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Indication: For the treatment of adult patients with anti–aquaporin 4 (AQP4) antibody–positive neuromyelitis optica spectrum disorder (NMOSD)
CADTH recommends that Ultomiris be reimbursed by public drug plans for the treatment of neuromyelitis optica spectrum disorder (NMOSD) if certain conditions are met.
Ultomiris should only be covered to treat adult patients with anti–aquaporin 4 (AQP4) antibody–positive NMOSD. Patients must have had at least 1 relapse (also known as an “attack”) of NMOSD in the 12 months before initiation. Patients must have an Expanded Disability Status Scale score of 7 points or less.
Ultomiris should only be reimbursed if prescribed by a neurologist with expertise in treating NMOSD and if the price is reduced by at least 73%. Ultomiris should not be initiated during an NMOSD relapse episode or when used in combination with rituximab, satralizumab, eculizumab, or inebilizumab.
NMOSD is a severe, chronic, and progressive disease of the central nervous system that causes inflammation in the optic nerve and spinal cord. NMOSD relapses are unpredictable and cause permanent neurological damage, leading to increasing amounts of irreversible impairment of vision and/or mobility and sometimes death due to respiratory failure. Over time, patients may experience progressively increasing disability, pain, and loss of independence due to the cumulative effect of repeat relapses. NMOSD is rare and disproportionately affects females. Systemic reviews based on data from several countries have estimated that the prevalence ranges from 0.51 per 100,000 people to 4.4 per 100,000 people, but there are no Canadian-specific estimates.
Patients with NMOSD expressed a need for accessible treatments that are effective in the prevention of NMOSD relapses because reducing or avoiding relapses may delay the progression of disability and increase patients’ ability to maintain independence and health-related quality of life.
Treatment with Ultomiris is expected to cost approximately $567,618 for the first year of treatment and $522,104 in subsequent years.
The Canadian Drug Expert Committee (CDEC) recommends that ravulizumab be reimbursed for the treatment of adult patients with anti–aquaporin 4 (AQP4) antibody–positive neuromyelitis optica spectrum disorder (NMOSD) only if the conditions listed in Table 1 are met.
One open-label, single-arm, phase III, multicentre, external placebo-controlled trial (CHAMPION-NMOSD; N = 58) in adult patients with AQP4 antibody–positive NMOSD who had at least 1 relapse within the prior 12 months demonstrated that treatment with ravulizumab resulted in a clinically important reduction in the probability of having an NMOSD relapse compared to placebo; the use of ravulizumab was associated with a hazard ratio (HR) of 0.014 (95% confidence interval [CI], 0.000 to 0.103) versus placebo. The median analysis follow-up time was 73.50 weeks (range, 11.00 to 117.71 weeks) for the ravulizumab group and 36.00 weeks (range, 1.86 to 117.71 weeks) for the placebo arm. Throughout the study follow-up, no patients in the ravulizumab group reported a primary outcome event of adjudicated on-trial relapse compared with 20 patients (42.6%) in the placebo group, yielding a relative relapse risk reduction of 98.6% (95% CI, 89.7% to 100.0%). Treatment with ravulizumab likely results in a clinically important reduction in the proportion of patients who have worsening scores from baseline on the Hauser Ambulation Index (HAI) compared to placebo (odds ratio [OR] = 0.155; 95% CI, 0.031 to 0.771). The use of ravulizumab may also result in a clinically important reduction in the proportion of patients who have worsening scores from baseline on the Expanded Disability Status Scale (EDSS) compared to placebo; however, the evidence has very low certainty.
Patients expressed a need to have access to therapy options that can reduce the risk of future relapses, maintain the current level of physical ability, and slow disease progression. CDEC concluded that ravulizumab met some important patient needs by reducing the risk of future relapses as well as slow disease progression.
Using the sponsor-submitted price for ravulizumab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for ravulizumab was $2,386,625 per quality-adjusted life-year (QALY) gained compared with satralizumab. At this ICER, ravulizumab is not cost-effective at a willingness to pay (WTP) threshold of $50,000 per QALY for adult patients with NMOSD. A price reduction is required for ravulizumab to be considered cost-effective at a WTP threshold of $50,000 per QALY gained.
Reimbursement Conditions and Reasons.
