Timing of Pediatric Drug Approval and Clinical Evidence Submitted to Regulatory Authorities: International Comparison Among Japan, the United States, and the European Union.

Many prescription drugs approved for adult use lack pediatric labeling information, resulting in their off-label use in children. Drug regulatory authorities have developed legal and regulatory frameworks to promote pediatric drug development. However, the current state of pediatric indication approval and quality of efficacy evidence, which forms the basis of regulatory approvals, is unknown. Here, we analyzed novel therapeutics approved in Japan, the United States, and the European Union during 2005-2014 to investigate the timing and frequency of pediatric indication approval, and characterized the design of pediatric studies supporting regulatory approval. We found that the United States and European Union experienced a higher frequency of supplemental indication approval in pediatrics based on better-designed studies than Japan. The speed and efficiency of pediatric drug development will improve by coordinating pediatric studies on an international basis. The results also implied the necessity for a robust system of postmarketing monitoring of pediatric efficacy and safety.

Factors distinguishing important identified risks from important potential risks in orphan and nonorphan drugs: An analysis of safety specifications of Japan and European Union risk management plans.

PURPOSE: The purposes of the study are to compare safety specifications between Japan and the European Union (EU) and to identify the factors affecting categorization of important identified or potential risks. METHODS: Safety specifications were collected from orphan and nonorphan drugs approved in Japan between 2014 and 2016, and in the EU as of October 2017. Outcome was defined dichotomously as listed as important identified risks or potential risks. A mixed-effects logistic regression was performed to estimate odds ratios of being listed as important identified risks. RESULTS: This study included 20 orphan and 33 nonorphan drugs. The number of safety specifications per drug and the distribution of risk categories were significantly different between Japan and the EU regardless of orphan status. In orphan drugs, the occurrence of serious adverse events (AEs) during clinical trials for new drug applications was associated with a higher probability of being listed as important identified risks in Japan, while AE rate (%) was positively associated with being listed as important identified risks in the EU. For nonorphan drugs in Japan, AE occurring at a high rate, adverse drug reactions (ADRs) listed as important identified risks in EU risk management plans, and clinically significant ADRs known in similar drugs were likely to be listed as important identified risks, whereas a ≥1.4 risk ratio was associated with a higher probability of being listed as important identified risks in the EU. CONCLUSIONS: Factors affecting risk categories were different between Japan and the EU, which might contribute to the difference in safety specifications between these 2 regions.

Human CD43+ B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally in healthy individuals.

CD20(+)CD27(+)CD43(+) B (CD43(+) B) cells have been newly defined among PBMCs and proposed to be human B1 cells. However, it is controversial as to whether they are orthologs of murine B1 cells and how they are related to other B-cell populations, particularly CD20(+)CD27(+)CD43(-) memory B cells and CD20(low)CD27(high)CD43(high) plasmablasts. Our objective is to identify phenotypically the position of CD43(+) B cells among peripheral B-lineage cell compartments in healthy donors, with reference to B-cell subsets from patients with systemic lupus erythematosus (SLE). We found that CD43(+) B cells among PBMCs from healthy subjects were indistinguishable phenotypically from memory B cells in terms of surface markers, and spontaneous in vitro Ig and IL-10 secretion capability, but quite different from plasmablasts. However, a moderate correlation was found in the frequency of CD43(+) B cells with that of plasmablasts in healthy donors but not in SLE patients. An in vitro differentiation experiment indicated that CD43(+) B cells give rise to plasmablasts more efficiently than do memory B cells, suggesting that they are more closely related to plasmablasts developmentally than are memory B cells, which is also supported by quantitative PCR analysis of mRNA expression of B-cell and plasma cell signature genes. Thus, we conclude that, in healthy individuals, CD43(+) B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally, although the developmental origin of CD43(+) B cells is not necessarily the same as that of plasmablasts.

[Long-term survival of a patient with extrahepatic cholangiocarcinoma treated with adjuvant radiotherapy for positive ductal margins after surgical resection].

