Methodological characteristics of academic clinical drug trials – a retrospective cohort study of applications to the Danish Medicines Agency 1993–2005

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• WHAT THIS STUDY ADDS• Our study shows that randomization, definition of primary endpoint, monitoring according to the principles of Good Clinical Practice (GCP monitoring), and control of medicine compliance form part of a significantly increasing percentage of academic clinical drug trials. This indicates an increasing quality of these trials.• However, high numbers of unblinded randomized controlled trials and randomized controlled trials utilizing unacceptable methods for generation of allocation sequence emphasize the potential for further improvement of the methodological quality. AIMThe aim of this study was to investigate the temporal trends in characteristics of academic clinical drug trials. We here report characteristics on trial methodology. METHODSA review of 386 approved applications of academic clinical drug trials submitted to the Danish Medicines Agency 1993-2005 was carried out. Data on 11 methodological characteristics were collected, e.g. statement of primary endpoint, use of control group, blinding, randomization, method for generation of allocation sequence, monitoring according to the principles of Good Clinical Practice (GCP monitoring) and publication. RESULTSStatement of primary endpoint increased from 60 to 90% of trials (P < 0.0001). Comparing the period before and after implementation of the Clinical Trials Directive in 2004, intention of GCP monitoring increased from 13% to 94%. Control of medicine compliance increased from 42% to 76% (P < 0.0001) among trials with self-administration of the investigational medicinal product. Among controlled trials use of randomization increased from 78% to 94% (P = 0.0063) of trials. Remaining characteristics did not change significantly. In total 68% (264/386) were randomized controlled trials. CONCLUSIONSOur study shows that randomization, definition of primary endpoint, GCP monitoring, and control of medicine compliance form part of a significantly increasing percentage of academic clinical drug trials. This indicates an increase in the quality of academic clinical drug research in Denmark 1993-2005. However, high numbers of unblinded randomized controlled trials and randomized controlled trials utilizing unacceptable methods for generation of allocation sequence emphasize the potential for further improvement of trial methodology.

Methodological Characteristics of Clinical Trials: Impact of Mandatory Trial Registration

“…Since some of these instruments have been actually devised to guide reporting of clinical trials, this precluded their use in toto to assess quality of trial protocols, the principle focus of our study. These selected criteria have been previously utilized in studies and are considered critical for deriving conclusions from research findings that are meaningful to actual clinical practice (26,27). A scoring method comprising of both methodological characteristics based on the design of study as well as concordance with GCP guidelines was used in this study.…”

“…A previous study by Berendt et al has demonstrated similar improvement trends in the reporting of primary outcomes in academic clinical trial applications submitted to drug regulatory authority. The study showed an improvement from 60% protocols reporting primary/secondary endpoints in 1995 to 92% in 2005 (27). The study examined the impact of European Clinical Trials Directive introduced in 2004.…”

“…An analysis of 250 controlled trials found that RCTs not employing double blind designs yielded significantly larger treatment effects with odds ratios being exaggerated by 17% (39). Among protocols submitted to Danish Medicines Agency from 1993-2005, only 54% of controlled studies were double blind (27).…”

“…In the study by Berendt et al. only 43% of 264 randomized trial protocols had described an acceptable method of generation of allocation sequence (27).…”

Editors' pick 2010

“…Some years ago we appealed for review papers about methods to study drug effects quantitatively. This appeal has not yet yielded a flood of papers but there has been a gratifying increase during 2010 [1,[3][4][5][6][7][8][9] and we hope that we will be able to refer to several more next year in our Editors' pick for 2011. While clinical pharmacologists have been closely involved for decades in the evaluation and monitoring of adverse drug reactions, a far more recent buzzword has been 'patient safety' .…”