1. Manufacturer’s Results

The manufacturer presented a cost analysis comparing treatment with vedolizumab to treatment with branded infliximab (Remicade) or adalimumab (Humira) in adults with moderately to severely active Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to immunomodulators or a TNF alpha antagonist; or who have inadequate response or intolerance to or have demonstrated dependence on corticosteroids. The perspective was that of a public drug plan, with a time horizon of two years in order to include both the initiation and maintenance phases of treatment. No discount was applied in the second year.

The cost comparison considered only drug costs, all other health care costs having been assumed to be equal for the different comparators. Drug unit costs were taken from Ontario Drug Benefit (ODB) Formulary Exceptional Access Program (EAP) list prices for infliximab and adalimumab, while vedolizumab costs were based on the submitted and current market prices. For year 1 of the analysis, the number of units was calculated by dividing the number of days per year (365.25) by seven days per week, then subtracting the number of weeks in the induction phase (14 for vedolizumab and infliximab, four for adalimumab), dividing by the number of weeks between maintenance treatments (eight for vedolizumab and infliximab, two for standard adalimumab, and one for escalated adalimumab), multiplying by the number of units per dose (one for vedolizumab and adalimumab, four for standard infliximab, and seven for escalated infliximab), and finally adding in the number of units used in the induction phase (three for vedolizumab, 12 for infliximab, and six for adalimumab). The same calculation was used for year 2, with only the induction phase components removed.

The base-case analysis assumed that 100% of vedolizumab patients would use the dosing recommended in the product monograph:² 300 mg on weeks 0, 2, and 6, and then every eight weeks thereafter. In contrast, the manufacturer assumed that 16% of infliximab patients and 22.9% of adalimumab patients would escalate to higher doses after the initiation phase during year 1, and 32% of infliximab and 45.8% of adalimumab patients would be on the escalated dose in year 2, based on the manufacturer’s interpretation of the number of patients escalating in the ACCENT I infliximab^3,4 and CLASSIC II adalimumab⁵ trials. (See Table 3.)

Table 3

Summary of Manufacturer’s Base Case Drug Acquisition Costs and Treatment Use.

Using the unit costs, the estimated number of units per regimen, and the proportions of patients escalating to the higher doses of infliximab and adalimumab assumed above (Table 3), the manufacturer concluded that two years of treatment with vedolizumab ($25,571 and $21,458 per patient in years 1 and 2, respectively) would cost less than adalimumab ($26,361 and $28,162 per patient in years 1 and 2, respectively) and infliximab ($32,965 and $31,948 per patient in years 1 and 2, respectively) (Table 4) .

Table 4

Manufacturer’s Base Case Total Drug and Incremental Costs (Savings) of Vedolizumab Versus Comparators.

The manufacturer also conducted a series of sensitivity analyses, exploring the impact of 47.2% of patients adding an extra vedolizumab dose at week 10, as well as varying the proportion of infliximab and adalimumab patients escalating to the higher recommended dosing schedule based on those found in the literature. None of these analyses had a substantial impact on the relative cost of comparators when compared with the base case.

2. CADTH Common Drug Review Results

In June of 2016, Inflectra (infliximab), a subsequent entry biologic (SEB) to Remicade, received a Notice of Compliance from Health Canada for the treatment of adult patients with moderately to severely active Crohn’s disease.⁸ Inflectra has a recommended dosing schedule that is identical to that of Remicade⁹ and is reimbursed on the ODB Formulary at a price of $525.00 per 100 mg vial, although ODB limited-use criteria for Inflectra do not yet include Crohn’s disease. Inflectra is currently under review by the CADTH Common Drug Review (CDR) for the treatment of Crohn’s disease; assuming it is reimbursed for Crohn’s disease by public drug plans, it will be an economic comparator of interest for vedolizumab and is thus included in all following CDR reanalyses.

CDR noted that the method of calculation employed by the manufacturer to determine the number of units used in year 1 was not consistent with the number of units that would be used by a patient in weeks 0 through 51 of therapy and that the number of units reported for year 2 was in fact the number of units that would represent an average maintenance year thereafter. The number of doses considered for CDR reanalyses represent the actual number of doses that would be needed for patients’ treatment in practice.

CDR’s reanalysis resulted in a year 1 cost of $26,320 per patient for vedolizumab at the monograph-recommended dose (“approved dose”), which is less than that of branded infliximab at standard ($31,602) or escalated doses ($46,415) as well as the escalated dose of adalimumab ($39,979), but more than either dose of SEB infliximab ($16,800 standard, $24,675 escalated) and standard-dose adalimumab ($22,211) (Table 5). Incremental costs in subsequent years follow similar patterns, with the exception of standard-dose vedolizumab ($21,458 per patient) being less expensive than escalated SEB infliximab ($23,970 per patient).

Table 5

The CADTH Common Drug Review’s Units, Costs, and Incremental Costs for Standard and Escalated Dosing, Including Subsequent Entry Biologic Infliximab.

Using the proportions of patients escalating doses assumed by the manufacturer in its base case and assuming that SEB infliximab has the same proportion as branded infliximab, the year 1 cost of approved-dose vedolizumab ($26,320 per patient) is $7,652 less than the dose-weighted average cost of branded infliximab ($33,972 per patient), but $40 more than that of adalimumab ($26,280 per patient), and $8,260 more than that of Inflectra-brand infliximab ($18,060). The average cost of approved-dose vedolizumab in subsequent years ($21,458 per patient) was $10,490 less than the dose-weighted average cost of branded infliximab ($31,948 per patient), and $6,704 less than that of adalimumab ($28,162 per patient), but $4,474 more than that of SEB infliximab ($16,984 per patient) (Table 6).