NMOSD is a rare, inflammatory disease that affects the central nervous system, specifically the optic nerves and spinal cord, often leading to permanent blindness and paralysis. It is distinct from multiple sclerosis (MS) by its association with serum AQP4 immunoglobulin G (IgG) antibodies (AQP4-IgG). Patients with NMOSD experience acute unpredictable relapses that can last days to weeks and cause worsening symptoms. These relapses are recurrent; they occur among 80% to 90% of patients, leading to permanent disabilities. The most common manifestation of an acute relapse involves the inflammation of optic nerves (optic neuritis), which leads to eye pain and vision loss in 1 eye or both eyes. The clinical presentation also involves inflammation of the spinal cord (transverse myelitis), resulting in weakness or paralysis of arms and legs, bladder or bowel control problems, sensory loss, and painful muscle spasms. NMOSD may involve brainstem syndromes, such as intractable nausea, vomiting, hiccups, facial nerve palsy, oculomotor dysfunction, or vertigo. Disease symptoms and cumulative damage associated with NMOSD are associated with poor HRQoL. At its worst, NMOSD can lead to fatal respiratory failure. Clinical deterioration in patients with NMOSD accumulates in a stepwise fashion after each relapse and is often irreversible. Therefore, prevention of relapse is the key goal of therapy in the overall management of patients with NMOSD to minimize the amount of irreversible damage.
NMOSD disproportionately affects females with a reported female:male ratio of 9:1 to 12:1 in patients with AQP4 antibody–positive NMOSD. The disease presents at a reported mean age at onset of 40 years. Prevalence data of NMOSD within Canada is not available. Based on data from various countries in previous systematic reviews, NMOSD prevalence ranges from 0.50 per 100,000 people to 4.00 per 100,000 people and its incidence ranges from 0.053 per 100,000 people to 0.40 per 100,000 people. Regarding mortality, recent studies reported NMOSD mortality rates from 3.3% to 7%. Other studies estimated worldwide mortality rates in NMOSD to range from 9% to 32%, depending on age, relapse rate, and recovery from relapses.
In Canada, NMOSD is diagnosed by a neurologist or specialized physician in demyelinating disorders. Diagnostic criteria follow the 2015 consensus-based criteria developed by the International Panel for NMO Diagnosis. Diagnosis is based on clinical characteristics, and AQP4 antibody testing.
Ravulizumab is a monoclonal antibody and a terminal complement inhibitor that binds to the complement protein C5 with high affinity and specificity, thereby inhibiting its cleavage to C5a (a proinflammatory anaphylatoxin) and C5b (the initiating subunit of the membrane attack complex [MAC or C5b-9]), and thus preventing the generation of MAC. Ravulizumab has been approved by Health Canada for the treatment of adult patients with AQP4 antibody–positive NMOSD. Ravulizumab is supplied as a 10 mg/mL or 100 mg/mL concentrate. The recommended ravulizumab IV maintenance dose in adult patients (≥ 18 years) with NMOSD with a body weight greater than or equal to 40 kg is based on the patient’s body weight. Maintenance doses are administered every 8 weeks, starting 2 weeks after the loading dose. Ravulizumab should be administered by a qualified health care professional.
To make its recommendation, the committee considered the following information:
Two patient groups, MS Canada and TSF, responded to CADTH’s call for patient input for the current review of ravulizumab.
MS Canada gathered information for this submission via a survey launched in 2023 targeting people in Canada living with NMOSD and their caregivers, which included 13 respondents. TSF gathered information through various surveys of patients and caregivers, patient narratives, focus groups, roundtables, discussions with key opinion leaders, ambassadors, TSF’s global medical advisory board, advisors, peer-reviewed medical literature, and TSF’s experience working in the NMOSD community.
The 2 patient groups indicated that NMOSD is more prevalent among women and that the disease is initiated with a severe episode and continues with subsequent devastating relapses that have a negative impact on vision, mobility, function, mental health, and quality of life of patients. The disease has a tremendous impact on all aspects of patients’ lives, including a negative effect on independence, their family and caregivers, employment, and social life.
The patient inputs stated that treatment for NMOSD involves IV steroids, IV immunoglobulin or plasmapheresis or plasma exchange, mofetil mycophenolate, as well as the use of off-label immunosuppressants to help prevent further relapses. These have varying levels of therapeutic benefit. Many patients suffer significant additional relapses and additional disability while cycling through off-label therapies, and others indicated these therapies partially managed their disease due to worsening symptoms and/or challenging side effects. There are some efficacious Health Canada–approved medications, such as eculizumab and satralizumab; however, access to these medications is very limited. Eculizumab is also administered by infusion every 2 weeks, which can be onerous and disruptive to the lives of individuals living with NMOSD. According to the patient inputs, patients need to have access to more treatment options that are able to prevent any further relapses with less frequent infusion dosing and fewer side effects.
