The use of randomized clinical trials in rehabilitation psychology.

Purpose: This article provides rehabilitation psychology researchers and clinicians with a tutorial approach to randomized clinical trials (RCTs), their basic assumptions and requirements, and a discussion of their potential applications and limitations to their use in rehabilitation and, more specifically, in rehabilitation psychology. Research Method/Design: The authors begin by reviewing a brief history and development of RCTs, definitions and considerations for clinical trials, and ethical issues. An overview of methodological issues related to designing trials including randomization and blinding, subject selection, and protocol development is provided. Results: The authors emphasize the need to establish clear and concise study objectives and to explicitly define interventions and expected outcomes. Conclusions/Implications: A summary is provided of the main points made by those supporting the use of RCTs versus those who highlight their limitations. Taking these into account, recommendations are made regarding the use of RCTs in addressing relevant needs in clinical practice and research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Some comments on frequently used multiple endpoint adjustment methods in clinical trials

Confirmatory clinical trials often classify clinical response variables into primary and secondary endpoints. The presence of two or more primary endpoints in a clinical trial usually means that some adjustments of the observed p-values for multiplicity of tests may be required for the control of the type I error rate. In this paper, we discuss statistical concerns associated with some commonly used multiple endpoint adjustment procedures. We also present limited Monte Carlo simulation results to demonstrate the performance of selected p-value-based methods in protecting the type I error rate.     

Summary measures and statistics for comparison of quality of life in a clinical trial of cancer therapy

Assessment of health related quality of life (QOL) has become an important endpoint in many clinical trials of cancer therapy. Most of these studies entail multiple QOL scales that are assessed repeatedly over time. As a result, the problem of multiple comparisons is a primary analytic challenge with these trials. The use of summary measures and statistics both reduces the number of hypotheses tested and facilitates the interpretation of trial results where the primary question is 'Does the overall QOL differ between treatment arms?' I present two classes of summary measures that are sensitive to consistent trends in the same direction across multiple assessment times or multiple QOL scales. Missing data strongly influences the choice between the two classes, where one class handles missing data on an individual basis, while the other class uses model-based strategies. I present the results from a clinical trial of adjuvant therapy for breast cancer that use summary measures with a focus on the practical issues that affect these analysis strategies, such as missing data and integration of QOL with efficacy endpoints such as survival.     

Use of composite endpoints in thrombolysis trials of acute myocardial infarction

Although preventing early mortality following acute myocardial infarction (MI) is the most important goal of thrombolytic therapy, insistence on its use as the only or principal endpoint in trials of acute MI will limit the number of new thrombolytic-antithrombotic regimens that can be tested, and thus may inhibit future progress of this important area of cardiovascular therapeutics. Trials of thrombolytic therapy over the past decade, as discussed in this article, have demonstrated that: (1) thrombolytic therapy improves both mortality and intermediate endpoints, and (2) intermediate nonfatal endpoints are strongly linked to long-term mortality. Taken together, these facts provide strong evidence that intermediate nonfatal events can be used as valid endpoints in future trials of thrombolytic therapy. The unsatisfactory outcome composite endpoint, which incorporates mortality and important intermediate endpoints, will make it possible to compare innovative new regimens in much smaller trials. Ultimately, both of these approaches (i.e., megatrials using a mortality endpoint and smaller trials utilizing a composite unsatisfactory outcome endpoint) can be used in a complementary fashion. A new regimen could first be tested using the unsatisfactory outcome endpoint; if it showed particular promise, it could then become a candidate for testing in a megatrial. Conversely, if it did not prove better than standard regimens, futile research in tens of thousands of patients might be prevented. Thus, the use of composite endpoints will expand the number of new thrombolytic-antithrombotic regimens that can be tested and, it is hoped, accelerate progress in the treatment of acute MI.     

