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Clinical Trials: Design, Conduct and Analysis
Abstract
This book starts with a general discussion of clinical trials. It goes on to describe the activities of a typical study, comparing single center and multicenter trials, reviewing cost factors and assessing the usefulness of clinical trials for the practice of medicine. The book then considers design principles and practices such as sample size estimates and the mechanics of treatment masking, and provides a detailed consideration of a variety of issues involved in implementation and analysis, including execution, follow-up, and quality assurance. The book also includes a three-chapter section on management and an in-depth treatment of reporting procedures.
... For comparison, a 24 month trial with observations every three months would require 296 subjects per arm using Eq. (12). Note that it is not necessary for the design of the pilot study (i.e., the number of observations and interval between observations) to match the design of the future trial, we only require that there are sufficient pilot data to estimate the variance parameters σ 2 b 1 and σ 2 ϵ . ...
... To evaluate the performance of Eq. (12) through (14) we have performed computer simulations assuming data following the model fit obtained in the Example above. We first performed simulations assuming a clinical trial with balanced design with six post-baseline time points with no loss to follow-up and with equal variance within arms consistent with Eq. (12). Simulating a series of clinical trials with sample size from 200 to 600 subjects per arm with effect size equal to a 25% reduction in the mean rate of decline observed in placebo (25% of the mean 4.06 points per year rate of decline observed in the pilot data (Table 1)) with 10,000 simulations per sample size simulated, we found that simulated power closely tracks the power predicted by Eq. (12) (top line, Figure 1). ...
... Simulated power closely tracks the power predicted by Eq. (14) power formula (Figure 2). Predictably [12,13], power is maximized when λ equals one, and declines as the allocation ratio deviates from one ( Figure 2). ...
We have previously derived power calculation formulas for cohort studies and clinical trials using the longitudinal mixed effects model with random slopes and intercepts to compare rate of change across groups [Ard & Edland, Power calculations for clinical trials in Alzheimer’s disease. J Alzheim Dis 2011;21:369–77]. We here generalize these power formulas to accommodate 1) missing data due to study subject attrition common to longitudinal studies, 2) unequal sample size across groups, and 3) unequal variance parameters across groups. We demonstrate how these formulas can be used to power a future study even when the design of available pilot study data (i.e., number and interval between longitudinal observations) does not match the design of the planned future study. We demonstrate how differences in variance parameters across groups, typically overlooked in power calculations, can have a dramatic effect on statistical power. This is especially relevant to clinical trials, where changes over time in the treatment arm reflect background variability in progression observed in the placebo control arm plus variability in response to treatment, meaning that power calculations based only on the placebo arm covariance structure may be anticonservative. These more general power formulas are a useful resource for understanding the relative influence of these multiple factors on the efficiency of cohort studies and clinical trials, and for designing future trials under the random slopes and intercepts model.
... Subsequently, the practice began to take its modern form [35] . John Haygarth demonstrated the importance of a control group to correctly identify the placebo effect in his celebrated study of an ineffective remedy called Perkins Tractors [36] . Further work in that direction was conducted in the 1860s by the eminent physician Sir William Gull [36] . ...
... John Haygarth demonstrated the importance of a control group to correctly identify the placebo effect in his celebrated study of an ineffective remedy called Perkins Tractors [36] . Further work in that direction was conducted in the 1860s by the eminent physician Sir William Gull [36] . Frederick Akbar Mahomed, who was employed at Guy's Hospital in London, made substantial contributions to the clinical trial process when he distinguished chronic nephritis with secondary hypertension from what we now call essential hypertension [37] . ...
... Sir Ronald A. Fisher proposed the importance of randomization or the random assignment of individuals to different groups for an experiment [38] . In the 1930s, the British Medical Research Council (MRC) established the Therapeutic Trials Committee to advise and assist in arranging properly controlled clinical trials [36] . In 1943, the MRC conducted the first double-blind controlled trial of patulin for the common cold [33] . ...
Medical companies consider India is above other countries worldwide as an alternative nation for clinical trials due to easily available sources and infrastructure. However, the developing Indian clinical trial industry has been negatively affected by noncompliance with regulations and by reports of unethical trials. Several studies on Indian clinical trial regulations have been conducted and various articles have been published, but only a few researchers evaluated awareness of investigators and members of the ethics committee about previously amended regulations. No study evaluated the knowledge of researchers on the new drugs and clinical trial rules issued in 2019 and also its impacts. Understanding the knowledge of Indian researchers on new drugs and clinical trial rules, including its effect is crucial to determine whether the trials are being conducted in compliance with the new rules and regulations. Thus, this review aimed to evaluate India’s clinical trial regulatory changes based on the existing literature, Indian researcher’s knowledge of the recent changes, and assessment of the impact of the new 2019 regulations, elaborating upon clinical trials in both the global and the Indian context.
... First, the clinical trials are carried out by the investigators using a small number of volunteers or patients. [4][5][6] The number of patients is expanded as soon as encouraging results on safety and efficacy are gathered. In addition, the clinical trials were conducted across multiple nations. ...
... [7][8] Phase 0 trials are for pharmacodynamic and pharmacokinetic investigations; Phase I is for screening and safety; Phase II is for testing protocol establishment; Phase III is for final testing; and Phase IV is for post-approval research. [4][5][6] Furthermore, clinical trial stages are the procedures where researchers do experiments under healthy supervision to obtain adequate evidence for methods that proved beneficial as medical treatments. [9][10] Pharmaceutical research goes through several stages starting with drug design and discovery. ...
Clinical trial as defined by the World Health Organization, is any research studies that allocate people prospectively to one or more interventions related to health in order to assess the impact on health outcomes. Global adoption has occurred of the use of clinical trial technique. During the drug discovery process, clinical research plays a crucial role in ensuring the safety and effectiveness of novel medications. Clinical trials are now required in the global scientific era to introduce improved and novel medications to the market. Clinical trials evaluate possible treatments on human participants, or subjects, in order to determine whether or not they should be licensed for broader usage in the general public. The study addresses clinical trials, namely those conducted in India. Phase 0 to phase IV are the five stages into which clinical studies can be separated. With reference to drug trials, the current review is to explore the different stages of clinical trials and their characterization.
... 2) sham 161 and placebo treatment by H.G. Sutton in 1863 as reviewed by 162 ; 3) blinding between different interventions (at best subjects and experimenters: "double-blind") 163 ; and 4) randomization of subjects into intervention groups 164 . In the 20 th century applications were randomized and multicentre trials were established until the first RDBPCT was performed in 1980 162 . By now, clinical trials follow an established structure including design, funding, and protocol development before patient recruitment can actually start, and the various roles of contributors, e.g. ...
... After final treatment of the volunteers, follow-up and patient close-out are mandatory procedures prior to final study conclusion 162 . ...
An efficient and safe drug development process is crucial for the establishment of new drugs on the market aiming to increase quality of life and life-span of our patients. Despite technological advances in the past decade, successful launches of drug candidates per year remain low. We here give an overview about some of these advances and suggest improvements for implementation to boost preclinical and clinical drug development with a focus on the cardiovascular field.
We highlight advantages and disadvantages of animal experimentation and thoroughly review alternatives in the field of three-dimensional cell culture as well as preclinical use of spheroids and organoids. Microfluidic devices and their potential as organ-on-a-chip systems, as well as the use of living animal and human cardiac tissues are additionally introduced.
In the second part, we examine recent gold standard randomized clinical trials and present possible modifications to increase lead candidate throughput: adaptive designs, master protocols and drug repurposing. In silico and N-of-1 trials have the potential to redefine clinical drug candidate evaluation. Finally, we briefly discuss clinical trial designs during pandemic times.
... After the exact dosage level is determined, the drug candidate will go through phase IIB where the drug candidate will be determined for its efficacy in a larger population. 22 Phase III clinical trials confirm the efficacy of the drug being studied in a larger population, usually several hundred to several thousand volunteers/patients. Randomized and multicentric trials (conducted in several places) compare the drugs studied with the best treatment or standard of care for certain diseases. ...
... Phase IV clinical trials have significant implications, including changing drug labels, contraindications, interactions, and even withdrawal of drugs that are already marketed. 21,22 Drug Design, Development and Therapy 2020:14 submit your manuscript | www.dovepress.com ...
An infectious disease, COVID-19, caused by a new type of coronavirus, has been discovered recently. This disease can cause respiratory distress, fever, and fatigue. It still has no drug and vaccine for treatment and prevention. Therefore, WHO recommends that people should stay at home to reduce disease transmission. Due to the quarantine, FDA stated that this could hamper drug development clinical trial protocols. Hence, an alternative sampling method that can be applied at home is needed. Currently, volumetric absorptive microsampling (VAMS) has become attention in its use in clinical and bioanalytical fields. This paper discusses the advantages and challenges that might be found in the use of VAMS as an alternative sampling tool in clinical trials and therapeutic drug monitoring (TDM) during the COVID-19 pandemic. VAMS allows easy sampling, can be done at home, storage and delivery at room temperature, and the volume taken is small and minimally invasive. VAMS is also able to absorb a fixed volume that can increase the accuracy and precision of analytical methods, and reduce the hematocrit effects (HCT). The use of VAMS is expected to be implemented immediately in clinical trials and TDM during this pandemic considering the benefits it has.