Ravulizumab is simply a more stable analogue of eculizumab and requires much less frequent dosing after initiation (every 8 weeks), which can improve treatment adherence.
NMOSD is a rare and severe disease with a generally poor natural trajectory and inherently high risk of relapse. Currently available therapies are often associated with an unacceptable harms profile and only provide suboptimal relapse prevention, resulting in accumulation of irreversible neurological disability, including paralysis and blindness. The clinical experts highlighted the unmet need of access to an effective treatment, which would make a great difference in the lives of patients and their caregivers.
There are no formal treatment guidelines in Canada that specify which interventions should be used as first- or second-line therapies. The clinical experts indicated that treatment of individuals with NMOSD differs by the province or territory based on differential access to drugs. The treatment goal of NMOSD is to prevent relapses, which is of upmost importance in prevention of neurological disability (including, but not limited to, paralysis and loss or impairment of vision) and mortality. There are many downstream desirable effects of early prevention and controlling the disease: maintaining neurological function will have a positive impact on the patients’ quality of life, decrease risk of complications related to neurological dysfunction, and, in turn, maintain independence, increase ability to maintain employment, and reduce burden on caregivers.
Oral glucocorticoids, azathioprine, mycophenolate mofetil, and rituximab are frequently used to prevent relapses in NMOSD; however, many individuals with NMOSD still have ongoing disease activity while receiving these treatments. As their efficacy is viewed as suboptimal, corticosteroids are often used as adjunct therapy, adding to the harms profile. Although approved in Canada, satralizumab and eculizumab are rarely attainable for persons living with NMOSD.
Access to ravulizumab is likely to cause a shift in the current treatment paradigm because it addresses the underlying disease process of NMOSD with high efficacy. All individuals with AQP4 antibody–positive NMOSD should be considered eligible to receive ravulizumab. The clinical experts emphasized that it would be inappropriate to recommend that patients try other treatments before initiating treatment with ravulizumab because it is paramount to control NMOSD’s irreversible progression as early as possible.
The appropriate settings for initiating and monitoring treatment with ravulizumab are neurology clinics with adequate expertise in NMOSD, including neurologists with expertise or subspecialty in MS or autoimmune neurology, and occasionally neuro-ophthalmology. Meningococcal vaccination should be mandatory in the patients planning to receive this therapy.
Although the absence of relapse would be ideal, this may not be realistic. The severity of a relapse, as well as accumulation of disability, are important factors to consider when determining response to therapy. Once stability is established, treatment response may be assessed every year. Patients may need to discontinue a treatment if they experience a severe relapse (e.g., requiring intubation and support on a ventilator), 2 or more relapses within 2 years (assessed on case-by-case basis depending on severity), or severe adverse events (SAEs) while on treatment.
One clinician group, the CNMSC (authored by 1 clinician), responded to CADTH’s call for clinician group input. Clinician perspectives from the CNMSC were obtained through clinical experience, knowledge of the medical literature, and from clinicians across the country who specialize in this therapeutic area.
According to the clinician group, there are a variety of treatments available in Canada that are not specifically indicated for NMOSD as well as other more efficacious therapies, such as monoclonal antibodies; however, access to these therapies is extremely limited due to their stringent funding coverage criteria. Failure of treatment, with even just 1 relapse, can lead to a profound, permanent disability, including blindness and paralysis.
As per the CNMSC, there is a large unmet need in Canada for high-efficacy, well-tolerated therapies for NMOSD that have a significant impact on preventing and/or reducing relapses. Use of some of the off-label therapies is limited because of many side effects and lack of efficacy. Also, eculizumab is given by an IV infusion every 2 weeks which is too onerous for some patients to tolerate. According to the clinician group, the best approach for patients is to use efficacious, safe, and tolerable therapy as soon as possible after the first episode to avoid any relapses, reduce the severity of relapses and the cumulative disability associated with them, and minimize adverse events (AEs) related to therapies. Ravulizumab would be the first therapy for patients diagnosed with a confirmed diagnosis of NMOSD, with a positive serum test for the AQP4 antibody after their first relapse and for those who have severe AEs on first-line therapy.
According to the CNMSC, avoidance of a new relapse, which includes vision loss, weakness, sensory impairment, or bladder/bowel dysfunction, is the outcome used to determine whether a patient is responding to treatment. The clinician group indicated that discontinuation of therapy should be considered in patients who have a new relapse on this therapy.
