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Although randomized control trials allow for a comparison of treatment arms with minimal concern for confounding by known and unknown factors, a randomized study is not feasible in certain disease settings. When a randomized design is not possible, incorporating external control data into the study design can be an effective way to expand the interpretability of the results of an experimental arm by introducing the ability to carry out a formal or an informal comparative analysis. This paper provides an introduction to the concepts of external controls in oncology trials, followed by a review of relevant and current research on this topic. The paper also focuses on general considerations for designing a trial that may incorporate external control data, followed by case studies of the marketing applications submitted to the Food and Drug Administration that included external control data., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Published by Elsevier Ltd.)

Objectives: Many trials conclude "no clinically meaningful detriment" to health-related quality of life (HRQL) or function between arms, even when notable differential toxicity is observed. Mean change from baseline analyses of function or HRQL can possibly obscure important change in subgroups experiencing symptomatic toxicity. We evaluate the impact of diarrhea, a key treatment arm toxicity, on patient-reported HRQL and functioning in clinical trials submitted to US Food and Drug Administration., Methods: This study used 4 randomized, breast cancer trials (adjuvant to late-line metastatic) as case examples. Diarrhea, physical functioning (PF), and global health status and quality of life (GHS/QoL) from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 were analyzed at baseline and approximately 3 and 6 months., Results: Generally, patients reporting very much diarrhea at months 3 and 6 had worse PF (9-19 points lower) and GHS/QoL (16-19 points lower) than patients reporting no diarrhea regardless of treatment arm. In the change from baseline analysis, patients reporting very much diarrhea also experienced a greater decrease in PF (6-13 points) and GHS/QoL (6-16 points) versus patients reporting no diarrhea in both arms., Conclusions: In trials with moderate to large differences in symptomatic toxicity by arm, reporting "no meaningful difference in functioning and HRQL between arms" based on mean change from baseline analysis is insufficient and may obscure important impacts on subgroups experiencing symptomatic adverse events. Additional exploratory analyses with simple data visualizations evaluating functioning or HRQL in patient subgroups experiencing expected symptomatic toxicities can further inform the safety and tolerability of an investigational agent., (Copyright © 2021 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Although the Adjuvant Paclitaxel and Trastuzumab (APT) trial has been adopted clinically, single-arm trials have limitations, and interest remains whether these patients with small node-negative human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) would benefit from more intensive chemotherapy. This analysis explored whether external controls can contextualize single-arm studies to add to clinical decision making in the use of de-escalated therapy in patients with low-risk HER2-positive EBC., Patients and Methods: Patient-level data from five randomized trials supporting drug approval in adjuvant HER2-positive EBC were pooled, and patients with low-risk EBC were selected (n = 1770). Patients treated concurrently with trastuzumab and either anthracycline/cyclophosphamide/taxane/trastuzumab (ACTH) or taxane/carboplatin/trastuzumab (TCH; n = 1366) were matched (1:1) to patients treated with paclitaxel and trastuzumab (TH) in the APT trial (n = 406) using propensity scores. Patients treated with anthracycline/cyclophosphamide/taxane (ACT; n = 374) were also matched (1:1) to those treated with TH. Propensity scores were estimated using covariates of age, tumor stage, estrogen receptor status, progesterone receptor status, and histological grade., Results: After matching, the estimated probabilities of invasive disease-free survival (iDFS) at 3 and 5 years were 98.6% and 96.5% in the TH arm, and 96.6% and 92.9% in the ACTH/TCH arm, respectively. The estimated probabilities of overall survival (OS) at 3 and 5 years were 99.7% and 99.3% in the TH arm, and 99.0% and 97.4% in the ACTH/TCH arm, respectively. Comparing the TH arm with the ACT arm in the matched sample, the estimated difference in iDFS was 7.5% (TH 98.8% and ACT 91.3%) at 3 years and 12.6% (TH 96.1% and ACT 83.5%) at 5 years. The estimated difference in OS was 2.6% (TH 100% and ACT 97.4%) at 3 years, and 5.3% (TH 99.3% and ACT 94.0%) at 5 years., Conclusions: Our analyses suggest that patients' outcomes in both arms were in general similar, thus providing additional reassurance regarding de-escalation of therapy., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Published by Elsevier Ltd.)

Objectives: Patients with cancer frequently use botanical medications. The concomitant use of such medications by patients on commercial trials has not been well-described, despite the importance of these trials for evaluating the safety and efficacy of new agents. We sought to describe the use of botanical medications taken by patients with prostate cancer enrolled on global commercial trials., Design: Retrospective study., Setting: Regulatory repository of commercial clinical trial data., Interventions: Anti-cancer therapy., Main Outcome Measures: Botanical and medication use data were pooled across six international commercial randomized trials for metastatic prostate cancer with detailed information on medication and indications. Botanical products were considered to have potential for drug interaction if they led to a change in drug exposure in human trials. Potential for interaction was ascertained by PubMed review. Descriptive statistics were used for analysis., Results: Of 7318 enrolled patients, 700 (10 %) reported botanical use at any time and 653 (9%) reported use of botanical products while on trial. Nearly half of botanical product types were not classified by plant (43 %). The highest proportion of botanical use was among patients in Asian countries (32 %), followed by patients in North America (13 %). Eighty-six different types of botanical products were used; of these, nineteen had a patient-reported anti-cancer indication., Conclusions: Botanical medicine use among patients with prostate cancer in commercial trials is moderate, although it varies by region. Practitioners should be aware of the use of botanical interventions in a clinical trial context., (Copyright © 2020 Elsevier Ltd. All rights reserved.)