... Shrout and Bolger (2002) posit that in the presence of a suppressing effect, the bivariate relationship between X and Y may not reflect the complexity of the causal relation between them. In this case, adjusting for the third variables (i.e., including NWGS as an independent variable in the equation) provides an undistorted estimate (Meinert, 1986). Therefore, the results from Figures 2 and 4, in which NWGS was controlled, provided a more accurate estimate of the effect of guilt on impression management. 2 We conducted an experimental study that further supported the proposed causal effect of NWGS on anxiety and guilt (see the Appendix for more details). ...
Drawing upon cognitive-motivational-relational theory, we offer a framework for understanding the mechanism underlying the effect of negative workplace gossip about supervisors (NWGS) on employees as gossip senders. We propose that NWGS can elicit two negative emotions, namely, anxiety and guilt, which further lead to employee behaviors that reflect avoidance and approach tendencies, respectively. We first tested these proposals in a survey study of graduate students (Study 1) and then replicated our findings among employees in the workplace (Study 2). In both studies, we found that NWGS is positively related to both anxiety and guilt, which in turn are linked to further avoidance-related workplace deviance and impression management directed toward the supervisor, respectively. Our results also show that the effects of NWGS on employees’ impression management through guilt are significant only when the employees score high on supervisors’ approval contingent self-worth. We discuss the implications of these results for managing workplace gossip in organizations.
... The harmonization of such a large, diverse team is central to the success of a study. Investigators must build a network of resource centers, common treatment and data collection protocols, and a coordinating center to receive and process study data [7]. The consortium expands even more with the addition of funding agency officers, internal and external committees, and vendors (e.g., central biorepositories, drug suppliers, and central pharmacies) (Fig. 2). ...
One challenge for multisite clinical trials is ensuring that the conditions of an informative trial are incorporated into all aspects of trial planning and execution. The multicenter model can provide the potential for a more informative environment, but it can also place a trial at risk of becoming uninformative due to lack of rigor, quality control, or effective recruitment, resulting in premature discontinuation and/or non-publication. Key factors that support informativeness are having the right team and resources during study planning and implementation and adequate funding to support performance activities. This communication draws on the experience of the National Center for Advancing Translational Science (NCATS) Trial Innovation Network (TIN) to develop approaches for enhancing the informativeness of clinical trials. We distilled this information into three principles: (1) assemble a diverse team, (2) leverage existing processes and systems, and (3) carefully consider budgets and contracts. The TIN, comprised of NCATS, three Trial Innovation Centers, a Recruitment Innovation Center, and 60+ CTSA Program hubs, provides resources to investigators who are proposing multicenter collaborations. In addition to sharing principles that support the informativeness of clinical trials, we highlight TIN-developed resources relevant for multicenter trial initiation and conduct.
... Randomising asymmetrically, for example, using a 2:1 treatment-to-control ratio is commonly used in drug trials, increasing the probability of a participant being assigned to active treatment and potentially improving recruitment at the expense of a small increase (12%) in overall sample size without compromising statistical integrity. 10 The approach also provides more data on the safety of a new therapy, although its appropriateness in confirmatory trials has been questioned. 11 ...
In the field of myopia control, effective optical or pharmaceutical therapies are now available to patients in many markets. This creates challenges for the conduct of placebo‐controlled, randomised clinical trials, including ethics, recruitment, retention, selective loss of faster progressors and non‐protocol treatments: Ethics: It is valid to question whether withholding treatment in control subjects is ethical.
Recruitment: Availability of treatments is making recruitment into clinical trials more difficult.
Retention: If masking is not possible, parents may immediately withdraw their child if randomised to no treatment.
Selective loss: Withdrawal of fast progressors in the control group leading to a control group biased towards low progression.
Non‐protocol treatment: Parents may access other myopia treatments in addition to those within the trial.
We propose that future trials may adopt one of the following designs: Non‐inferiority trials using an approved drug or device as the control. The choice will depend on whether a regulatory agency has approved the drug or device.
Short conventional efficacy trials where data are subsequently entered into a model created from previous clinical trials, which allows robust prediction of long‐term treatment efficacy from the initial efficacy.
Virtual control group trials based on data relating to axial elongation, myopia progression or both, accounting for subject's age and race.
Short‐term control data from a cohort, for example, 1 year or less, and applying an appropriate, proportional annual reduction in axial elongation to that population and extrapolating to subsequent years.
Time‐to‐treatment‐failure trials using survival analysis; once a treated or control subject progresses or elongates by a given amount, they exit the study and can be offered treatment.
In summary, the future development of new treatments in myopia control will be hampered if significant changes are not made to the design of clinical trials in this area.
... A clinical trial (CT) is an experiment on comparable groups of human beings which evaluates the efficacy of a treatment or medical intervention by comparing the effects with other testing treatments or control treatments (Meinert, 2012;Ramalhinho and Castelo-Branco, 2021). Participants volunteer to register in CT to test these interventions, such as drugs, cells and other biological products, surgical procedures, radiological procedures, devices, behavioral treatments, and preventive care (World Health Organization, 2020). ...
Context: Clinical trial is an experiment on comparable groups of human beings which evaluates the efficacy of a treatment or medical intervention by comparing the effects with other testing treatments or control treatments. Clinical trials help develop alternative treatment solutions or a preventative method for disease as well as support participants with medical and healthcare services during the trial period. Other benefits of clinical trials include gaining information, ensuring health issues, detecting early disease symptoms, and reducing medical services costs.
Aims: To evaluate willingness to participate (WTP) in clinical trials (CT) in Ho Chi Minh city and examine the factors associated with it.
Methods: A cross-sectional study was conducted through the online sampling method and gathered 581 valid responses during two weeks in February 2022.
Results: Among 581 respondents, 71.6% stated they were willing to participate in CT, while 48.2% stated that they would let their family enroll. WTP in CT was higher in participants of younger age, single, not having children, healthy, and without chronic disease. Vietnamese age was associated with WTP in CT.
Conclusions: Assessing WTP in CT helps state management agencies, organizations and research institutes design suitable CT models and increase the voluntary participation rate in CT.
... Randomised controlled trials (RCT) are a rigorous way of establishing the clinical effectiveness and safety of treatments for VLU [12,13]. However, for findings to be useful, the reported outcomes in RCTs need to be clinically meaningful, consistently reported across trials, and fully documented. ...
Background
Venous leg ulceration is a chronic, recurring, condition causing significant patient morbidity. Randomised controlled trials evaluating treatments for venous leg ulceration provide evidence for clinical decision-making. For trial findings to be useful, outcomes measured need to be clinically meaningful, and consistently and fully reported across trials.
A core outcome set is an agreed and standardised set of outcomes which should be, as a minimum, reported in all trials for a given indication.
Aim
To identify the outcome domains and outcomes reported in trials of interventions for venous leg ulceration.
Methods
A scoping review of the literature was carried out. Randomised controlled trials within Cochrane systematic reviews looking at venous leg ulceration interventions and qualitative studies exploring venous leg ulceration were included.
Results
The review identified 807 outcomes from randomised controlled trials and 15 outcomes from qualitative studies, and these were grouped into 11 outcome domains: healing, patient reported symptoms, clinician reported symptoms, carer reported symptoms, life impacts, clinical signs, clinical measurement, performance of the intervention, resource use (supplies and clinician time) and adverse events.
The outcome domain ‘healing’ included 111 outcomes, ‘symptoms’ 109, ‘life impacts’ 30, ‘clinical signs’ 88, ‘clinical measurement’ 184, ‘performance of the intervention’ 58, ‘resource use’ 52 and ‘adverse events’ 190.
Conclusion
The scoping review identified a large number of outcomes (n = 822) across 11 related outcome domains, supporting the need for a core outcome set.
... Researchers also need to stay current on the growing number of available novel designs when simpler designs cannot answer the research question, and understand how to appropriately select, execute, and analyze results from them. Many textbooks on clinical and experimental research design in the behavioral health sciences emphasize "conventional" experimental or quasi-experimental designs, including (but not limited to) two-group parallel arm, factorial, withdrawal, crossover, and pragmatic trial designs (Friedman et al. 2010;Shadish, Campbell, and Cook 2001;Windsor et al. 2001;Meinert 1986). While such designs are essential to the experimentalist's toolkit, novel or less well-known variations on these designs may be useful. ...
To date, nutritional epidemiology has relied heavily on relatively weak methods including simple observational designs and substandard measurements. Despite low internal validity and other sources of bias, claims of causality are made commonly in this literature. Nutritional epidemiology investigations can be improved through greater scientific rigor and adherence to scientific reporting commensurate with research methods used. Some commentators advocate jettisoning nutritional epidemiology entirely, perhaps believing improvements are impossible. Still others support only normative refinements. But neither abolition nor minor tweaks are appropriate. Nutritional epidemiology, in its present state, offers utility, yet also needs marked, reformational renovation. Changing the status quo will require ongoing, unflinching scrutiny of research questions, practices, and reporting-and a willingness to admit that "good enough" is no longer good enough. As such, a workshop entitled "Toward more rigorous and informative nutritional epidemiology: the rational space between dismissal and defense of the status quo" was held from July 15 to August 14, 2020. This virtual symposium focused on: (1) Stronger Designs, (2) Stronger Measurement, (3) Stronger Analyses, and (4) Stronger Execution and Reporting. Participants from several leading academic institutions explored existing, evolving, and new better practices, tools, and techniques to collaboratively advance specific recommendations for strengthening nutritional epidemiology.