Input was obtained from the drug programs that participate in the CADTH Reimbursement Review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for ravulizumab:
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
One study was reviewed, CHAMPION-NMOSD (n = 58), which was an external placebo-controlled, open-label, phase III, multicentre trial designed to evaluate the efficacy and safety of ravulizumab in adult patients with AQP4 antibody–positive NMOSD who had at least 1 relapse within the prior 12 months. The study had a single-arm treatment design, utilizing the placebo group from the PREVENT study as an external placebo comparator. PREVENT is a recent study that evaluated the efficacy and safety of eculizumab in preventing relapses in patients with AQP4 antibody–positive NMOSD who had at least 2 relapses within the prior 12 months or 3 relapses within the prior 24 months, at least 1 of which occurring within the prior 12 months. Patients were randomly assigned in a 2:1 ratio to receive either eculizumab (n = 96) or a matching-administration placebo (n = 47) every 2 weeks.
The primary outcome in the study was time to first adjudicated on-trial relapse, which was defined as a new onset of neurological symptoms or worsening of existing neurological symptoms, with an objective change on neurological examination that persists for more than 24 hours as confirmed by the treating physician. Neurological signs and symptoms had to be attributed to NMOSD (e.g., not caused by other identifiable causes such as an infection). On-trial relapses were independently reviewed by the relapse adjudication committee, which consisted of physicians with expertise in NMOSD who conduct independent reviews of all on-trial relapses.
Secondary outcomes in the study included function, as measured by the HAI, which is a rating scale developed to assess mobility by evaluating the time and effort used by the patient to walk 8 m. The scale ranges from 0 to 9, with 0 being the best score (asymptomatic; fully ambulatory with no assistance) and 9 being the worst (complete lack of independent mobility). Function was also assessed using the EDSS score, an ordinal clinical rating scale that ranges from 0 (normal neurological examination) to 10 (death) in half-point increments. The EDSS quantifies disability in the 7 Kurtzke functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, and cerebral). In conjunction with ambulation, they are rated in the context of a standard neurological examination, then these ratings are used together with observations and information concerning the patient’s mobility, gait, and use of assistive devices to assign a score.
Secondary outcomes in the study included HRQoL, which was assessed using the EQ-5D, a generic preference-based HRQoL instrument, consisting of a visual analogue scale (VAS), and a composite index score of 5 dimensions: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. HRQoL was also assessed as an exploratory outcome using the Short Form (36) Health Survey (SF-36), a patient self-administered questionnaire designed to assess generic HRQoL in adult populations with and without disease. The SF-36 consists of 36 items organized into the 8 scales (physical function, social function, role limitations [physical and emotional], bodily pain, general medical health, mental health, vitality, and health transition). The questionnaire also yields 2 summary measures of physical health and mental health derived from scale aggregates. Higher global scores are associated with better quality of life.
Finally, visual acuity was assessed as an exploratory outcome using the Optic-Spinal Impairment Scale (OSIS), a generic instrument assessing visual acuity and motor, sensory, and urinary sphincter functions. Scores are assessed for each individual domain and range from 0 to 8 for visual acuity and from 0 to 5 for the other domains; a lower score indicates better functioning.
The outcome of relapse was considered the preferred and most reliable end point by clinical experts. In patients with AQP4 antibody–positive NMOSD, the use of ravulizumab was associated with a HR of 0.014 (95% CI, 0.000 to 0.103) versus placebo. The log-rank test yielded a P value less than 0.0001. The median analysis follow-up time was 73.50 weeks (range, 11.00 to 117.71 weeks) for the ravulizumab group and 36.00 weeks (range, 1.86 to 117.71 weeks) for the placebo group. Throughout the study follow-up, no patients in the ravulizumab group reported a primary outcome event of adjudicated on-trial relapse compared with 20 patients (42.6%) in the placebo group from the PREVENT study, yielding a relative relapse risk reduction of 98.6% (95% CI, 89.7% to 100.0%). Therefore, treatment with ravulizumab resulted in a clinically important reduction in the probability of having an NMOSD relapse compared to placebo.
Results from sensitivity analyses, which aimed to assess whether any imbalances in observed baseline characteristics due to trial design could be sufficient to confound the observed treatment effect, were similar with those from the primary analysis. Results were also consistent across prespecified and post hoc subgroups.
Treatment with ravulizumab likely results in a clinically important reduction in the proportion of patients with worsening from baseline in HAI score at the primary data cut-off compared to placebo (OR = 0.155; 95% CI, 0.031 to 0.771). The proportions of patients with clinically important worsening from baseline through the end of the study period in HAI score were 3.4% (2 patients of 58) in the ravulizumab arm and 23.4% (11 patients of 47) in the placebo arm.
