Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘Furthermore, Pocock et al. reported that publication in a well-respected journaldoes not always correlate with ideal study design. They reviewed 45 reportspublished in the BMJ, the New England Journal of Medicine, and The Lancet.They found that the interpretation of large amounts of data was complicated bya common failure to specify in advance the intended size of a trial or statisticalstopping rules for interim analyses, leading to a tendency to exaggerate treatmentdifferences [6]. This problem is not unexpected: the reviewers assessing thestudy report might be experts in the disease area but they are not necessarilystatistical experts, or experts in trial design.2. How relevant is the question being asked by the study?The introductory paragraph of a study report should state the exact questionbeing asked. The reader then has to decide on the importance and relevance ofthe research question to the way he/she conducts his/her daily practice:• Will the answer to the question alter the way in which patientsare managed?• Does the question relate to a substantial proportion of their routinepractice or to a minority of patients?• Has standard treatment changed since the beginning of the trial,so that the trial results are less relevant to current day practice?An example of problems that can arise in prolonged trials was seen in a substudyof the very large ALLHAT (Anti-hypertensive and Lipid-lowering Treatment toPrevent Heart Attack Trial) study. In ALLHAT, patients with well-controlledhypertension, moderate dyslipidemia, and an additional cardiovascular risk factorwere randomized to receive either pravastatin (40 mg daily) or “usual care” [7].The aim of the study was to show that the addition of a statin to usual care wouldreduce all-cause mortality (the primary outcome measure) and/or coronary heartdisease mortality (the secondary outcome measure).A total of 10,355 patients were randomized to this substudy and followed for upto 8 years, but the substudy failed to show a significant difference in primary orsecondary outcome measures. One of the possible explanations for this somewhatdisappointing result was that the usual care in most practices included statintherapy for secondary prevention, and 26% of patients in the usual care arm wereon a statin at the end of the trial. Such a significant treatment crossover wasunlikely to have been expected at the beginning of the study, demonstrating howpractice patterns can change faster than a trial can be completed and published.429