... A computer-generated allocation algorithm [25] was inserted in the application for the integrated management of breast cancer screening of the L.H.U. Women who turned out to have a negative screening episode and were eligible for the study were consecutively allocated (1:1) to the short communication or to the detailed information study arm according to the random list. ...
Women attending mammography screening may benefit from family history (FH) assessment for the identification of Hereditary Breast Ovarian Cancer (HBOC). Few studies explored the efficacy of tailored educational interventions in driving the attention on FH-associated risk among these women. To compare the efficacy of two educational tools in increasing attention towards FH, 6.802 women with a negative mammography were randomized to receive a note on FH of breast/ovarian cancer (letter A, n = 3.402) or a note with details on possible implication of FH patterns (letter B, n = 3.200). Upon women’s request, a brief questionnaire was administered on phone at the Screening Unit (S.U.) to select those eligible for an in-depth FH evaluation at the Genetic Unit (G.U.). Each affected relative was scored 1–3 according to type of cancer, age at diagnosis, gender, position in the family tree. In all, 401 women contacted the S.U.: 244 (6.6%) in group A and 177 (5.2%) in group B (adjOR 1.27; 95%CI 1.03–1.56). FH scored ≥ 3 for 164 women: 177 (47.5%) in group B and 224 (35.7%) in group A, (adjOR 1.59, 95%CI 1.06–2.38). The G.U. traced and interviewed 148 women, 65 (43.9%) were offered an in-person consultation: 38 attended and 30 were eligible for testing. A test was performed for 24 women: no BRCA pathogenic variant was found. Among mammographic screening attendees, educational material with a simple description of FH may improve self-referral of women deserving an in-depth evaluation for HBOC identification. Additional educational efforts are needed to enhance the efficiency of the intervention.
... Longer block size will help to protect against predicting the treatment sequence. 62 Therefore, block randomization will be used with a block size of 6 in this study. An independent statistician who will not participate in any other parts of the study will generate the random sequence. ...
Purpose:
This paper reports the methodology for undertaking a randomized controlled trial to assess the combined effect of cognitive behavioral therapy (CBT) and activity pacing on fatigue experienced by breast cancer patients undergoing chemotherapy.
Method:
Fifty-eight patients experiencing severe fatigue will be randomized to a CBT group or usual care group. The intervention will be given for 6 sessions by a trained oncology nurse. Primary and secondary outcome measures will be assessed at baseline, the sixth week of intervention and at the third month post intervention. The primary outcome measure is fatigue (Brief Fatigue Inventory) and secondary outcome measures include depression (Patient Health Questionnaire) and quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire). The protocol is designed using the SPIRIT guidelines which is one of the EQUATOR checklists.
Discussion:
This is the first RCT that will determine the efficacy of CBT by integrating with activity pacing to reduce fatigue among breast cancer patients receiving chemotherapy. The intervention design is novel in addressing multiple precipitating and perpetuating factors of fatigue and integrated with activity pacing in CBT.
Conclusion:
If the intervention is effective, this therapeutic approach can be incorporated into a routine health care for breast cancer patients receiving chemotherapy.
Trial registration:
The study have been registered in Pan-African Clinical Trial Registry (website) on August 24, 2020. The trial registration number is PACTR202008881026130.
... Given that the development of clinical research goes in the direction of targeting specific groups of patients, which entails the problem of a potentially small number of subjects in studies, multicenter studies are becoming even more significant as a tool to provide a sufficient number of subjects in such studies [27][28][29][30] . The importance of the new Regulation is reflected in the fact that the harmonization of requirements for the conduct of clinical trials across the European Union sets the basis for facilitating the conduct of multicenter trials. ...
... A two-tailed t-test was used to compare the arch height, arch height ratio, navicular drop, rearfoot eversion, AI of arch height, AI of arch height ratio, AI of navicular drop, and AI of rearfoot eversion between PRE and POST the marathon. The Bonferroni correction adjusted the significance level at p < 0.006 because of the increased risk of Type I error (Meinert & Oxford University, P 2012). The effect sizes (Pearson's r) were interpreted following the Cohen's guideline (Cohen, 1988). ...
Long-distance running results in lowering of the foot medial longitudinal arch, but it is unknown whether the left and right arches decrease equally. This study aimed to determine whether foot arch asymmetry increases upon completion of a full marathon and to identify factors capable of explaining the degree of asymmetry of navicular height and navicular height displacement. The three-dimensional foot posture data of 74 collegiate runners were obtained using an optical foot scanner system before (PRE) and immediately after (POST) a full marathon. The navicular height and arch height ratio (normalised navicular height by foot length) of both feet significantly decreased from PRE to POST full marathon completion (44.3 ± 6.3 mm versus 40.8 ± 6.5 mm, 17.8 ± 2.5 versus 16.6 ± 2.7, respectively; p < 0.001, both). The asymmetry of the arch height ratio was significantly greater POST than PRE marathon. Multiple linear regression analysis indicated that the POST-race Asymmetry Index (AI) of navicular height was significantly predicted by the PRE-race AI of navicular height; navicular height displacement was predicted by PRE-race navicular height and the marathon time. Full marathon running induced increasing asymmetry and lowering of the medial longitudinal arch in runners.
... More formally, restricted allocation procedures work to correct the limitations of simple random assignment (see Lachin, 1988b;Lipsey, 2002;Meinert & Tonascia, 1986). In these procedures, the researcher still uses randomisation, but in a more structured way (Friedman et al., 1985) -hence the name: a 'restriction' on the pureness of the random allocation of all cases in the pool. ...
The fourth book in The SAGE Quantitative Research Kit, this resource covers the basics of designing and conducting basic experiments, outlining the various types of experimental designs available to researchers, while providing step-by-step guidance on how to conduct your own experiment.
As well as an in-depth discussion of Random Controlled Trials (RCTs), this text highlights effective alternatives to this method and includes practical steps on how to successfully adopt them. Topics include:
· The advantages of randomisation
· How to avoid common design pitfalls that reduce the validity of experiments
· How to maintain controlled settings and pilot tests
· How to conduct quasi-experiments when RCTs are not an option
Practical and succinctly written, this book will give you the know-how and confidence needed to succeed on your quantitative research journey.
... Confounding refers to a relationship between an intervention and outcome that is falsely obscured or accentuated by a third variable, which often is a characteristic of participants (Meinert, 1986). In impact evaluation research, the differences in outcome measures between treatment and comparison groups can systematically differ due to confounding variables. ...
Given calls for more rigorous research able to measure the impact of entrepreneurship education, this study proposes guidelines for enhancing methodological and reporting practices. First, drawing on prior research syntheses, we developed a descriptive validity framework that outlines key elements for rigorous evaluation research. Second, we use this framework to examine 61 quantitative, university-based entrepreneurship education impact studies to identify and describe methodological and reporting practices that are most prevalent. The result is a set of Impact Evaluation Research Standards for entrepreneurship educators and scholars wishing to improve education evaluation research.
... Calculating even a few correlation coefficients increases risk of a type I error (Curtin & Schulz, 1998). For this reason, when looking for significant correlations, to keep the overall-alpha at 5%, the alpha'level of each correlation must be divided by k (Meinert, 1986). Correlation sizes were interpreted following recommendations by Cohen (1992), with correlation coefficients of 0.10, 0.30, and 0.50 representing low, medium and high effect sizes, respectively. ...
The current investigation tested life satisfaction (LS), a cognitive component of subjective well-being, among emerging adults, in the context of individualism (I) and collectivism (C), by distinguishing both cultural and individual levels of analysis, considering their horizontal (H) and vertical (V) dimensions, and controlling age and gender effects. Emerging adults (N = 1760 university students, aged 18-25, Mage = 19.46, SDag = 1.50) located across four countries, namely China, Italy, Russia, and the USA, known to differ in the individualism index value (IDV), completed measures on the Horizontal and Vertical Individualism and Collectivism and Life Satisfaction. At the cultural level, an ANCOVA showed a significant country effects on LS. The post hoc comparisons indicated that the higher the country IDV score, the higher the average LS score, in the following order: Americans, Italians, Russians, and Chinese. At the individual level, LS was unrelated to HI and VI. Instead, it was associated with HC and VC. The positive link between LS and VC suggested an important role of family connectedness on LS across different cultures during emerging adulthood. However, contrary to previous studies, LS was unrelated to HI and VI.
... Elementary clinical trials have been conducted for hundreds of years (Meinert & Tonascia, 1986). The most famous early example is the proof that sailors' scurvy can be cured by the consumption of citrus fruit (Lind, 2014) performed by James Lind in the 18th century. ...
Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n = 120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n = 80), and 2) sham: deactivated negative ion generator (n = 40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in <10% of those enrolled, incomplete/missing data was present in <15% of key outcome variables, and overall fidelity adherence to the intervention was >85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.