CD4 cell count as a surrogate endpoint in HIV clinical trials: a meta-analysis of studies of the AIDS Clinical Trials Group

OBJECTIVE: To evaluate initial changes in CD4 cell count as a surrogate endpoint for clinical outcome in HIV-infected patients. DESIGN: Meta-analysis of all relevant Phase II and III randomized clinical trials undertaken by the Adult AIDS Clinical Trials Group. METHODS: Individual patient data were obtained from each clinical trial, and the difference between a pair of treatments in their effect on clinical outcome (AIDS or death, or death alone) during 2 years of follow-up was evaluated. The proportion of treatment effect explained (PTE) was the proportion of this difference explained by the change in CD4 cell count 6 months after starting treatment, evaluated using proportional hazards models. A weighted average PTE across treatment comparisons was obtained. The association between the difference between treatments in clinical outcome, expressed as hazard ratio, and the difference in mean change in CD4 cell count was evaluated using regression analysis. RESULTS: There were 15 clinical trials involving 24 treatment comparisons. The weighted average PTE for both progression to AIDS or death was 0.16 [95% confidence interval (Cl), 0.07-0.26] and for death was 0.10 (95% Cl, 0.00-0.20). There were significant associations between treatment differences in effect on AIDS or death, and on death alone, and the difference in mean change in CD4 cell count. A difference in mean change in CD4 cell count of 30 or 40 x 10(6)/l or more in favor of the test treatment indicated with high probability that there was a corresponding difference in progression to AIDS or death. CONCLUSIONS: The small PTE suggest that other mechanisms of drug action not captured by initial change in CD4 cells are important. CD4 cell count is a weak surrogate endpoint, but has some value as an aid for screening treatments for drug development or preliminary regulatory approval.     

Thrombolytic therapy for unstable angina

Thrombolytic therapy for unstable angina has not gained acceptance as a primary treatment for unstable angina (UA) despite the evidence showing a reduction in mortality when these agents are given for myocardial infarction. The purpose of this review is to examine the clinical value of thrombolytic therapy for UA. The multiple lines of evidence supporting intracoronary thrombus formation as a key mechanism in the pathogenesis of UA are reviewed. Studies examining the effect of thrombolytic therapy on angiographic endpoints have shown little effect on the extent of luminal narrowing, but do reveal a decrease in angiographically detected thrombus. Twelve randomized, controlled trials of thrombolytic agents in 611 UA patients with predefined clinical endpoints have been published. These trials varied widely in design and adjunctive therapy both in treated and control grops. Review of these trials show a tendency to fewer clinical events such as death, infarction, and need for revascularization in treated patients, with a corresponding increase in bleeding complications. Clinical efficacy of thrombolytic therapy cannot be excluded by the available data, perhaps in part because of insufficient numbers of patients treated. Determination of the net clinical value of thrombolytic therapy must await larger and more definitive trials.     

Clinical trials of antibacterial agents: a practical guide to design and analysis. Statisticians in the Pharmaceutical Industry Working Party

Guidelines on the conduct of clinical trials of antibacterial agents produced by the US Food and Drug Administration, the British Society for Antimicrobial Chemotherapy, the Infectious Diseases Society of America and a European Working Party have been reviewed. Although very informative, these guidelines provide limited practical guidance on the design and statistical aspects of phase III studies of antimicrobial agents. This paper describes the differences between antibacterial trials and clinical studies in other therapeutic areas with regard to subjective endpoints, dual clinical and bacteriological endpoints, frequent protocol violations and difficulty of using placebo controls. The importance of a detailed protocol and planned analysis strategy is emphasized. The choice of comparator agents, practical issues with the blinding of trial materials and the documentation of patients excluded from study entry are discussed. The use of different patient groups and different endpoints in analyses are described. The principles of equivalence and their application to trials of antibacterial agents are discussed, together with an approach to calculating sample size. A variety of statistical analyses of results are compared for different situations indicating some of the problems that can arise. Different methods of presentation of study data are included with emphasis on regulatory submissions rather than scientific publications. Some graphical presentations are recommended and issues regarding data across different studies are discussed.     

Developing systems for cost-effective auditing of clinical trials

Auditing a clinical trial is a complex process designed to ensure that the trial will provide a reliable answer to the question being posed. Traditional auditing methods are expensive, and escalate the cost of clinical trials. This paper describes approaches to cost-effective monitoring of clinical trials, such as integrating them with clinical practice and focusing the data being collected. Sampling methods for source documentation can be used to eliminate costs incurred by reviewing every record. These measures, coupled with prospective clinical judgment about areas of concern in the conduct of trials, can reduce complications and costs without sacrificing quality.     

