Table 4.

Outline of the use-results comparison survey.

Objective	To evaluate the efficacy and safety of Delytact Injection in patients with malignant glioma. In addition, to compare Delytact Injection with the conventional treatment (control group) by investigating the applicable efficacy data retrospectively.
Survey method	All-case surveillance system
Population	• Delytact Injection group: all patients who received Delytact Injection. • Control group: all patients diagnosed with malignant glioma at centers with Delytact Injection delivered during a certain period 2 years before the day of the first dose of Delytact Injection (a period of 6 months from 2.5 to 2 years before the day of the first dose).
Survey period	7 years from day of approval
Follow-up period	• Delytact Injection group: period from the day of diagnosis of malignant glioma (day of primary or recurrent*1 diagnosis) to 2 years after the first dose of Delytact Injection. For patients who survive more than 2 years after the first dose, follow-up will be continued until the end of the survey period. • Control group: 2 years from the day of diagnosis of malignant glioma (day of primary or recurrent*1 diagnosis). For patients who survive more than 2 years after the day of diagnosis of malignant melanoma, follow-up will be continued until the end of the survey period as a part of a prospective survey.
Major efficacy endpoint and method of evaluation	OS (from the day of diagnosis*1 of malignant glioma to death from any cause): For each population of patients with primary glioblastoma*2 and recurrent glioblastoma,*3 conduct a trend score matching*4 so that the Delytact Injection and control groups include the same number of patients (1:1) and perform a log-rank test using a two-sided significance level of 5% for OS in the sample population. For patients with Grade III malignant glioma (anaplastic oligodendroglioma and anaplastic astrocytoma),*5 conduct a trend score matching as done for patients with glioblastoma and check whether or not the point estimate of the hazard ratio of OS in the sample population calculated using the Cox proportional hazards model is below 1.
Safety specifications	Pyrexia, brain edema, cytopenia, seizure, hemorrhage, infection, normal pressure hydrocephalus, and autoimmune diseases involving the central nervous system.
Target sample size	Target sample size of patients with glioblastoma • Delytact Injection group: A total of 250 patients with glioblastoma, including 150 patients with primary lesions and 100 patients with recurrent lesions. • Control group: A total of 500 patients with glioblastoma, including 300 patients with primary lesions and 200 patients with the recurrent lesions. A target sample size of patients with Grade III malignant glioma • Delytact Injection group: 30-50 patients with anaplastic oligodendroglioma and 30–50 patients with anaplastic astrocytoma. • Control group: 60-100 patients with anaplastic oligodendroglioma and 60–100 patients with anaplastic astrocytoma.

*1 The “day of diagnosis of malignant glioma” for patients with the recurrent lesion is the day on which the diagnosis of recurrence is established by the survey investigator based on a documented increase in tumor size [both ≥20% and ≥5 mm (absolute value) increase in the sum of the tumor diameters] after chemoradiotherapy relative to the size at the start of initial chemoradiotherapy, the appearance of a new tumor on diagnostic imaging, such as MRI, without any tumor increase relative to the image at the start of initial chemoradiotherapy, or malignant transformation (from Grade III malignant glioma to glioblastoma).

*2 The control group should include patients who have not responded to the initial chemoradiotherapy in terms of tumor size.

The Delytact Injection group should include patients who have not responded to the initial chemoradiotherapy in terms of tumor size and then received a Delytact Injection.

*3 The control group should include patients diagnosed with recurrence (except for malignant transformation) for the first time ≥3 months after the initial chemoradiotherapy. Recurrence is defined as a case where the size of the tumor increased relative to that at the start of initial chemoradiotherapy [both ≥20% and ≥5 mm (absolute value) increase in the sum of the tumor diameters] or a new tumor has appeared on diagnostic imaging, such as MRI, without any tumor increase relative to the image at the start of initial chemoradiotherapy.

The Delytact Injection group should include patients diagnosed with recurrence (except for malignant transformation) for the first time ≥3 months after the initial chemoradiotherapy and then received Delytact Injection. Recurrence is defined as that in the control group.

*4 Factors used for trend score matching estimation include 10 factors affecting the prognosis of malignant glioma [tissue type (Grade), age, KPS, extent of resection, mental status, duration of neurologic symptom, overall radiation dose, neural function (capability of working or lack thereof), methylation of MGMT promoter, and IDH1/2 gene mutation (yes or no)].

*5 The Delytact Injection group should include patients who received Delytact Injection ≥ 3 months after the initial chemoradiotherapy.