国立保健医療科学院 保健医療経済評価研究センター
Center for Outcomes Research and Economic
Evaluation for Health (C2H), National Institute ofPublic Health (NIPH) | URL:https://c2h.niph.go.jp

September 22, 2023

[C2H2202] Summary of cost-effectiveness evaluationof clazosentan (PivlazⓇ)
1. Indication
Prevention of cerebral vasospasm, vasospasm-related cerebral infarction (CI),and cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage(aSAH) securing.
2. Price of the drug
Clazosentan has been reimbursed since April 2022 at JPY 80,596 (as of
September 2023). The price was calculated based on the cost-calculation method.
This product was designated as an H1 cost-effectiveness evaluation item.
3. Scope of cost-effectiveness evaluation
The scope of evaluation agreed upon at the first session of the Expert Committeeof Cost-Effectiveness Evaluation (ECCEE) is described below. This product is used
to prevent cerebral vasospasm, vasospasm-related CI, and cerebral ischemic
symptoms after aSAH securing.
Population

Patients with aSAH securing

Comparator

Postoperative intensive care and management

4. Evaluation of additional benefits
The manufacturer performed a systematic review of randomized controlled trials(RCTs) and identified seven trials reported in six papers. Of these, they used AC054-305 and AC-054-306 trials, which are RCTs including only Japanese patients,for evaluating additional benefits for the following reasons: both RCTs are theprime confirmatory trials used to deduce the efficacy and safety of clazosentan
during the regulatory approval in Japan; they judged that both RCTs were morereliable than others as a result of the quality evaluation; and the merged analysisof both RCTs is suited for the scope of cost-effectiveness evaluation because each
RCT included patients secured by clipping and coiling, respectively. The
manufacturer used (i) the incidence proportion of vasospasm-related delayedischemic neurological dropout (DIND) and CI, and death from any reason within
six weeks after aSAH securing; (ii) the incidence proportion of DIND, CI, anddeath from any reason within six weeks after aSAH securing; and (iii) theproportions of mRS 0-2* (mild), mRS 3-5 (severe), and mRS 6 (death) as theevaluation items. Clazosentan showed statistically significant efficacy for theseitems; thereafter, the manufacturer insisted on the additional benefits ofclazosentan over the comparator. Based on the mRS, the academic groupexamined the availability of other trials identified in the systematic review but
not used for evaluating additional benefits. Subsequently, the academic groupclarified that the distribution of mRS differed between trials that included
Japanese individuals and those that did not. This difference is probably due totrial design and population. Therefore, the academic group judged that anevaluation based on trials, including the Japanese patients, was appropriate.
Additionally, although the academic group considered the availability of the AC054-202 trial—an RCT including Japanese and Korean patients—there wereconcerns; for example, the trial set the dose differed from the dose approved inregulatory. Afterwards, the academic group judged that the manufacturer’smethod for evaluating additional benefits of clazosentan based on the AC-054305 and AC-054-306 trials was appropriate. Furthermore, the academic groupconfirmed that clazosentan was still superior to the comparator, although thistendency was reduced when referring to the results of the merged analysis ofAC-054-305, AC-054-306, and AC-054-202 (Japanese only).
*mRS(modified Rankin Scale): Seven levels of 0-6 indicating the degree ofdisability in the subject’s daily activities (0 = no symptoms and 6 = death).
5. Results of the cost-effectiveness analysis
The manufacturer performed a cost-effectiveness analysis using a decision treemodel expressing the acute phase of aSAH (initial six months) and a Markov
model expressing the chronic phase of aSAH (after six months). The decision treemodel was used to determine the distribution of mRS by defining death from anyreason as mRS 6, the incidence of vasospasm-related DIND and CI as mRS 3-5,and others as mRS 0-2. The academic group judged that the manufacturer’s
setting was not appropriate for the following reasons: other reasons excluding
vasospasm also caused DIND and CI; the incidence of DIND and CI did notnecessarily correspond to mRS 3-5; and the distribution of mRS itself wasmeasured in the AC-054-305 and AC-054-306 trials. The academic group revised
the distribution of the mRS, and a scenario analysis considering the AC-054-202
trial was performed. The ECCEE accepted the following results.
Base-case
Population

Patients

withsecuringComparator
aSAH Postoperative intensive care andmanagement

ICER (JPY/QALY)
2,886,110

Scenario analysis considering the AC-054-202 trial
Population

Patients
securingwith

Comparator
aSAH Postoperative intensive care andmanagement

ICER (JPY/QALY)
4,195,896