Designation Products: Boron Neutron Capture Therapy for Head and Neck Carcinoma.

The Japanese Ministry of Health, Labour and Welfare approved a drug called borofalan (10 B), a treatment system, and a dose calculation program for boron neutron capture therapy (BNCT) in March 2020. The application pertaining to the products submitted to the Pharmaceuticals and Medical Devices Agency was supported by a Japanese, open-label, uncontrolled trial (Study 002) in patients with unresectable, locally recurrent head and neck squamous cell carcinoma after chemoradiotherapy or radiotherapy, or in those with unresectable locally advanced or locally recurrent (LA/LR) head and neck nonsquamous cell carcinoma. The drug was administered as a single intravenous dose using infusion rates of 200 mg/kg per hour for the first 2 hours after the start of administration and 100 mg/kg per hour during irradiation. Neutron irradiation was performed using the devices at a single dose of 12 Gy-equivalent for oral, pharyngeal, or laryngeal mucosa for up to 60 minutes from 2 hours after the start of drug administration. The primary endpoint was the overall response rate (ORR). The results of Study 002 showed that the ORR based on an assessment of the Independent Central Review Committee per RECIST version 1.1 was 71.4% (90% confidence interval [CI], 51.3%-86.8%). The lower limit of the 90% CI exceeded the prespecified threshold for ORR. When BNCT is applied to patients with unresectable LA/LR head and neck cancer, precautions should be taken, and patients should be monitored for possible onset of dysphagia, brain abscess, skin disorder, crystal urine, cataract, and/or carotid hemorrhage. IMPLICATIONS FOR PRACTICE: Borofalan (10 B), a treatment system and a dose calculation program for boron neutron capture therapy (BNCT), demonstrated significant efficacy in an open-label, uncontrolled trial in which overall response rate was the primary endpoint for patients with unresectable locally advanced or locally recurrent head and neck cancer. Although no information about survival benefits was obtained, BNCT will become an effective treatment option that is expected to manage local lesions that are intractable with any standard therapy. In addition, BNCT is expected to maintain quality of life of the intended patient population, on account of its high tumor selectivity and low invasiveness.

Characteristics of pharmacogenomics/biomarker-guided clinical trials for regulatory approval of anti-cancer drugs in Japan.

Pharmacogenomics (PGx) or biomarker (BM) has the potential to facilitate the development of safer and more effective drugs in terms of their benefit/risk profiles by stratifying population into categories such as responders/non-responders and high-/low-risks to drug-induced serious adverse reactions. In the past decade, practical use of PGx or BM has advanced the field of anti-cancer drug development. To identify the characteristics of the PGx/BM-guided clinical trials for regulatory approval of anti-cancer drugs in Japan, we collected information on design features of 'key trials' in the review reports of anti-cancer drugs that were approved after the implementation of the 'Revised Guideline for the Clinical Evaluation of Anti-cancer drugs' in April 2006. On the basis of the information available on the regulatory review data for the newly approved anti-cancer drugs in Japan, this article aims to explain the limitations and points to consider in the study design of PGx/BM-guided clinical trials.

Malignant melanoma treatment using brachytherapy: Two case reports and 15 case series.

Malignant melanoma (MM) is usually resistant to radiotherapy. Brachytherapy may be an option in patients with bleeding or pain, and those in whom surgery is difficult. Brachytherapy has few side effects and can be used in combination with external beam radiotherapy or chemotherapy. We summarize the demographic and clinical characteristics of 15 patients who received brachytherapy for MM at our hospital and describe two of these representative cases. Patient 1 had an approximately 10-mm, dark-red nodule near the external urethral meatus. Excision was not performed to preserve urethral function. A gradual improvement was observed after 48 Gy of remote afterloading system (RALS) brachytherapy and nivolumab therapy. Patient 2 had a 38-mm, black tumor on the vagina. Post-resection, RALS brachytherapy was administered to treat the residual black macule and a lesion quickly disappeared. In all 15 cases, nine patients received radiotherapy for local control and six patients received palliative radiotherapy to reduce symptoms such as bleeding and pain. The irradiation site was the vagina in six patients, lymph node metastasis in five, head and neck in two, skin or subcutaneous metastases in two, and the anus in one. Treatment effect for local control and palliative care was 75% and 83% of patients, respectively. In particular, disappearance of the tumor or disappearance of symptoms was observed in half of the cases of brachytherapy to the vagina. On the other hand, brachytherapy was not very effective for lymph node metastases. Immediately after radiotherapy, eight (53%) patients experienced dermatitis or mucositis. Due to the histological and structural characteristics of mucosal melanoma of the luminal organs, brachytherapy may be an effective therapy. Hence, widespread use of brachytherapy with an appropriate irradiation technique aiming for local control and palliative care in case of unresectable MM should be considered.