Echogenic needles improve the reflection of the ultrasound beam. The aim of the study was to compare needle performance during ultrasound-guided cannulation of the infraclavicular axillary vein with an in-plane needle approach, using echogenic needles or non-echogenic standard needles. One hundred adult patients undergoing surgical procedures that required a central venous catheter were randomized for either echogenic or non-echogenic needles. The primary outcome was access time. Secondary outcomes encompassed total procedure time, success in first attempt, number of attempts, number of skin punctures, change of site for vascular access, catheter placement, subjective experience with needle visualization and needle procedure, and adverse events. Median (IQR) [range] venous access time was 21 (15–56) [6–440] in echogenic needle group and 26 (14–91) [6–925] in the non-echogenic needle group (p = 0.40). No statistically significant differences were found in the secondary outcome measures. One patient (non-echogenic needle group) experienced pneumothorax. In three patients in each group (6%) arterial puncture occurred. Echogenic needles did not significantly improve needle control or safety when used for infraclavicular axillary vein cannulation with an in-plane needle approach. The results indicate that standard needles are appropriate for ultrasound guided subclavian vascular access in a perioperative situation.
Background:
In medical education, the teaching of the concept of “placebo response” prevails without recognizing that the clinical responses that occur are due to the patient’s meanings and that they cannot be produced by inert substances.
Objective:
To explore the learning, opinions, and meanings about the concept of “response to meaning” and its contrast with the idea of response to placebo among the participating residents.
Materials and methods:
A qualitative study was carried out with design and analysis in accordance with the grounded theory. Three family medicine residents red and discussed in a Balint group an article that criticizes the concept of response to placebo and that proposes the concept of response to meaning. The group discussions carried out were recorded, transcribed, and coded according with the grounded theory method.
Results:
The residents could describe the concept of response to meaning and described their version of its components based on their experiences with patients.
Conclusions:
The response to meaning is generated by empathic at-tention, focusing on the person, appropriate communication and generating trust; it is influenced by culture and its character is changing. The meaning is powerful for doctor and patient, training is required in this regard, the doctor must accept that patients respond clinically to the meanings of the doctor-patient relationship and that this should be as horizontal as possible.
It is perhaps most useful to approach the Doctor-Patient relationship (DPR) by admitting that it’s complicated. We review some of the strategies that have been employed to mitigate this complexity, zeroing in on one that promises to capture the main features of the DPR without eliminating some of its more important, existential components; pieces of the puzzle that must be retained if we are to avoid oversimplification and the errors that can arise by ignoring important foundational properties. We believe that a useful way to look at the DPR and to capture essential features that must be balanced in the process is provided by Partnership Theory and its definition in terms of the so-called domination and partnership systems. We apply this theory to the DPR and investigate the implications of this application to health care. We see that in the absence of mitigating circumstances, adoption of the patient-as-partner model serves healthcare well and is flexible enough to accommodate circumstances that dictate modifications.
Research has argued that the symbolic benefits of bureaucratic representation for marginalized social groups may come at the expense of the attitudes of the majority group. In this study, we investigate whether recategorization—that is, reframing previously separate groups as an inclusive common ingroup—can shift the majority group's perception of bureaucratic representation from a threat to a benefit. We conducted two vignette experiments with a representative sample of U.S. adults (n = 1,040), in which we tested the same treatments in two policy domains: policing and healthcare. The results support our main hypothesis in the policing context. The effect of police chiefs’ race being African American on white respondents’ trust in the chief shifted from negative to positive when the chiefs portrayed African Americans discriminated by the police as members of American community, a superordinate common ingroup that encompasses every race, rather than simply as African Americans.
Introduction
Ready-to-use therapeutic foods (RUTFs) have successfully promoted recovery from severe wasting and increased treatment coverage. However, RUTFs do not sufficiently improve linear growth, leaving many survivors of severe wasting at risk of persistent stunting, which is associated with high mortality risk, poor child development and non-communicable diseases in adulthood. High protein quantity and quality can stimulate linear growth.
Aim
The trial aims to assess whether higher-protein-RUTF leads to higher concentrations of markers of linear growth compared to standard RUTF among 6–23 months old children with severe wasting.
Methods
We designed a higher protein quantity and quality RUTF for a proof-of-concept (PoC) double-blind randomized controlled trial.
Outcomes
The primary outcome is a change in insulin-like growth factor-1 (IGF-1), a hormone positively associated with linear growth after four weeks of treatment. Secondary outcomes include changes in ponderal and linear growth and in body composition from baseline to eight weeks later; plasma amino acid profile at four weeks; acceptability and safety.
Implications
These findings will help in informing the potential impact of increased protein in RUTF on linear growth when treating severe wasting towards conducting a larger clinical trial.
Trial registration
The trial has been registered on clinicaltrial.gov (NCT05737472).
Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.
Background:
Older adult Veterans are at high risk for adverse health outcomes following hospitalization. Since physical function is one of the largest potentially modifiable risk factors for adverse health outcomes, our purpose was to determine if progressive, high-intensity resistance training in home health physical therapy (PT) improves physical function in Veterans more than standardized home health PT and to determine if the high-intensity program was comparably safe, defined as having a similar number of adverse events.
Methods:
We enrolled Veterans and their spouses during an acute hospitalization who were recommended to receive home health care on discharge because of physical deconditioning. We excluded individuals who had contraindications to high-intensity resistance training. A total of 150 participants were randomized 1:1 to either (1) a progressive, high-intensity (PHIT) PT intervention or (2) a standardized PT intervention (comparison group). All participants in both groups were assigned to receive 12 visits (3 visits/week over 30 days) in their home. The primary outcome was gait speed at 60 days. Secondary outcomes included adverse events (rehospitalizations, emergency department visits, falls and deaths after 30 and 60-days), gait speed, Modified Physical Performance Test, Timed Up-and-Go, Short Physical Performance Battery, muscle strength, Life-Space Mobility assessment, Veterans RAND 12-item Health Survey, Saint Louis University Mental Status exam, and step counts at 30, 60, 90, 180 days post-randomization.
Results:
There were no differences between groups in gait speed at 60 days, and no significant differences in adverse events between groups at either time point. Similarly, physical performance measures and patient reported outcomes were not different at any time point. Notably, participants in both groups experienced increases in gait speed that met or exceeded established clinically important thresholds.
Conclusions:
Among older adult Veterans with hospital-associated deconditioning and multimorbidity, high-intensity home health PT was safe and effective in improving physical function, but not found to be more effective than a standardized PT program.
Consumer-based voice assistants have the ability to deliver evidence-based treatment, but their therapeutic potential is largely unknown. In a pilot trial of a virtual voice-based coach, Lumen, delivering problem-solving treatment, adults with mild-to-moderate depression and/or anxiety were randomized to the Lumen intervention (n = 42) or waitlist control (n = 21). The main outcomes included changes in neural measures of emotional reactivity and cognitive control, and Hospital Anxiety and Depression Scale [HADS] symptom scores over 16 weeks. Participants were 37.8 years (SD = 12.4), 68% women, 25% Black, 24% Latino, and 11% Asian. Activation of the right dlPFC (neural region of interest in cognitive control) decreased in the intervention group but increased in the control group, with an effect size meeting the prespecified threshold for a meaningful effect (Cohen’s d = 0.3). Between-group differences in the change in activation of the left dlPFC and bilateral amygdala were observed, but were of smaller magnitude (d = 0.2). Change in right dlPFC activation was also meaningfully associated (r ≥ 0.4) with changes in self-reported problem-solving ability and avoidance in the intervention. Lumen intervention also led to decreased HADS depression, anxiety, and overall psychological distress scores, with medium effect sizes (Cohen’s d = 0.49, 0.51, and 0.55, respectively), compared with the waitlist control group. This pilot trial showed promising effects of a novel digital mental health intervention on cognitive control using neuroimaging and depression and anxiety symptoms, providing foundational evidence for a future confirmatory study.
Objective:
The aim of this study was to investigate the influence of morning versus evening exercise on weight loss, cardiometabolic health, and components of energy balance.
Methods:
A total of 100 inactive adults with overweight or obesity were randomized to morning exercise (AMEx; 06:00-09:00), evening exercise (PMEx; 16:00-19:00), or wait-list control (CON). AMEx and PMEx were prescribed 250 min·wk-1 of self-paced aerobic exercise for 12 weeks. Anthropometry and body composition, physical activity, and dietary intake were assessed at baseline, 6 weeks, and 12 weeks. Cardiorespiratory fitness (V̇O2 peak), resting metabolic rate, and blood markers were assessed at baseline and 12 weeks. Body composition and V̇O2 peak were also measured at 3- and 6-month follow-up.
Results:
AMEx and PMEx lost weight during the intervention (mean [SD], AMEx, -2.7 [2.5] kg, p < 0.001; PMEx, -3.1 [3.4] kg, p < 0.001). V̇O2 peak significantly increased in both intervention groups, and these changes were different from CON (AMEx, +4.7 mL·kg-1 ·min-1 , p = 0.034; PMEx, +4.2 mL·kg-1 ·min-1 , p = 0.045). There were no between-group differences for resting metabolic rate or physical activity. At 12 weeks, total energy intake was significantly reduced in both AMEx and PMEx versus CON (AMEx, -3974 kJ, p < 0.001; PMEx, -3165 kJ, p = 0.001).
Conclusions:
Adults with overweight and obesity experience modest weight loss in response to an exercise program, but there does not appear to be an optimal time to exercise.
Importance
To our knowledge, there are no published randomized clinical trials of recruitment strategies. Rigorously evaluated successful recruitment strategies for children are needed.
Objective
To evaluate the feasibility of 2 recruitment methods for enrolling rural children through primary care clinics to assess whether either or both methods are sufficiently effective for enrolling participants into a clinical trial of a behavioral telehealth intervention for children with overweight or obesity.