The use of ravulizumab may result in a clinically important reduction in the proportion of patients with worsening from baseline in EDSS score at the primary data cut-off compared to placebo; however, the evidence is very uncertain because the CI for the difference between groups includes the possibility of no difference. The proportions of patients with clinically important worsening from baseline through the end of study period in EDSS score were 10.3% (6 patients of 58) in the ravulizumab arm and 23.4% (11 patients of 47) in the placebo arm, yielding an OR of 0.332 (95% CI, 0.106 to 1.042).
Treatment with ravulizumab may result in a clinically important difference in HRQoL at the primary data cut-off compared to placebo, as measured by the EQ-5D index score, the EQ-5D VAS score, and ||| ||||| |||||||| ||||||||| ||||||; however, the evidence is very uncertain because the CI for difference between groups includes the possibility of no difference. The mean change from baseline through the end of the study period in the EQ-5D index score was 0.01 (SD = 0.15) in the ravulizumab arm and −0.04 (SD = 0.21) in the placebo arm, yielding a difference in least square (LS) means of ranks of 11.15 (95% CI, −0.32 to 22.62). For the EQ-5D VAS score, the mean change from baseline to end of study period was 2.6 (SD = 14.1) in the ravulizumab arm and 0.6 (SD 16.4) in the placebo arm; the difference in LS means of ranks was 13.38 (95% CI, 1.35 to 25.41). Finally, for the ||||| |||||||| ||||||||| |||||| ||| |||| |||||| |||| |||||||| || ||| || ||||| |||||| ||| ||||| |||||||| || ||| ||||||||||| ||| ||| |||| ||| |||||| || ||| ||||||| |||| || ||||||| || |||||||||| ||||||| ||||| ||| ||||||||.
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The evidence || |||| ||||||||| ||||| ||| |||||| || ||||||||||| || |||| || ||| ||||||| |||| ||||||| |||||||| || |||||||| ||| |||| |||||| |||| |||||||| ||||||| ||| ||| || ||||| |||||| ||| |||||| ||| ||||||| || ||| ||||||||||| ||| ||| |||||| ||| ||||||| || ||| ||||||| |||| || ||||||| || |||||||||| ||||||| ||||| ||| |||||||| || || ||||||||| || ||| |||||||||||| ||||||||||| |||||||| || ||||||| ||| |||||||||||||| ||| |||| |||| ||||| ||| |||||||||||| |||||| |||| |||||||| || |||||||||| |||| ||| ||||||| || |||||||| || ||| ||||||||||| ||||| ||| |||| ||| |||| ||||| |||||| || |||||||| |||| |||||||| ||||||||| ||| ||||| ||||| || ||| ||||||| |||||||||| |||||| || ||||||||||| || ||||| || ||||| |||||| ||| || ||||||||||||||| |||||| |||||| || |||| ||||||||| |||| |||||||| |||| ||| ||||||||||| || ||| ||||||| || ||||||||||| ||||| ||||| ||| || |||||| |||| |||||||| || ||| ||||||||||| ||||| || ||||| || ||||| |||||| || || ||||||||||||||| |||||| ||||||| || |||| ||| |||||||| ||| ||| ||||||| ||||| |||||||||||||||| ||||||||.
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A total of 93% of patients receiving ravulizumab reported at least 1 AE and 19% of patients reported at least 1 SAE, of which the most frequently reported involved infections and infestations. However, treatment with ravulizumab appeared to be well tolerated because only 1 patient discontinued due to AEs; the reason for withdrawal from the study drug was infection. No deaths were reported in the study. Meningococcal infection was an AE of special interest. Two patients experienced meningococcal infection during the primary treatment period. No new meningococcal infections were reported during the long-term extension period.
The clinical experts indicated that the overall harms profile of ravulizumab in CHAMPION-NMOSD did not raise any particular safety signal, with the exception of meningococcal infections. As such, all patients should receive meningococcal vaccination before the start of ravulizumab therapy, as per the product monograph.
The CHAMPION-NMOSD trial had a single-arm treatment design, utilizing the placebo group from the PREVENT study as an external placebo comparator; this may have introduced a risk of bias leading to uncertainty surrounding the estimates. However, the overall assessment suggests that the 2 trials likely feature sufficient similarity to ensure a valid comparison, and that differences observed in patient populations might not substantially affect results for the primary outcome of relapse prevention. According to the clinical experts consulted by CADTH, the differences observed in the number of historical relapses between groups is not expected to have a substantial impact on the risk of future relapses; in addition, the annualized relapse rate within the prior 12 months and 24 months between treatment groups were consistent with the assumption that both groups actually had a relatively similar evolution in terms of relapse frequency. Some level of uncertainty could be mitigated by the magnitude of relapse risk reduction with ravulizumab treatment observed in the CHAMPION-NMOSD trial. In addition, results from sensitivity analyses of the primary outcome suggest that the findings are robust and statistically infer that imbalances in patient populations were not likely to have a meaningful impact on the estimates.
