Quality of life instruments in the evaluation of new drugs.

The importance of measuring changes in a patient's quality of life when evaluating the efficacy of new drugs is increasingly recognised. In this paper, we review the steps associated with this process--recognising the opportunity and the need to include quality of life instruments during the investigation, choosing the most suitable instrument(s) and interpreting the results. To be useful in clinical trials, quality of life measures must be both responsive (able to detect all important differences) and valid.

Clinical usefulness of n-of-1 randomized controlled trials in patients with nonreversible chronic airflow limitation.

To determine if n-of-1 randomized controlled trials (n-of-1 RCT) are useful in the care of patients with nonreversible chronic airflow limitation (CAL). Individual trials had a double-blind, randomized, multiple crossover design. Patients with CAL were recruited from several respirology practices.

Interpreting changes in quality-of-life score in N of 1 randomized trials.

To provide additional evidence regarding the plausible range of the differences in health-related quality of life (HRQL) questionnaire scores within which the minimal important difference (MID) falls, we reviewed the results of 32 randomized controlled trials in individual subjects (N of 1 RCTs) with chronic diseases. These trials had been conducted to establish whether a patient was obtaining more good than harm from a medication. Each N of 1 RCT included a series of pairs of treatment periods, one period on active drug, and one on placebo or alternative drug.

Clinical usefulness of amitriptyline in fibromyalgia: the results of 23 N-of-1 randomized controlled trials.

Twenty-three double blind, randomized, multiple crossover trials (N-of-1 RCT) of amitriptyline were conducted in patients with fibromyalgia. The benefit of amitriptyline was assessed using a symptom questionnaire and count of tender points. To assess the usefulness of the method, the proportion of trials that provided a definite answer was examined.

Mechanism of bronchodilator effect in chronic airflow limitation.

Objective: To examine the mechanisms through which two bronchodilators (theophylline and salbutamol) influence dyspnea during daily activities.

Methods: Twenty-four patients with chronic airflow limitation participated in a multiple crossover, randomized, placebo-controlled trial. The effect of theophylline and salbutamol, alone or combined, on pulmonary function and dyspnea during daily activities was examined.

Randomized trials in the study of antihypertensive drugs.

Heterogeneity in response to antihypertensive drugs can be addressed by randomized trials in individual subjects. In such a trial a patient receives pairs of treatment periods (one period of each pair active drug, one matched placebo, in random order); patient and clinician are blinded to allocation, and treatment targets are monitored. These trials can optimize antihypertensive therapy in clinical practice and facilitate the investigation of new drugs and the study of pathophysiology.

N of 1 randomized trials for investigating new drugs.

Presently, in the process of new drug development, large sample parallel group randomized trials are often begun without the detailed knowledge of optimal dose, most responsive patient group, and optimal outcomes which would be desirable. We propose that randomized trials in individual subjects (N of 1 RCTs) could be used to elucidate these issues at an early stage of drug development. In appropriate conditions N of 1 RCTs can be used to define the rapidity with which a drug begins and ceases its clinical action, the likely range of the optimal drug dose, and the optimal outcomes on which subsequent trials should focus.

To what extent do congestive heart failure patients in sinus rhythm benefit from digoxin therapy? A systematic overview and meta-analysis.

Purpose: To reappraise the effectiveness of digoxin for the treatment of congestive heart failure (CHF) in patients with sinus rhythm in light of data from recently published randomized controlled trials and to quantitatively assess its usefulness.

Study Identification: Computerized searches of the MEDLINE database were performed, and the reference list of each retrieved article was reviewed.

Study Selection: Review of more than 360 citations and the reference lists of 19 review articles and 61 potentially relevant articles revealed seven double-blind randomized controlled trials that were included in this overview.

The n-of-1 randomized controlled trial: clinical usefulness. Our three-year experience.

Objective: To review the feasibility and effectiveness of n-of-1 randomized controlled trials (n-of-1 trials) in clinical practice.

Design: Individual trials were double-blind, randomized, multiple crossover trials. The impact of n-of-1 trials was determined by eliciting physicians' plans of management and confidence in those plans before and after each trial.

A comparison of seven-point and visual analogue scales. Data from a randomized trial.

Many controlled trials rely on subjective measures of symptoms or quality of life as primary outcomes. The relative merits of different response options for these instruments is an important issue. Therefore, we compared the responsiveness and validity of seven-point versus visual analogue scales (VAS) in a questionnaire measuring quality of life in chronic heart failure in a double-masked crossover trial of digoxin versus placebo.

Measurement of health status. Ascertaining the minimal clinically important difference.

In recent years quality of life instruments have been featured as primary outcomes in many randomized trials. One of the challenges facing the investigator using such measures is determining the significance of any differences observed, and communicating that significance to clinicians who will be applying the trial results. We have developed an approach to elucidating the significance of changes in score in quality of life instruments by comparing them to global ratings of change.

Research methods for obtaining primary evidence.

The use of new therapeutic and diagnostic technologies has become commonplace in modern medical practice. To avoid both clinical disappointment and the waste of money, health, and lives, the introduction of these technologies will have to be based on evidence that these technologies will do more good than harm. The evidence supporting their use should be derived using research methods designed to deal with placebo effects, confounders, and biases.

Why different trials on digitalis give conflicting data.

Taking a careful look at each of the outcomes measured in randomized, controlled trials of digoxin suggest that discrepancies in results may be more apparent than real. Digoxin does work, but clinically important benefit is restricted to a relatively small proportion of congestive heart failure (CHF) patients. The play of chance, the dose of digoxin used, and the severity of heart failure in patients enrolled in the studies are other factors that may explain the variability in results that were observed.