Neoadjuvant androgen ablation for localized prostatic cancer: pathology methods, surgical end points and meta-analysis of randomized trials

PURPOSE: At least 7 centers or collaborative groups have performed randomized clinical trials of neoadjuvant androgen ablation and radical prostatectomy versus radical prostatectomy alone for localized prostatic cancer. Our objectives were to analyze treatment results in terms of 2 standard outcome measures, to identify patient characteristics and other factors that explain outcome differences between trials, and to use pooled data to test the hypothesis that neoadjuvant treatment alters outcomes. MATERIALS AND METHODS: Trials were identified by MEDLINE search and review of published bibliographies, and examined for pathological techniques used to assign surgical end points. An attempt was made to contact trial group members for clarification and updated information. The resulting data were transformed as needed into standardized end points of pT stage and negative surgical margin. A series of contingency tables were used to study relationships between treatment outcomes and various risk factors. RESULTS: In addition to neoadjuvant treatment, numerous risk factors related to treatment regimen and patient characteristics apparently influenced treatment outcome, and should be reanalyzed when future followup trial data become available. CONCLUSIONS: In radical prostatectomy there is a need for uniform ways to process specimens, assign surgical stage and establish standardized surgical end points. Despite differences in risk factors, the trials were similar in overall design. Within these constraints neoadjuvant androgen ablation was significantly associated with low pT stage and negative surgical margin. Longer followup is needed to validate these measures as good surrogates for tumor specific survival.     

Feverfew as a preventive treatment for migraine: a systematic review

BACKGROUND: Feverfew is a popular herbal remedy advocated for the prevention of migraine. AIM: The aim of this systematic review was to look at the evidence for or against the clinical effectiveness of feverfew in migraine prevention. DATA SOURCES: Literature searches were performed using the following databases: Medline, Embase, Biosis, CISCOM, and the Cochrane Library (all from their inception to April 1998). STUDY SELECTION: Only randomized, placebo-controlled, double-blind trials were included. DATA EXTRACTION: All articles were read by two independent reviewers. Data were extracted in a predefined, standardized fashion. The methodological quality of all trials was evaluated using the Jadad score. MAIN RESULTS: Five trials met the inclusion/exclusion criteria. The majority favor feverfew over placebo. Yet important caveats exist. CONCLUSION: The clinical effectiveness of feverfew in the prevention of migraine has not been established beyond reasonable doubt.     

Impact of treatment changes on the interpretation of the Concorde trial

BACKGROUND: The Concorde trial compared two policies of therapy with zidovudine (ZVD) in individuals with asymptomatic HIV infection: immediate or deferred ZDV. Participants in both groups could stop their blinded trial therapy for several reasons and/or could start open-label ZDV. The difference in survival and disease progression between the two groups was estimated allowing for treatment changes. METHODS: The relationship between latest CD4 count, treatment changes and time to AIDS-related complex (ARC), AIDS or death was investigated using time-updated proportional hazards models, but these models gave seriously biased estimates of the effect of ZDV. Therefore, a method based on the comparison of the randomized groups was used. A model relating a participant's events times to the treatment actually received was used to estimate what would have been observed if the deferred group had not received ZDV before ARS or AIDS, and to explore alternative policies for starting Pneumocystis carinii pneumonia (PCP) prophylaxis. RESULTS: The major treatment changes during the trial were the termination of blinded therapy because of adverse events or personal reasons (575 out of 1749 participants), starting open-label ZDV (745 participants), and starting PCP prophylaxis (613 participants). Starting open-label ZDV and PCP prophylaxis were strongly related to latest CD4 count. The uncorrected hazard ratios for immediate compared with deferred groups were 0.89 for time to ARC, AIDS or death [95% confidence interval (CI), 0.75-1.05], 1.01 for time to AIDS or death (95% CI, 0.82-1.24), and 1.26 for time to death (95% CI, 0.93-1.70). After correction for treatment changes, these hazard ratios were 0.79 (95% CI, 0.57-1.11), 1.01 (95% CI, 0.81-1.26), and 1.37 (95% CI, 0.91-2.08), respectively. Correction for PCP prophylaxis made little difference to the results. CONCLUSIONS: Open-label ZDV before ARC or AIDS in the deferred group was likely to have diluted any differences between the immediate and deferred groups. After correction for this dilution, both the estimated benefit of immediate treatment in delaying progression to ARC, AIDS or death and the estimated disadvantage of immediate treatment in accelerating death were somewhat increased, but both remained consistent with chance alone. This study demonstrated the large potential bias inherent in non-randomization-based methods of analysis of clinical trials.     