Design, Setting, and Participants
This cluster-randomized clinical trial of 2 recruitment methods was conducted at 4 primary care clinics in 4 separate states. Each clinic used both recruitment methods in random order. Clinic eligibility criteria included at least 40% pediatric patients with Medicaid coverage and at least 100 potential participants. Eligibility criteria for children included a rural home address, age 6 to 11 years, and body mass index at or above the 85th percentile. Recruitment began February 3, 2020, and randomization of participants occurred on August 17, 2020. Data were analyzed from October 3, 2021, to April 21, 2022.
Interventions
Two recruitment methods were assessed: the active method, for which a list of potential participants seen within the past year at each clinic was generated through the electronic health record and consecutively approached by research staff based on visit date to the clinic, and the traditional method, for which recruitment included posters, flyers, social media, and press release. Clinics were randomized to the order in which the 2 methods were implemented in 4-week periods, followed by a 4-week catch-up period using the method found most effective in previous periods.
Main Outcomes and Measures
For each recruitment method, the number and proportion of randomized children among those who were approached was calculated.
Results
A total of 104 participants were randomized (58 girls [55.8%]; mean age, 9.3 [95% CI, 9.0-9.6] years). Using the active method, 535 child-parent dyads were approached and 99 (18.5% [95% CI, 15.3%-22.1%]) were randomized. Using the traditional method, 23 caregivers expressed interest, and 5 (21.7% [95% CI, 7.5%-43.7%]) were randomized. All sites reached full enrollment using the active method and no sites achieved full enrollment using the traditional method. Mean time to full enrollment was 26.3 (range, 21.0-31.0) days.
Conclusions and Relevance
This study supports the use of the active approach with local primary care clinics to recruit children with overweight and obesity from rural communities into clinical trials.
Trial Registration
ClinicalTrials.gov Identifier: NCT04142034
A parallel process growth model is often limited to the developments of two main trends due to model complexity. Two major parallel processes are only modeled to examine how the changes in two longitudinal processes might be related without considering other growth models possibly related to the two main processes. However, the exclusion of a third LGM risks introducing bias into key associations while capturing the relations between only two growth processes, since they are not controlled. This study presents a method to address the effect of spurious relationship while minimizing convergence issues when other processes are not considered. The suggested method utilizes the factor score estimates for other relevant growth models to control the spurious effect. Results revealed the superiority of the parallel process model using the factor scores over the typical parallel process model and illustrated the importance of considering growth models relevant to the parallel process model.
Translating laboratory discoveries into successful therapeutics can be difficult. Clinical Trials in Neurology aims to improve the efficiency of clinical trials and the development of interventions in order to enhance the development of new treatments for neurologic diseases. It introduces the reader to the key concepts underpinning trials in the neurosciences. This volume tackles the challenges of developing therapies for neurologic disorders from measurement of agents in the nervous system to the progression of clinical signs and symptoms through illustrating specific study designs and their applications to different therapeutic areas. Clinical Trials in Neurology covers key issues in Phase I, II and III clinical trials, as well as post-marketing safety surveillance. Topics addressed include regulatory and implementation issues, outcome measures and common problems in drug development. Written by a multidisciplinary team, this comprehensive guide is essential reading for neurologists, psychiatrists, neurosurgeons, neuroscientists, statisticians and clinical researchers in the pharmaceutical industry.
Experimental criminology is a part of a larger and increasingly expanding scientific research and evidence-based movement in social policy. The essays in this volume report on new and innovative contributions that experimental criminology is making to basic scientific knowledge and public policy. Contributors explore cutting-edge experimental and quasi-experimental methods and their application to important and topical issues in criminology and criminal justice, including neurological predictors of violence, peer influence on delinquency, routine activities and capable guardianship, early childhood prevention programs, hot spots policing, and correctional treatment for juvenile and adult offenders. It is the first book to examine the full scope of experimental criminology, from experimental tests - in the field and in the laboratory - of criminological theories and concepts to experimental and quasi-experimental evaluations of crime prevention and criminal justice interventions.
Proactivity at work is generally assumed to be preceded by positive motivational states with positive outcomes for employees. However, recent perspectives suggest downsides to proactive behavior, including that it can be driven by negative emotions or experienced as depleting for employees. Bringing these previously disconnected ideas together, we utilize cognitive-motivational-relational and self-determination theories to holistically examine the negative antecedents of proactivity and its outcomes. We argue that employees, particularly those with high impression management motives, experience burnout when financial precarity and fear drive them to proactively learn new skills. We test and show support for these hypotheses in a four-wave study of 1,315 university employees during the beginning of the COVID-19 pandemic, an external event that threatened employees’ financial security. Theoretically, our findings broaden our understanding of the antecedents and consequences of proactivity, while expanding the role of fear at work beyond “flight” responses to include motivating protective effort. Practically, our findings help to understand both how employees proactively develop their skills in light of financial precarity and how these proactive efforts are experienced as depleting.
Publication of findings in a scientific journal, in an electronic or print format, is an obligation of those who conduct clinical trials, whether as investigators or sponsors. The process of preparing manuscripts for publication in the multicenter, multidisciplinary setting typically is subject to the trial’s publication policy that may specify authorship models, internal review, and approval, creation and expectations of writing teams, and dissemination of findings before journal publication. Publication in a peer-reviewed, indexed journal validates the design, methods, and findings of the study for dissemination to the healthcare community. The focus of this chapter is on practices commonly followed in publicly funded multicenter randomized clinical trials and may not address issues and policies commonly found in trials with industry sponsorship.
After clinical trial participants have consented, provided baseline data, and been randomized, each participant begins study treatment and follow-up. This chapter covers administering a participant’s randomly assigned treatment regimen and collecting the participant’s trial data through the end of their time in the study, along with tracking and reporting data on timeliness and quality of treatment administration and of follow-up visit attendance and trial data collection. Treatment administration can include providing study medications or, in a lifestyle intervention trial, teaching the participant to follow a diet, exercise, or smoking cessation intervention. Trial data collection includes, for example, questionnaires completed via smartphone, laboratory sample collection details and results of lab analyses, imaging data, treatment adherence data, measurements taken at clinic visits, and adverse event data. Monitoring participant follow-up and capturing reasons why patients discontinue treatment or end follow-up early can aid in interpretation of a trial’s results. Treatment administration, treatment adherence, and participant follow-up metrics should be captured in real time, with the Data Coordinating Center (DCC) providing continuous performance feedback to study leadership and to the participating sites themselves. These aspects of trial conduct are described in the context of a multicenter trial in which two or more clinical sites enroll participants and study data are managed in a centrally administered database. Timeliness and accuracy of study treatment administration is key to the success of a trial. Participants providing required data according to the protocol-defined schedule allow a trial to attain its goals.
Data capture, data management, and quality control processes are instrumental to the conduct of clinical trials. Obtaining quality data requires numerous considerations throughout the life cycle of the trial. Case report form design and data capture methodology are crucial components that ensure data are collected in a streamlined and accurate manner. Robust data quality and validation strategies must be employed early on in data collection to identify potential systemic errors. Data management guidance documents provide an opportunity to set clear expectations for stakeholders and establish communication pathways. These tools need to be supplemented with adequate training and ongoing support of trial staff. Trials may be conducted in a single or multicenter setting, which has implications for data management. Risk-based monitoring is one approach that can help data managers target quality issues in a multicenter setting. Evolving technologies such as electronic medical record and electronic data capture system integration, artificial intelligence, and big data analytics are changing the landscape of data capture and management.
Background:
The SINODAR-ONE trial is a prospective noninferiority multicenter randomized study aimed at assessing the role of axillary lymph node dissection (ALND) in patients undergoing either breast-conserving surgery or mastectomy for T1-2 breast cancer (BC) and presenting one or two macrometastatic sentinel lymph nodes (SLNs). The endpoints were to evaluate whether SLN biopsy (SLNB) only was associated with worsening of the prognosis compared with ALND in terms of overall survival (OS) and relapse.
Methods:
Patients were randomly assigned (1:1 ratio) to either removal of ≥ 10 axillary level I/II non-SLNs followed by adjuvant therapy (standard arm) or no further axillary treatment (experimental arm).
Results:
The trial started in April 2015 and ceased in April 2020, involving 889 patients. Median follow-up was 34.0 months. There were eight deaths (ALND, 4; SNLB only, 4), with 5-year cumulative mortality of 5.8% and 2.1% in the standard and experimental arm, respectively (p = 0.984). There were 26 recurrences (ALND 11; SNLB only, 15), with 5-year cumulative incidence of recurrence of 6.9% and 3.3% in the standard and experimental arm, respectively (p = 0.444). Only one axillary lymph node recurrence was observed in each arm. The 5-year OS rates were 98.9% and 98.8%, in the ALND and SNLB-only arm, respectively (p = 0.936).
Conclusions:
The 3-year survival and relapse rates of T1-2 BC patients with one or two macrometastatic SLNs treated with SLNB only, and adjuvant therapy, were not inferior to those of patients treated with ALND. These results do not support the use of routine ALND.
