Confirmatory Phase Research Articles

Identification of variables and their influence on the human resources planning in the territorial level

Purpose: The purpose of this paper lies in the use of experimental way through empirical tools for identification of the set of variables and their interrelationships and influences on the human resources planning at the territorial level.Design/methodology/approach: The methodology used to verify the existence of the variables that affect the planning of human resources at the territorial level consists of two phases: a qualitative study of the variables that influence the planning of human resources, where the explicit variables are measured and / or implied raised in the literature analyzing the main contributions and limitations expressed by each of the authors consulted. Then it proceeds to confirmatory phase (quantitative) to prove the existence of the dimensions of the planning of human resources in the territorial level through the use of multivariate statistics through the combination of expert analysis and techniques of factorial grouping.Findings: Identification is achieved by using empirical methods, variables that affect human resources planning at the territorial level, as well as their grouping essential dimensions, while the description of a theoretical model that integrates the dimensions is made essential and relationships that affect human resource planning at the regional level, which is characterized by the existence of systemic and prospective nature.Originality/value: The literature shows two streams that address a wide range of approaches to human resources planning. The first is oriented from the business object and the second part of the management in highlighting a limited territorial level to address this latest theoretical development, an element that has contributed to the fragmented treatment of human resources planning and management in general at this level. The originality of this paper is part of the creation and adaptation, on a scientific basis of a theoretical model developed from the conceptual contribution of this process at the territorial level where the key variables that affect this process are integrated, highlighting the systemic approach prospective based on solid scientific foundations.

N08C9 (Alliance): A Phase 3 Randomized Study of Sulfasalazine Versus Placebo in the Prevention of Acute Diarrhea in Patients Receiving Pelvic Radiation Therapy

To provide confirmatory evidence on the use of sulfasalazine to reduce enteritis during pelvic radiation therapy (RT), following 2 prior single-institution trials suggestive that benefit existed. A multi-institution, randomized, double-blind, placebo-controlled phase 3 trial was designed to assess the efficacy of sulfasalazine versus placebo in the treatment of RT-related enteritis during RT including the posterior pelvis (45.0-53.5Gy) and conducted through a multicenter national cooperative research alliance.Patients received 1000mg of sulfasalazine or placebo orally twice daily during and for 4weeks after RT. The primary endpoint was maximum severity of diarrhea (Common Terminology Criteria for Adverse Events version 4.0). Toxicity and bowel function were assessed by providers through a self-administered bowel function questionnaire taken weekly during RT and for 6weeks afterward. Eighty-seven patients were enrolled in the trial between April 29, 2011, and May 13, 2013, with evenly distributed baseline factors. At the time of a planned interim toxicity analysis, more patients with grade ≥3 diarrhea received sulfasalazine than received placebo (29% vs 11%, P=.04). A futility analysis showed that trial continuation would be unlikely to yield a positive result, and a research board recommended halting study treatment. Final analysis of the primary endpoint showed no significant difference in maximum diarrhea severity between the sulfasalazine and placebo arms (P=.41). Sulfasalazine does not reduce enteritis during pelvic RT and may be associated with a higher risk of adverse events than placebo. This trial illustrates the importance of confirmatory phase 3 trials in the evaluation of symptom-control agents.

How We Treat Patients with Acute Lymphoblastic Leukemia

How We Treat Patients with Acute Lymphoblastic Leukemia

Methods for flexible sample-size design in clinical trials: Likelihood, weighted, dual test, and promising zone approaches