Language bias in randomised controlled trials published in English and German

BACKGROUND: Some randomised controlled trials (RCTs) done in German-speaking Europe are published in international English-language journals and others in national German-language journals. We assessed whether authors are more likely to report trials with statistically significant results in English than in German. METHODS: We studied pairs of RCT reports, matched for first author and time of publication, with one report published in German and the other in English. Pairs were identified from reports round in a manual search of five leading German-language journals and from reports published by the same authors in English found on Medline. Quality of methods and reporting were assessed with two different scales by two investigators who were unaware of authors' identities, affiliations, and other characteristics of trial reports. Main study endpoints were selected by two investigators who were unaware of trial results. Our main outcome was the number of pairs of studies in which the levels of significance (shown by p values) were discordant. FINDINGS: 62 eligible pairs of reports were identified but 19 (31%) were excluded because they were duplicate publications. A further three pairs (5%) were excluded because no p values were given. The remaining 40 pairs were analysed. Design characteristics and quality features were similar for reports in both languages. Only 35% of German-language articles, compared with 62% of English-language articles, reported significant (p < 0.05) differences in the main endpoint between study and control groups (p = 0.002 by McNemar's test). Logistic regression showed that the only characteristic that predicted publication in an English-language journal was a significant result. The odds ratio for publication of trials with significant results in English was 3.75 (95% CI 1.25-11.3). INTERPRETATION: Authors were more likely to publish RCTs in an English-language journal if the results were statistically significant. English language bias may, therefore, be introduced in reviews and meta-analyses if they include only trials reported in English. The effort of the Cochrane Collaboration to identify as many controlled trials as possible, through the manual search of many medical journals published in different languages will help to reduce such bias.     

Has high-frequency ventilation been inappropriately discarded in adult acute respiratory distress syndrome?

OBJECTIVES: To review the basic physiologic principles that support the role for high-frequency ventilation (HFV) in acutely lung-injured patients, to critically assess clinical trial data in this area, and discuss why a metasummary is not feasible and a large-scale clinical trial is needed. DATA SOURCES: We searched a computerized database (MEDLINE) from 1976 to January 1997 using the text words "high-frequency ventilation" and "acute respiratory distress syndrome" to retrieve all relevant candidate articles. STUDY SELECTION: We retrieved all English language clinical studies conducted in tertiary care centers that employed HFV in adult acute respiratory distress syndrome (ARDS) patients. DATA EXTRACTION: Only prospective, randomized trials, cohort/case-control studies, and case series evaluating HFV vs. conventional mechanical ventilation in adult ARDS patients were included. DATA SYNTHESIS: We independently screened 3,166 articles on ARDS and 494 papers on HFV in our computer search. We checked reference lists and contacted experts in the field of mechanical ventilation in ARDS to ensure that no relevant studies had been missed. Only four articles met our inclusion criteria and were evaluated in detail. CONCLUSIONS: Current clinical studies are statistically under-powered and a metasummary is not feasible because of study quality, as well as lack of similar clinical end points and measures of magnitude of benefit. A large, multicenter trial should be initiated to define the role of HFV in the treatment of adult ARDS.     

