Safety and Evidence of Off-Label Use of Approved Drugs at the National Cancer Center Hospital in Japan

2020 ◽  
pp. OP.20.00131
Author(s):  
Seiko Bun ◽  
Kan Yonemori ◽  
Hiroko Sunadoi ◽  
Rena Nishigaki ◽  
Emi Noguchi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Pharmaceutical Products ◽  
National Cancer Center Hospital ◽  
Phase Iii ◽  
Cancer Center ◽  
Off Label Use ◽  
Pharmaceutical Development ◽  
Off Label ◽  
Center Hospital ◽  
Label Use

PURPOSE: In Japan, for pharmaceutical products to be covered by public medical insurance, their efficacy and safety must first be confirmed in clinical trials. To our knowledge, this study is the first investigation into the off-label use of pharmaceutical products at a high-volume cancer treatment center in Japan. The objective of this study is to explore the framework necessary for future pharmaceutical development and regulatory approval in the field of oncology by surveying the frequency of and indications for off-label use of pharmaceutical products at the National Cancer Center Hospital in Tokyo, Japan. MATERIALS AND METHODS: The pharmaceutical products used off-label in daily practice from 2003 to 2015 at the National Cancer Center Hospital were retrospectively examined based on applications that had been submitted to an internal review committee requesting off-label use. RESULTS: A total of 1,390 applications were submitted during the study period. The most frequently used supporting documents were the results of phase II trials, followed by case series and phase III trials. The cancer most frequently treated with off-label drugs was sarcoma (15.1%), followed by urologic cancer (9.2%) and GI cancer (7.6%). CONCLUSION: As reported in previous studies, pharmaceutical products were generally used off-label for the treatment of rare cancers, for which large-scale clinical trials are difficult to conduct. Continued discussion of the types of frameworks that are needed to guide pharmaceutical development is necessary.

scholarly journals Quantifying the increasing use of anti-vascular endothelial growth factor therapy in ophthalmology

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Jonathan Micieli ◽  
Andrew Micieli
Keyword(s):  
Clinical Trials ◽  
Growth Factor ◽  
Case Reports ◽  
Retinal Pigment ◽  
Phase Iii ◽  
Off Label Use ◽  
Off Label ◽  
Phase Iii Clinical Trials ◽  
Age Related ◽  
Label Use

Introduction: Bevacizumab (Avastin; genetech Inc., South San fran- cisco, CA) and ranibizumab (Lucentis, genetech Inc.) are two anti-Vascular Endo- thelial growth factor (VEgf) agents used in increasing amounts off-label to treat  ocular conditions. To date, no study has quantifed how far reaching these therapies have been in treating eye disease and compared their off-label use to the number of clinical trials performed. Method: A systematic search of Ovid MEdLINE using the keywords bevacizumab and ranibizumab limited to “Case Reports” was used as an index of the number of diseases treated. Each keyword was also limited to “Clinical Trials, All” and “Phase III Clinical Trials” to discern the quality of evidence for these uses.Results: Bevacizumab has been utilized for the treatment of 58 different ocular conditions, but only 14 conditions were studied in a trial, and none were part of a phase III clinical trial. Ranibizumab has been used for 17 different eye conditions,  with only 6 studied in a trial and only 1 disease, “wet” age-related macular degenera- tion reported in 4 phase III trials. In the case reports, there were 21 different adverse  events ascribed to bevacizumab and 2 to ranibizumab with retinal pigment epithelial tears being the most common. Conclusion: Bevacizumab is one of the most far reaching drugs in ophthalmology and even medicine, but it is not yet supported by high quality evidence. The much higher cost of ranibizumab may be responsible for bevacizumab’s popularity among eye specialists. Patients should be fully informed about the off-label use of bevacizumab and the associated risks with its use.

Chapter 6 - Clinical trials and off-label use of drugs

2016 ◽  
Vol 17 (3-4) ◽  
pp. 409-430
Author(s):  
Giovanni Maria Cavo
Keyword(s):  
Clinical Trials ◽  
Off Label Use ◽  
Off Label ◽  
Label Use

scholarly journals Impact of Autologous Transplantation Vs. Chemotherapy Plus Lenalidomide in Newly Diagnosed Myeloma According to Patient Prognosis: Results of a Pooled Analysis of 2 Phase III Trials

