Regulatory Issues: PMDA – Review of Sakigake Designation Products: Oncolytic Virus Therapy with Delytact Injection (Teserpaturev) for Malignant Glioma

Abstract

In June 2021, the Ministry of Health, Labor and Welfare approved Delytact Injection as a regenerative medical product for oncolytic virus therapy. The active substance of Delytact Injection is teserpaturev, a genetically engineered herpes simplex virus type 1 (strain F) in which the α47 gene and both copies of the γ34.5 gene have been deleted and the infected cell protein 6 (ICP6) gene has been inactivated by the insertion of the lacZ gene from Escherichia coli. Delytact Injection, when intratumorally administered to patients with malignant glioma, is expected to exert the following effects: (1) the mutant virus selectively replicates in tumor cells and destroys the infected cells through the replication process, exerting a cytocidal effect, and (2) the administration leads to induction of tumor-responsive T cells, which activates antitumor immunity and thus prolongs the survival of patients with malignant glioma. A Japanese phase II study (Study GD01) was conducted in patients with glioblastoma who had residual or recurrent tumors after radiotherapy with concomitant temozolomide. In Study GD01, however, stable disease continued for an extended period in some patients with glioblastoma. Hence, Delytact Injection is expected to be effective to a certain level. In line with this, Delytact Injection has been approved as an option for the treatment of malignant glioma, with one of the 3 approval conditions including conducting a use-results comparison survey and resubmission of the marketing authorization application within the granted time period of 7 years, under the conditional and time-limited approval scheme described in Article 23–26 of Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices.

Based on the submitted data, Delytact Injection (teserpaturev) was granted conditional and time-limited approval by the Ministry of Health, Labor and Welfare of Japan for the treatment of malignant glioma. This article summarizes the regulatory review that led to this approval.

Implications for Practice.

Delytact Injection, a regenerative medical product for oncolytic virus therapy, has demonstrated likely predicted efficacy for glioblastoma based on the results of an open-label, uncontrolled Japanese phase II study (Study GD01). Although the information on the efficacy and safety of Delytact Injection is limited at present, the Delytact Injection will become an effective treatment option for malignant glioma under an early approval scheme. The applicant is then required to conduct a post-marketing approval condition assessment to evaluate the predicted efficacy, including survival benefits and safety, and resubmit the marketing authorization application within 7 years.

Introduction

Glioma

Glioma is primary brain tumor originating from glial cells that support neurons. Glioma is highly invasive and intractable with a very limited possibility of complete remission. Based on histopathological findings and clinical malignancy data, it can be classified into Grades I–IV. Glioma classified as highly malignant Grade III (anaplastic astrocytoma and anaplastic oligodendroglioma) and Grade IV (glioblastoma) lesions are referred to as malignant glioma. Estimates show that approximately 20 000 individuals develop primary brain tumors annually in Japan.¹ When percentages of patients with brain tumors of each grade reported in the Brain Tumor Registry of The Japan Neurosurgical Society (2005-2008) are applied to the above number, approximately 1260 and 2400 individuals are presumed to develop Grade III malignant glioma and Grade IV glioblastoma annually, respectively. The standard of care for primary malignant glioma in Japan is multidisciplinary treatment including surgical resection, radiotherapy (RT), and use of temozolomide (TMZ).² Most patients, however, experience recurrence within several months to several years after the initial treatment. Although stereotactic radiosurgery, chemotherapy such as bevacizumab, nimustine, carmustine, and tumor treating fields are used for the treatment of recurrent malignant glioma, no standard of care has been established.^2,3 Patients with Grades III and IV malignant glioma have 5-year survival rates of only 43.2%-63.3% and 15.5%, respectively, with poor outcomes, leading to high demand for the development of a new treatment.

