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There is no clear parallel to that initiative in the COVID-19 pandemic, but as Dr Dean stressed, effective communication with the population at risk - essentially, the entire public for COVID-19 - is very important. Dr Platt focuses on population-level validation of vaccine effectiveness and postapproval vaccine safety surveillance, an extremely important issue given the "warp speed" at which vaccines were developed and deployed. She also highlights the important methodological contributions of the HIV Vaccine Trials Network statisticians to the COVID-19 vaccine effort, and points out that the strategy of repurposing infrastructure put in place for earlier needs is essential during a fast-emerging pandemic. [Extracted from the article]

The world has experienced three global pandemics over the last half-century: HIV/AIDS, H1N1, and COVID-19. HIV/AIDS and COVID-19 are still with us and have wrought extensive havoc worldwide. There are many differences between these two infections and their global impacts, but one thing they have in common is the mobilization of scientific resources to both understand the infection and develop ways to combat it. As was the case with HIV, statisticians have been in the forefront of scientists working to understand transmission dynamics and the natural history of infection, determine prognostic factors for severe disease, and develop optimal study designs to assess therapeutics and vaccines. [ABSTRACT FROM AUTHOR]

Within the field of randomized clinical trials (RCTs), the randomized double-blind placebo-controlled clinical trial is considered the most efficient means of simultaneously assessing the efficacy and safety of a medical therapy in a single trial. While many RCTs are conducted without blinding (open label), it is rare to encounter a blinded trial that does not randomize its subjects. Clinical trials for chronic liver diseases have adopted many of the practices set forth by RCTs in other chronic diseases, but blinding has often been difficult to properly implement. This review examines the rationale for blinding, common challenges to successful blinding, different mechanisms of unintentional unblinding in clinical trials for viral hepatitis and nonalcoholic steatohepatitis, and recommendations for blinding and design in future trials of treatments for liver disease. [ABSTRACT FROM AUTHOR]

Yarmush and Ramadan comment on the magnitude of the difference in pain measures we observed on postoperative day 1 in patients randomly assigned to spinal versus general anesthesia. Finally, Dr. Toda and colleagues note that postoperative pain could differ for patients with and without pathologic fractures. [Extracted from the article]

BACKGROUND Testosterone treatment in men with hypogonadism improves bone density and quality, but trials with a sufficiently large sample and a sufficiently long duration to determine the effect of testosterone on the incidence of fractures are needed. METHODS In a subtrial of a double-blind, randomized, placebo-controlled trial that assessed the cardiovascular safety of testosterone treatment in middle-aged and older men with hypogonadism, we examined the risk of clinical fracture in a time-to-event analysis. Eligible men were 45 to 80 years of age with preexisting, or high risk of, cardiovascular disease; one or more symptoms of hypogonadism; and two morning testosterone concentrations of less than 300 ng per deciliter (10.4 nmol per liter), in fasting plasma samples obtained at least 48 hours apart. Participants were randomly assigned to apply a testosterone or placebo gel daily. At every visit, participants were asked if they had had a fracture since the previous visit. If they had, medical records were obtained and adjudicated. RESULTS The full-analysis population included 5204 participants (2601 in the testosterone group and 2603 in the placebo group). After a median follow-up of 3.19 years, a clinical fracture had occurred in 91 participants (3.50%) in the testosterone group and 64 participants (2.46%) in the placebo group (hazard ratio, 1.43; 95% confidence interval, 1.04 to 1.97). The fracture incidence also appeared to be higher in the testosterone group for all other fracture end points. CONCLUSIONS Among middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo. The fracture incidence was numerically higher among men who received testosterone than among those who received placebo. [ABSTRACT FROM AUTHOR]

The article discusses the use of randomized controlled trials (RCTs) and other alternative methods to study the effects of medical treatments, and it mentions resistance to RCTs based on ethical grounds, treatments for diseases such as AIDS, and information about patients' treatment expectations. Uncontolled research studies and the Cardiac Arrhythmia Suppression Trial (CAST) are examined, along with the 2014-2015 Ebola Virus Disease epidemic and AIDS activists' views.

