over 3 years was $0 versus $1,706,445 without versus with FMBL, respectively, corresponding to a drug cost difference of $1,706,445 at the plan level. The total medical cost over 3 years was $50,236,719 versus $48,390,410 without versus with FMBL, respectively, corresponding to a medical cost saving of $1,846,309 at the plan level (Table 3).

Budget Impact Among Patient at First rCDI

In the population with 164 patients at first rCDI, on a PMPM basis, the average total costs over 3 years without and with FMBL corresponded to a cost saving of $0.0139 PMPM. On a PTMPM level, without and with FMBL average total costs corresponded to a cost saving of $84.78. On a plan level, the total costs of without and with FMBL corresponded to a cost saving of $500,022 over 3 years (Table 4).

Table 4 Budget impact results among patients at first rCDI (drug costs of initial antibiotic treatment before model entry were not included)
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Deterministic Sensitivity Analyses Results

The results of the DSA among patients with ≥ 1 rCDI are shown on a PMPM basis in Fig. 3. The tornado diagram presents the results of sensitivity analyses from the most to the least influence on budget impact. Across the sensitivity analyses, the budget impact of FMBL relative to no FMBL ranged from -$0.0517 to $0.0357 PMPM. The most influential model drivers included treatment success rates of SOC and FMBL at 8 weeks and the inclusion of a second course of FMBL or antibiotic treatment. With a higher treatment success rate for SOC, the budget impact is $0.0357 PMPM and, with a lower treatment success rate for SOC, the budget impact is cost saving by $0.0376 PMPM. With a higher treatment success rate for FMBL, the budget impact is cost saving by $0.0271 PMPM and with a lower treatment success rate for FMBL, the budget impact is $0.0219 PMPM. Including a second course of FMBL in the FMBL arm led to a cost saving of $0.0517 PMPM (Appendix Table 6). With a second course of FMBL in the FMBL arm and a second course of antibiotic treatment in the SOC arm, the budget impact is $0.0333 PMPM. With a second course of antibiotic treatment in both arms, the budget impact is $0.0223 PMPM.

Discussion

Primary CDI and rCDI are associated with a large economic burden due to an increased use of healthcare resources, which could include hospitalizations, post-acute care stays, and surgical interventions for severe patients [12, 24, 25]. Despite current treatment with antibiotics, patients with rCDI are at a higher risk for recurrence and may experience substantially worse outcomes compared to those without a recurrence, resulting in detrimental health-related quality of life and possibly higher mortality [26]. This study evaluated the budget impact of FMBL, the first-in-class microbiota-based live biotherapeutic, for rCDI prevention. Over a 3-year time horizon with market shares of FMBL increased from 5% in year 1 to 15% in year 2 and 20% in year 3, the market introduction of FMBL for preventing rCDI was estimated to have a cost-saving budget impact among patients with ≥ 1 rCDI from a US third-party payer perspective (an average of $0.0039 PMPM, an average of $8.30 PTMPM, a total of $139,865 on a plan level over 3 years in a hypothetical plan with 1 million covered lives). The cost-saving of FMBL was due in part to the small size of the target population and the improved efficacy of FMBL over SOC to prevent rCDI and thus the associated reduction in HRU, including hospitalizations. The lower medical costs, attributed to its treatment efficacy, offset the drug acquisition and administration costs of FMBL. Most notably, treatment of first rCDI with FMBL was also cost saving by an average of $0.0139 PMPM, by an average of $84.78 PTMPM, and by a total of $500,022 on a plan level over 3 years. The first rCDI subgroup had greater cost saving than the overall population with ≥ 1 rCDI due to the greater treatment effect of FMBL vs. SOC in preventing rCDI and subsequently rCDI-related medical costs.

Results from the DSA demonstrated the robustness of the model, supporting the base case findings. As expected, the budget impact was most sensitive to variations in efficacy of FMBL and SOC at the first 8 weeks. The model was also sensitive to the inclusion of a second course of FMBL and/or antibiotics. While the addition of a second course of FMBL increased the budget impact due to a higher drug cost associated with FMBL, the budget impact remained minimal at $0.0333 PMPM in the analysis of having a second course of FMBL for patients treated with FMBL and a second course of antibiotics for patients treated with SOC, respectively.