G47Δ

G47Δ, the product code name for which is Delytact Injection, is a genetically engineered replication-competent herpes simplex virus type 1 (HSV-1). G47Δ is derived from HSV-1 strain F in which the γ34.5 and α47 genes necessary for replication in normal cells have been deleted and the infected cell protein 6 (ICP6) gene has been inactivated by the insertion of the marker lacZ gene to ensure selective replication in tumor cells and enhanced antitumor immunity. Studies have shown that G47Δ replicated and exerted cytocidal activity in multiple cultured cell lines, including the glioma cell line.^4,5 In addition, G47Δ precluded MHC class I downregulation in cell lines expressing MHC class I at a high level. When cocultured with G47Δ-infected cancer cell lines and tumor-infiltrating T cells, IFN-γ was secreted in response to stimulation.⁴ In vivo studies have shown that G47Δ administration induced complete tumor regression in 8 of 12 model mice transplanted with a glioma cell line.⁴ When intracerebrally administered to A/J strain mice susceptible to HSV-1 as a single dose, Delytact was mainly distributed in the central nervous system around the injection site.

G47Δ, when intratumorally administered to patients with malignant glioma, is expected to exert the following effects: (1) the mutant virus selectively replicates in tumor cells and destroys the infected cells through the replication process, exerting a cytocidal effect, and (2) the administration induces tumor-responsive T cells, which activates antitumor immunity, thereby prolonging the survival of patients with malignant glioma.

Clinical Data

G47Δ was designated as an orphan regenerative medical product with the intended indication or performance of “malignant glioma” dated July 10, 2017 (Orphan Regenerative Medical Product Designation No. 4 of 2017 [29 sai]). In addition, G47Δ was designated as a regenerative medical product with the intended indication or performance of “malignant glioma” to be reviewed under the SAKIGAKE Designation System (SAKIGAKE Regenerative Medical Product Designation No. 2 of 2015 [27 sai]) dated February 10, 2016. The SAKIGAKE Designation System was established in 2015 by The Ministry of Health, Labor and Welfare (MHLW) to promote research and development aiming at the early practical application of innovative pharmaceutical products, medical devices, and regenerative medical products initially developed in Japan.^6,7

The applicant submitted evaluation data on the efficacy and safety of one Japanese phase II study (Study GD01) (UMIN00015995).⁸ Study GD01 was conducted as an investigator-initiated trial under the Practical Research for Innovative Cancer Control program of the Japan Agency for Medical Research and Development. In addition, the applicant submitted reference data from one Japanese phase I/II study conducted as a non-GCP-compliant study (UMIN000002661).⁹ In the Japanese phase I/II study, safety was confirmed in patients who received G47Δ at 1 × 10⁹ PFU per session. Although a cohort for doses at 3 × 10⁹ PFU was initially planned, the Independent Data Monitoring Committee determined 1 × 10⁹ PFU as the maximum tolerated dose. Thus, in Study GD01, the dose of G47Δ was specified at 1 × 10⁹ PFU.

Data from Study GD01 were reviewed as the key study evaluating the efficacy and safety of the G47Δ. Based on the submitted data, the Pharmaceuticals and Medical Devices Agency (PMDA) concluded that Delytact Injection is expected to have a certain level of efficacy in the treatment of malignant glioma, has acceptable safety, and is a meaningful treatment option for patients with residual or recurrent tumor who received prior treatment with RT and TMZ in clinical settings. In the following sections, the regulatory review conducted with the efficacy and safety data from Study GD01 will be summarized.

Materials and Methods

Study GD01

An open-label, uncontrolled study was conducted to evaluate the efficacy and safety of G47Δ in patients with residual or recurrent glioblastoma involving one lesion who had received prior treatment with RT and TMZ (target sample size, 30 subjects) at a single study center in Japan. Table 1 shows the major inclusion and exclusion criteria. After trephining with a stereotaxic instrument, up to 6 doses of G47Δ at 1 × 10⁹ PFU were intratumorally administered at a slow rate. The first and second doses were separated by 1 week (range, 5-14 days), whereas the third and subsequent doses were separated from the previous dose by 4 weeks (range, 4 ± 2 weeks). In this study, the primary endpoint was specified as the 1-year survival rate. A test of hypothesis was performed for the 1-year survival rate in a single arm against a threshold of 15% where a statistical significance with the one-sided significance level of 5% was required to demonstrate the efficacy of G47Δ. An interim analysis was planned to decide whether the study should be terminated early for futility or for efficacy when 13 patients completed the 1-year follow-up period. The z statistic calculated from the 1-year survival rate and the concerned termination criteria during interim analysis were specified according to the Lan-DeMets procedure using the O’Brien-Fleming alpha-spending function.