Importance: Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk.Objective: To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume.Design, Setting, and Participants: Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014.Intervention: Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.Main Outcomes and Measures: The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis).Results: Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group.Conclusions and Relevance: Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding.Trial Registration: clinicaltrials.gov Identifier: NCT00799617. [ABSTRACT FROM AUTHOR]

The article discusses the monitoring of clinical trial progress in the U.S. which were being monitored by data monitoring committees (DMCs) to assess treatment risk versus benefit. It offers information on the responsibilities of DMCs including review of protocol, data quality assessment and review of trial presentations, and the selected classic cases of early termination such as Beta-Blocker Heart Attack Trial (BHAT) and Cardiac Arrhythmia Suppression Trial (CAST).

Randomized clinical trials are the most reliable approaches to evaluating the effects of new treatments and vaccines. During the 2014-2015 West African Ebola epidemic, many argued that such trials were neither ethical nor feasible in an environment of limited health infrastructure and severe disease with a high fatality rate. Consensus among the numerous organizations providing help to the affected areas was never achieved, resulting in fragmented collaboration, delayed study initiation and ultimately failure to provide definitive evidence on the efficacy of treatments and vaccines. Randomized trials were in fact approved by local ethics boards and initiated, demonstrating that randomized trials, even in such difficult circumstances, are feasible. Improved planning and collaboration among research and humanitarian organizations, and affected communities, in the interepidemic periods are needed to ensure that questions regarding the efficacy of vaccines and treatments can be definitively answered during future public health emergencies. [ABSTRACT FROM AUTHOR]

Background: Adenotonsillectomy (AT) is commonly performed for childhood OSA syndrome (OSAS), but little is known about prognosis without treatment.Methods: The Childhood Adenotonsillectomy Trial (CHAT) randomized 50% of eligible children with OSAS to a control arm (watchful waiting), with 7-month follow-up symptom inventories, physical examinations, and polysomnography. Polysomnographic and symptomatic resolution were defined respectively by an apnea/hypopnea index (AHI) <2 and obstructive apnea index (OAI) <1 and by an OSAS symptom score (Pediatric Sleep Questionnaire [PSQ]) < 0.33 with ≥ 25% improvement from baseline.Results: After 194 children aged 5 to 9 years underwent 7 months of watchful waiting, 82 (42%) no longer met polysomnographic criteria for OSAS. Baseline predictors of resolution included lower AHI, better oxygen saturation, smaller waist circumference or percentile, higher-positioned soft palate, smaller neck circumference, and non-black race (each P < .05). Among these, the independent predictors were lower AHI and waist circumference percentile < 90%. Among 167 children with baseline PSQ scores ≥ 0.33, only 25 (15%) experienced symptomatic resolution. Baseline predictors were low PSQ and PSQ snoring subscale scores; absence of habitual snoring, loud snoring, observed apneas, or a household smoker; higher quality of life; fewer attention-deficit/hyperactivity disorder symptoms; and female sex. Only lower PSQ and snoring scores were independent predictors.Conclusions: Many candidates for AT no longer have OSAS on polysomnography after 7 months of watchful waiting, whereas meaningful improvement in symptoms is not common. In practice, a baseline low AHI and normal waist circumference, or low PSQ and snoring score, may help identify an opportunity to avoid AT.Trial Registry: ClinicalTrials.gov; No.: NCT00560859; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Several adaptive design methods have been proposed to reestimate sample size using the observed treatment effect after an initial stage of a clinical trial while preserving the overall type I error at the time of the final analysis. One unfortunate property of the algorithms used in some methods is that they can be inverted to reveal the exact treatment effect at the interim analysis. We propose using a step function with an inverted U-shape of observed treatment difference for sample size reestimation to lessen the information on treatment effect revealed. This will be referred to as stepwise two-stage sample size adaptation. This method applies calculation methods used for group sequential designs. We minimize expected sample size among a class of these designs and compare efficiency with the fully optimized two-stage design, optimal two-stage group sequential design, and designs based on promising conditional power. The trade-off between efficiency versus the improved blinding of the interim treatment effect will be discussed. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Jerome Cornfield was one of the leading biostatisticians of the mid-20th century and made major contributions to the methods and practice of statistics in many areas. One of Cornfield's major areas of interest was clinical trials. He considered and wrote about many of the issues that continue to concern clinical trialists today. His work ranged from philosophical treatises about the approaches to inference from clinical trials, all the way to assessing the details of the conduct of a particular trial to determine how to best interpret the results. It is interesting to see how many of today's 'hot topics' in clinical trials methodology were addressed in Cornfield's works in the 1960s and 1970s. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

An essay is presented on the protection of clinical trial participants and aspects of data monitoring. It explores the independence of data monitoring committees (DMCs) and the reduction of conflicts of interests among scientists and statisticians. It also discusses the need to understand the early stopping guidelines of clinical trials, the liability of DMC members, and the approaches of interim data monitoring.