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 198-198 ◽  
Author(s):  
Francesca Gay ◽  
Chiara Cerrato ◽  
Roman Hajek ◽  
Francesco Di Raimondo ◽  
Tommaso Caravita ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Stage I ◽  
Phase Iii ◽  
P Value ◽  
Off Label Use ◽  
Advisory Committees ◽  
Off Label ◽  
Cytogenetic Profile ◽  
Label Use

Abstract Background: Autologous stem cell transplantation (ASCT) improves outcome in comparison with chemotherapy (CC) innewly diagnosed multiple myeloma (NDMM) patients. The primary objective of our analysis was to compare progression-free survival (PFS) and overall survival (OS) of patients randomized to ASCT vs. chemotherapy (CC): we tested the hypothesis that benefit of ASCT could vary in different subsets of patients defined according to baseline prognostic features and response to induction. Methods: Data of 2 phase III multicenter randomized trials (RV-MM-PI-209 and RV-MM-EMN-441) enrolling patients younger than 65 years were pooled together. In both trials, patients received lenalidomide-dexamethasone induction and stem cell mobilization. Patients were randomized to either consolidation with 2 courses of Melphalan 200 mg/mq followed by ASCT (Mel200-ASCT) or 6 cycles of CC plus lenalidomide (CC+R) (RV-MM-PI-209: melphalan-prednisone-lenalidomide; RV-MM-EMN-441: cyclophosphamide-dexamethasone-lenalidomide). We evaluated PFS and OS of Mel200-ASCT vs. CC+R patients in the following subgroups, defined according to baseline features (Karnofsky performance status (PS) [60-70%, 80-100%], International Staging System (ISS) stage [I, II, III], cytogenetic profile [presence of del17 or t(4;14) or t(14;16); absence of del17, t(4;14) and t(14;16)]) and response to induction (≥very good partial response [VGPR], <VGPR). Data cut-off was June, 2014. Results: 791 patients were enrolled in the two trials; 529 were eligible for consolidation: 268 patients received Mel200-ASCT and 261 patients received CC+R. Median follow-up for survivors was 4 years. Mel200-ASCT significantly prolonged PFS (median: 42 vs. 24 months, HR 0.52, 95%CI 0.41-0.65, P<0.001) and OS (4-year: 83% vs. 68%, HR 0.59, 95%CI 0.40-0.90 P=0.012) in comparison with CC+R. Mel200-ASCT significantly improved PFS in all the subgroups of patients analyzed. (Table). The most significant OS benefit was noticed in patients with a Karnofsky PS 80-100% (4-year: 85% vs. 73%, HR 0.55, 95% CI 0.35-0.88, P=0.013), with ISS Stage I disease (4-year: OS 89% vs. 77%, HR 0.43, 95% CI 0.20-0.91, P=0.027), with absence of del17, t(4;14) and t(14;16) (4-year: 87% vs. 78%, HR 0.57, 0.33-0.98, P=0.040), and in patients achieving ≥VGPR after lenalidomide-dexamethasone induction (4-year: 84% vs. 65%, HR 0.46, 95% CI 0.22-0.96, P=0.039). Conclusions: In NDMM patients, Mel200-ASCT significantly improved PFS and OS in comparison with CC+R. The most significant OS advantage was observed in patients with baseline Karnofsky PS 80-100%, ISS Stage I, with absence of del17, t(4;14) or t(14;16) and in patients achieving ≥VGPR after induction. These data suggest intensifying treatment in good-prognosis patients and in patients with a chemo-sensitive disease. More effective novel agents are needed for patients with a more aggressive disease. Table Subgroup analysis of PFS and OS in Mel200-ASCT vs CC+R patients PFS OS HR 95% CI P-value HR 95% CI P-value ISS Stage I Stage II Stage III 0.430.610.60 0.30-0.630.42-0.900.36-0.98 <0.0010.0120.042 0.430.690.75 0.20-0.910.33-1.420.38-1.47 0.0270.3150.397 Cytogenetic profile No del17, t(4;14), t(14;16) Del17 or t(4;14) or t(14;16) 0.610.44 0.44-0.860.27-0.70 0.004<0.001 0.570.60 0.33-0.980.31-1.15 0.0400.120 Karnofsky PS 60-70% 80-100% 0.460.52 0.26-0.810.40-0.68 0.008<0.001 0.720.55 0.29-1.730.35-0.88 0.4500.013 Response to induction ≥VGPR<VGPR 0.480.53 0.30-0.800.40-0.70 <0.001<0.001 0.460.71 0.22-0.960.43-1.18 0.0390.193 Disclosures Gay: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Off-label use of Lenalidomide.. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Di Raimondo:Janssen-Cilag: Honoraria; Celgene: Honoraria. Caravita:Celgene: Honoraria. Patriarca:Merck Sharp & Dohme: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Offidani:Janssen-Cilag: Honoraria; Mundipharma: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Ria:Janssen-Cilag: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy. Cavallo:Onyx: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria. Boccadoro:Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Spencer:Celgene: Honoraria. Palumbo:Sanofi Aventis: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Array BioPharma: Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Prevalence of Off-Label Use of Oral Oncolytics at a Community Cancer Center