Table 1.

Major inclusion and exclusion criteria (Study GD01).

Inclusion criteria

• Patients with glioblastoma confirmed by histological diagnosis before enrollment

• Patients with residual or recurrent tumors who received prior treatment with RT and TMZ

• Patients with lesions measuring ≥1.0 cm confirmed on MRI within 14 days of eligibility assessment

• Patients with KPS ≥ 60%

Exclusion criteria

• Patients with extracranial metastases

• Patients with multiple intracranial lesions

• Patients with tumors involving the cerebral ventricle, brainstem, or posterior cranial fossa

• Patients with tumors requiring access through the cerebral ventricle for Delytact administration

• Patients with subependymal or subarachnoidal dissemination

• Patients who underwent prior brain tumor resection or prior treatment with bevacizumab within 30 days before Delytact administration

Among the 28 patients who provided informed consent for the interim analysis (data cutoff on June 14, 2018), 19 were enrolled in this study after excluding 9 patients who failed to meet the inclusion criteria or satisfied the exclusion criteria. Among the 19 patients, 16 were included in the full analysis set (FAS) and efficacy analysis after excluding 3 patients who were deemed unevaluable. In addition, a population of 19 patients who received at least one dose of G47Δ was included in the safety analysis. Details regarding the protocol of Study GD01 are indicated in the online data supplement (see Online Supplement Materials and Methods).

Results

Efficacy Data

The 1-year survival rate [95% CI] (%), specified as the primary endpoint in Study GD01, was 92.3 [64.0, 99.8] in the 13 patients included in the interim analysis (data cutoff on June 14, 2018). Given that the results from the interim analysis satisfied the predetermined criterion for early termination for efficacy, Study GD01 was terminated early for efficacy in accordance with the recommendation from the Independent Data Monitoring Committee. The secondary efficacy endpoints specified included investigator-assessed progression-free survival (PFS) and tumor reduction effect. Overall survival (OS) was calculated from the day of the first G47Δ dose.

Disease progression events and tumor reduction criteria applied for the assessment of PFS were not in accordance with the Response Assessment in Neuro-Oncology criteria, which are widely used in clinical studies for glioblastoma treatment but were in accordance with the criteria originally specified, referring to the guideline for response assessment on immunotherapy for solid tumors (immune-related Response Criteria [irRC]).¹⁰Table 2 and Fig. 1 show the results for investigator-assessed PFS and the Kaplan-Meier curves during the additional analysis (data cutoff on December 31, 2018). Disease progression was observed in 14 of the 19 patients, and PFS [95% CI] was 4.8 months [3.6, 19.6]. Furthermore, Table 3 and Fig. 2 show the results for OS and the Kaplan-Meier curve as of April 22, 2020.

Table 2.

Results on tumor reduction effects during additional analysis (investigator’s assessment, FAS, data cutoff on December 31, 2018).

Best overall response	Number of patients (%)
	FAS, n = 19
CR	0
PR	1 (5.3)
SD	18 (94.7)
PD	0
Response (CR + PR)	1
Response rate [95% CI])	(5.3 [0.1, 26.0])

Abbreviations: CR, complete response; FAS, full analysis set; PR, complete response; PD, progressive disease; SD, stable disease.

Figure 1.

Kaplan-Meier curve for PFS during additional analysis (FAS, data cutoff on December 31, 2018).

Table 3.

Results on OS after G47∆ initiation (FAS, as of April 22, 2020).

	FAS
Number of patients	19
Number of events (%)	16 (84.2)
Median [95% CI] (months)	20.2 [14.5, 31.4]

Abbreviations: FAS, full analysis set; OS, overall survival.

Figure 2.

Kaplan-Meier curve for OS (FAS, as of April 22, 2020).