A 57-year-old man with abdominal discomfort visited our hospital. Abdominal computed tomography (CT) revealed no tumorous lesions. Endoscopic retrograde cholangiography (ERC) revealed a tumorous lesion in the middle bile duct. Peroral cholangioscopy-assisted biopsy was performed, and the lesion was diagnosed as a papillary adenocarcinoma. Extra bile duct resection and regional lymph node dissection were performed; however, residual carcinoma in situ was detected at the ductal margins by intraoperative frozen section analysis. Therefore, external radiation therapy at a dose 50.4 Gy/28 Fr was administered after the operation. No complication due to radiotherapy occurred. The patient remains alive and recurrence -free for more than 7 years after the operation. We report the long-term disease-free survival of a patient with extrahepatic cholangiocarcinoma who was treated with external radiation therapy for positive ductal margins after surgical resection.

Total body irradiation followed by bone marrow transplantation: comparison of once-daily and twice-daily fractionation regimens.

PURPOSE: The purpose of this study was to evaluate the results of two sequential total body irradiation (TBI) regimens, especially focusing on pulmonary complications. MATERIALS AND METHODS: Patients with malignant disease who underwent TBI followed by bone marrow transplantation were retrospectively reviewed. There were 86 patients (51 males, 35 females). Altogether, 36 patients were treated on twice-daily fractions of 2 Gy for 3 days to a total 12 Gy (group A). Another 50 patients were treated on once-daily fractions of 2.4 or 3.0 Gy for 4 or 5 days to a total 12 Gy (group B). RESULTS: The 5-year overall survival rate was 49.2%, and relapse-free survival was 44.3%. There were no significant differences between the two groups regarding overall survival (P = 0.1237) or relapse-free survival (P = 0.1548). Two patients in group A had interstitial pneumonitis of grade 3 or higher severity compared with three patients in group B. There was no significant difference between patients in group A (5-year probability rate was 7.6%) and patients in group B (5-year probability rate was 13.9%) (P = 0.9519). CONCLUSION: We concluded that our once-daily TBI regimen is feasible and had the benefit of reducing the complexity of TBI. We believe that further investigation of the TBI regimen is needed.

Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone.

PURPOSE: To determine how the omission of whole brain radiotherapy (WBRT) affects the neurocognitive function of patients with one to four brain metastases who have been treated with stereotactic radiosurgery (SRS). METHODS AND MATERIALS: In a prospective randomized trial between WBRT+SRS and SRS alone for patients with one to four brain metastases, we assessed the neurocognitive function using the Mini-Mental State Examination (MMSE). Of the 132 enrolled patients, MMSE scores were available for 110. RESULTS: In the baseline MMSE analyses, statistically significant differences were observed for total tumor volume, extent of tumor edema, age, and Karnofsky performance status. Of the 92 patients who underwent the follow-up MMSE, 39 had a baseline MMSE score of < or =27 (17 in the WBRT+SRS group and 22 in the SRS-alone group). Improvements of > or =3 points in the MMSEs of 9 WBRT+SRS patients and 11 SRS-alone patients (p = 0.85) were observed. Of the 82 patients with a baseline MMSE score of > or =27 or whose baseline MMSE score was < or =26 but had improved to > or =27 after the initial brain treatment, the 12-, 24-, and 36-month actuarial free rate of the 3-point drop in the MMSE was 76.1%, 68.5%, and 14.7% in the WBRT+SRS group and 59.3%, 51.9%, and 51.9% in the SRS-alone group, respectively. The average duration until deterioration was 16.5 months in the WBRT+SRS group and 7.6 months in the SRS-alone group (p = 0.05). CONCLUSION: The results of the present study have revealed that, for most brain metastatic patients, control of the brain tumor is the most important factor for stabilizing neurocognitive function. However, the long-term adverse effects of WBRT on neurocognitive function might not be negligible.

Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.

CONTEXT: In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. OBJECTIVE: To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. INTERVENTIONS: Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients). MAIN OUTCOME MEASURES: The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death. RESULTS: The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation. CONCLUSIONS: Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: C000000412.

Radiation pneumonitis following concurrent accelerated hyperfractionated radiotherapy and chemotherapy for limited-stage small-cell lung cancer: Dose-volume histogram analysis and comparison with conventional chemoradiation.