Secondary efficacy and exploratory outcomes of function, HRQoL and visual acuity were assessed adequately using appropriate tools; however, no studies assessed their validity or reliability in NMOSD specifically. Minimal clinically important differences were established through clinical expert input because none could be identified in the literature for this patient population. The thresholds used in the study for dichotomous outcome assessment (HAI and EDSS) were considered appropriate and consistent with clinical practice according to the clinical experts. The clinical experts indicated that loss of function and quality of life is cumulative over time, and that the magnitude of worsening depends on the severity of the relapse; therefore, measurement of these outcomes may be less sensitive to changes in the context of a clinical trial. The goal for patients receiving active treatment would be to maintain a stable status; patients in the placebo group would be expected to have a worsening status based on natural disease trajectory. Because follow-up only went until the first on-trial relapse for ethical reasons (median follow-up time in CHAMPION-NMOSD was 73.50 weeks for the ravulizumab group and 36.00 weeks for the placebo group), assessment of these outcomes may lead to an underestimation of active treatment effect over time.
Findings from the CHAMPION-NMOSD trial can be considered generalizable to patients with NMOSD in Canada because the study population was considered representative of patients in clinical practice; disability was consistent with what is expected within an NMOSD population. The primary outcome of relapse prevention is consistent with the treatment goals of NMOSD in clinical practice according to the clinical experts. Relapse assessment in the trial was performed in a similar manner as in clinical practice. The clinical experts confirmed that follow-up duration was long enough for the trial to adequately capture relapses, considering the inherently high risk of relapse in patients with AQP4 antibody–positive NMOSD.
For nonrandomized comparative studies, such as a single-arm trial with an external control, CADTH followed the GRADE approach. The CADTH review team assessed study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because of the inherent risk of bias from the absence of randomization and differences in patient populations, the certainty of evidence for single-arm trials started at low certainty, with opportunity for rating up.
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 assessment 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:
Summary of Findings for Ravulizumab Versus Placebo for Patients With AQP4 Antibody–Positive NMOSD in CHAMPION-NMOSD (PREVENT Placebo Group as External Control).
The sponsor submitted indirect evidence in the form of a |||||||| ||| which objective was to obtain relative treatment effects between ravulizumab, ||||||||||| ||||||||||||| ||| |||||||||||| for the treatment of adult patients with AQP4 antibody–positive NMOSD. Analyses were performed for |||||||||||||| ||||| || ||||| ||||||||| ||||||||| |||||||||||| ||||||||||| |||||||| ||| ||||| |||||||||||||||| |||||||. Outcomes of interest for evaluation included |||||||| ||||| || ||||| |||||||| |||||||||| ||||||| |||||||||| ||| |||||||||||||| ||||||| || |||| ||||||| ||||||||| ||| |||||||| |||||||||| |||||| ||||| ||||||| ||||||| ||||||||||| ||||||||||||| |||||||| |||||| |||||||||| ||||| ||||| |||||| |||||||| |||||| ||||| ||||| |||||| ||| ||||||| ||||| |||| |||||| ||||| |||.
A total of ||||| unique clinical trials were included into the evidence base for the NMA: ||||||||||||||| |||||||| ||||||||||| |||||||||| ||| ||||||||||| ||| |||||||||||| ||||| |||||||||||| ||| |||||||||||| |||||| ||||||||||| ||||||||||| |||||||| |||||||| |||||||||||| ||||||| patients; however, patients who were ||||| were excluded from analyses. All patients from |||||||||||||| ||| ||||||| ||| ||||||||| |||||||||| at enrolment.
The start date of the studies ranged from |||| || ||||. Treatment duration ranged from ||||| |||||. All studies had a ||||||| treatment group except for ||||||||. Sample size ranged from |||||| ||||||||. ||||||||||| ||| was not required in any trial but was permitted in ||||||||| ||||||| ||| |||||||||. The mean age of patients ranged from ||||| ||||| across the trials.