Sample size plays a crucial role in clinical trials. Flexible sample-size designs, as part of the more general category of adaptive designs that utilize interim data, have been a popular topic in recent years. In this paper, we give a comparative review of four related methods for such a design. The likelihood method uses the likelihood ratio test with an adjusted critical value. The weighted method adjusts the test statistic with given weights rather than the critical value. The dual test method requires both the likelihood ratio statistic and the weighted statistic to be greater than the unadjusted critical value. The promising zone approach uses the likelihood ratio statistic with the unadjusted value and other constraints. All four methods preserve the type-I error rate. In this paper we explore their properties and compare their relationships and merits. We show that the sample size rules for the dual test are in conflict with the rules of the promising zone approach. We delineate what is necessary to specify in the study protocol to ensure the validity of the statistical procedure and what can be kept implicit in the protocol so that more flexibility can be attained for confirmatory phase III trials in meeting regulatory requirements. We also prove that under mild conditions, the likelihood ratio test still preserves the type-I error rate when the actual sample size is larger than the re-calculated one.

Idelalisib Monotherapy and Durable Responses in Patients with Relapsed or Refractory Small Lymphocytic Lymphoma (SLL)

Idelalisib Monotherapy and Durable Responses in Patients with Relapsed or Refractory Small Lymphocytic Lymphoma (SLL)

Dose-Finding Trials: Optimizing Phase 2 Data in the Drug Development Process.

Clinical trials in drug development are commonly divided into 3 categories or phases. The first phase aims to find the range of doses of potential clinical use, usually by identifying the maximum tolerated dose. The second phase aims to find doses that demonstrate promising efficacy with acceptable safety. The third phase aims to confirm the benefit previously found in the second phase using clinically meaningful end points and to demonstrate safety more definitively. Dose-finding trials—studies conducted to identify the most promising doses or doses to use in later studies—are a key part of the second phase and are intended to answer the dual questions of whether future development is warranted and what dose or doses should be used. If too high a dose is chosen, adverse effects in later confirmatory phase 3 trials may threaten the development program. If too low a dose is chosen, the treatment effect may be too small to yield a positive confirmatory trial and gain approval from a regulatory agency. A well-designed dose-finding trial is able to establish the optimal dose of a medication and facilitate the decision to proceed with a phase 3 trial. Selection of a dose for further testing requires an understanding of the relationships between dose and both efficacy and safety. These relationships can be assessed by comparing the data from each dose group with placebo, or with the other doses, in a series of pairwise comparisons. This approach is prone to both false-negative and false-positive results because of the large number of statistical comparisons and the relatively small number of patients receiving each dose. These risks can be mitigated by combining data from patients receiving multiple active doses into a single treatment group for comparison with placebo (“pooling”), but only if it is possible to reliably predict which doses are likely to be effective. In general, dose-response relationships are best examined through dose-response models that make flexible, justifiable assumptions about the potential dose-response relationships and allow the integration of information from all doses used in the trial. This can reduce the risk of both false-negative and false-positive results; incorporating all data into the estimates of efficacy and safety for each dose produces more accurate estimates than evaluating the response to each dose separately. In this issue of JAMA, Gheorghiade et al 1 report the results of

Will Biosimilars Change the Treatment Paradigm in Psoriasis?

Prof Augustin opened the meeting and reviewed the use of systemic treatments recommended for moderate-to-severe psoriasis. Data indicating a lack of access to biologic treatments were presented, and barriers to the use of biologics, including both patient and physician-related cost, were discussed. The opportunity for improved access to biologic treatment options, portrayed by the availability of biosimilars, and the potential to improve healthcare for patients with psoriasis was presented. Dr Schiestl explained that the demonstration of biosimilarity for regulatory requirements is based on the totality of evidence generated from analytical, non-clinical, and clinical data. The physicochemical and biological assessments performed for comparison of the proposed biosimilar and the originator molecule, using state-of-the-art technology, are most sensitive. Comparative, analytical, and functional testing therefore represent the major part of the comparability exercise, proving that the biosimilar and originator product contain essentially the same active substance. After demonstration of similarity at an analytical and functional level, suitable comparative pharmacodynamics (PDs) and/or pharmacokinetics (PKs) and/or safety studies in animal models are performed. Comparative clinical PKs/PDs and safety is assessed in healthy volunteers as an essential part of the clinical development programme. A final confirmatory Phase III clinical study is conducted in a sensitive patient population to confirm similar safety and efficacy of the biosimilar compared to the originator molecule. Dr Gerdes explained why psoriasis is a sensitive and robust indication for confirming clinical efficacy of a biosimilar. He presented data from the EGALITY confirmatory study of the etanercept biosimilar (GP2015) in patients with moderate-to-severe psoriasis to compare safety and efficacy, and provided data on multiple switches between the originator etanercept (ETN) and the biosimilar. The trial confirmed the clinical equivalence of the efficacy and safety of GP2015 with ETN; no new safety signals were observed. Switching between the originator and biosimilar had no effect on safety or efficacy over the 52-week study.