PURPOSE: The aim of this study was twofold: to determine whether the dose-volume metrics are valuable in predicting radiation pneumonitis (RP) in small-cell lung cancer (SCLC) patients treated with accelerated hyperfractionated radiotherapy and chemotherapy (AHFRT + CT); and to clarify how AHFRT influences the risk of RP in comparison to conventional once-daily radiotherapy and chemotherapy (QDRT + CT). METHODS AND MATERIALS: Study subjects were 43 patients with SCLC treated with AHFRT + CT. Radiotherapy was delivered at 1.5 Gy/fraction (fr) twice daily to 45 Gy/30 fr/3 weeks. We analyzed the relation between RP incidence and several dosimetric factors. We also compared this series data with our previously published data from lung cancer patients treated with QDRT + CT. RESULTS: Radiation pneumonitis Grades 1, 2, and 3 were observed in 28 patients, 7 patients, and 1 patient, respectively. Univariate analysis revealed that the percentage of lung volume receiving more than 15 Gy, 20 Gy, and 30 Gy (V15, V20, V30) and normal tissue complication probability were of predictive value for the development of RP. The 12-month cumulative incidences of RP greater than Grade 2 were 0%, 7.1%, 25%, and 42.9% in patients with a V20 of < or =20%, 21-25%, 26-30%, and > or =31%, respectively. These incidences were lower than that of our patients treated with QDRT + CT. CONCLUSIONS: Dosimetric factors are valuable in predicting RP in SCLC patients treated with AHFRT + CT. Regarding the incidence of RP, AHFRT appears to have some advantage over QDRT.

Prospective trial of radiotherapy for patients 80 years of age or older with squamous cell carcinoma of the thoracic esophagus.

PURPOSE: To assess the safety and efficacy of external beam radiotherapy for elderly patients with esophageal cancer. METHODS AND MATERIALS: A trial testing external beam radiotherapy (66 Gy within 6.5 weeks) as a single-modality treatment was performed for biopsy-proven squamous cell carcinoma of the thoracic esophagus clinically staged as Stage I and IIA (T1-T3N0M0, International Union Against Cancer, 1987) in patients aged > or =80 years. RESULTS: From January 1999 through December 2002, 51 evaluable patients (35 men and 16 women) with a median age of 83 years (range, 80-91 years) were enrolled from 22 institutions. Of the 51 patients, 18 (35%) had Stage T1 and 33 (65%) had Stage T2-T3 disease. Radiotherapy could be completed in 47 patients (92%) within 43-58 days (median, 49). The actuarial incidence of Grade 3 or worse cardiopulmonary complications at 3 years was 26%, with 3 early deaths, and correlated significantly with the size of the anteroposterior radiotherapy portals. The median survival time and overall survival rate at 3 years was 30 months and 39% (95% confidence interval, 25-52%), respectively. CONCLUSION: The results of high-dose radiotherapy in octogenarians are comparable to those in younger patients, but meticulous treatment planning and quality control is required.

[Survey of patients' impressions of radiotherapy and their need for additional medical information: Japanese domestic survey of 1,529 patients in 2002].

PURPOSE: We clarified the images, impressions, and information about radiotherapy in standard Japanese patients and, at the same time, investigated their need for information about radiotherapy, in order to identify what we, as radiation oncologists, should do to decrease patient anxiety and create good physician-patient relationships. MATERIALS AND METHODS: We handed out 10 questionnaires to 1529 patients from April 2002 through July 2002 in 22 Japanese institutions that were equipped with radiotherapy machines. Questionnaires contained 10 items asking about patients' background, their impression of radiotherapy, frequency of exposure to information about radiotherapy, need to obtain information about radiotherapy, and ideal additional medical informational resources or their content. RESULTS: About 60% of patients had had the opportunity to obtain information about radiotherapy "sometimes" or "often," but 80% of them were not satisfied with the availability of information and answered that it was inadequate. Ten percent responded that they had no idea about radiotherapy. Thirty percent felt unspecified anxiety concerning radiotherapy, and those who had less chance to be exposed to information about radiotherapy felt more anxiety than the others (33.2% vs. 25.2%, p=0.0008). The need for "explanation and information about adverse effects" was the top priority, followed by "explanation of outcome." Although they generally obtained information from their physician (radiation oncologist), they also wanted additional information via written media (662 patients, 43%). However, patients who were over 60 years old most wanted to obtain additional medical information directly from their own radiation oncologist (37.7%). CONCLUSION: Information about radiotherapy given to patients and the general public is still insufficient in Japan. To fully utilize radiotherapy, which is a very effective treatment option against cancer, and to reduce anxiety about radiotherapy among cancer patients, more information is necessary.

