Criterion

Treatment with vedolizumab should be discontinued if a clinical response is not achieved prior to the administration of a fourth dose of vedolizumab.

Conditions

1. The cost of treatment with vedolizumab should not exceed the drug plan cost of the least costly alternative biologic treatment option.
2. Patients treated with vedolizumab should be under the care of a specialist physician with experience in the diagnosis and management of CD.

Patient Input Information

Two patient groups responded to the CDR call for patient input (the Gastrointestinal Society and Crohn’s and Colitis Canada). Information was collected through discussions and interviews with patients, caregivers, and gastroenterologists; surveys and questionnaires; and a review of published reports and information. CDEC heard the following:

• CD can have profound effects on a patient’s physical, emotional, and social well-being. Patients often experience debilitating symptoms, including bloody diarrhea, bloating, abdominal pain, fatigue, and a lack of control over bowel movements.
• Patients may experience fear, anxiety, and stress due to the uncertainty regarding where and when they may experience an urgent bowel movement or a disease flare. These symptoms can significantly limit their ability to participate in the activities of daily living, including work and school.
• Patient groups indicated that individuals with CD found biologic drugs worked well when other treatments have failed; however, not everyone responds to the currently available treatments, so more options are needed.
• Patient groups expressed an understanding of the potential risks associated with biologic treatments and noted that those living with CD are often willing to accept these risks rather than undergo surgery, which they consider to be a last resort.

Clinical Trials

The CDR systematic review included two pivotal, multi-centre, double-blind RCTs (GEMINI II and GEMINI III). Both studies enrolled adults with moderate to severe active CD who failed treatment with one or more TNF alpha antagonists, immunomodulators, and/or corticosteroids. The GEMINI II study included a six-week induction phase followed by a 48-week maintenance phase (i.e., total treatment duration of 52 weeks). The six-week induction phase of GEMINI II enrolled a total of 1,115 patients in the following two cohorts: A double-blind cohort, who were randomized (3:2) to receive vedolizumab or placebo (n = 368); and an open-label cohort, who were treated with open-label vedolizumab (n = 748) and were not included in the induction analysis set. Patients in the double-blind cohort were scheduled to receive either 300 mg vedolizumab or placebo at weeks 0 and 2 (i.e., a total of two infusions). Those in the open-label cohort received unmasked 300 mg vedolizumab at weeks 0 and 2. In the maintenance phase of GEMINI II, patients from both the double-blind and open-label cohorts of the induction phase who received vedolizumab in the induction phase and who demonstrated a clinical response (CDAI score at least 70 points lower than baseline) at six weeks were randomized (1:1:1) to double-blind treatment with vedolizumab every four weeks, vedolizumab every eight weeks, or placebo. The maintenance phase began at the week 6 visit and concluded after 52 weeks.

GEMINI III was a phase 3, multinational, randomized, double-blind, placebo-controlled study (N = 416). The study was designed such that 75% of the study population was to have failed previous treatment with at least one TNF alpha antagonist and 25% were to have been naive to TNF alpha antagonist therapy. Patients were randomized (1:1) to receive either vedolizumab or placebo at weeks 0, 2, and 6 (i.e., a total of three infusions).

Outcomes

Outcomes were defined a priori in the CDR systematic review protocol. Of these, CDEC discussed the following:

• Clinical remission (CDAI score ≤ 150)
• Durable clinical remission (CDAI score ≤ 150 points at 80% or more of study visits during the maintenance phase)
• Corticosteroid-free clinical remission
• Enhanced clinical response (CDAI score at least 100 points lower than baseline)
• Short Form (36) Health Survey (SF-36)
• Inflammatory Bowel Disease Questionnaire (IBDQ)
• EuroQol 5-Dimensions Questionnaire (EQ-5D)
• Serious adverse events, total adverse events, and withdrawals due to adverse events.

Clinical remission at six weeks and enhanced clinical response (CDAI score at least 100 points lower than baseline) at six weeks were the co-primary end points of the induction phase of GEMINI II. Clinical remission in the overall study population at 52 weeks was the primary end point of the maintenance phase of GEMINI II. Clinical remission at six weeks in the TNF alpha–failure subpopulation was the primary end point in GEMINI III.

Efficacy

Harms (Safety and Tolerability)

The manufacturer conducted safety analyses for the induction phase and for the combined induction and maintenance phases. Data from the induction phase of GEMINI III were pooled with data from the induction phase of GEMINI II for the manufacturer’s induction safety analysis, and data from both phases of GEMINI II were used in the evaluation of safety in the induction/maintenance population.

A similar proportion of patients in the vedolizumab and placebo groups experienced at least one adverse event in the induction population (57% and 60%, respectively) and in the induction/maintenance population (88% versus 84%, respectively). The proportion of patients who experienced at least one serious adverse event was the same in the vedolizumab and placebo groups in the induction population (7% in each group) and slightly greater with vedolizumab in the induction/maintenance population (18% versus 15%, respectively). Withdrawals due to adverse events were more common in the placebo group compared with the vedolizumab group in both the induction (5% versus 3%, respectively) and induction/maintenance populations (10% versus 8%, respectively). For the vedolizumab group, there were no other adverse events leading to discontinuation that were reported for more than one patient.

Cost and Cost-Effectiveness

Vedolizumab is available in 300 mg/20 mL vials for intravenous infusion at the current market price of $3,290 per vial. At the recommended dosing of vedolizumab for CD of 300 mg at zero, two, and six weeks followed by every eight weeks thereafter, the cost of vedolizumab is $26,320 per patient in the first year and an average of $21,458 per patient in subsequent years. The manufacturer submitted a cost comparison of vedolizumab to branded infliximab (Remicade) and adalimumab in adults with CD. The perspective was that of a public drug payer with a time horizon of two years to incorporate both the induction and maintenance phases of treatment. The assumption of clinical similarity was based on a manufacturer-funded indirect treatment comparison. Only drug costs were considered; all other health care costs were assumed to be equal among comparators. Proportions of patients using standard versus escalated doses of infliximab and adalimumab in the base case, and the approved dose versus a single extra dose of vedolizumab in a sensitivity analysis, were derived from the ACCENT I, CLASSIC II, and GEMINI II trials, respectively.

Key limitations in the manufacturer’s analysis included uncertainty regarding the clinical similarity of comparators, the availability of a new and less expensive SEB infliximab, and uncertainty regarding the comparability and relative proportions of patients using escalated dosing for each treatment.

In CDR’s reanalysis, in the first year, at the approved dose of vedolizumab and standard doses of the comparators, the cost of branded infliximab ($31,602 per patient) is $5,282 (20%) more than the cost of vedolizumab ($26,320 per patient); adalimumab ($22,211 per patient) is $4,109 (16%) less than vedolizumab; and SEB infliximab ($16,800 per patient) is $9,520 (36%) less than vedolizumab when considering comparator drug costs based on Ontario Drug Benefit Formulary Exceptional Access Program. In subsequent years, at the approved dose of vedolizumab and standard doses of the comparators, the cost of branded infliximab ($25,765 per patient) is $4,306 (20%) more than the cost of vedolizumab ($21,458 per patient); adalimumab ($19,315 per patient) is $2,143 (10%) less than vedolizumab; and SEB infliximab ($13,697 per patient) is $7,762 (36%) less than vedolizumab. The reanalysis is based on the assumptions of clinical similarity among comparators, for which there is considerable uncertainty, and it was not possible for CDR to develop a robust comparative assessment considering escalated dosing.