Phase 1 Dose-Escalation Study of Tomotherapy Based Stereotactic Body Radiation Therapy for Primary Hepatocellular Carcinoma

Tomotherapy-based SBRT is often utilized for treating brain or spine lesions; however, its role in treating intrahepatic tumors has not been explored. A phase 1 dose-escalation trial was conducted to determine the feasibility and toxicity of Tomotherapy-based SBRT for primary HCC. Eligible patients had Child-Turcotte-Pugh’s Class (CTP) A or B, were not candidates for resection, had 1-3 lesions and cumulative tumor diameter less than or equal to 6 cm. Abdominal compression and 4-dimensional computed tomography was used during SBRT simulation. Dose-escalation began at 36 Gy in 4 fractions (9 Gy/fraction) with a subsequent planned escalation of 2 Gy/fraction per dose level. All patients were treated every-other-day with on-board mega-voltage CT for image-guidance. Dose-limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events v3.0 grade 3 or greater gastrointestinal toxicity. Modified Response Criteria in Solid Tumors (mRECIST) was used to evaluate treatment response and survival was measured from the last day of SBRT. Eighteen patients with 22 lesions were enrolled. The median cumulative tumor diameter was 2.1 cm (range, 1.0-4.4 cm). Dose was initially escalated to 52 Gy (13 Gy/fraction) without DLT. The protocol was amended for a further escalation to 60 Gy (15 Gy/fraction). Radiologic complete response (CR) was achieved in 16 patients (88.9%) with median time to CR of 6.0 months (range, 0.7-12.3 months). Changes in alpha fetoprotein (AFP) level were well correlated with radiologic response among patients with initial AFP elevation. Nine patients experienced disease progression: 2 local, 5 outfield intrahepatic, and 2 distant failures. No local failure occurred at dose levels 3 and 4. Dose-limiting toxicity was not reached. Grade 3 hematologic toxicity was reported in five patients: all of these patients had grade 1 or 2 hematologic events prior to SBRT. No GI toxicity greater than grade 1 occurred. With median follow-up of 20 months (range, 8-33 months), 1 and 2-year local control rates were 76.9% and 70.5%, progression-free survival (PFS) were 54.3% and 47.5%, and overall survival were 100% and 70.0%. Multi-segmental recurrences prior to SBRT was associated with poor PFS in univariate (P = .038) and multivariate analyses (P = .056). Tomotherapy-based SBRT was well tolerated with encouraging preliminary results. A confirmatory phase 2 trial is currently underway.

Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity

Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept(™) 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. This was a post hoc analysis of adept(™) 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.

Oligodendrogliomas: a short history of clinical developments.