Severe complications in advanced esophageal cancer treated with radiotherapy after intubation of esophageal stents: a questionnaire survey of the Japanese Society for Esophageal Diseases.

PURPOSE: A questionnaire survey was performed to evaluate the complications and prognosis of esophageal cancer treated with esophageal intubation before or during radiotherapy. METHODS AND MATERIALS: Clinical data were accumulated on a total of 47 patients treated at 17 institutions in Japan. Five patients had Stage II, 30 Stage III, and 11 Stage IV, and the stage was unknown in 1 patient. Covered expandable metallic stents were inserted in 30 patients, uncovered expandable metallic stents in 13, plastic or silicon prosthesis in 3, and an unknown type in 1 patient. Esophageal stenting was performed before the start of RT for 23 patients and during the course of RT for 24 patients. The reasons for the stenting were severe stricture in 32 patients (Group 1) and esophageal fistula in 15 patients (Group 2). RESULTS: The most frequent toxicity was formation or worsening of esophageal fistulas in 13 patients (28%), followed by massive hematemesis or GI bleeding in 10 patients (21%). In total, 24 patients (51%), including 10 patients with possible treatment-related deaths (Grade 5), had nonhematologic toxicities of Grade 3-5. The interval from the start of RT to the nonhematologic toxicity ranged from 16 to 312 days (median 78). The incidence of toxicities was higher for Group 1 (59%) than for Group 2 (33%), although the difference was not statistically significant. The median survival time for those with Stage II-III and Stage IV was 5 and 3.5 months, respectively. CONCLUSIONS: Patients with esophageal intubation before or during RT have a high risk of life-threatening complications, especially for those with severe esophageal stricture. Because long survival is expected for a substantial proportion of patients with locally advanced esophageal cancer after chemoradiotherapy, palliative intubation should be delayed until radiotherapy or chemoradiotherapy appears to have failed.

Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer.

PURPOSE: To clarify whether the percentage of pulmonary volume irradiated to >20 Gy (V20) is related to the incidence and grade of radiation pneumonitis (RP) in cases of lung cancer treated with concurrent chemoradiation. METHODS AND MATERIALS: The subjects comprised 71 patients with lung cancer who were treated with conventionally fractionated definitive concurrent chemoradiation. The chemotherapy agents were carboplatin or cisplatin combined with taxane for most patients. Radiotherapy was delivered at 1.8-2.0 Gy fractions once daily to a total of 48-66 Gy (median 60). We analyzed the relation between RP grade and V20. Univariate and multivariate analyses were performed to assess patient- and treatment-related factors, including age, gender, smoking history, pulmonary function (forced expiratory volume in 1 s), tumor location (upper lobe vs. middle/lower lobe), chemotherapy regimen (platinum + taxane vs. other), total dose, overall radiation periods in addition to V20. RESULTS: With a median follow-up of 7.5 months, an RP grade of 0, 1, 2, 3, and 5 was observed in 16, 35, 17, 1, and 2 patients, respectively; the corresponding mean V20 values were 20.1%, 22.0%, 26.3%, 27.0%, and 34.5%. The 6-month cumulative incidence of RP greater than Grade 2 was 8.7%, 18.3%, 51%, and 85% in patients with a V20 of or=31%, respectively (p <0.0001). According to both univariate and multivariate analyses, V20 was the only factor associated with RP of Grade 2 or greater. CONCLUSION: The incidence and grade of RP are significantly related to the V20 value. Thus, V20 appears to be a factor that can be used to predict RP after concurrent chemoradiation for lung cancer.

Subcutaneous fibrosis after whole neck irradiation.