Table 6

The CADTH Common Drug Review’s Reanalysis Dose-Weighted Average Costs and Incremental Costs (Savings) of Vedolizumab Versus Comparators.

The escalation rate of 32% at the start of year 2 derived by the manufacturer for infliximab from the ACCENT I trial appears higher than those rates reported in two observational studies. One reported an escalation rate of 1.4% per patient-month (roughly 31% at the end of year 2) for infliximab patients on 5 mg/kg who had received at least one maintenance dose,¹⁵ while the other reported 55.7 months as the bottom of the interquartile range for time to secondary loss of response, and thus slightly less than 25% of patients had experienced secondary loss of response and dose escalation by the end of year 1.¹⁶ It is worth noting that neither of these studies specified that escalation needed to be to 10 mg/kg every eight weeks.

CDR conducted a sensitivity analysis in which 2.8% of infliximab patients were assumed to escalate to the 10 mg/kg dose every eight weeks after the induction period, to reflect the 1.4% per patient-month dose-escalation rate for infliximab patients with Crohn’s disease estimated in the first observational study above.¹⁵ The dose-weighted average year 1 cost of branded infliximab was $32,431 per patient using this method, while that of SEB infliximab was $17,241.

However, the statistics used by the manufacturer to estimate the proportion of patients who would escalate, along with the timing of those escalations, are not comparable between drugs:

• Infliximab 32% represents 181 ACCENT I patients who had initially responded to infliximab at week 2 and were randomized to 5 mg/kg of infliximab every eight weeks after induction, but who escalated to 10 mg/kg by week 54 (58 of 181 = 32%). Of note, only 36 of these 58 patients (62%) continued therapy to week 54.³
• Adalimumab 45.8% represents 204 CLASSIC II patients who were not in remission at weeks 0 and 4 and moved to a 40 mg adalimumab biweekly open-label cohort. 131 of 204 patients completed 56 weeks of treatment, 60 of whom had been escalated to 40 mg adalimumab weekly (60 of 131 = 45.8%).⁵
• Vedolizumab 47.2% in sensitivity analysis represents the 412 of 873 GEMINI II patients who had not achieved clinical response by week 6 and who were then assigned to 300 mg vedolizumab every four weeks (412 of 873 = 47.2%), and not to a single additional dose at week 10 as assumed in the manufacturer’s sensitivity analysis. Of note, only 69 of these 412 patients continued therapy to week 52 (17%), most due to lack of efficacy.⁷

These differences make it unlikely that the proportions of patients the manufacturer assumed would escalate to and remain on higher doses on each drug are comparable or reflect clinical practice. Of particular importance, the absence of a recommended dose escalation in the vedolizumab product monograph² does not imply that the approved-dose vedolizumab is equally effective to escalated doses or a proportional mix of patients on standard and escalated doses of either infliximab or adalimumab; the manufacturer’s submitted indirect treatment comparison was conducted using standard-dose trial data for each comparator (see CDR Clinical Report, Appendix 6), and thus any assumption of clinical similarity, uncertain as it may be, should also be based on the standard-dose schedules.

The clinical expert consulted by CDR believed it highly probable that vedolizumab patients with a secondary loss of response would be escalated to treatment every four weeks as per the higher-exposure arm in the GEMINI II trial⁶ as well as those patients who had not adequately responded by week 6 in GEMINI II, despite this dosing schedule (and that assumed in the manufacturer’s sensitivity analysis) not being included in the Health Canada–approved product monograph.²

CDR conducted an exploratory analysis assuming a varying proportion of patients escalating to the higher dosing regimen for each comparator (Table 7). Prices can then be compared at differing escalation rates under varying scenarios or as data become available. For example, if 30% of infliximab patients are using 10 mg/kg every eight weeks, while 50% of adalimumab patients are using 40 mg weekly and 50% of vedolizumab patients are using 300 mg every four weeks (i.e., escalation proportions similar to those cited by the manufacturer), then the average annual cost of maintenance vedolizumab ($32,194 per patient) is $632 more than that of branded infliximab ($61,562 per patient), $3,221 more than that of adalimumab ($28,973 per patient), and $15,416 more than that of SEB infliximab ($16,779 per patient).

Table 7

The CADTH Common Drug Review’s Exploratory Analysis Varying Proportion of Patients Escalating Across All Comparators.

It is important to note that the analyses conducted by both the manufacturer and CDR fail to account for the relative likelihood of patients discontinuing therapy on any given comparator, and who thus stop accruing both costs and benefits during the two-year time horizon, as well as patients who switch treatments. CDR estimated cost per patient and cost per completer analyses after one year of therapy for all comparators, but concluded that there were too many differences in trial design, patient characteristics, and reported information regarding timing of discontinuation between ACCENT I, CLASSIC II, and GEMINI II for the results to be appropriately compared.

Finally, the clinical expert consulted by CDR emphasized that a variety of escalation regimens are used in Canadian clinical practice rather than only those specified in the manufacturer’s submission or the product monographs. For example, infliximab may be increased to 5 mg/kg every six weeks before escalation to 10 mg/kg dosing is attempted based on individual patient response. The expert believed it likely that escalation of vedolizumab based on patient response would eventually follow similar patterns once clinicians became familiar with its use.