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|||| || ||||| ||||||| ||||||| |||||||||| || |||||||| || ||||||||||| || ||||||||||| ||||||| were reported in |||| trials evaluating ravulizumab |||| |||||||||||||| ||| |||||||||||||||. The relative treatment effect of ||||||||||||||| ||| |||||||| || ||||||||| ||| ||||||| || |||||||||| ||||||||||||| ||| ||||||||| |||||||||||| |||||||| patients taking ravulizumab | ||| |||||| |||||| || ||||||||||||||| ||||||| |||| |||||||||||||| |||| ||||| ||| |||| ||||| ||||| ||| |||| |||||| || ||||||||||||||| ||||||| |||| |||||||||| |||| ||||| ||| |||| ||||| |||||.
|||||||||| ||||||| |||| ||||||||| |||||||| |||||||||| || |||||||| || ||||||||||| || ||||||||||| therapy were reported in |||| trials evaluating ravulizumab |||| |||||||||||||| ||| |||||||||||||||| |||| |||||||||||||| ||| ||||||||||||| ||| |||| ||||||||||| |||| ||||||||||||||| ||||||||| |||| ||| |||| || ||||||| |||| |||||||||||||| ||| ||| ||||| |||||||| || ||||||||||||||| |||| ||||| ||| |||| ||||| |||||| ||| |||| || ||||||| |||| ||||||||||||| ||| ||| ||||| |||||||| || ||||||||||||||| |||| ||||| ||| |||| ||||| |||||| ||||||| || |||||||||||||| |||||| ||||||||||||| |||| ||||||||||.
||||||||| |||||||| ||| |||||||||||||||| || ||||| |||||||||||| || ||||| ||||||| ||||||||||||| ||||||| ||||||||||||| ||||||| were reported in |||| trials evaluating ravulizumab||||||||||| ||||||||||||| ||| ||||||||||||| || ||| |||||||||| ||||| |||||||| || ||||||||||| ||||||||||| |||| ||| |||| |||||| || ||||||||||||||| ||||||| |||| |||||||||||| ||||||||||| |||| ||||| ||| |||| ||||| ||||| ||| ||| |||| |||| |||||| || ||||||||||||||| ||||||| |||| |||||||||||| ||||||||||| |||| ||||| ||| |||| ||||| |||||| ||||||||| ||||||| |||| |||||||||| ||| ||||||||||| || ||||||||||| |||| |||||||||||.
|||||||||| ||||||| |||| ||||||||| ||||||||||||| ||||||| ||||||||||||| ||||||| were reported in |||| trials evaluating ravulizumab|||||||||| ||||||||||||| ||| ||||||||||||| ||| |||| || |||||| |||| ||||||||||| ||||||||||| ||| ||| ||||| |||||||| || |||||||||||| ||||||||||| |||| ||||| ||| |||| ||||| ||||| ||| |||||||| || |||||||||||| ||||||||||| |||| ||||| ||| |||| ||||| |||||| ||| ||||||||| |||||| || ||||||||||| ||| |||||||||| ||||||||||||| |||| ||||||||||.
||||||||| |||||||| ||| ||||||||||| |||||||||||| || ||||| |||||||||||| || ||||| ||||||| || |||||||| ||||||| ||||||||||||| ||||||| ||||||| were reported in ||||| trials evaluating ravulizumab |||| |||||||||||||| ||| |||||||||||||||| || ||| |||||||||| ||||| |||||||| || |||||||||||||| |||| ||| |||| |||||| || ||||||||||||||| ||||||| |||| |||| ||||||||||||||| |||| ||||| ||| |||| ||||| |||||.
|||||||||| ||||||| |||| ||||||| || |||||||| ||||||| ||||||||||||| ||||||| ||||||| were reported in ||||| trials evaluating ravulizumab |||| |||||||||||||| ||| |||||||||||||||| ||||| |||||||||||||| |||||| ||| ||||||||| |||||||| | |||||| |||||||||| ||| ||||||||||| || ||| |||||||| ||||||||| |||||| ||||||||| ||||||| ||||||||| ||||||||||||| |||| ||| ||||| |||||||| |||| ||| ||||||||||| ||||||||| || |||||| |||| ||||||||.
|||||||||| || |||||||||| ||||||||| ||||| ||||| |||| ||||| ||| ||| ||||| ||| ||| ||| ||||| ||||||||| ||||||||| |||| ||||||||| ||||||||| ||||||| |||| |||||||||| |||||| ||| |||| ||||||||||||| ||| |||||||| ||||||| |||||||||||||||| ||||||||||| |||| |||||| ||| |||||||| ||||||||| |||| |||| ||| ||||||||| ||||| || || ||||| |||||||| |||||||||| |||| ||| |||||||||||| || |||||||| || ||| |||||| |||| ||||||| || ||||||.
||||| |||| ||| |||||||| || ||| ||||||||| ||||.