Minimization is among the most common methods for controlling baseline covariate imbalance at the randomization phase of clinical trials. Previous studies have found that minimization does not preserve allocation randomness as well as other methods, such as minimal sufficient balance, making it more vulnerable to allocation predictability and selection bias. Additionally, minimization has been shown in simulation studies to inadequately control serious covariate imbalances when modest biased coin probabilities (≤0.65) are used. This current study extends the investigation of randomization methods to the analysis phase, comparing the impact of treatment allocation methods on power and bias in estimating treatment effects on a binary outcome using logistic regression. Power and bias in the estimation of treatment effect was found to be comparable across complete randomization, minimization, and minimal sufficient balance in unadjusted analyses. Further, minimal sufficient balance was found to have the most modest impact on power and the least bias in covariate-adjusted analyses. The minimal sufficient balance method is recommended for use in clinical trials as an alternative to minimization when covariate-adaptive subject randomization takes place.
This chapter applies the above-outlined conceptual framework to examine whether and to what extent de facto exclusive control over IPD can be justified as a means of internalising R&D externalities. The analysis seeks to define and qualitatively weigh up innovation-related benefits and costs of exclusive control over vis-à-vis unrestricted access to IPD as a knowledge resource for research and innovation. The policy conclusion is drawn as to whether regulatory intervention by access measures can be justified on the grounds of promoting drug innovation.
Proponents of access to data argued that secondary analyses of clinical trial data—especially individual patient-level data—can generate knowledge far beyond original research hypotheses and the benefit-risk profile of investigational products. The chapter explores this proposition. Admittedly, such task goes beyond a legal inquiry. However, without a detailed understanding of the role of secondary IPD analysis in medical research and drug R&D, arguments—both de lege lata and de lege ferenda—regarding the applicable legal framework lack a substantive basis. The overview of potential implications of secondary IPD analysis presented here is by no means exhaustive. Instead, insights drawn from the general medical literature are systematised to inform and illustrate the subsequent legal analysis.
Background/purpose: Few studies have detailed the awareness and opinions of investigators and the ethics member about the past rules. However, no study studies the perception and perspectives of Indian researchers about the latest drugs and clinical trial rules 2019 (NDCTR-19). The purpose of the current research is to address this limitation. Methods: A web-based online survey was developed using a widely accepted Google form with an already validated questionnaire based on the Checklist for Reporting Results of Internet E-Surveys. A web link was created for participants to perceive the survey. The data was collected by sending the link to various researchers across India between July 2019 and September 2019. The perception and perspectives of Indian researchers were described in the count (%) and means (standard deviations). Results: Of 106 researchers, 75 (70.8%) had a perception of the NDCTR-19, including from all zones (100%, p <.0001). The modification in the timeline, open post-trial drug passage, and welcoming equality were accepted by 36 (63.2%), 32 (53.1%), and 31 (54.5%), respectively. The recent advances in severe adverse effects and compensation were accepted by 37 (64.9%). Also, most reported that sharing the NDCTR-19 with other researchers, especially from the central zone, said that the NDCTR-19 would change the working environment (100%, p <.0001, respectively). Conclusion: The results indicate that the NDCTR-19 can facilitate speed-up trials and extend India's pharma industry. The findings will be of interest to the investigators and pharmaceutical companies' stakeholders at national and international levels.
Precision refers to a mode of action, being exact and accurate, while personalized refers to attention to an individual person. Optimally treatment should be both precise and personalized. Each individual is different. Patients live in a very complex social, civic, cultural, economic, religious, and philosophic environment. Treating physicians must understand and diagnose the cause of the patient’s symptoms and illness in as much detail as possible. They also must understand the person and the milieu. A very detailed history, physical and neurological examination, laboratory testing, and technological advances in brain and vascular imaging now make it possible for physicians to acquire the data needed to be able to direct management to complex individual patients. Randomized trials, the basis of the so-called evidence-based medicine, yield general information but often do not provide a road map to treat individual patients.
PERCEPTION OF RISK FACTORS IN WORK ACCIDENTS ANALYSIS: A STUDY IN AN INDUSTRIAL DEVELOPED CITY IN A SOUTH-EASTERN STATE IN BRAZIL, 1992-1993.
Key words: Accidents-Occupational-Prevention-and-control; Risk factors; Case-control studies; occupational injuries; accident epidemiology; musculoskeletal injuries; epidemiologic methods; social perception; stress, psychological; retrospective studies; regression analysis.
A B S T R A C T
A case-control study was performed based on 164 cases of randomly selected work-related accidents and 325 controls amongst employees of private or publicly owned firms, in Campinas, São Paulo, 1992-93. The main objective was developing and validating an specific data collection instrument for perceived psycho-social risks for work accidents with injuries recalling the last seven days. A questionnaire with 29 questions to be answered marking a visual analogue scale was built. Using logistic regression eight variables were found to discriminate cases from controls and were subsequently modeled. Having fought with superiors; having witnessed catastrophic events in the workplace; having been a victim of aggression outside the workplace; leaving an ill family member at home; having suffered police questioning because of accusations by neighbors or others and having self problems with health were found to be aggressive. Protective variables were time experience under the job title and point out having worked on undesirable tasks. Incident cases were used to simulate a retrospective cohort. A survival regression analysis was found to fit an exponential model. Variables in this model which increased risk were: death of a beloved person; having criticized the precariousness of safety conditions at work and "other factors regarding relationships with superiors and the process of production". A short time to failure was found associated with the interaction between "having fought with a superior and "having criticized equipment". Protective association was found with point out the lack of safety measures and training and the interaction between the variables "having fought with a superior" and "having an ill family member at home". The perceptions of individual workers of key aspects of the psycho-social relations within the workplace, are related to factors which confer greater or lesser risk to workers. These perceptions may be obtained using a single instrument for epidemiologic data collection.
Background
The role of androgen deprivation therapy (ADT) in combination with radiotherapy (RT) in intermediate-risk prostate cancer (IRPC) remains controversial, particularly in patients receiving dose-escalated RT (DERT). We compared outcomes between patients with IRPC treated with ADT and two different doses of RT vs. RT alone.
Methods
From December 2000 to September 2010, 600 patients with IRPC were randomised to a three-arm trial consisting of 6 months of ADT plus RT 70 Gy (ADT + RT70) vs. ADT plus a DERT of 76 Gy (ADT + DERT76) vs. DERT of 76 Gy alone (DERT76). Primary end-point was biochemical failure (BF), and secondary end-points were overall survival (OS) and toxicity. RT toxicity was assessed by Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria.
Findings
With a median follow-up of 11.3 years (interquartile range: 10.9–11.7), patients receiving DERT76 alone, compared with patients receiving ADT + RT70 and ADT + DERT76, had higher rates of BF (32%, 18% and 14%, respectively, p < 0.001), higher rates of prostate cancer progression (12%, 4.5% and 3.3%, respectively, p = 0.001) and more deaths due to prostate cancer (6.5%, 3.0% and 1.5%, respectively, p = 0.03) with no significant difference seen between ADT + RT70 and ADT + DERT76. There was no significant difference in OS between the 3 arms. A higher dose of RT (76 Gy) increased late gastrointestinal (GI) toxicity grade ≥ II compared with lower dose (70 Gy) (16% vs 5.3%, p < 0.001) with no statistical difference for late genitourinary toxicity.
Interpretation
In IRPC, the addition of 6 months of ADT to RT70 or DERT76 significantly improves BF and appears to decrease the risk of death from prostate cancer compared with DERT76 alone with no difference in OS. In the setting of IRPC, ADT plus RT 70 Gy yields effective disease control with a better GI toxicity profile.
Clinicaltrials.gov#NCT00223145.
The federal Freedom of Information Act (FOIA) has the potential for affecting the social scientist at almost every stage of his or her research. Whenever a researcher files information with the federal government that subsequently becomes an "agency document," this information becomes responsive, and hence disclosable, to an FOIA requester. This information may be in the form of a grant or contract research proposal, raw data, results of preliminary analyses, or a final report. This article addresses the research issues raised in several recent federal cases and outlines their implications for the possible abrogation of a researcher's property rights in his or her data and the potential breach of the confidential researcher-subject relationship. Suggestions are made for methods to minimize FOIA intrusion into this area and for remedial legislation to prevent future uncertainties. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The Anturane Reinfarction Trial is a randomized, double blind, multicenter clinical trial comparing sulfinpyrazone (200 mg four times a day) and placebo in the prevention of cardiac mortality among patients with a recent documented myocardial infarction. Results represent data accumulated on 1475 eligible patients entered 2 to 35 days after myocardial infarction and followed for an average of 8.4 mth. The data reflect excellent randomization, compliance with therapy and tolerance of the drug. All 69 deaths were of a cardiovascular nature (68 cardiac and one cerebrovascular). For cardiac deaths, the annual death rate was 9.5% in the placebo group and 4.9% in the sulfinpyrazone group, representing an observed reduction of 48.5% (P=0.018). The annual sudden-cardiac-death rate was 6.3% for the placebo and 2.7% for the sulfinpyrazone group, representing a 57.2% reduction in sudden-cardiac-death rate P equals 0.015). Sulfinpyrazone appears to be effective in reducing cardiac deaths during the first year after myocardial infarction.