Sequential designs, permitting the possibility of early termination, have become commonly used in clinical trials of treatments for serious diseases. Some level of judgment is always involved in using these designs, both at the design stage (how extreme do we want the results to be before we stop and declare that we know the answer?) and at the implementation stage (are there reasons to continue the study, despite the fact that the data now meet the criteria for early stopping?). Those serving on data and safety monitoring committees inevitably have access to much information not widely available, making "second-guessing" a risky enterprise. For most trials, early stopping for benefit is not a consideration, for very good reasons. It must be recognized that many more trials address relief of symptoms over a short period of observation than address serious and irreversible health outcomes in long-term studies; for the former types of trials, there is generally no ethically compelling basis to stop early due to efficacy findings, and there are very good reasons why designs permitting early stopping in these settings are unwarranted. [ABSTRACT FROM AUTHOR]

Public concerns about the safety of vaccines arise on a regular basis. In November 2000, a workshop titled "Evaluation of New Vaccines: How Much Safety Data?" was convened by US Public Health Service agencies, including the Food and Drug Administration, the National Institutes of Health, the Centers for Disease Control and Prevention, and the Health Resources and Services Administration, to discuss appropriate methods for evaluating the safety of new vaccines. Workshop presentations addressed the current standards and approaches for new vaccine evaluation and postlicensure surveillance, as well as public views about vaccine safety and alternative approaches that could be considered. The advantages and disadvantages of conducting large controlled trials before licensure or widespread use of a new vaccine were discussed. We summarize these presentations and discussions. [ABSTRACT FROM AUTHOR]

The development of combination vaccines is important to facilitate protection of people from potentially life-threatening infectious diseases. As with all vaccines, the safety of these products is of critical importance. Although combination vaccines generally include components that have been studied and used previously, the possibility of new or more severe reactions arising from combining components cannot be dismissed. Controlled safety studies are needed for new combination vaccines to determine reliably whether risks are increased compared with administration of individual components. Such studies will generally be smaller than studies of vaccines with new immunogens, but the size of the study will depend on the types and rates of the reactions expected, given the vaccine's components, and on the level of increased risk that would be important to detect. [ABSTRACT FROM AUTHOR]

Placebo controls are commonly used in clinical trials of investigational treatments because they have important advantages. In recent years, some have criticized the use of placebo-controlled trials when effective alternative therapy exists, regardless of the expected effect of the therapy. In part 1 of this paper, ethical arguments are addressed and the interpretive problems inherent in the use of active-control equivalence trials to establish efficacy of a new treatment are clarified. However, uncertainties may complicate decisions about appropriate use of placebo controls in some situations. Part 2 discusses more fully the ethical considerations for using placebo controls in particular medical settings. The value and relevance of placebo-controlled trials of new agents in situations in which proven effective therapy is available are also explored. [ABSTRACT FROM AUTHOR]

In recent years, several authors have argued that placebo-controlled trials are invariably unethical when known effective therapy is available for the condition being studied, regardless of the condition or the consequences of deferring treatment. Some have also disputed the value of placebo-controlled trials in such a setting, asserting that the comparison of new treatment with old treatment is sufficient to establish efficacy and is all that should be of interest. This article considers the ethical concerns about use of placebo controls and describes the limited ability of active-control equivalence (also known as noninferiority) trials to establish efficacy of new therapies in many medical contexts. The authors conclude that placebo-controlled trials are not uniformly unethical when known effective therapies are available; rather, their acceptability is determined by whether the patient will be harmed by deferral of therapy. If patients are not harmed, such trials can ethically be carried out. Furthermore, active-control trials, although valuable, informative, and appropriate in many circumstances, often cannot provide reliable evidence of the effectiveness of a new therapy. [ABSTRACT FROM AUTHOR]

In the 11 years since AIDS became a defined disease, programs for the development and evaluation of new drugs for this disease have grown rapidly. Although the fundamental principles that drive the design, conduct, and analysis of clinical trials are as applicable to AIDS as to other diseases, there is no question that we have been confronted with unusually difficult challenges in studying therapeutic approaches for this disease. These include the multiple treatment needs of individual patients, identification of appropriate endpoints, rapidly changing "natural history," and the need for interaction with an informed and vocal patient community that continues to express dissatisfaction with the pace of research. In this context, statisticians have taken a leadership role in identifying and addressing important methodological issues in the evaluation of AIDS drugs. [ABSTRACT FROM AUTHOR]

Provides information about vaccination as an essential component of modern public health programs and the most effective medical interventions. Side effects of vaccine-preventable diseases; Common reactions of vaccines; Complicated task of monitoring vaccine safety; Different approaches to vaccine safety monitoring in children.