Evolving Acceptance and Use of RWE for Regulatory Decision Making on the Benefit/Risk Assessment of a Drug in Japan.

There is growing interest in the utilization of real-world data (RWD) and real-world evidence (RWE) for regulatory purposes. However, there are challenges in the practical utilization of RWD to provide RWE as a basis for regulatory decision making. This article presents the regulatory initiatives in Japan and efforts taken to promote the utilization of RWD/RWE for regulatory decision making at the pre- and postapproval stages of a drug. There has been a rapid increase in the number of RWD cases evaluated for drug safety assessment in Japan. Nevertheless, more regulatory experiences and considerations are necessary for the utilization of RWD in the efficacy evaluation of a drug. Based on past experiences, data reliability and appropriateness of the methodology for analysis are the major discussion points in utilizing RWD and RWE for regulatory decision making. International harmonization of regulatory requirements is another important area in utilizing RWD and sharing the RWE globally. We describe our perspective on providing RWE, which is useful for regulatory decision making throughout a drug's life cycle.

Type 1 diabetes associated with immune checkpoint inhibitors for malignant melanoma: A case report and review of 8 cases.

Advanced malignant melanoma (MM) is treated with immune checkpoint inhibitor (ICI) therapy, which often results in several immune-related adverse events. Fulminant type 1 diabetes mellitus (T1DM) is a rare, rapidly progressive, life-threatening disease. Here, we summarize 8 cases of MM with ICI-induced T1DM and describe one case that developed fulminant T1DM due to nivolumab therapy. We retrospectively reviewed patients treated with ICI from 2014 to 2021 at our hospital. The clinical features and risk factors of ICI-induced T1DM were discussed. ICIs were administered to 426 MM patients at our hospital. Among these, nivolumab was administered in 5 cases, pembrolizumab in 1 case, and the combination of nivolumab and ipilimumab in 2 cases. The frequency of ICI-associated T1DM was 1.88%. The mean glycated hemoglobin level at T1DM onset was 8.0 ± 1.0%. Of the patients, 75% were diagnosed with fulminant T1DM, 62.5% developed diabetic ketoacidosis, and 25% had glutamic acid decarboxylase (GAD) antibodies (an early predictive marker for T1DM). The mean interval between the first ICI administration and T1DM development was 201 ± 187 days. The mean duration of resumption was 13 ± 7 days. We should monitor for T1DM development following treatment with ICIs. ICI can be continued to be used to treat MM if insulin therapy successfully controls T1DM. A 67-year-old patient who received adjuvant nivolumab therapy developed fulminant T1DM and thyrotoxicosis 57 days later and tested positive for GAD antibodies. Subsequently, he developed hypophysitis and an isolated adrenocorticotropin deficiency. He continued receiving nivolumab along with self-injected insulin without developing recurrence.

Classification of drugs for evaluating drug interaction in drug development and clinical management.

During new drug development, clinical drug interaction studies are carried out in accordance with the mechanism of potential drug interactions evaluated by in vitro studies. The obtained information should be provided efficiently to medical experts through package inserts and various information materials after the drug's launch. A recently updated Japanese guideline presents general procedures that are considered scientifically valid at the present moment. In this review, we aim to highlight the viewpoints of the Japanese guideline and enumerate drugs that were involved or are anticipated to be involved in evident pharmacokinetic drug interactions and classify them by their clearance pathway and potential intensity based on systematic reviews of the literature. The classification would be informative for designing clinical studies during the development stage, and the appropriate management of drug interactions in clinical practice.

Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information.

Drug interactions, in particular with concomitant drugs having a narrow therapeutic range, sometimes cause serious adverse drug reactions or attenuation of the therapeutic effect. Therefore, evaluation of the characteristics and severities of possible drug interactions in drug development is essential to understand such interactions to help prevent any potential risk for patients. In Japan, a regulatory document which was notified in 2001 to outline the basic principles of drug interaction studies during drug development was revised as a new guideline after 17 years to present general procedures that are currently considered scientifically valid. This article aims to present an overview of development process of the new Japanese guideline for investigating drug interactions and show the impact of implementating this guideline on drug interaction evaluations, thereby providing future perspectives of regulatory activities on drug interactions.

