Authors' objectives: The academic technology assessment group (ATAG) reviewed a report on clazosentan's additional benefits and cost-effectiveness compared to postoperative intensive care and management in patients with aneurysmal subarachnoid hemorrhage (aSAH) securing submitted by the manufacturer of clazosentan (Idorsia Pharmaceuticals Japan). This report summarizes the results of the review and the re-analysis by the ATAG. In evaluating the additional benefits of clazosentan over postoperative intensive care and management, the manufacturer submitted data from the AC-054-305 and AC-054-306 trials with the following reasons: both randomized controlled trials (RCTs) were 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 more reliable as a result of the quality evaluation; and the merged analysis of both RCTs was suited for the scope of cost-effectiveness evaluation. The manufacturer used three endpoints, including the proportions of the modified Rankin Scale (mRS) 0-2 (mild disability), mRS 3-5 (severe disability), and mRS 6 (death). Clazosentan showed statistically significant efficacy for these endpoints; thereafter, the manufacturer insisted on the additional benefits of clazosentan over the comparator. Based on the mRS, the ATAG examined the availability of other trials identified in its systematic review. Subsequently, the ATAG clarified that the distribution of mRS differed between trials that included Japanese individuals and those that did not. This difference is probably due to trial design and population. Therefore, the ATAG judged that an evaluation based on trials, including the Japanese patients, was appropriate. Additionally, although the ATAG considered the availability of the AC-054-202 trial (an RCT including Japanese and Korean patients) there were concerns; for example, the trial-set dose differed from the dose approved in regulatory. The ATAG judged that the manufacturer's method for evaluating the additional benefits of clazosentan based on the AC-054-305 and AC-054-306 trials was appropriate. Thus, as performing the cost-effectiveness analysis was appropriate, the ATAG examined the manufacturer's analysis. The manufacturer developed a decision tree model to simulate the acute phase of aSAH (initial six months) and a Markov model to simulate the chronic phase of aSAH (after six months). The decision tree model was used to determine the distribution of mRS by defining death from any reason as mRS 6, the incidence of vasospasm-related delayed ischemic neurological dropout (DIND) and cerebral infarction (CI) as mRS 3-5, and others as mRS 0-2. The ATAG revised the distribution of the mRS because 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 not necessarily correspond to mRS 3-5; and the distribution of mRS itself was measured in the AC-054-305 and AC-054-306 trials. The base-case analysis showed that clazosentan incurred an additional cost of JPY 2,215,691 and conferred an additional 0.77 quality-adjusted life years (QALYs) compared to postoperative intensive care and management. This resulted in an incremental cost-effectiveness ratio (ICER) of JPY 2,886,110 per QALY gained. Moreover, a scenario analysis considering the AC-054-202 trial showed that clazosentan incurred an additional cost of JPY 2,256,426 and conferred an additional 0.54 QALYs compared to postoperative intensive care and management. This resulted in an ICER of JPY 4,195,896 per QALY gained. In conclusion, for patients with aSAH securing, the results by the ATAG suggested that the ICER for clazosentan compared to postoperative intensive care and management was likely to belong to the interval between JPY 2 and 5 million per QALY from the perspective of public healthcare payer in Japan.

Project Status: Completed

URL for project: https://c2h.niph.go.jp/en/

Year Published: 2023

URL for published report: https://c2h.niph.go.jp/en/results/C2H2202.html

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Japan

Organisation Name: Center for Outcomes Research and Economic Evaluation for Health

Contact Address: 2-3-6 Minami, Wako-shi, Saitama 351-0197 Japan

Contact Name: Takeru Shiroiwa

Contact Email: t.shiroiwa@gmail.com