Background: The REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture) trial found similar ambulation and survival at 60 days with spinal versus general anesthesia for hip fracture surgery. Trial outcomes evaluating pain, prescription analgesic use, and patient satisfaction have not yet been reported.Objective: To compare pain, analgesic use, and satisfaction after hip fracture surgery with spinal versus general anesthesia.Design: Preplanned secondary analysis of a pragmatic randomized trial. (ClinicalTrials.gov: NCT02507505).Setting: 46 U.S. and Canadian hospitals.Participants: Patients aged 50 years or older undergoing hip fracture surgery.Intervention: Spinal or general anesthesia.Measurements: Pain on postoperative days 1 through 3; 60-, 180-, and 365-day pain and prescription analgesic use; and satisfaction with care.Results: A total of 1600 patients were enrolled. The average age was 78 years, and 77% were women. A total of 73.5% (1050 of 1428) of patients reported severe pain during the first 24 hours after surgery. Worst pain over the first 24 hours after surgery was greater with spinal anesthesia (rated from 0 [no pain] to 10 [worst pain imaginable]; mean difference, 0.40 [95% CI, 0.12 to 0.68]). Pain did not differ across groups at other time points. Prescription analgesic use at 60 days occurred in 25% (141 of 563) and 18.8% (108 of 574) of patients assigned to spinal and general anesthesia, respectively (relative risk, 1.33 [CI, 1.06 to 1.65]). Satisfaction was similar across groups.Limitation: Missing outcome data and multiple outcomes assessed.Conclusion: Severe pain is common after hip fracture. Spinal anesthesia was associated with more pain in the first 24 hours after surgery and more prescription analgesic use at 60 days compared with general anesthesia.Primary Funding Source: Patient-Centered Outcomes Research Institute. [ABSTRACT FROM AUTHOR]

The article discusses the article by Cascinu et al. about a study on how negative results of adjuvant therapy for gastric cancer can help patients .

It has long been a fundamental principle of clinical trials that interim comparative data should be kept confidential, with such data accessible only to a small number of individuals responsible for its analysis and monitoring. The rationale for keeping investigators and sponsors blinded to interim data has been extensively discussed, but the possible conflicts of interest that could arise for the statistician who performs the analysis of the interim data and presents it to a data monitoring committee has received little attention. We describe these potential conflicts, and the advantages and disadvantages of approaches that might be taken to minimize them. We have invited commentary on this issue from several statisticians with substantial experience in clinical trials and interim data monitoring. Published in 2004 by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This JAMA Guide to Statistics and Methods discusses the stepped-wedge apporach to cluster randomized clinical trial design, in which clusters are randomized to the order in which they receive the experimental regimen. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Testosterone, estradiol, and dihydrotestosterone share common ligand binding sites on sex hormone binding globulin and albumin. It is unknown whether and how changes in testosterone, dihydrotestosterone, and estradiol concentrations during testosterone replacement therapy affect free testosterone fraction.To determine the effect of changes in testosterone, dihydrotestosterone, and estradiol concentrations on free testosterone fraction during testosterone replacement therapy of men with hypogonadism.Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and dihydrotestosterone concentrations over 12 months of testosterone replacement therapy with changes in free testosterone fraction, measured using equilibrium dialysis. We used random forests to evaluate the associations of predicted mean changes in free testosterone fraction with changes in circulating concentrations of each hormone at low, mean, or high change in the other two hormones.Testosterone replacement therapy not only increased total testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations, but also the percent free testosterone, even though sex hormone binding globulin levels did not change. The predicted changes in free testosterone fraction during testosterone replacement therapy exhibited a non‐linear relationship with changes in each of total testosterone, dihydrotestosterone, and estradiol concentrations. Greater increases in testosterone, dihydrotestosterone, and estradiol levels during testosterone replacement therapy were each associated with higher model‐predicted percent free testosterone. Substantially smaller changes in molar concentrations of estradiol and dihydrotestosterone had a greater effect on percent free testosterone than those in testosterone.During testosterone replacement therapy of men with hypogonadism, changes in testosterone, dihydrotestosterone, and estradiol concentrations each altered percent free testosterone non‐linearly. Small changes in estradiol concentrations exerted much larger effect on the free testosterone fraction than testosterone and dihydrotestosterone, suggesting complex interactions of the three hormones with the binding proteins. Assessment of changes in free testosterone during testosterone replacement therapy should include consideration of changes in all three hormones. [ABSTRACT FROM AUTHOR]