A case of drug-induced Stevens-Johnson syndrome-like eruption predominating in mucosa: A case report.

Atypical Stevens-Johnson syndrome (SJS) is a variant of SJS with complete absence of or only few cutaneous manifestations. It usually affects children with Mycoplasma-induced respiratory infection. It was unique because our case was induced by drug and occurred in an adult.

[Current PMDA Activities for Use of Biomarkers in Drug Evaluation].

Biomarkers (BM) are gradually being recognized as useful tools to evaluate drugs from development through post-approval periods. In the past decade, practical use of BM has advanced particularly in the field of anti-cancer drug development. Regardless of the use of BM, approximately 10% of key clinical trials for new drug applications of anti-cancer drugs were conducted as multiregional clinical trials. In the era of globalization of drug development, common understanding regarding the usefulness and limitations of BM availabilities in drug evaluation will contribute to provide better evidence in multiple clinical trials. However, only two guidelines regarding BM, i.e., terminologies of pharmacogenomics (E15 guideline) and document format in BM qualification submission to regulatory agencies (E16 guideline), have been harmonized in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) so far. It is important to strengthen international harmonization and collaboration among academia, industry, and regulatory agencies, followed by the establishment of an international guideline on the application of BM in drug evaluation. This article outlines the regulatory perspective on remaining challenges and current Pharmaceuticals and Medical Devices Agency (PMDA) activities for use of BM in drug evaluation.

Metabolic activity of dextromethorphan O-demethylation in healthy Japanese volunteers carrying duplicated CYP2D6 genes: duplicated allele of CYP2D6*10 does not increase CYP2D6 metabolic activity.

BACKGROUND: This study was designed to assess the metabolic activities of dextromethorphan O-demethylation in healthy Japanese subjects carrying duplicated CYP2D6 alleles, CYP2D6*1 x 2, CYP2D6*2 x 2 or CYP2D6*10 x 2. METHODS: Forty-one unrelated healthy Japanese subjects containing carriers who had previously been genotyped as CYP2D6*1 x 2/*2, CYP2D6*1/*2 x 2, and CYP2D6*10/*10 x 2 were phenotyped with dextromethorphan. RESULTS: The metabolic ratios of dextromethorphan/dextrorphan in subjects with CYP2D6*1 x 2/*2 or CYP2D6*1/*2 x 2 were lower than those in subjects with CYP2D6*1/*2, while the metabolic ratios in subjects with CYP2D6*10/*10 x 2, as well as homozygotes for CYP2D6*10, were significantly (P<0.01) higher than those in homozygotes for CYP2D6*1. CONCLUSIONS: The results suggested that carriers with three functional CYP2D6 genes, CYP2D6*1 x 2/*2 or CYP2D6*1/*2 x 2, are ultrarapid metabolizer phenotypes in Japanese. The results also suggested that there is no gene-dose effect with the dextromethorphan O-demethylation activities between carriers with two and three CYP2D6*10 mutated genes per genome. Therefore, CYP2D6*10 x 2 may play an important role for the treatment of Japanese patients as well as CYP2D6*10 which is mainly responsible for the intermediate metabolizers in Japanese.

A long PCR assay to distinguish CYP2D6*5 and a novel CYP2D6 mutant allele associated with an 11-kb EcoRI haplotype.

BACKGROUND: We found a genomic DNA (N=1) associated with an unidentified 11-kb EcoRI haplotype of CYP2D6 and with amplification of the CYP2D6*5 specific polymerase chain reaction (PCR) product without the 11.5-kb XbaI haplotype in a Japanese woman. We developed a long PCR assay to distinguish CYP2D6*5 and the novel mutant allele, and we evaluated the PCR method on 162 different genomic DNA samples. METHODS: Long PCR assays were performed to amplify a fragment specific for the novel mutant allele and to exclude coamplification of CYP2D6*5. RESULTS: A 1692-bp PCR product was amplified from the DNA sample with the novel mutant allele, while the PCR product was not amplified from any of the 162 DNA samples. CONCLUSIONS: The long PCR assay enabled the detection of the novel mutant allele associated with an 11-kb EcoRI haplotype. Further population studies are required to confirm the frequency of the novel mutant allele in various populations, as it may be contained in samples reported as CYP2D6*5.

Frequent occurrence of CYP2D6*10 duplication allele in a Japanese population.