*Brain Tumor Center at Erasmus MC Cancer Center, Erasmus MC, Rotterdam, The Netherlands; m.vandenbent@erasmusmc.nl oligodendroglioma: the early days Oligodendrogliomas have in particular attracted attention once it became clear that these are chemotherapy sensitive tumors. Although since the first description in 1926 and 1929 of oligodendroglial tumors it has been clear that these tumors are a special brand with a relatively good prognosis, they were taken for just another glioma subtype for many years thereafter [1]. Indeed, apart from a relatively more favorable prognosis of oligodendroglioma in comparison to their astrocytic counterparts and their often calcified lesions allowing a first diagnosis even at the time CT scans were not yet available, little pointed toward a specific significance for these tumors. This histological identification was somewhat complicated by the existence of another group with histological characteristics of both astrocytoma and oligodendroglioma, labeled mixed oligoastrocytoma. All these tumors were considered among the grade II and III glioma, and trials on grade II and high-grade glioma usually considered both astrocytoma, oligodendroglioma and mixed oligoastrocytoma. Furthermore, trials on high-grade glioma usually lumped both grade III and grade IV (glioblastoma) under the heading ‘anaplastic glioma’. As a consequence, grade III tumors were in general treated as grade IV tumors, albeit with the clear notion their outcome was better. oligodendroglioma: the chemotherapy sensitive glioma This clinical significance of the diagnosis ‘oligodendroglioma’ radically changed when Cairncross et al. in 1988 and again in 1992 reported remarkably high response rates to procarbazine, CCNU (lomustine) and vincristine (PCV) chemotherapy in relapsing anaplastic oligodendroglioma [2]. This lead to confirmatory Phase II studies, and subsequently to studies in newly diagnosed anaplastic oligodendroglial tumors [3,4]. At that time, still no distinction was made between pure oligodendroglial tumors and mixed oligodendroglioma. At least in part driven by the wish not to miss oligodendroglial tumors the percentage of patients with oligodendroglioma showed a steep incline, from 5% of all glioma in historical series to no less than 20% of all glioma cases [5]. A clear change in diagnostic criteria was part of that increase, already pointing to the lack of objective criteria for the histological diagnosis of glioma in general but more in particular of oligodendroglial tumors.

Sequential actions as markers of behavioural and cognitive processes: Extracting empirical pathways from data streams of complex tasks

This paper presents a novel exploratory method to extract information about behavioural and cognitive processes that occur during the performance of complex tasks. The methodology is framed in a structure where process data on interactions between the task performer and the task space environment are captured in a data stream for big data analytics.We begin by describing a reductionist approach that involves deconstructing complex processes into constituent parts. We extend this approach by looking at sequences of these constituent parts with the aim of detecting patterns in a person's action pathways. We propose the exploration of these pathways as indicators of underlying behavioural and cognitive processes. Current sequence-based approaches are presented and a proposed approach in dealing with sequences as empirical pathways is demonstrated using data stream from an interactive and collaborative online-administered complex task. These empirical pathways were visualised as directed graphs and an exploratory network analysis is proposed to examine specific features of the emergent paths.General challenges encountered during the development of such a method are described and specific future challenges that we foresee in transitioning from an exploratory phase to a confirmatory phase are examined. Finally, possibilities for further research as well as future applications are discussed.

Sample Size Re-estimation Designs In Confirmatory Clinical Trials—Current State, Statistical Considerations, and Practical Guidance

A sample size re-estimation (SSR) design is a flexible, adaptive design with the primary purpose of allowing sample size of a study to be reassessed in the mid-course of the study to ensure adequate power. In real world drug product, biologic, and device development, there may be large uncertainty in key factors that drive the sample size estimation for a confirmatory clinical trial. For example, early phase studies may have encouraging results but could be of shorter duration, or use a different endpoint than what is required for confirmatory phase clinical trials. The negative impact of high uncertainty at design stage for a confirmatory trial can be mitigated by an SSR design. Recent surveys have reported an encouraging upward trend in the use of SSR designs in clinical trials since the release of the draft guidance for adaptive design clinical trials for drugs and biologics by the U.S. Food and Drug Administration in 2010 (U.S. Food and Drug Administration (FDA) (February, 2010), Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics). To support broad understanding and acceptance of SSR designs in confirmatory settings, especially unblinded SSR designs, we summarize statistical methods pertaining to SSR designs, including recent development in this field, and discuss design alternatives among blinded SSR, unblinded SSR, and conventional group sequential designs. To support appropriate implementation of SSR designs, we make recommendations on operational logistics for trial conduct based on accumulated experience in recent years, and provide points to consider for final data analysis and reporting for studies where the sample size has been increased following either a blinded or an unblinded SSR algorithm.