Monitoring clinical trials: experience of, and proposals under consideration by, the Cancer Therapy Committee of the British Medical Research Council

The accumulating data from all randomized trials conducted by the Cancer Therapy Committee (CTC) of the British Medical Research Council are monitored on a regular basis. However, for important practical reasons the form of this data monitoring may vary from trial to trial. Thus a trial addressing what is considered a major question in the treatment of cancer patients, (a 'pivotal' or 'high profile' trial), has a formal data monitoring committee (DMC). This is usually made up of two clinicians and one statistician who are completely independent of the trial organization and do not enter patients into the trial. Other trials, which constitute the majority, are monitored by a less formal trial progress group made up of the clinical co-ordinator and trial statistician, sometimes supplemented by a trial participant. Experience with this dual system has led to a new proposal: if the trial progress group wish to modify or stop a trial then they are required to set up and consult an ad hoc DMC for independent advice. This proposal has many advantages, including maximizing the use of resources available, while achieving the degree of objectivity in decision-making required for the many different types of cancer trials conducted by the CTC.     

Reporting errors in studies of the diagnostic performance of self-administered questionnaires: Extent of the problem, recommendations for standardized presentation of results, and implications for the peer review process.

Diagnostic efficiency statistics include sensitivity, specificity, and positive and negative predictive power. In reviewing the literature on the performance of self-report questionnaires to screen for depression, errors were found in several published articles in which these statistics were computed. To determine the extent of this problem, all studies of the diagnostic performance of self-report scales published between 1980 and 1991 in the Journal of Consulting and Clinical Psychology and Psychological Assessment: A Journal of Consulting and Clinical Psychology were examined. 26 relevant studies were found. Nine had an error in the calculation of diagnostic efficiency statistics and 3 made calculations based on unconventional definitions of the terms. Moreover, no study reported all 4 diagnostic statistics together with the total and chance-corrected level of agreement between the scale and the diagnostic gold standard. Recommendations for standardized reporting are suggested, and the implications of these findings are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differences in the extent of inflammation caused by intratracheal exposure to three ultrafine metals: role of free radicals

The Concorde trial compared immediate (Imm) with deferred (Def) AZT monotherapy in asymptomatic HIV-positive participants. Haematological and immunological markers and weight were measured throughout, and correlated with clinical endpoints. Markers associated with disease progression (CD4 lymphocyte count and percentage, platelets, p24 antigen and beta 2 microglobulin favoured Imm: those associated with toxicity (haemoglobin, neutrophils and white cell count) favoured Def. CD8 and total lymphocyte count did not differ significantly between groups. In multivariate analysis, the combination of baseline CD4, p24 antigen and beta 2m was the best baseline predictor of disease. Including change in CD4 and beta 2m at 12 weeks, or changes over follow-up in these markers significantly improved the fit. Markers were also incorporated into the definition of 'clinical' endpoints. Hazard ratio estimates from end-points that included CD4 < 50 and CD4 < 25 were closest to those for AIDS or death alone, but added very few extra events. Use of other landmark CD4 counts (100 or greater) or relative decreases in counts (25% or more) increased the number of events, but overestimated the effect of immediate AZT. Although AZT had a beneficial effect on the surrogate markers of efficacy evaluated, these changes did not predict clinical outcome, nor could the markers be usefully incorporated into an endpoint definition.     

Phase III, large-scale chemoprevention trials. Approach to chemoprevention clinical trials and phase III clinical trial of tamoxifen as a chemopreventive for breast cancer--the US National Cancer Institute experience

Clinical trials to evaluate interventions for cancer prevention are designed as early (phase I, IIa, and IIb) or late-phase studies. Whereas the former are small and generally rely on intermediate endpoint biomarkers of carcinogenesis, the latter are large-scale, long-term, randomized, phase III studies that address endpoints such as cancer incidence. The Breast Cancer Prevention Trial, P-1, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), is discussed as an example of a large, extended, phase III trial designed to answer the question of whether tamoxifen reduces the incidence of breast cancer in women who are at increased risk for the disease.     

