Risk indicator taxonomy for supervision of clinical trials on medicinal products

<p><b>Aim:</b> To facilitate a risk-based approach for the supervision of clinical trials on medicinal products, we identified and categorized indicators that may present an elevated safety and/or ethical risk for participants, and/or for data integrity. The indicators are relevant for all stakeholders including participants, regulatory bodies, health care inspectorates, sponsors and trial sites.</p> <p><b>Methods:</b> The sources of indicators included Medline (using the search terms risk-based/-triggered/-driven oversight/monitoring/inspection), relevant documents from websites of regulatory authorities in Europe, North America and Australia, and results of a brainstorm session organized for experts working in the field. Indicators were classified according to risk area (safety and ethical, data integrity, or both).</p> <p><b>Results:</b> In total, we identified 69 risk indicators that were categorized into six branch-levels of the taxonomy. We visualized the taxonomy in a tree structure to clearly distinguish individual indicators. In addition to readily detectable risk indicators, more context-related aspects determine the final impact of the trial and constitute further components in risk assessment. Context-related aspects include potential high media attention, consequences for the reputation of medical research, and the socioeconomic situation in the geographic region and have to be considered on a case-by-case basis.</p> <p><b>Conclusions:</b> We identified a wide array of risk indicators for clinical trials on medicinal products and we used a tree structure to incorporate the indicators identified to clearly distinguish individual indicators and to enable efficient use of the indicators. The overview of indicators may facilitate multiple stakeholders in developing structured risk assessment (identification and analysis) for supervising clinical trials on medicinal products. Stakeholders can interpret and prioritize the indicators from their own perspective.</p

Elderly postmenopausal patients with breast cancer are at increased risk for distant recurrence:A Tamoxifen Exemestane Adjuvant Multinational Study Analysis

textabstractIntroduction. For postmenopausal patients with hormonesensitive breast cancer, outcome is worse with increasing age at diagnosis. The aim of this study was to assess the incidenceof breast cancer recurrence (locoregionalanddistant), and contralateral breast cancer by age at diagnosis. Methods. Patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. Primary endpoints were locoregional recurrence, distant recurrence, and contralateralbreastcancer.Ageatdiagnosiswascategorizedas younger than 65 years, 65-74 years, and 75 years or older. Results. Overall, 9,766 patients were included, of which 5,349 were younger than 65 years (reference group), 3,060 were 65-74 years, and 1,357 were 75 years or older. With increasing age, a decreased administration of radiotherapy after breast conserving surgery (94%, 92%, and 88%, respectively) and adjuvant chemotherapy (51%, 23%, and 5%, respectively) was observed. Risk of distant recurrence increased with age at diagnosis; multivariable hazard ratio for patients aged 65-74 years was 1.20 (95% confidence interval [CI]: 1.00 -1.44), hazard ratio for patients aged 75 years or older was 1.39 (95% CI: 1.08 -1.79). Risks of locoregional recurrence and contralateral breast cancer were not significantly different across age groups. Conclusion. Elderly patients with breast cancer were at increased risk for distant recurrence. Other studies have shown that the risk of distant recurrence is mainly affected by adjuvant systemic therapy. All TEAM patients received adjuvant endocrine treatment; however, chemotherapy was administered less often in elderly patients. These findings are suggestive for consideration of chemotherapy in relatively fit elderly breast cancer patients with hormonesensitive disease

Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors:An international tamoxifen exemestane adjuvant multinational trial analysis

Purpose Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Patients and Methods Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. Results A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. Conclusion Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy. </jats:sec

Estrogen Receptor and Progesterone Receptor As Predictive Biomarkers of Response to Endocrine Therapy: A Prospectively Powered Pathology Study in the Tamoxifen and Exemestane Adjuvant Multinational Trial

Purpose The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included a prospectively planned pathology substudy testing the predictive value of progesterone receptor (PgR) expression for outcome of estrogen receptor-positive (ER-positive) early breast cancer treated with exemestane versus tamoxifen. Patients and Methods Pathology blocks from 4,781 TEAM patients randomly assigned to exemestane versus tamoxifen followed by exemestane for 5 years of total therapy were collected centrally, and tissue microarrays were constructed from samples from 4,598 patients. Quantitative analysis of hormone receptors (ER and PgR) was performed by using image analysis and immunohistochemistry, and the results were linked to outcome data from the main TEAM trial and analyzed relative to disease-free survival and treatment. Results Of 4,325 eligible ER-positive patients, 23% were PgR-poor (Allred = 5). No treatment-by-marker effect for PgR was observed for exemestane versus tamoxifen (PgR-rich hazard ratio [HR], 0.83; 95% CI, 0.65 to 1.05; PgR-poor HR, 0.85; 95% CI, 0.61 to 1.19; P = .88 for interaction). Both PgR and ER expression were associated with patient prognosis in univariate (PgR HR, 0.53; 95% CI, 0.43 to 0.65; P < .001; ER HR, 0.66; 95% CI, 0.51 to 0.86; P = .002), and multivariate analyses (P < .001 and P = .001, respectively). A trend toward a treatment-by-marker effect for ER-rich patients was observed. Conclusion Preferential exemestane versus tamoxifen treatment benefit was not predicted by PgR expression; conversely, patients with ER-rich tumors may derive additional benefit from exemestane. Quantitative analysis of ER and PgR expression provides highly significant information on risk of early relapse (within 1 to 3 years) during treatment.Surgical oncolog