An Innovative Approach to Stakeholder Theory: application in spanish transnational corporations

Objective – This paper describes a different perspective on the application of stakeholder theory, concentrating only on the interests of stakeholders rather than on their roles. The purpose of this article is to provide an option for solving Jensen’s “problem of governance”; this approach will allow the agent to manage the stakeholders having ascertained that the needs of stakeholders overlap and, accordingly, the agent should be able to monitor multiple stakes as they are aligned. Design/methodology/approach – A Delphi method was used with the aim to achieve consensus about the interests of stakeholders for companies in Spain. The confirmatory phase was based on interviews to test whether the interests identified in the preliminary study match the interests that the IBEX-35 firms recognized in relation with their stakeholders. Findings – The main contributions are: the addition of a new interestbased perspective to the different classifications made by stakeholder theory; a solution to the diversity of indicators between stakeholders and shareholders; and, finally, a proposal for an integrated accounting system, incorporating economic as well as social issues employing a common metric (monetary). Practical implications – A new perspective focusing on stakeholder interests and the confirmation that interests may converge permits the control and management of multiple principals in transnational corporations operating in different countries. Originality/value – There is a gap in the applicability of stakeholder management that the interest-based perspective can help resolve; moreover the monetization of social value is an option to efficiently manage transnational corporations.

Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer.

To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer. Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts. In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a "breakthrough therapy" designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P < 0.001). Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer.

CDK4/6 inhibitors in breast cancer.

Deregulation of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) axis can occur through a number of mechanisms and contributes towards the unrestrained growth witnessed in a variety of cancers including breast cancers. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising preclinical and clinical results in breast cancer and other tumours. A number of trials assessing antitumour efficacy in various disease settings and combinations are ongoing. The cyclin D1-CDK-Rb axis and its role in the cell cycle of normal and cancer cells are delineated. The early pan-CDK inhibitor flavopiridol and subsequent preclinical and clinical development of selective CDK4/6 inhibitors are described. Ongoing studies in breast cancer with novel CDK4/6 inhibitors (palbociclib, abemaciclib and ribociclib) are explored. A literature search of these topics was performed through PubMed. Abstracts from major oncology meetings were also reviewed. Selective CDK4/6 inhibitors, as represented by the competing compounds currently in clinical development, comprise a novel, safe and, thus far, promisingly efficacious group of drugs. Considerable resources are being devoted towards exploring the efficacy of these drugs in combination with endocrine therapies, an approach that has yielded encouraging results and accelerated approval by the US Food and Drugs Administration for one of these agents (palbociclib). The results of confirmatory phase 3 trials are, however, awaited. We discuss further therapy combinations in development and highlight potential areas for caution including the potential for antagonistic interactions with cytotoxic chemotherapies.

PTU-187 Sample size calculation in confirmatory trials in irritable bowel syndrome with constipation: experience with linaclotide (constella®): Abstract PTU-187 Table 1

