Guidance on the need for contraception related to use of pharmaceuticals: the Japan Agency for Medical Research and Development Study Group for providing information on the proper use of pharmaceuticals in patients with reproductive potential.

BACKGROUND: The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have published guidelines on the use of cancer treatments in young people of reproductive potential. However, no such guideline is available in Japan. Therefore, this project aimed to gather relevant data and draft a respective guidance paper. METHODS: From April 2019 to March 2021, the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential at the Japan Agency for Medical Research and Development gathered opinions from experts in reproductive medicine, toxicology, and drug safety measures. The group considered these opinions, the FDA and EMA guidelines, and relevant Japanese guidelines and prepared a guidance paper, which they sent to 19 related organizations for comment. RESULTS: By November 2020, the draft guidance paper was completed and sent to the related organizations, 17 of which provided a total of 156 comments. The study group finalized the guidance paper in March 2021. CONCLUSIONS: The "Guidance on the Need for Contraception Related to Use of Pharmaceuticals" (The report of the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential, Research on Regulatory Science of Pharmaceuticals and Medical Devices, Japan Agency for Medical Research and Development: JP20mk0101139) is expected to help Japanese healthcare professionals provide fertility-related care and advice to adolescents, and young adults with cancer and their families.

[International Comparison of Clinical Information Related to Contraception of Medicines].

Most of the warnings about the contraceptive period when using medicines are described as"fixed period"in the package insert, and it is necessary for healthcare professionals to provide information on the specific contraceptive period when using medicines that require contraception. There are many situations where we have trouble. Furthermore, the presence or absence of a description that requires contraception and the contraceptive period differ even though the drugs are the same in Japan and overseas. For example, paclitaxel injection(albumin suspension type)in the package insert in Japan, an appropriate contraceptive period for a certain period have been given to female and male are required. In contrast, different warnings of contraception have been given to female and male another in Europe for 1 month and 6 months after administration, and in the United States for 6 months and for 3 months. The description of the contraceptive period in the package insert in Japan needs to be described after clearly stating the specific period, and it is necessary to describe detailed information including the contraceptive method in materials such as interview forms.

Dyspnea, relative youth and low daily doses of opioids predict increased opioid dosage in the last week of a terminal cancer patient's life.

OBJECTIVE: Most cancer patients become increasingly anxious toward the end of their life. The objective of this study was to identify predictors of increased opioid dosage in the last week of a terminal cancer patient's life. METHODS: We retrospectively reviewed charts of patients who died in our palliative care unit. We assigned the patients to increased group or decreased group according to changes in oral morphine equivalent dosage in their last 7 days. Logistic regression analysis was used to identify predictors of increased oral morphine equivalent dosage. RESULTS: We analyzed data of 158 patients (female: 43.7%, median age: 64 years). The median oral morphine equivalent dosages on Days 7 and 1 before death were 50 mg (interquartile range: 24-122) and 61 mg (28-129), respectively. Independent predictors of increased oral morphine equivalent dosage included dyspnea (odds ratio: 11.5, 95% confidence interval: 4.98-28.83, P < 0.01), age <65 years (odds ratio: 2.3, 95% confidence interval: 1.04-5.26, P = 0.04) and oral morphine equivalent dosage <50 mg on Day 7 before death (odds ratio: 3.7, 95% confidence interval: 1.68-8.89, P < 0.01). The median oral morphine equivalent dosages on Days 7 and 1 before death were 48 mg (interquartile range: 20-126) and 75 mg (36-170) in patients with dyspnea, and 50 mg (25-120) and 57 mg (25-124) in patients with pain, respectively. CONCLUSIONS: Dyspnea, relative youth and oral morphine equivalent dosage <50 mg on Day 7 before death were predictive of increased oral morphine equivalent dosage in the last 7 days. Our findings may help oncologists to more accurately inform patients about expected opioid requirements and thus relieve their end-of-life anxiety.

BIG BANG study (EPOC1703): multicentre, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy with binimetinib, encorafenib and cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer.

BACKGROUND: While the BRAF V600E mutation occurs in 5%-15% of metastatic colorectal cancer (mCRC), BRAF non-V600E mutations were recently reported to range from 1.6% to 5.1%. We have previously reported that BRAF non-V600E mutations could have a negative impact on efficacy outcomes as well as BRAF V600E mutation for antiepidermal growth factor receptor (EGFR) antibody treatment for pretreated patients with mCRC. Recently, simultaneous inhibitions of mitogen-activated protein kinase kinase (MEK), BRAF and EGFR exhibited relevant antitumour activities in patients with BRAF V600E mutant and also in BRAF non-V600E mutant but only in the preclinical model. TRIAL DESIGN: The BIG BANG (study is a multicentre, phase II study to assess the efficacy, safety and proof of concept of the combinations of binimetinib+encorafenib+cetuximab in patients with BRAF non-V600E mutated mCRC, identified by either tumour tissue (tumour tissue group) or blood samples (liquid biopsy group). Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1, mCRC with BRAF non-V600E mutant and RAS wild type, refractory or intolerant to at least one fluoropyrimidine-based regimen and no prior history of regorafenib, and no prior history of anti-EGFR antibody treatment (primary analysis cohort and liquid biopsy cohort) or refractory to prior anti-EGFR antibody treatment in patients with class 3 BRAF mutations (anti-EGFR antibody refractory class three cohort). Enrolled patients receive binimetinib (45 mg, two times per day), encorafenib (300 mg, once a day) and cetuximab (initially 400 mg/m2 and subsequently 250 mg/m2, once per week). The primary endpoint is the confirmed objective response rate in the primary analysis cohort. TRIAL REGISTRATION NUMBERS: UMIN000031857 and 000031860.