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.
•Considerations for the use of external controls in oncology clinical trials are multifaceted and depend on the intended use.•Review of recent research and some marketing applications describe current usage of external control data in oncology.•Including external controls for primary evidence of efficacy requires careful pre-specification of study design elements.
The kinetics and quantitative and qualitative effects of grape proanthocyanidin (PA) adsorption to grape skin-derived cell wall material (CWM) were investigated in five different temperature–ethanol ...conditions. Progress curves for each condition were constructed by monitoring the decrease in concentration of PA solutions after exposure to CWM over 720 min. Adsorption isotherms were constructed for each condition, and a Langmuir equation model was applied to each via regression analysis. Compositional changes in the PA solutions after exposure to CWM were determined using phloroglucinolysis and gel permeation chromatography (GPC). A negative correlation between PA adsorption and both the temperature and ethanol concentration was found. Progress curves suggested that both the temperature and ethanol affect the equilibration rate of the adsorption reactions. Additionally, equilibration rates for lower temperature and ethanol concentration conditions were found to be much longer than previously reported, taking up to 720 min. Phloroglucinolysis results showed no discernible correlation between the temperature or ethanol concentration and percent galloylation or percent gallo units of adsorbed compounds. Analyses by phloroglucinolysis and GPC indicate a preferential adsorption of larger molecular weight PAs under all conditions, although no discernible impact on PA composition was detected. Additionally, findings suggest that both the temperature and ethanol concentration impact the percent reduction in molar mass of the PA solution. Data from this study were ultimately utilized to develop a computational model for predicting phenolic extraction during red wine fermentations.
Caloric restriction (CR), the consumption of fewer calories while avoiding malnutrition, decelerates the rate of aging and the development of age-related diseases. CR has been viewed as less ...effective in older animals and as acting incrementally to slow or prevent age-related changes in gene expression. Here we demonstrate that CR initiated in 19-month-old mice begins within 2 months to increase the mean time to death by 42% and increase mean and maximum lifespans by 4.7 (P = 0.000017) and 6.0 months (P = 0.000056), respectively. The rate of age-associated mortality was decreased 3.1-fold. Between the first and second breakpoints in the CR survival curve (between 21 and 31 months of age), tumors as a cause of death decreased from 80% to 67% (P = 0.012). Genome-wide microarray analysis of hepatic RNA from old control mice switched to CR for 2, 4, and 8 weeks showed a rapid and progressive shift toward the gene expression profile produced by long-term CR. This shift took place in the time frame required to induce the health and longevity effects of CR. Shifting from long-term CR to a control diet, which returns animals to the control rate of aging, reversed 90% of the gene expression effects of long-term CR within 8 weeks. These results suggest a cause-and-effect relationship between the rate of aging and the CR-associated gene expression biomarkers. Therefore, therapeutics mimicking the gene-expression biomarkers of CR may reproduce its physiological effects.
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.
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.
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.
Our analyses suggest that patients' outcomes in both arms were in general similar, thus providing additional reassurance regarding de-escalation of therapy.
•The Adjuvant Paclitaxel and Trastuzumab (APT) trial, a single-arm trial in patients with small node-negative human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, showed favorable outcomes.•However, single-arm trials have limitations and interest remains whether these patients would benefit from more intensive chemotherapy.•Our innovative analyses used existing Food and Drug Administration patient-level data as an external control from five randomized controlled trials (RCTs) compared with the APT trial.•We describe long-term outcomes (invasive disease-free survival and overall survival) of patients from the APT trial versus matched external controls from the five RCTs.•Patients' outcomes in both arms were in general similar, thus providing additional reassurance regarding de-escalation of therapy.
•Use of concomitant botanical products by patients with prostate cancer enrolled on commercial clinical trials is moderate (10 %).•However, use can be high in some regions and countries.•Protocols ...and post-marketing materials do discuss the use of concomitant botanical products.
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.
Retrospective study.
Regulatory repository of commercial clinical trial data.
Anti-cancer therapy.
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.
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.
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.
Binding MOAD (Mother of All Databases) is a database of 9836 protein-ligand crystal structures. All biologically relevant ligands are annotated, and experimental binding-affinity data is reported ...when available. Binding MOAD has almost doubled in size since it was originally introduced in 2004, demonstrating steady growth with each annual update. Several technologies, such as natural language processing, help drive this constant expansion. Along with increasing data, Binding MOAD has improved usability. The website now showcases a faster, more featured viewer to examine the protein-ligand structures. Ligands have additional chemical data, allowing for cheminformatics mining. Lastly, logins are no longer necessary, and Binding MOAD is freely available to all at http://www.BindingMOAD.org.
People living with dementia may call out repetitively, sometimes called disruptive vocalisation, or verbal agitation. In literature and policy, patients who call out repetitively are assumed to be ...expressing an unmet need, which should be met. Yet there has been little systematic study of this patient group in an acute hospital setting.
To better understand patients who call out repetitively and to identify what care looks like in an acute hospital setting.
Ethnography.
Ten acute geriatric medical wards in two hospitals.
30 cognitively impaired patients who were calling out repetitively, and 15 members of hospital staff.
Semi-structured interviews with hospital staff, 150 h of ward observations and informal conversations with staff, scrutiny of medical and nursing documentation, and measures of patient health status.
Patients who called out were moderately or severely cognitively impaired, often had delirium, were very physically disabled, and many were approaching the end of life. Most hospital staff were found to hold contradictory views: that calling out represents distress or unmet need, but that nothing can be done to alleviate the calling out. During informal conversations, most staff also tended to say that they intuitively recognised when intervening was likely to alleviate calling out. During observations, many staff appeared to and spoke of the ability to ‘block’ calling out. As a result we argue that social, emotional and physical needs may get overlooked. We argue that some calling out is due to a need that is unmeetable. We also found that while staff would talk about strategies for identifying need, observations and hospital documentation did not support evidence of systematic attempts to identify potential need.
Calling out repetitively within a hospital setting is difficult for staff to understand and to respond to. This is because many of these patients are severely cognitively impaired, often immobile and dependent on their professional carers. We argue that a form of socialised care futility is communicated between staff and is used to rationalise becoming unresponsive to calling-out. We explain this phenomenon as resulting from two protective mechanisms: defence of staff's professional identity as competent practitioners; and defence of staff as having personal morality. Socialised care futility risks good quality care, therefore systematic strategies to assess and manage possible need should be developed, even if calling out remains irresolvable in some cases.
Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary ...(food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the μ-OR sub-type. In a sample of healthy volunteers, we used (11)C-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50 = 7.10 ng ml(-1)) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-β-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption.
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