Introduction Sample size (SS) calculation with sufficient power to detect significant and clinically meaningful differences vs placebo is necessary to ensure the validity of confirmatory Phase 3 pivotal trials in irritable bowel syndrome with constipation (IBS-C). Method Using data from a pilot Phase 2b study of linaclotide (Constella®; LIN) in IBS-C (Study 202) and the pivotal Phase 3 LIN trials (Trial 302; Trial 31), we compared 2 statistical assumptions for the Phase 3 SS calculation for the European Medicines Agency (EMA) co-primary endpoints: 1) minimally important clinical differences (MICD) and 2) replication of Phase 2b 290 µg/day results. Protocol design, patient population and endpoints of the trials were also compared. Results There were no relevant differences in protocol design or patient population in the Phase 2b/3 trials. For endpoint assessments, only the range of the pain/discomfort scale differed (Phase 2b: range 1–5; Phase 3: range 0–10). For both EMA endpoints, Phase 2b data showed a higher placebo effect and greater improvement vs placebo compared with Phase 3 data (both not statistically significant; Table 1). The SS for the Phase 3 trials was estimated to have ≥95% global power to detect an MICD of 15% in both endpoints. Based on replication of Phase 2b results, an SS of 134 patients per treatment arm would have been sufficient to achieve ≥95% global power to detect an effect size comparable to Phase 2b. However, this sample size would have only 46% and 67% overall power to detect the actual observed results of Trials 31 and 302, respectively, and even less overall power (13% and 47%, respectively) when the MICD is reduced to 10%. Conclusion In the LIN IBS-C clinical programme, Phase 2b results were not a good predictor of Phase 3 outcome, even without major differences in study design. Caution is needed when calculating SS for Phase 3 IBS-C trials to ensure sufficient power to detect clinically relevant differences vs placebo. Disclosure of interest M. Falques Employee of: Almirall S. A., C. Diaz Employee of: Almirall S. A., D. Vilardell Employee of: Almirall S. A., J. Fortea Employee of: Almirall S. A., J. Johnston Employee of: Ironwood Pharmaceuticals.

Reinventing clinical trials: a review of innovative biomarker trial designs in cancer therapies.

Recently, new clinical trial designs involving biomarkers have been studied and proposed in cancer clinical research, in the hope of incorporating the rapid growing basic research into clinical practices. Journal articles related to various biomarkers and their role in cancer clinical trial, articles and books about statistical issues in trial design, and regulatory website, documents, and guidance for submission of targeted cancer therapies. The drug development process involves four phases. The confirmatory Phase III is essential in regulatory approval of a special treatment. Regulatory agency has restrictions on confirmatory trials 'using adaptive designs'. No rule of thumb to pick the most appropriate design for biomarker-related trials. Statistical issues to solve in new designs. Regulatory acceptance of the 'newly proposed trial designs'. Biomarker-related trial designs that can resolve the statistical issues and satisfy the regulatory requirement.

Development and validation of the Student Attitudes and Beliefs about Authorship Scale: a psychometrically robust measure of authorial identity

One approach to plagiarism prevention focuses on improving students' authorial identity, but work in this area depends on robust measures. This paper presents the development of a psychometrically robust measure of authorial identity – the Student Attitudes and Beliefs about Authorship Scale. In the item generation phase, a pool of items was developed and assessed for content validity by subject matter experts. In the exploratory phase, data from 439 higher education students were used to identify a latent variable model with three factors: ‘authorial confidence’, ‘valuing writing’ and ‘identification with author’. In the confirmatory phase, data from 306 higher education students were used to test the three-factor model's reliability and validity. The three-factor structure was confirmed, and the results showed that the SABAS has a stronger psychometric basis than previously available measures. This measure of authorial identity can be used with confidence in research and pedagogy to help students improve their authorial identity.

Using simulation to optimize adaptive trial designs: applications in learning and confirmatory phase trials

Failures in Phase III clinical trials have a major impact on escalating drug development costs. Clinical trial simulation can improve decisions made in learning Phase I and Phase II studies, leading to better designs and reduced chance of failure in high-cost, confirmatory Phase III trials. In adaptive design trials – which use early findings to modify the trial toward the most promising dose, sample size or patient population – simulation is instrumental in guiding selection of optimal design modifications. In this article, the authors present case studies demonstrating the benefits of simulations to identify maximum tolerated dose in Phase I, define dose–response relationships in Phase II, and determine the best type and timing of interim analyses in Phase III.

Primary tumor location as a prognostic factor in metastatic colorectal cancer.

We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC). We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided. Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location. These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.