Allele-specific long-polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (RFLP) and haplotype analysis using XbaI and EcoRI were used to determine whether gene duplication of CYP2D6*10 exists in a Japanese population of 162 healthy subjects. Based on the results of PCR and haplotype analysis, the frequencies of CYP2D6*1X2, CYP2D6*2X2 and CYP2D6*10X2 in the Japanese population were estimated to be 0.3, 0.3 and 0.6%, respectively. The results suggest that duplicated alleles of CYP2D6*10 exist in the Japanese population and that it may be one of the factors affecting the capacity of Japanese to metabolize various CYP2D6 substrate drugs.

Regulatory perspective on remaining challenges for utilization of pharmacogenomics-guided drug developments.

Pharmacogenomics-guided drug development has been implemented in practice in the last decade, resulting in increased labeling of drugs with pharmacogenomic information. However, there are still many challenges remaining in utilizing this process. Here, we describe such remaining challenges from the regulatory perspective, specifically focusing on sample collection, biomarker qualification, ethnic factors, codevelopment of companion diagnostics and means to provide drugs for off-target patients. To improve the situation, it is important to strengthen international harmonization and collaboration among academia, industries and regulatory agencies, followed by the establishment of an international guideline on this topic. Communication with a regulatory agency from an early stage of drug development is also a key to success.

Prediction of severe adverse drug reactions using pharmacogenetic biomarkers.

Severe adverse drug reactions (ADRs) are a major issue for drug therapy because they can cause serious disorders and be life-threatening. Many severe ADRs appear to be idiosyncratic and unpredictable. Genetic factors may underlie susceptibility to severe ADRs, and identification of predisposing genotypes may improve drug therapy by facilitating prescreening of carriers for specific genetic biomarkers. In this review, we clarify the current status of ADRs in Japan from open ADR data sources. Then, we introduce recent progress in the field of pharmacogenetic biomarkers for severe cutaneous ADRs, liver injury, and statin-induced myopathy. Key challenges for discovery of predictable risk alleles for these severe ADRs are also discussed.

Current Japanese regulatory situations of pharmacogenomics in drug administration.

Pharmacogenomics (PGx) has the potential impact to improve drug-development efficiencies and proper usages of drugs in clinical practice. However, in order to translate PGx into practical applications, multidisciplinary challenges, such as cost and time in development, processes of genomic biomarker qualification, PGx test availabilities and reimbursements, and education on PGx, still remain in clinical, pharmaceutical and regulatory settings. Japanese regulatory bodies for drug approval (i.e., Ministry of Health, Labour and Welfare and Pharmaceutical and Medical Devices Agency) have been taking proactive actions, both internally and internationally, toward translating PGx from bench to bedside. In this article, we summarize the current situations and projects in regulatory implementations of PGx in drug administrations in Japan, including activities to promote PGx-based drug/device developments and therapies. Moreover, we also discuss the future tasks for utilization of PGx in drug evaluations and clinical practices.

High-throughput detection of multiple genetic polymorphisms influencing drug metabolism with mismatch primers in allele-specific polymerase chain reaction.

Because of genetic polymorphisms of drug-metabolizing enzyme genes, the activities of the enzymes in humans vary widely and alter the metabolism of commonly used clinical agents. Severe adverse effects or resistance to therapy may result. We have developed a rapid and high-throughput genotyping method for detecting polymorphisms of the drug-metabolizing enzyme genes CYP2C9*3, CYP2C19*2, *3, CYP2D6*2, *4, *10, *14, *21, NAT2*5, *6, *7, and TPMT*3 using allele-specific polymerase chain reaction (PCR) with mismatch primers (ASPCR-MP) and CYP2D6*5, *36, and CYP2D6xN using stepdown PCR with detection by SYBR Green I. We analyzed genomic DNA from 139 Japanese volunteers. Identical genotyping results were obtained by using ASPCR-MP, stepdown PCR, and conventional PCR. We found that the methods clearly differentiate three specific profiles with no overlap in the signals. Moreover, both ASPCR-MP and stepdown PCR for genotyping took less than 3-4h. To our knowledge, this is the first report of successful simultaneous detection of multiple genetic polymorphisms with point mutations using ASPCR-MP or multiple genetic polymorphisms with large structural alterations using stepdown PCR. In conclusion, ASPCR-MP and stepdown PCR appear to be suitable for large clinical and epidemiological studies as methods that enable highly sensitive genotyping and yield a high-throughput.