Safety Data

Serious adverse events reported in Study GD01 included pyrexia in 3 patients (15.8%) and death, cerebral infarction, hemiplegia, syncope, urinary tract infection, postprocedural infection, and subcutaneous abscess in 1 patient (5.3%) each. A causal relationship between pyrexia and G47Δ could not be ruled out in one patient. Among the patients treated with G47Δ, 12 (disease progression in 11 and death in 1) died by April 2020. Postprocedural infection in 1 patient (5.3%), for which a causal relationship with G47Δ was ruled out, was an adverse event leading to treatment discontinuation. Based on the following evaluation, adverse events requiring special attention in patients with residual or recurrent glioblastoma receiving G47Δ alone or concomitantly with TMZ include symptoms associated with immune reaction, bone marrow suppression, seizure, brain edema, and intracranial tumor hemorrhage.

Symptoms Associated With Immune Reaction

No symptom associated with immune reaction caused death or treatment discontinuation. The median time to the first onset of a symptom associated with immune reaction (range) was 11.0 (2-93) days. Among the hypersensitivity in 2 patients, one involved hypersensitivity to the MRI contrast agent, whereas the other one involved an allergic reaction to TMZ. For either event, a causal relationship with G47Δ was ruled out.

Bone Marrow Suppression

A causal relationship between Grade ≥3 adverse events in Study GD01 and G47Δ could not be ruled out given that lymphocyte count decreased in 5 patients (26.3%), whereas white blood cell count and neutrophil count decreases in 1 patient (5.3%) each. No serious bone marrow suppression causing to death or treatment discontinuation was observed. The median time to the first onset of bone marrow suppression (range) was 7.0 (2-129) days.

Seizure

A causal relationship with G47Δ was ruled in 6 of the 9 patients who experienced seizure in Study GD01, which was caused by disease progression, effects of surgery, and exacerbation of brain edema. No serious seizure leading to death or treatment discontinuation was observed. The median time to the first onset of the seizure (range) was 63.0 (1-277) days.

Brain Edema

A causal relationship with G47Δ was ruled in 9 of the 12 patients who experienced brain edema in Study GD01, which was caused by disease progression. No serious brain edema leading to death or treatment discontinuation was observed. The median time to the first onset of brain edema (range) was 94.5 (16-801) days.

Intracranial Tumor Hemorrhage

Three tumor hemorrhage events occurred. The median time to the first onset of intracranial tumor hemorrhage (range) was 17.5 (1-34) days.

Conclusion

Given the limitations of Study GD01, which is detailed in the following list, and the PMDA considers it difficult to conclude that G47Δ is effective solely based on the 1-year survival rate exceeding the threshold:

• Although Study GD01 is an open-label, uncontrolled study conducted only at a single study center in Japan, there are limitations when comparing the results from Study GD01 with those from the meta-analysis on foreign clinical studies, which serve as an external control, considering that the results on 1-year survival rate and time-to-event in Study GD01 were affected by patient characteristics.

• All foreign clinical studies included in the meta-analysis, which provided a rationale for specifying the threshold in Study GD01, was published at least 20 years ago (1980-2001). Thus, the threshold was not specified based on current clinical practices in Japan.

• Patients with glioblastoma involving mutations of the isocitrate dehydrogenase 1 (IDH1) gene had a relatively benign outcome.¹¹ Among the patients with glioblastoma, only approximately 5% are reported to have IDH1 mutations in clinical settings; however, in Study GD01, 6 of the 19 patients (31.6%) had IDH1 mutations. There are limitations when comparing the results from Study GD01 with those from the meta-analysis on foreign clinical studies where the percentage of patients with IDH1 mutations was unknown.

• Patients to be included in the analysis of the 1-year survival rate were prescribed after the cutoff date (June 14, 2018) for the interim analysis. Considering the design of Study GD01, which was an open-label, uncontrolled study, we cannot rule out the possibility that the analysis target was fixed based on results from the interim analysis.

Regarding the tumor reduction effect, results from Study GD01 did not suggest that G47Δ would be effective in tumor reduction given the response rate [95% CI] (%) of 27.6 [12.7, 47.2] in a Japanese phase II study¹² of bevacizumab alone in patients with recurrent malignant glioma who prior treatment with RT and TMZ, the same patient population included in Study GD01.