2015 ◽  
Vol 11 (2) ◽  
pp. e139-e143 ◽  
Author(s):  
Joseph A. Kalis ◽  
Simon J. Pence ◽  
Robert S. Mancini ◽  
Dan S. Zuckerman ◽  
Joseph R. Ineck
Keyword(s):  
Current Practice ◽  
Cancer Center ◽  
Off Label Use ◽  
Off Label ◽  
Oral Oncolytics ◽  
Label Use

The authors conclude that oral chemotherapies are more often used on-label than off-label in current practice at their community cancer center.

Promoting the Off–label Use of Medicines: Where to Draw the Line?

2016 ◽  
Vol 7 (2) ◽  
pp. 426-433
Author(s):  
Genevra Forwood ◽  
James Killick
Keyword(s):  
Public Health ◽  
Clinical Trials ◽  
Patient Safety ◽  
Marketing Authorisation ◽  
Regulatory System ◽  
Eu Law ◽  
Off Label Use ◽  
Compassionate Use ◽  
Off Label ◽  
Label Use

In Europe, medicines can only be marketed once they have passed through a strict regulatory process, designed primarily to protect patient safety. It is only after in–depth testing on the targeted disease population, including three phases of clinical assessment and clinical trials, that a medicine will obtain a ‘marketing authorisation’. Given its primary goal of ensuring patient safety, EU law only allows a few narrow exceptions to the requirement of amarketing authorisation. Adrug can only be used “off–label”, meaning outside the limits of its marketing authorization, in authorised clinical trials or under one of the strictly defined exceptions, such as severe public health risk, compassionate use for groups of patients or for individual patients on a named patient basis.However, in recent years, a trend has emerged Among Member States to push the boundaries of the existing regulatory system, and actively promote the off–label use of medicines on the ground that they are cheaper than the alternative, authorised medicine. It is questionable whether this trend is in line with EU law.

scholarly journals Regulatory changes after the enforcement of the new Clinical Trials Act in Japan

2020 ◽  
Vol 50 (4) ◽  
pp. 399-404
Author(s):  
Kenichi Nakamura ◽  
Taro Shibata
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
National Cancer Center Hospital ◽  
Ethical Review ◽  
Cancer Center ◽  
Ethical Guidelines ◽  
Clinical Trial Registry ◽  
Medical Devices Act ◽  
Center Hospital ◽  
The Government

Abstract Objective To describe changes in Japanese clinical trial regulations after the implementation of the Clinical Trials Act in April 2018. Methods First, how to apply multiple regulations after the enforcement of Clinical Trials Act was described. Second, the changes in the number of clinical trials in the National Cancer Center Hospital under each regulation were compared before and after the implementation of Clinical Trials Act. Third, new requirements imposed by Clinical Trials Act and their influences were discussed. Results In April 2018, Clinical Trials Act was enacted and academic clinical trials were classified into the following three categories: (i) investigator-initiated registration-directed trial under the Pharmaceuticals and Medical Devices Act; (ii) clinical trial under Clinical Trials Act; and (iii) clinical trial under the Ethical Guidelines. While 90% (205/227) of interventional studies were conducted under the Ethical Guidelines before the implementation of Clinical Trials Act in 2018, 46% (94/204) were subject to Clinical Trials Act in 2019 at the National Cancer Center Hospital. Under the Clinical Trials Act, investigators receive a scientific/ethical review by a certified review board (CRB). The identification of investigators in charge is mandated and they are required to submit the conflict of interest management plan to CRB. After the CRB review, the principal investigator must submit the trial plan to the government, and the content is uploaded to the newly established clinical trial registry site, the Japan Registry of Clinical Trials. Conclusions The enforcement of the new Clinical Trials Act was supposed to improve the reliability of academic clinical trials in Japan; however, the financial and administrative burden may reduce clinical trial activity in the years to come.

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