PURPOSE: To identify the risk factors for moderate to severe subcutaneous fibrosis after whole neck irradiation. MATERIALS AND METHODS: We analyzed 233 cases of patients who had undergone whole neck irradiation with 4-MV X-ray or 8-10-MeV electrons, or both, and had been followed with regard to their skin condition for at least 1 year. The prescribed dose to the whole neck ranged from 19.2 to 72.4 Gy (median 50). The skin-absorbed dose was specified as that at a depth of 4.1 mm (d4.1-mm(depth)), and a biologically equivalent dose (BED) of d4.1-mm(depth) was also estimated (BED(1.8) 4.1-mm(depth)). RESULTS: Univariate analysis revealed that previous neck dissection, concurrent chemotherapy, corticosteroid administration as a part of chemotherapy, fractionation, and BED(1.8) 4.1-mm(depth) were significant prognostic variables. Multivariate analysis showed that BED(1.8) 4.1-mm(depth) and previous neck dissection were the only prognostic variables for moderate to severe subcutaneous fibrosis. CONCLUSION: A high dose to a 4.1-mm depth of the skin and a history of neck dissection were identified as the predominant risk factors for moderate to severe subcutaneous fibrosis after whole neck irradiation. A subcutaneous dose should be considered in radiotherapy treatment planning involving the whole neck, especially in cases in which patients have undergone previous neck dissection.

Angiosarcoma treated with radiotherapy: impact of tumor type and size on outcome.

PURPOSE: Angiosarcoma is a rare and highly malignant vascular neoplasm. The purpose of this study was to elucidate the tumor characteristics and evaluate the efficacy of radiotherapy (RT) for angiosarcoma. MATERIALS AND METHODS: Thirty patients with angiosarcoma (20 males and 10 females, age range 4-89 years, median 66) who received RT from 1986 to 1999 were enrolled in the study. Twenty-four patients had angiosarcoma of the face and scalp (AFS), and 6 patients had angiosarcomas at other sites. AFS was classified into two categories (according to the macroscopic features): nodular AFS (14 patients) and endophytic AFS (10 patients). The median prescribed irradiation dose was 68 Gy. Surgery had been previously performed in 9 patients, and adjuvant immunotherapy using recombinant interleukin-2 (rIL-2) was combined during and after RT in 20 patients. Univariate analyses and calculation of survival by Kaplan-Meier methods were performed. RESULTS: Local tumor control was obtained in 17 patients (57%). However, 7 (47%) of them developed distant metastases. The median survival time for all patients was 8 months (7 months for AFS), and the 13-year overall survival rate was 25% (20% for AFS). Twenty-one patients died of angiosarcoma, with the cause of death local failure in 7 patients, distant failure in 7, and both in 7. Tumor type and size were found to be significant prognostic factors (p = 0.004 and p = 0.007, respectively), and age, total amount of rIL-2, gender, radiation dose, and surgery were not. Six patients (4 with nodular AFS and 2 with angiosarcoma in other parts) survived >2 years. No patient with endophytic AFS survived >2 years. Ten patients (33%) died of respiratory failure secondary to pulmonary metastases. High-dose rIL-2 administration suppressed the occurrence of distant metastases (p = 0.006). Two patients developed radiation dermatitis (Radiation Therapy Oncology Group Grade 4). CONCLUSION: RT, combined with complete resection or adjuvant rIL-2 immunotherapy, could be a promising treatment strategy, leading to prolonged survival in patients with angiosarcoma.

[Second malignancies following radiotherapy: an analysis of 54 cases accumulated by mail survey in Japan].

The increasing incidence of second malignant neoplasms after radiotherapy, while due in part to increasing numbers of survivors, is also thought to be related to new modalities of radiotherapy and/or increasingly more intensive combined modality treatment. From a mail survey conducted in 2000 concerning secondary neoplasms following radiotherapy, 62 patients were collected from 22 hospitals in Japan. The following patients were excluded: benign (4 cases) or unknown (2) first primary diseases, unknown histology of a second malignancy (1), and short latent period (from initial radiotherapy to diagnosis of second neoplasm) (1). Fifty-four patients with second malignancies were analyzed. The most common histology of second malignancies was squamous cell carcinoma (24 cases), followed by sarcoma (16), glioma (5), adenocarcinoma (3), leukemia (3), and others (3). The mean latent period was 17.7 (2-38) years. We investigated the correlation of the latent period with patient's characteristics or initial therapeutic factors. Multivariate analysis revealed that the latent period was significantly shortened in patients with combined chemotherapy and radiotherapy.