To speed the development of vaccines against SARS-CoV-2, the United States Federal Government has funded multiple phase 3 trials of candidate vaccines. A single 11-member data and safety monitoring board (DSMB) monitors all government-funded trials to ensure coordinated oversight, promote harmonized designs, and allow shared insights related to safety across trials. DSMB reviews encompass 3 domains: (1) the conduct of trials, including overall and subgroup accrual and data quality and completeness; (2) safety, including individual events of concern and comparisons by randomized group; and (3) interim analyses of efficacy when event-driven milestones are met. Challenges have included the scale and pace of the trials, the frequency of safety events related to the combined enrollment of over 100 000 participants, many of whom are older adults or have comorbid conditions that place them at independent risk of serious health events, and the politicized environment in which the trials have taken place. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to several articles including "Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children" and "Respiratory syncytial virus--successful immunoprophylaxis at last," in the November 1993 issue.

Presents the author's response on the comments done regarding the statistical issues in Acquired Immune Deficiency Syndrome (AIDS) clinical trial program. Nonrandomized trials in AIDS clinical trials. Observations related to AIDS for methodological research; Agreement with the need for studies designed prospectively to evaluate the reliability of early markers as surrogate endpoints in clinical trials.

Both individually and cluster randomized study designs have been used for vaccine trials to assess the effects of vaccine on reducing the risk of disease or infection. The choice between individually and cluster randomized designs is often driven by the target estimand of interest (eg, direct versus total), statistical power, and, importantly, logistic feasibility. To combat emerging infectious disease threats, especially when the number of events from one single trial may not be adequate to obtain vaccine effect estimates with a desired level of precision, it may be necessary to combine information across multiple trials. In this article, we propose a model formulation to estimate the direct, indirect, total, and overall vaccine effects combining data from trials with two types of study designs: individual‐randomization and cluster‐randomization, based on a Cox proportional hazards model, where the hazard of infection depends on both vaccine status of the individual as well as the vaccine status of the other individuals in the same cluster. We illustrate the use of the proposed model and assess the potential efficiency gain from combining data from multiple trials, compared to using data from each individual trial alone, through two simulation studies, one of which is designed based on a cholera vaccine trial previously carried out in Matlab, Bangladesh. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES: Accurate estimates of clinically important difference (CID) are required for interpreting the clinical importance of treatments to improve physical function, but CID estimates vary in different disease populations. We determined the CID for two common measures of walking ability in mobility‐limited older men. Design: Longitudinal, multisite placebo‐controlled trial. Setting/Participants: Men enrolled in the Testosterone Trials who had self‐reported mobility limitation and gait speed less than 1.2 m/second (n = 429). Testosterone‐ and placebo‐allocated participants were combined for this study. RESULTS: Mean changes from baseline, adjusting for time‐in‐intervention and site, were 29.6, 13.2, 12.5, −2.4, and −32.6 m for 6MWD, and 15.4, 7.2, 2.1, −3.4, and −7.2 for PF10 in men who reported their mobility was "very/much better," "little better," "no change," "little worse," or "much worse," respectively. CID estimates using regression, ROC, and eCDF varied from 5.0–29.6 m for 6MWD, and 5.0–15.2 points for PF10. CONCLUSION: CID estimates vary by the population studied and by the method and precision of measurement. Increases of 16 to 30 m for 6MWD and 5 to 15 points for PF10 over 12 months appear to be clinically meaningful in mobility‐limited, older hypogonadal men. These CID estimates may be useful in the design of efficacy trials of therapies to improve physical function. [ABSTRACT FROM AUTHOR]

The author addresses the need for the accelerated approval of anti-cancer drugs. She explains the amendment of U.S. Food and Drug Administration (FDA) investigational new drug policies for accelerated drug approval. She introduces an article about the FDA experience with accelerated approval of oncological drugs and biologics. She considers the arguments involving the impact of accelerated approval on the availability of new oncology drugs.