The PMDA, therefore, decided to evaluate images from MRI examinations [contrast-enhanced T1-weighted images and fluid-attenuated inversion-recovery (FLAIR) images] of patients in Study GD01.

Assessment results on MRI images were as follows:

• For 1 patient in whom the best overall response was assessed as partial response (PR), the FLAIR image showed an extensive hyperintense lesion.

• Among the 18 patients in whom the best overall response was assessed as stable disease (SD), some (4 patients) were confirmed to have maintained SD for an extended period during G47Δ treatment.

Given that glioblastoma is malignant tumors characterized by very rapid progression, most patients cannot maintain SD for an extended period. However, MRI imaging showed that some patients with glioblastoma maintained SD for an extended period. As such, G47Δ is expected to be effective to a certain extent. No clinical studies in children have been conducted, and the use of G47Δ in children is not recommended.

Although attention should be paid to the aforementioned adverse events of G47Δ, the PMDA has concluded that its administration is tolerable provided that appropriate measures, such as monitoring and controlling of the adverse events and discontinuation of G47Δ treatment, are taken by physicians with adequate knowledge and experience in glioblastoma treatment and neurosurgical procedures.

The Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices (PMD Act) provides the option of a new approval scheme “conditional and time-limited approval,” only for regenerative medical products to achieve early practical application.^13,14 Based on the submitted data, the PMDA has concluded that the product is expected to have a certain level of efficacy in the treatment of malignant glioma and that the product has acceptable safety. Given the limited information at present, the applicant should continue evaluating the efficacy of the product even after the market launch.

The potential intended population for Delytact Injection is patients suffering from glioblastoma given that the exploratory study results from Study GD01 included patients with glioblastoma. However, limiting the “Indication or Performance” of Delytact Injection to glioblastoma is hardly needed considering that the number of patients with Grade III malignant glioma according to WHO classification is very small and that available treatment options apart from the aforementioned applicant’s explanation are limited. The PMDA has therefore concluded that the “Indication or Performance” and “Precautions Concerning Indication or Performance” of Delytact Injection should be specified as shown below.

Indication or Performance

Malignant Glioma.

Precautions Concerning Indication or Performance

• Delytact Injection should be used in patients who received prior treatment with RT and TMZ.

• Eligible patients must be selected by physicians who carefully weigh the benefits and risks with a full understanding of the information presented in the “clinical studies” section, including the characteristics of patients (presence of glioblastoma, tumor location, etc.) included in the clinical studies and the possibility of up to six brain punctures, as well as the efficacy and safety of Delytact Injection.

The PMDA considered it acceptable to specify the “Dosage and Administration or Method of Use” based on the condition in Study GD01 and concluded that the “Indication or Performance” and “Precautions Concerning Indication or Performance” of Delytact Injection should be as shown below.

Dosage and Administration or Method of Use

The usual adult dosage is 1 mL (1 × 10⁹ PFU) of Delytact Injection administered intratumorally. In principle, the first and second doses are separated by 5-14 days, whereas the third and subsequent doses are separated from the previous dose by 4 weeks. Up to 6 doses may be administered.

Precautions Concerning Dosage and Administration or Method of Use

• Should other concomitant antineoplastic agents be needed, TMZ should be used.

• Each dosage is intended to target the whole tumor lesion in the brain. When there is a need to target ≥2 sites, the dosage should be administered in divided doses.

• No results from a clinical study where Delytact Injection was administered by means other than a stereotaxic technique are available.

• No results from a clinical study where Delytact Injection was administered into the infratentorial lesion are available. Thus, the eligibility of Delytact Injection should be carefully considered with the risk of complications associated with the injection procedure. Administration into brainstem lesions should be avoided given the extremely high risk it poses.

• Delytact Injection should be thawed under protection from light and, after being thawed, administered immediately. Should there be a need to store it after being thawed, it should be stored at 2-8°C under protection from light and used within 24 h. In addition, the residual fluid should be appropriately discarded.