Age-related changes in gastric mucosal repair and proliferative activities in rats exposed acutely to aspirin

OBJECTIVES: (1) To determine whether and how outcome measurements in the ECASS trial are influenced by a shorter time window (0-3 vs. 3-6 h) between onset of symptoms and start of thrombolytic therapy using recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke. (2) To discuss the results of the ECASS 0- to 3-hour cohort with the results of the National Institute of Neurological Disorders and Stroke Study (NINDSS). DESIGN AND ANALYSIS: Analysis of the 0- to 3-hour and the 3- to 6-hour cohort in accordance with the ECASS protocol. Comparative analysis of the ECASS and NINDSS results following the NINDSS protocol using dichotomized endpoints. MAIN OUTCOME MEASURES: Primary endpoints: modified Rankin Scale, Barthel Index; secondary endpoints: combined Barthel/Rankin, long-term Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, mortality at 30 and 90 days, occurrence of intracranial hemorrhage. NINDS trial endpoint: favorable outcome as defined in the NINDS trial. RESULTS: In ECASS, 87 patients were randomized within 3 h of stroke onset. Differences in favor of rt-PA treatment can be found for all primary and secondary outcome measures in the ECASS 0- to 3-hour cohort, except for mortality at day 30, which is somewhat higher in the rt-pA-treated group. However, due to the small sample size, the differences do not reach statistical significance. Early infarct signs (as defined by the ECASS protocol) are found as early as 2 h after stroke onset. Parenchymal hemorrhages are found significantly more often among rt-PA-treated patients. The results in the ECASS 0- to 3-hour cohort fit well with the results in NINDSS. CONCLUSION: Data from the 3-hour ECASS cohort support the efficacy of early thrombolytic therapy in acute hemispheric stroke patients. Comparing bleeding complications between the ECASS and NINDSS is difficult because of differences in the definition and occurrence of hemorrhagic events.     

A power study of a sequential method of p-value adjustment for correlated continuous endpoints

In the course of clinical (or preclinical) trial studies, it is a common practice to conduct a relatively large number of tests to extract the maximum level of information from the study. It has been known that as the number of tests (or endpoints) increases, the probability of falsely rejecting at least one hypothesis also increases. Single-step methods such as the Bonferroni, Sidák, or James approximation procedure have been used to adjust the p-values for each hypothesis. To reduce the conservatism (i.e., underestimating type I error) possessed by the aforementioned methods, Holm proposed a so-called "free-step-down" procedure. This adjustment can be made even less conservative by incorporating the dependence structure of endpoints at each adjustment step of the procedure. That is done by sequentially applying James's approximation procedure for correlated endpoints at each step, referred to as the Free-James method. This article primarily compares the power of the Free-James method to the power of the Bonferroni and James single-step-down and the Holm free-step-down methods. Two definitions of power are considered: (a) the probability of correctly rejecting at least one hypothesis when it is true, and (b) the probability of correctly rejecting all hypotheses that are true. Monte Carlo simulations show that the Free-James method is as good as other methods under definition (a) and the most powerful under definition (b) for various sample sizes, numbers of endpoints, and correlations.     

Response rate accuracy in oncology trials: reasons for interobserver variability. Groupe Fran?ais d'Immunothérapie of the Fédération Nationale des Centres de Lutte Contre le Cancer

PURPOSE: We evaluated the impact of an evaluation committee (EC) on patients' overall response status in a large multicenter trial in oncology. We identified reasons for disagreements between investigators and the EC. MATERIALS AND METHODS: The Cancer Renal Cytokine (CRECY) study was a French multicenter trial that tested cytokine therapy in 489 patients with metastatic renal cell carcinoma. Objective response (OR) evaluation included medical imaging and was studied according to international guidelines. A blinded peer review of all responders and litigious cases was performed by an EC. RESULTS: Major disagreements occurred in 40% and minor disagreements in 10.5% of the reviewed files. The number of significant tumor responses was reduced by 23.2% after review by the EC. Reasons for disagreements included errors in tumor measurements, errors in selection of measurable targets, intercurrent diseases, and radiologic technical problems. These reasons for disagreements are analyzed and discussed. CONCLUSION: We conclude that all therapeutic trial results should be reviewed by peer analysis of all presumed responders by an EC. International guidelines for response evaluation should be updated by including more reliable methods of measurements and definition of minimal imaging procedures.