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In preparation to the launch of a pharmaceutical product, an estimate of its shelf life via stability testing is required by regulatory agencies. The ICH-Q1E guidance has been the worldwide reference to reach this objective, but in recent years several authors have criticized many of its aspects. To that end we discuss a complete Bayesian transcript of the ICH-Q1E, treating all the apparent shortcomings, while also addressing the presence of multiple batches using a linear mixed model (LMM) for proper shelf life prediction by explicitly modelling the batch-to-batch variability. This comprises a redefinition of the linear models proposed in the ICH-Q1E by suitable LMM counterparts, and a Bayesian analogue for model selection, which is more intuitive and remedies detrimental features of the ICH approach. In that context, a proper mathematical foundation of shelf life is provided that we use to investigate and mathematically compare the two available approaches to shelf life determination via shelf life distribution and batch distribution. The discussed method is then tested and evaluated using real data in comparison with the ICH-Q1E approach demonstrating their approximate equivalency for 6 batches. As a major objective, we extended the LMM with auxiliary fixed effects, here the concentration, which interconnect data sets allowing a prediction of shelf lives for concentrations lacking a sufficient number of batches. This establishes a novel approach to accelerate the speed to submission while retaining the patients' safety. Both case studies underline the inherent superiority of LMMs within a Bayesian framework regarding predictability and interpretability, and we hope that the relevant authorities will accept this approach in the future. [ABSTRACT FROM AUTHOR]

• The optimal management of severe COVID-19 represents an unmet clinical need. • Programmed cell death-1/interleukin-6 receptor blockade might restore immunocompetence and interrupt hyperinflammation. • COPERNICO assessed pembrolizumab plus tocilizumab and standard of care (SOC) compared with SOC in high-risk patients with COVID-19. • The addition of pembrolizumab plus tocilizumab to SOC reduced the hospitalization period. • The addition of pembrolizumab plus tocilizumab to SOC reduced the rate of discharge without sequelae. Severe COVID-19 is associated with immune dysregulation and hyperinflammation (lymphocyte exhaustion and elevated interleukin 6. Pembrolizumab (P; immune-activating anti-programmed cell death-1 antibody) plus tocilizumab (TCZ; anti- interleukin 6 receptor antibody) might interrupt the hyperinflammation and restore cellular immunocompetence. We assessed the efficacy and safety of P + TCZ + standard of care (SOC) in high-risk, hospitalized patients with COVID-19 pneumonia without mechanical ventilation. Randomized, controlled, open-label, phase II trial in patients with severe SARS-CoV-2 infection to assess the hospitalization period to discharge. A total of 12 patients were randomized (P + TCZ + SOC, n = 7; SOC, n = 5). Nine (75%) were males, with a median age of 68 (41-79) years. The median time to discharge for P + TCZ + SOC and SOC was 10 and 47.5 days (P = 0.03), with zero (n = 1 patient had P-related grade 5 myositis) and two COVID-19-related deaths, respectively. The addition of P and TCZ to SOC reduced the hospitalization period, with higher and faster discharges without sequelae than SOC alone. [ABSTRACT FROM AUTHOR]

The paper aims to evaluate the efficacy and safety of 223Ra in patients who progressed after first-line androgen deprivation therapy. EXCAAPE (NCT03002220) was a multicentre, single-arm, open-label, non-controlled phase IIa trial in 52 patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases who have progressed on abiraterone acetate or enzalutamide, up to six doses of 223Ra (55 kBq/kg of body weight per month). The primary end-point was radiographic progression-free survival (rPFS). Secondary end-points included rPFS based on androgen receptor splice variant 7 (AR-V7) expression in circulating tumour cells (CTCs), overall survival, and safety. Median rPFS was 5.5 months (95% CI 5.3–5.5). Median rPFS of patients with AR-V7(−) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2–not reached) and was significantly greater for AR-V7(−) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01). 223Ra was well tolerated; anaemia and thrombocytopenia were the most common grade 3/4 adverse events (5.8% and 11.5%, respectively). 223Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile. • 223Ra had a promising antitumour activity in patients with metastatic castration-resistant prostate cancer with asymptomatic bone metastases. • 223Ra showed an acceptable safety profile similar to that reported in other studies. • Overall survival of androgen receptor splice variant 7 (−) patients was significantly higher than androgen receptor splice variant 7 (+) patients. [ABSTRACT FROM AUTHOR]