The applicant will conduct a use-results comparison survey (Table 4) to further evaluate the efficacy and safety of Delytact Injection after the market launch by comparing information in patients receiving Delytact Injection with that in patients not receiving it. Regarding efficacy, the therapeutic goal of Delytact Injection is prolonging survival in eligible patients with malignant glioma. The PMDA therefore considers it appropriate to specify OS as the primary efficacy endpoint. Regarding the primary efficacy endpoint (comparison between groups), an analysis with confounding factors adjusted using a trend score model is planned. Based on reports on prognostic factors of malignant glioma^15,16 and survey items, 10 factors [tissue type (Grade), methylation of MGMT promoter, IDH1/2 gene mutation, etc.] have been specified as confounding factors affecting the prognosis of malignant glioma. In the use-results comparison survey, the control group deliberately included patients diagnosed with malignant glioma (primary or recurrent) at centers with Delytact Injection delivered during a certain period 2 years before the date of the first dose of Delytact Injection (a period of 6 months from 2 to 2.5 years before the date of the first dose). The use of the nonrandomized control group has limitations in ensuring a fair comparison between the groups. Moreover, such a control group would not provide information comparable to that from a prospective study in terms of quality and volume. The survey should preferably utilize a randomized, double-blind, ­parallel-group design. When Delytact Injection becomes available in clinical settings, however, randomized controlled studies would likely be impractical. The PMDA therefore considers it inevitable to evaluate the efficacy and safety of Delytact Injection by comparing retrospective data using a control group comprising patients who were eligible for Delytact Injection but did not receive the same, as presented by the applicant, on the condition that the design ensures further fair comparison between the groups and thereby objective evaluation and assessment.

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.

A commitment toward promoting the optimization of the use of innovative drugs was incorporated, as reform measures for social security, in the “Basic Policy on Economic and Fiscal Management and Reform 2016” (Cabinet decision on June 2, 2016). In response to this, the MHLW decided that Optimal Clinical Use Guidelines for regenerative medical products would be prepared to provide products to the most appropriate patients. The guidelines require the description of the necessary requirements, principles, and points to consider for promoting the optimization of product use based on the medical/pharmaceutical and scientific viewpoints obtained upon the publication of the guidelines. The “Optimal Clinical Use Guidelines for Delytact Injection” was published on https://www.pmda.go.jp/review-services/drug-reviews/review-information/ctp/0011.html (Japanese).

The Act on the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms (Act No. 97 of 2003) (The Cartagena Act) aims to ensure biodiversity in an international cooperation. The Cartagena Protocol on Biosafety to the Convention on Biological Diversity is an international agreement that aims to ensure the safe handling, transport, and use of living modified organisms (LMOs) resulting from modern biotechnology that may have adverse effects on biological diversity while also taking into account the risks to human health. The Cartagena Act is a law that covers the use of LMOs as pharmaceuticals in Japan.¹⁷ In line with this, the use of Delytact Injection falls under Type 1 Use of genetically modified living organisms under Article 4 of the Cartagena Act, and approval for the provisions under Type 1 Use of genetically modified living organisms under Article 4 of the Cartagena Act has been obtained (Approval number, 14-36V-0002).

In summary, the Committee on Regenerative Medical Products of the Pharmaceutical Affairs and Food Sanitation Council, MHLW has concluded that the product may be approved for the indication or performance and dosage and administration or method of use described above, with the following approval conditions and the conditional time-limit under Article 23-26 of PMD Act. The granted time period is 7 years.

Approval Conditions

1. The applicant is required to ensure that the product is used by a physician with adequate knowledge and experience in malignant glioma treatment and neurosurgical procedures and those who have been fully informed of results and adverse events in clinical studies of the product in an environment where appropriate measures, such as monitoring and management with laboratory tests, are available at a medical institution capable of responding to emergencies.

2. The applicant is required to conduct a post-marketing approval condition assessment in all patients treated with the product until submission of the marketing application after the conditional time-limited authorization.

3. The applicant is required to take the necessary measures to ensure that the product is used in compliance with provisions for Type 1 Use approved under the “Act on the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms (Act No. 97 of 2003),” such as the announcement of the provisions for use.

Funding

No funding was received for this work.

Conflict of Interest

All authors declared no competing interest for this work.

Author Contributions

All authors contributed equally to this work in conception/design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript.

Data Availability

No new data were generated or analyzed in support of this research.