A response from the authors of the article "Effects of testosterone treatment in older men" in the 2016 issue is presented.

A response by Michael J. Smith and colleagues to a letter to the editor about their article "Media Coverage of the Measles-Mumps-Rubella Vaccine and Autism Controversy and Its Relationship to MMR Immunization Rates in the United States" is presented.

OBJECTIVE To describe development and initial psychometric testing of an owner-reported questionnaire designed to standardize measurement of general quality of life (QOL) in dogs with cancer. DESIGN Key-informant Interview's, questionnaire development, and field trial. SAMPLE Owners of 25 dogs with cancer for item development and pretesting and owners of 90 dogs with cancer for reliability and validity testing. PROCEDURES Standard methods for development and testing of questionnaire instruments intended to measure subjective states were used. Items were generated, selected, scaled, and pretested for content, meaning, and readability. Response items were evaluated with exploratory factor analysis and by assessing internal consistency (Cronbach α) and convergence with global QOL as determined with a visual analog scale. Preliminary tests of stability and responsiveness were performed. RESULTS The final questionnaire--which was named the Canine Owner-Reported Quality of Life (CORQ) questionnaire--contained 17 items related to observable behaviors commonly used by owners to evaluate QOL in their dogs. Several items pertaining to physical symptoms performed poorly and were omitted. The 17 items were assigned to 4 factors--vitality, companionship, pain, and mobility--on the basis of the items they contained. The CORQ questionnaire and its factors had high internal consistency (Cronbach α = 0.68 to 0.90) and moderate to strong correlations (r = 0.49 to 0.71) with global QOL as measured on a visual analog scale. Preliminary testing indicated good test-retest reliability and responsiveness to improvements in overall QOL. CONCLUSIONS AND CLINICAL RELEVANCE The CORQ questionnaire was a valid, reliable owner-reported questionnaire that measured general QOL in dogs with cancer and showed promise as a clinical trial outcome measure for quantifying changes in individual dog QOL occurring in response to cancer treatment and progression. [ABSTRACT FROM AUTHOR]

Focuses on the identification of the markers for survival in AIDS. Use of surrogate end points in clinical trials; Association of the changes of in β[sub 2] microglobulin concentrations with the survival time; Importance of drugs biological markers for establishing therapeutic efficacy.

A letter to the editor is presented in response to the article "Stopping Randomized Trials Early for Benefit and Estimation of Treatment Effects: Systematic Review and Meta-Regression Analysis," by Dirk Bassler and colleagues in the 2010 issue.

A letter to the editor is presented in response to the article "Homocysteine as a Predictive Factor for Hip Fracture in Older Persons," by McLean, et al. in the May 13, 2004 issue.

Background: Clinical trials are needed to study topics relevant to older adults with serious illness. Investigators conducting clinical trials with this population are challenged by how to appropriately define, classify, report, and monitor serious and non-serious adverse events (SAEs/AEs), given that some traditionally reported AEs (pressure ulcers, delirium) and SAEs (death, hospitalization) are common in persons with serious illness, and may be consistent with their goals of care. Objectives: A multi-stakeholder group convened to establish greater clarity on and new approaches to address this critical issue. Participants: Thirty-two study investigators, members of regulatory and sponsor agencies, and patient stakeholders took part. Approach: The group met virtually four times and, using a collaborative approach, conducted a survey, select interviews, and reviewed regulatory guidance to collectively define the problem and identify a new approach. Results: SAE/AE challenges fell into two areas: (1) definitions and classifications, including (a) implausible relationships, (b) misalignment with patient-centered care goals, and (c) well-known associations, and (2) reporting and monitoring, including (a) limited guidance, (b) inconsistent standards across regulators, and (c) Data Safety Monitoring Board (DSMB) member knowledge gaps. Problems largely reflected practice norms rather than regulatory requirements that already support context-specific and aggregate reporting. Approaches can be improved by adopting principles that better align strategies for addressing adverse events with the type of intervention being tested, favoring routine and aggregate over expedited reporting, and prioritizing how SAE/AEs relate to patient-centered care goals. Reporting plans and decisions should follow an algorithm underpinned by these principles. Conclusions: Adoption of the proposed approach—and supporting it with education and better alignment with regulatory guidance and procedures—could improve the quality and efficiency of clinical trials' safety involving older adults with serious illness and other vulnerable populations. [ABSTRACT FROM AUTHOR]