Objective: To validate the translated and cross culturally adapted Chilean version of the 8 and 18month Ages and Stages Questionnaire (ASQ-CL) in a community sample.Methods: Participants: Parents of 1572 term children (82.9%) and 324 children at risk for developmental delay (17.1%) were included.Instrument: ASQ-3rd edition translated and culturally adapted for Chilean urban population.Main Measures: 8 and 18months ASQ-CL reliability, validity and mean scores. Feasibility was assessed using qualitative methods in healthcare professionals and mothers.Results: ASQ-CL mean scores were comparable to U.S. normative data. The overall total score and all domains were reliable (Cronbach alpha 0.66-0.85). Test-retest and inter-rater reliability were high (Pearson's r range 0.73-0.94; intraclass correlation r range 0.68-0.93). Early preterm infants were more likely to fail on several criteria. Qualitative methods confirmed ASQ-CL as a feasible tool in this Chilean urban community.Conclusions: ASQ-CL is a valid, reliable and feasible tool for assessing development in children at 8 and 18months in Chilean urban population. [ABSTRACT FROM AUTHOR]

Background: Several de-escalation approaches are under investigation in patients with HER2-positive, early-stage breast cancer. We assessed early metabolic responses to neoadjuvant trastuzumab and pertuzumab using 18F-fluorodeoxyglucose (18F-FDG)-PET (18F-FDG-PET) and the possibility of chemotherapy de-escalation using a pathological response-adapted strategy.Methods: We did a multicentre, randomised, open-label, non-comparative, phase 2 trial in 45 hospitals in Spain, France, Belgium, Germany, the UK, Italy, and Portugal. Eligible participants were women aged 18 years or older with centrally confirmed, HER2-positive, stage I-IIIA, invasive, operable breast cancer (≥1·5 cm tumour size) with at least one breast lesion evaluable by 18F-FDG-PET, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a baseline left ventricular ejection fraction of at least 55%. We randomly assigned participants (1:4), via an interactive response system using central block randomisation with block sizes of five, stratified by hormone receptor status, to either docetaxel (75 mg/m2 intravenous), carboplatin (area under the concentration-time curve 6 mg/mL  per  min intravenous), trastuzumab (subcutaneous 600 mg fixed dose), and pertuzumab (intravenous 840 mg loading dose, 420 mg maintenance doses; group A); or trastuzumab and pertuzumab (group B). Hormone receptor-positive patients allocated to group B were additionally given letrozole if postmenopausal (2·5 mg/day orally) or tamoxifen if premenopausal (20 mg/day orally). Centrally reviewed 18F-FDG-PET scans were done before randomisation and after two treatment cycles. Patients assigned to group A completed six cycles of treatment (every 3 weeks) regardless of 18F-FDG-PET results. All patients assigned to group B initially received two cycles of trastuzumab and pertuzumab. 18F-FDG-PET responders in group B continued this treatment for six further cycles; 18F-FDG-PET non-responders in this group were switched to six cycles of docetaxel, carboplatin, trastuzumab, and pertuzumab. Surgery was done 2-6 weeks after the last dose of study treatment. Adjuvant treatment was selected according to the neoadjuvant treatment administered, pathological response, hormone receptor status, and clinical stage at diagnosis. The coprimary endpoints were the proportion of 18F-FDG-PET responders in group B with a pathological complete response in the breast and axilla (ypT0/is ypN0) as determined by a local pathologist after surgery after eight cycles of treatment, and 3-year invasive disease-free survival of patients in group B, both assessed by intention to treat. The definitive assessment of pathological complete response was done at this primary analysis; follow-up to assess invasive disease-free survival is continuing, hence these data are not included in this Article. Safety was assessed in all participants who received at least one dose of study drug. Health-related quality-of-life was assessed with EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline, after two cycles of treatment, and before surgery. This trial is registered with EudraCT (2016-002676-27) and ClinicalTrials.gov (NCT03161353), and is ongoing.Findings: Between June 26, 2017, and April 24, 2019, we randomly assigned 71 patients to group A and 285 to group B. Median follow-up was 5·7 months (IQR 5·3-6·0). 227 (80%) of 285 patients in group B were 18F-FDG-PET responders, of whom 86 (37·9%, 95% CI 31·6-44·5; p<0·0001 compared with the historical rate) of 227 had a pathological complete response. The most common haematological grade 3-4 adverse events were anaemia (six [9%] of 68 patients in group A vs four [1%] of 283 patients in group B), neutropenia (16 [24%] vs ten [4%]), and febrile neutropenia (14 [21%] vs 11 [4%]). Serious adverse events occurred in 20 (29%) of 68 patients in group A versus 13 (5%) of 283 patients in group B. No deaths were reported during neoadjuvant treatment. Global health status declined by at least 10% in 65·0% (95% CI 46·5-72·4) and 35·5% (29·7-41·7) of patients in groups A and B, respectively INTERPRETATION: 18F-FDG-PET identified patients with HER2-positive, early-stage breast cancer who were likely to benefit from chemotherapy-free dual HER2 blockade with trastuzumab and pertuzumab, and a reduced impact on global health status. Depending on the forthcoming results for the 3-year invasive disease-free survival endpoint, this strategy might be a valid approach to select patients not requiring chemotherapy.Funding: F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