This progress report on the prospective randomized study of the effect of coronary bypass surgery on prognosis presents the results of a minimum follow-up of 4 years. Seven hundred sixty-eight patients were recruited; all were men younger than age 65 years who had mild-to-moderate angina pectoris, at least two-vessel disease, and good left ventricular function. Of these, 373 were randomized to medical treatment and 395 to surgical treatment. Although 83 'medical' patients subsequently underwent surgery and 27 'surgical' patients did not undergo surgery, these patients were not excluded from the analysis, and the group randomized to coronary bypass surgery was compared with the group randomized to medical treatment. The surgical treatment group showed significantly better survival than the medical treatment group in the total patient population (p<0.001), particularly among patients with three-vessel disease (p<0.001). Although the 24% higher survival among surgical patients with left main coronary artery disease failed to reach statistical significance, the trend is probably meaningful. No significant difference in survival between medical and surgical treatment groups was noted in patients with two-vessel disease.
The University Group Diabetes Program (UGDP), a long-term prospective clinical trial, provided little evidence that insulin treatment was any better than diet alone in altering the course of vascular complications in stable adult-onset diabetes. This was true whether insulin was given in a fixed dose based on patient's height and weight or in doses adjusted to maintain blood glucose within defined levels. Blood glucose was monitored by fasting and 1-h values from an abbreviated glucose tolerance test, performed at every quarter except at the annual examinations, and by the sum of glucose values from a 3-h glucose tolerance test, performed at the annual examinations. All three of these measures showed similar treatment effects. Only 14.6% of patients treated with variable doses of insulin had poor control (70% or more fasting blood glucose values ≥ 130 mg/dl) compared with 33.7% in the insulin-standard treatment group and 44.6% in the group treated with diet alone. Mortality rates among the treatment groups were comparable. The differences in the occurrence of non-fatal vascular complications among the patients in these three treatment groups were small and only one of the drug-placebo differences was considered significant by the study criterion, and that was the insulin-standard versus placebo comparison for the occurrence of elevated serum creatinine levels (8.3% versus 18.5%, P value = 0.005). The occurrence of serious microvascular complications was surprisingly low. The latter finding as well as the slow progression of the macrovascular complications underscores the differences in the course and the nature of the two principal types of diabetes mellitus, the rather stable and non-ketosis-prone maturity-onset type (type II) and the relatively unstable insulin-dependent juvenile-onset type (type I).
This article has no abstract; the first 100 words appear below.
To the Editor: Ever since I set up the first collaborative controlled clinical trial in this country in the early 1950s, I have noted the profound difference between what M.D.s considered ethical and what I (as a biostatistician and public-health scientist) considered ethical. Even today, some M.D.s do not regard the randomization necessary for a fair clinical trial as ethical, whereas getting a predetermined result by selection of the patients is considered ethical. The Laetrile trial* reported in the January 28 issue is a good example of what doctors call ethical but I would call unethical. From the standpoint of . . .
This article has no abstract.
768 men aged under 65 with angina pectoris, at least 50% obstruction in two or more major vessels, and a left-ventricular ejection fraction≥0.5 took part in a prospective randomised trial of the effect of coronary-artery bypass on prognosis. 373 patients were allowed to medical and 395 to surgical treatment. There was no significant difference between the 2 groups in the distribution of variables recorded at the time of randomisation. 1 'surgical' patient was lost to follow-up. 26 'surgical' patients did not undergo surgery and 50 'medical' patients were operated on. All these 76 patients were retained in their original treatment groups for the analysis. At 2 years there was no significant difference in mortality between the 2 groups. A significant difference was, however found in the subset of patients with three-vessel disease, survival being significantly better for surgical patients. Operative (in hospital) mortality was 3.6% in all operated patients and 1.5% in the last third: On average, 1.9 grafts per patient were inserted in the two-vessel-disease subgroup and 2.4 grafts per patient in the three-vessel-disease subgroup. Graft-patency rate was 90% within 9 months and 77% between 9 and 18 months after surgery. Symptomatic improvement was significantly better and deterioration was less in the surgical group.
The Aspirin Myocardial Infarction Study (AMIS) was a National Heart, Lung, and Blood Institute-sponsored, multicenter, randomized, double-blind, and placebo-controlled trial designed to test whether the regular administration of aspirin to men and women who had experienced at least one documented myocardial infarction (MI) would result in a significant reduction in total mortality over a three-year period. Cause-specific mortality, nonfatal events, and side effects were also evaluated. Over a 13-month period, 4,524 persons between the ages of 30 and 69 years were randomized to either 1 g of aspirin per day (2,267 persons) or placebo (2,257 persons). High levels of patient compliance to study protocol were indicated by various measures. Total mortality during the entire follow-up period was 10.8% in the aspirin group and 9.7% in the placebo group. Three-year total mortality was 9.6% in the aspirin group and 8.8% in the placebo group. The percentage of definite nonfatal MI was 8.1% in the placebo group and 6.3% in the aspirin group. Coronary incidence (coronary heart disease mortality or definite nonfatal MI) was 14.1% in the aspirin group and 14.8% in the placebo group. Symptoms suggestive of peptic ulcer, gastritis, or erosion of gastric mucosa occurred in 23.7% of the aspirin group and 14.9% in the placebo group. Based on AMIS results, aspirin is not recommended for routine use in patients who have survived an MI.
Gail and Gart (1973) present tables showing the required sample size, n, for the Fisher-Irwin exact conditional test for 2 x 2 tables to achieve a power of at least 0.50, 0.80 and 0.90 against one-sided alternatives at the nominal .05 and .01 significance levels. However, calculations for n > 35 were based on the Arc sine approximation, which was found to underestimate the actual required sample size by as much as 34%. The purpose of this note is to revise the Gail-Gart tables, giving exact sample sizes in all cases. The problem of nominal versus actual significance levels when the underlying probability of response is low is also briefly discussed.
k-Ratio t tests have been developed for tests of all pairwise differences and practically all contrasts among n equally replicated means. In place of choosing an α, these new t tests depend on choosing an error-seriousness ratio k. They depend also on the overall data through the between-treatments F ratio and its degrees of freedom q and f. This paper extends these k-ratio t tests to cases with unequally replicated means or with treatment estimates which are heteroscedastic and correlated. The critical t value t(k, F, q, f) is the same except that for example, the overall F and q are replaced by an 'effective' F ratio Fij with an effective qij based on a simple approximation due to Satterthwaite (1946). The rule is thus not completely optimum as is true in the Bayes sense for the rule for equal replications. It does, however, have virtually the same adaptive dependence on the data through the effective F ratio. This allows it to be anything from extremely cautious and conservative to being quite powerful and sensitive according to the intuitive needs, thus avoiding serious objections to the comparable α-level multiple comparisons rules.
This article traces the development of the design of experiments from origins in the mind and professional experience of R.A. Fisher between 1922 and 1926. The article indicates how the analysis of variance procedure stimulated design, being justified by the principle of randomization that Fisher introduced with the analysis, and exploited by his use of blocking and replication. The article indicates the radically new form and efficiency of factorial block designs, shows the further advantages accruing to factorial arrangements through confounding, and suggests how Fisher's close collaboration with experimenters stimulated these developments.
The literature on sequential estimation is reviewed, with special reference to inverse binomial sampling, double sampling, and asymptotic theory. An approximate distribution for the sample size is found for a certain type of sequential sampling rule, in which a cumulative sum of independent random variables all having the same continuous distribution is plotted against their number until a fixed boundary is first reached or crossed. Approximate methods are given for solving a number of particular problems, including (i) estimating the mean of a normal population by a confidence interval of prescribed width and coefficient, when the population variance is unknown, and (ii) estimating the parameters of a simple birth‐death process so that the difference between the birth rate and the death rate is estimated with prescribed standard error. The possible usefulness of sequential estimation procedures is discussed.
Closure of the family of hypotheses tested by the Newman-Keuls procedure has been proposed in order to avoid excessive Type I errors. This proposal is examined in some detail, and a practical procedure for carrying it out is described and programmed in FORTRAN. The relation of such closure to other multiple comparison procedures is discussed, and its relatively high power is pointed out.
This article contains a bibliography of papers on multiple comparisons between 1966 and 1976. A discussion of some of the more important developments during this period precedes the bibliography.
Data from a panel study of the impact of a low-income cooperative on its members are employed to compare the relative advantages of three different methods of measuring change. Although analysis confirmed the often reported unreliability of retrospective compared to true panel measurements, it also showed that "pseudo panel" retrospective approximations of panel measurements are greatly superior to change assessments made by respondents themselves. Finally, the three different types of change measures are compared in actual estimations of the impact of project participation on members. Results of this comparison confirm that, although true longitudinal designs arepreferable, pseudo panel measures of change may sometimes be acceptable and should definitely be preferred to the third, more subjective assessments of change.
Data from a split-ballot experiment show that offering respondents an alternative position on an issue not only affects the
marginals, it also influences whether respondents will give an opinion at all. Furthermore, the study demonstrates that these
form effects can occur despite the use of filter questions which theoretically screen out those who tend to be most susceptible
to such effects: the less educated or uninformed. The analysis does provide evidence, however, that less educated respondents
are indeed more affected by differences in question format and that they are much more likely to “acquiesce” to one-sided
agree/disagree forms. In discussing the results the authors develop an information-processing model of question form effects
and a methodological strategy to generate further research on a much-needed theory of the survey instrument.