Prior studies have evaluated the budget impact of oral antibiotics entering the market for rCDI [27]. In Watt (2016), the 1-year budget impact associated with fidaxomicin per patient was $635.77 in Germany (converted to 2022 USD from €461 2016 euros using historical exchange rates and consumer price indices) for patients with at least one recurrence [28]. Given the differences in healthcare systems, it is difficult to compare the per patient cost in Germany for fidaxomicin to the PMPM cost of FMBL in the US; however, both models showed that higher drug costs were offset by the reduction in medical costs associated with rCDI. A recent US model by Jiang et al. [29] was developed from a hospital perspective and demonstrated a minimal budget impact of fidaxomicin in the US. In addition, two prior studies evaluated the budget impact of bezlotoxumab plus antibiotics compared to antibiotics alone in patients for the prevention of recurrence from a hospital perspective in Germany and the US, respectively [30, 31]. Both studies found that bezlotoxumab plus antibiotics was cost-saving with the higher treatment costs of bezlotoxumab being offset by the lower rCDI rate and lower hospitalization costs among patients treated with bezlotoxumab, which correlates with our study finding that FMBL was cost-saving given its high efficacy in preventing rCDI and subsequently low rCDI-related medical cost; thus, it may offer additional advantages to a US health plan.

A few limitations of the model should be noted. Our model considered FMBL vs. SOC only as proxied by the placebo arm of the PUNCH CD3 trial following a course of antibiotic treatment. In clinical practice, incremental antibiotics or other therapeutic options could have been considered and used sooner, which may result in treatment effectiveness rates different from the SOC efficacy rates in the PUNCH CD3 trial (and may also have a subsequent impact on drug costs). Sensitivity analyses by varying efficacy rates of FMBL and SOC allowed us to test the robustness of the model findings. Even with an assumed higher efficacy rate for SOC (i.e., the upper bound of the 95% confidence interval), the budget impact of FMBL is expected to be small (0.0357 PMPM). Further research may consider using real-world efficacy data to confirm the model findings when such data are available. Our model also assumed a three-node decision tree with critical time points at week 8 and month 6 to reflect the clinical trial design and thus data availability from the trial. In practice, physicians could evaluate treatment success or failure at different times and hence deviate the HRU and costs for rCDI from our model estimates. The model was developed from a US third-party payer perspective, and the findings may not be generalizable to specific payers. For example, their patient population (e.g., age distribution) and market shares might differ from the model assumptions. The medical costs considered in this model came from the literature, including the unit prices for medical services. The actual values could differ for a specific payer. For example, WAC prices were used to calculate drug acquisition costs. Such prices may not reflect the actual costs borne by the payer. Future studies should evaluate the budget impact of FMBL among different types of payers. Additionally, the distribution of vancomycin use vs. fidaxomicin use as the subsequent antibiotic treatment was assumed to be constant over 3 years after FMBL introduction, and assumptions on the projected market uptake of FMBL are yet to be tested when more data from the real world become available. Lastly, treatments that are not approved by the FDA or have limited use in real-world practice (e.g., fecal microbiota transplant [FMT], bezlotoxumab) were not considered in our study [6, 32]. FMT is not FDA approved for rCDI prevention while bezlotoxumab is indicated for use in conjunction with antibiotic therapy to reduce rCDI, rather than after antibiotic therapy, and for patients with congestive heart failure, bezlotoxumab can only be used when benefit outweighs the risks. Both treatments have limited use in real-world practice. For example, a recent study found that only 8.5% of episodes were treated using bezlotoxumab or FMT, and bezlotoxumab was used mostly in immunosuppressed patients [32]. It is anticipated that other FDA-approved rCDI treatments will become available in future years, and the budget impact model of FMBL suspension will need to be revisited when these new live biotherapeutic products become available.

Conclusion

FMBL, a novel microbiota-based live biotherapeutic, for prevention of rCDI was demonstrated to be cost saving from a US third-party payer perspective, attributable to reductions in direct medical costs through recurrence prevention and associated reduction in HRU, including hospitalizations. Given its high efficacy, FMBL showed further cost savings among patients at first recurrence, suggesting additional benefits of FMBL with early initiation of the therapy.