Pembrolizumab has modest activity if used in patients with hormone-receptor–positive (HR+), HER2-negative, previously treated metastatic breast cancer (BC). Our study investigated whether there would be any clinical benefit in combining chemotherapy with pembrolizumab in a similar patient population. This single-arm, phase Ⅱ trial enrolled women aged ≥18 years with HR+, HER2-negative, inoperable, locally recurrent or metastatic BC. Patients were previously treated with hormonal therapy and 1–2 chemotherapy regimens for locally recurrent and/or metastatic BC. On each 21-day cycle, patients received intravenous pembrolizumab 200 mg on day 1 and eribulin 1∙23 mg/m2 on days 1 and 8. The primary endpoint was the clinical benefit rate. Analysis of safety and activity was carried out in all patients who met the screening criteria and received at least 1 dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT03222856. Of the 44 patients enrolled between January 29 and October 17, 2018, clinical benefit was achieved in 25 (56∙8%, 95% confidence interval [CI]: 41∙0–71∙7) , objective response in 18 (40∙9%, 95% CI: 26∙3–56∙8), median progression-free survival was 6∙0 months (95% CI: 3∙7–8∙4), and 1-year overall survival was 59∙1% (95% CI: 45∙8–76∙2). The most common treatment-emergent adverse events (AEs) of any grade were neutropenia (20 [45∙5%]), anaemia (17 [38∙6%]), alopecia (19 [43∙2%]), asthenia (19 [43∙2%]), diarrhoea (14 [31∙8%]), fatigue (14 [31∙8%]), and peripheral neuropathy (12 [27∙3%]). Serious AEs occurred in 14 (31∙8%) patients including febrile neutropenia (3 [6∙8%]), neutropenia (2 [4∙5%]), fever (2 [4∙5%]) and peripheral neuropathy (2 [4∙5%]). Immune-related AEs occurred in 11 (25∙0%) patients. One (2∙3%) patient died of cardiac arrest unrelated to study treatment. Pembrolizumab plus eribulin demonstrates encouraging antitumour activity in patients with heavily pre-treated, HR+, HER2-negative, locally recurrent or metastatic BC. The safety and tolerability of the combination is similar to eribulin or pembrolizumab monotherapy. • Pembrolizumab + eribulin showed clinical benefit in luminal metastatic breast cancer (BC). • Objective responses were achieved regardless of programmed death ligand 1 status. • Its safety profile is similar to eribulin or pembrolizumab monotherapy. • New predictive biomarkers are required in endocrine-resistant BC. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether a longitudinal association exists between differential disciplinary parenting practices at 3 years of age and later child psychopathology at 11 years.Method: Data were obtained from the Millennium Cohort Study, a UK-wide cohort. Discipline style was assessed using a validated maternal reported questionnaire at 3 years of age for which later outcome data were available. "Active" (including smacking, shouting, and telling off) and "withdrawal" (including ignoring, removal of privileges, and sending to bedroom) approaches were distinguished. Child emotional and behavioral problems were assessed at 3 and 11 years of age using the maternally completed Strengths and Difficulties Questionnaire (SDQ). The independence of associations between early discipline and later child mental health was investigated using mutually adjusted regression analyses and potential reverse causality was considered by looking at changes in SDQ subscale scores from 3 to 11 years.Results: Differential associations with change in child psychopathology according to discipline type were observed. Active and withdrawal forms of discipline were associated with a decrease in conduct problems from 3 to 11 years (active, β = -0.28, 95% CI -0.34 to -0.21, p < .001; withdrawal, β = -0.19, 95% CI -0.24 to -014, p < .001). However, active approaches also were associated with an increase in emotional problems (β = 0.07, 95% CI 0.00-0.14, p = .03) not observed for withdrawal approaches.Conclusion: Different approaches to discipline appear to have differential associations with later child mental health. Further research accounting for a larger number of parent and child characteristics is needed to assess whether such associations are causal. [ABSTRACT FROM AUTHOR]