IN the considerable literature that has appeared on the randomized response technique (RRT), only one study (Lamb and Stem, 1978) has addressed its validity. However, this study utilized a convenience sample of rather small size, thereby limiting generalizability of results. Originally proposed by Warner (1965), RRT is a method designed to obtain reliable information when dealing with sensitive issues on surveys. In instances where the technique was used, it has been assumed that "reliable information" meant valid information. In the technical sense, this, of course, is not necessarily so. Therefore, it is the purpose of this research to investigate the validity of the technique, using a nationwide probability sample of adults. The split-sample version of the RRT developed by Moors (1971) was used in the present study. Parameters for maximizing the effectiveness of this technique in a field situation were established by Zdep and Rhodes (1976). Determining the validity of a method such as RRT is not easy, precisely because RRT offers an alternative to direct questioning in situations where direct questioning is likely to result in obtaining socially desirable responses rather than truthful responses. Validation, then, requires that RRT results be compared with some other estimate of the sensitive characteristic in the population. To be sure, if this estimate were available, there would be no need for using RRT, which is costly and inefficient to administer.
There appears to be both theoretical and practical appeal to the likelihood ratio approach to evaluating results from clinical trials involving a multiplicity of data reviews, treatment comparisons, endpoints, and patient subgroups. I would encourage further development of practical applications of the likelihood ratio approach so that its strengths and weaknesses can be properly evaluated in comparison to the approaches based on classical inference. This, to my mind, would be much more fruitful than the development of compromise solutions which do justice to neither the P value nor the likelihood principle.
This is a reply to Professor Anscombe's review article of the author's book, “Sequential Medical Trials.” It is suggested that the use of likelihood inference may have misleading consequences. Anscombe's optimal sequential designs, while giving insight into the problem of designing clinical trials, would be difficult to put into practice and may be based on unacceptable ethical assumptions.
The University Group Diabetes Program (UGDP), a long-term prospective clinical trial, was designed to evaluate the effects of various hypoglycemic agents on vascular complications in patients with asymptomatic, adult-onset diabetes. This study provided no evidence that phenformin was more efficacious than diet alone or than diet and insulin in prolonging life for the patients studied. In fact, the observed mortality from all causes and from cardiovascular causes for patients in the phenformin treatment group was higher than that observed in any of the other treatment groups. In addition, there was no evidence that phenformin was more effective than any of the other treatments in preventing the occurrence of nonfatal vascular complications associated with diabetes. For these reasons, the use of phenformin has been terminated in the UGDP. Data collection in this study is continuing for all surviving patients. The additional information obtained over a longer period of follow-up on patients in the two insulin groups compared with the patients in the placebo group will provide a more adequate basis for the assessment of the long-term effects of insulin.
The manner of use of three prescription drugs for hospitalized patients (cephalexin, allopurinol, and propranolol hydrochloride) was compared with the labeling recommendations that are approved by the Food and Drug Administration (FDA). Each drug was prescribed frequently for therapeutic indications not mentioned in the approved labeling (cephalexin in 78.3% of cases, allopurinol in 57.1%, and propranolol in 64.7%). Thus, a gap has developed between current medical practice and FDA-approved recommendations for therapeutic use. We suggest that for cephalexin and allopurinol, the FDA-approved recommendations agreed with the current medical literature, and the prescribing habits of physicians were inappropriate. With propranolol, however, the FDA-approved recommendations were lagging behind both good medical practice and the current medical literature. The implications of these findings are discussed with respect to prescribing habits and drug regulation.
(JAMA 229:1744-1748, 1974)
The treatment of lobar pneumonia with a specific antibacterial serum has been under discussion for many years. It is now the opinion of those having no recent experience with the antibacterial serum that it is somewhat useful in type I cases, of doubtful value in type II cases, and useless in type III and group IV cases. All are agreed that the large doses of crude serum necessary to give sufficient antibody are a serious disadvantage. Recent investigations, however, have given us a more favorable outlook.Seven years ago, at a meeting of the Influenza Commission of the Metropolitan Life Insurance Company, it was decided to make a serious attempt to determine the value and limitations of refined antibacterial serum and to stimulate attempts to improve it. The active members of the commission, McCoy, Jordan, Rosenau, Frost and Park, differing in their views from skepticism to optimism, were thought to
Doubts have been expressed concerning the validity of questionnaire data. Sensitive data collected via questionnaire are of even more doubtful validity, and unobtrusive ways to gather information have been suggested in the literature. Nevertheless questionnaires appear necessary when the nature of the data is either private or cognitive. The random response technique may be a solution to this problem. D. S. Fidler and R. E. Kleinknecht's (see record
1978-20067-001) paper on this technique is discussed, and criticisms concerning cost of the random device, areas of investigation, and place of interview are formulated. Such improvements as the use of a die as the random device and having people interviewed in public places by male and female interviewers were implemented in the present study with 405 university students. Data on a variety of sensitive matters are presented. Suggestions are made for a better utilization of the technique, and interpretations of the data collected are discussed. (23 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Three series of experiments with a total of 686 undergraduates and adults each examined a different aspect of efficient data collection, using formalized question and answer protocols. In Series 1, Ss were faster endorsing an answer (e.g., circle what does apply) than negating one (e.g., delete what does not apply). In Series 2, Ss were faster responding to statements offering multiple alternatives within a sentence frame (e.g., I am single/married) than responding to yes/no questions (e.g., Are you married?). However, this advantage for sentence frame questions depended on the multiple alternatives being at the end of the sentence rather than at the beginning. Series 3 addressed administrative issues. It was found that (a) error-checking procedures were faster when the form-filler endorsed rather than negated items and (b) many form-fillers ignored instructions about how to respond. The implications of these findings for the revision of forms to meet the requirements of automated data processing facilities are discussed. The economic consequences of good form design are emphasized. (22 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
1.1. This report, one of a series relating to the effect of untreated acquired syphilis in the male Negro, contains a history of the study and a description of the current status of the study population.2.2. Included in the present study group are 408 syphilitic individuals and 192 nonsyphilitic controls who have maintained their status since the beginning of the study. Of the 408 in the syphilitic group, 51 per cent are living, 39 per cent are dead, and 10 per cent are of unknown status. In the nonsyphilitic group, 65 per cent are living, 26 per cent are dead, and 9 per cent are of unknown status.3.3. On the basis of the individuals examined during the 1951–1952 survey, it is estimated that 70 per cent of the syphilitic group have remained untreated, 22.5 per cent have had inadequate treatment, and 7.5 per cent have been adequately treated. However, in terms of man-years, the study represents an aggregate of 5,494.5 man-years of untreated disease, 122 man-years of inadequately treated disease, and 28.5 man-years of adequately treated disease.4.4. Physical examinations in this survey consisted of a review of the body systems, blood pressure determinations, funduscopic examinations, and neurologic examinations. Stethographic and electrocardiographic records were obtained on the patients.5.5. Blood was drawn from syphilitic and nonsyphilitic patients for VDRL and Kahn quantitative testing, as well as for the TPI test.6.6. This report has been prepared for the purpose of presenting information relating to the study group, which will serve as a basis for the discussion of the results of twenty years of clinical observation, to be presented in a subsequent report.7
Long-term clinical trials often include more than one active treatment group. These may be discontinued independently if found to be ineffective or possibly harmful. Certain subgroups of patients may be discovered, in the course of a clinical trial, who do not respond satisfactorily and are, therefore, excluded during the course of a trial. Yet another kind of termination comes when we have a therapeutic breakthrough or when hope has to be abandoned for demonstrating beneficial effects for one, several, or all treatments included in a trial. Examples from the authors' experience are presented, as are successful and unsuccessful techniques in managing terminations of various types.
The typical multicenter trial involves several clinical centers, a data center, and other specialty centers as well. A common structure for large-scale trials funded by the National Institutes of Health )NIH) involves two or three key committees. One of these is comprised exclusively of investigators from the study (steering committee) and is responsible for operation of the trial. A second committee, usually comprised of individuals not involved in the study, is responsible for overseeing the trial and providing advice to the NIH regarding the study. A third committee—sometimes part of the second committee and comprised largely of individuals not involved in the trial—is responsible for monitoring the study results for evidence of adverse or beneficial treatment effects as the trial proceeds. The organizational design of a trial may be as important as the experimental design is in the success of the trial. Attention to organizational questions at the start of the study and periodic review and revision of the structure as the trial proceeds can help identify problems before they become major impediments to progress in the trial. Such ongoing monitoring and periodic review is especially important in the long-term multicenter trial.
This paper studies the sequential decision model known as the two-armed-bandit with finite memory. It was introduced by Robbins [8] in 1956 and studied further by Isbell [5] in 1959. In this paper, a set of rules is defined which are uniformly better than those given in [5] and [8]. A much larger class of rules is then defined, one member of which is conjectured to be a uniformly best rule.
An analysis of “approval of hitting” questions on the General Social Surveys finds evidence of correlated error. Respondents
frequently ignore the absolute phrasing of questions. As a result, they often contradict themselves by approving of specific
uses of hitting after having rejected any use of such force. These contradictors tend to have lower education and less support
for punitive responses on other items.
Home and hospital management of patients with suspected myocardial infarction were compared in a randomised trial in which a hospital-based team responded to calls from general practitioners. 500 calls were received, and 349 patients (70%) were suspected of having myocardial infarction. Of these, 24% were excluded from the trial on predetermined medical and social grounds; for the remainder (76%) there was no significant difference in the 6-week mortality between the home group (13%) and the hospital group (11%). For the majority of patients to whom a general practitioner is called because of suspected infarction, hospital admission confers no clear advantage.