The sponsor conducted an NMA using a |||||||| |||||||| ||||| ||||| ||||||| |||||| for all outcomes. This was a reasonable method to apply given the availability of |||||||||| ||||||| |||| for only 2 of the included studies.
Comparisons in all NMA analyses were based on a ||||| |||||| of trials and ||||| ||||||| of patients in each trial. The networks were linked to ravulizumab through a |||||| ||||||| ||||| that was not part of the ||||||||||| trial. The validity of the ravulizumab comparative results relies entirely on the putative comparability of the |||||||| ||||||| || ||| ||||||||||| ||||| || ||||||||. The possibility of residual confounding exists when 2 nonrandomized groups ||||| ||||||||||| ||||||||| ||| ||| |||||||| |||||||| are being compared.
The sponsor’s decision to perform |||||||| NMA analyses based on the potential effect modifier of |||||||||| ||||||||||||||||| |||||||, was appropriate. The disadvantage of doing this was to create ||||| |||||||| |||| ||||| ||||||| || ||||||. There were other sources of heterogeneity that were not explored in the NMA analyses, and it is not clear if the homogeneity assumption is correct. These sources include the following:
The sponsor used a |||||||||| ||||| |||||||| in their sensitivity analyses for the outcome of |||||||. The factors selected by the sponsor for adjustment in the |||||||||| ||||| were reasonable, but there was not enough information provided to assess the validity of the sensitivity analyses. Some analyses in the base case results that favoured |||||||||||, no longer favoured ||||||||||| ||||| ||| ||| ||||||||||| |||||||| were performed for the |||| || ||||| ||||||| ||||. These included comparisons to |||||||||| ||||||||||||||||| ||||||||| ||||||||||| ||||||||| ||||||||||| ||||||| ||||||||| ||| |||||||||||| |||||||||||| ||||||| ||||||||||.
Results of the sponsor’s NMA favoured ||||||||||| || |||| ||||||||||| |||||||| but the results were ||| |||||||||| |||||| ||| |||||||||| |||| || |||||||| ||| ||||||| |||||||| ||||||||||| |||| |||||||||| || ||| |||||||||||||||| ||||||| ||||||| ||| ||| ||| ||| ||||||||||| ||||||| || ||| ||||||||||| ||||||| |||||||| ||||||| |||||||| ||||||||||| |||| |||||||||||| ||| ||| |||||||||||||||| ||||||| ||| ||||||||||| ||||||| ||| ||| ||| ||| ||||||||||| ||||||| |||||||| ||||||| |||||||| ||||||||||| |||| |||||||||||| || ||| ||||||||||| |||||||| ||||| |||||||| ||||| ||||||||| ||| ||||||||||| || |||||||| ||||||||||| ||||||| || ||||| ||||||| || ||||||||||||| ||||||| ||| ||||||| || ||| |||||||||| |||||||||||||||||||||| |||||||||| || |||||||||||| |||| ||||||||||| ||| ||| |||||||| ||| ||| || ||| ||||||| ||||||||| ||| ||||| ||||||| |||| ||||||||| || ||||||||| ||||||| ||||| |||| || ||||| ||||||||||| ||||||| ||| ||||||||||| ||| ||| || ||| ||||||||||| || ||| || ||| ||||| |||||||| ||| ||||| ||||||||||| ||| ||||| ||||| |||| || |||| ||| || ||| |||||||.
Cost and Cost-Effectiveness.
CADTH reanalysis included updating the cost of rituximab to reflect current publicly available list prices and updating the market shares for satralizumab and rituximab in the reference scenario and updating the market shares for ravulizumab, rituximab, and satralizumab in the new drug scenario. With these changes, the CADTH reanalysis shows that the reimbursement of ravulizumab for the treatment of adult patients with anti-AQP4 positive NMOSD would be associated with a budgetary increase of $13,381,657 in year 1, $24,956,594 in year 2, $34,497,100 in year 3, with a 3-year total incremental cost of $72,835,350.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Edward Xie, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Peter Jamieson, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Trudy Huyghebaert, Dr. Danyaal Raza, and Dr. Peter Zed.
Meeting date: January 25, 2024
Regrets: One expert committee member did not attend.
Conflicts of interest: None
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Indication: For the treatment of adult patients with anti–aquaporin 4 (AQP4) antibody–positive neuromyelitis optica spectrum disorder (NMOSD)
Sponsor: Alexion Pharma GmbH
Recommendation: Reimburse with conditions
Copyright © 2024 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
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