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      Clinical drug trials in general practice: how well are external validity issues reported?

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          Abstract

          Background

          When reading a report of a clinical trial, it should be possible to judge whether the results are relevant for your patients. Issues affecting the external validity or generalizability of a trial should therefore be reported. Our aim was to determine whether articles with published results from a complete cohort of drug trials conducted entirely or partly in general practice reported sufficient information about the trials to consider the external validity.

          Methods

          A cohort of 196 drug trials in Norwegian general practice was previously identified from the Norwegian Medicines Agency archive with year of application for approval 1998–2007. After comprehensive literature searches, 134 journal articles reporting results published from 2000 to 2015 were identified. In these articles, we considered the reporting of the following issues relevant for external validity: reporting of the clinical setting; selection of patients before inclusion in a trial; reporting of patients’ co-morbidity, co-medication or ethnicity; choice of primary outcome; and reporting of adverse events.

          Results

          Of these 134 articles, only 30 (22%) reported the clinical setting of the trial. The number of patients screened before enrolment was reported in 61 articles (46%). The primary outcome of the trial was a surrogate outcome for 60 trials (45%), a clinical outcome for 39 (29%) and a patient-reported outcome for 25 (19%). Clinical details of adverse events were reported in 124 (93%) articles. Co-morbidity of included participants was reported in 54 trials (40%), co-medication in 27 (20%) and race/ethnicity in 78 (58%).

          Conclusions

          The clinical setting of the trials, the selection of patients before enrolment, and co-morbidity or co-medication of participants was most commonly not reported, limiting the possibility to consider the generalizability of a trial. It may therefore be difficult for readers to judge whether drug trial results are applicable to clinical decision-making in general practice or when developing clinical guidelines.

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          Most cited references36

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          The PRECIS-2 tool: designing trials that are fit for purpose.

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            Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review.

            Selective eligibility criteria of randomized controlled trials (RCTs) are vital to trial feasibility and internal validity. However, the exclusion of certain patient populations may lead to impaired generalizability of results. To determine the nature and extent of exclusion criteria among RCTs published in major medical journals and the contribution of exclusion criteria to the representation of certain patient populations. The MEDLINE database was searched for RCTs published between 1994 and 2006 in certain general medical journals with a high impact factor. Of 4827 articles, 283 were selected using a series technique. Trial characteristics and the details regarding exclusions were extracted independently. All exclusion criteria were graded independently and in duplicate as either strongly justified, potentially justified, or poorly justified according to previously developed and pilot-tested guidelines. Common medical conditions formed the basis for exclusion in 81.3% of trials. Patients were excluded due to age in 72.1% of all trials (60.1% in pediatric populations and 38.5% in older adults). Individuals receiving commonly prescribed medications were excluded in 54.1% of trials. Conditions related to female sex were grounds for exclusion in 39.2% of trials. Of all exclusion criteria, only 47.2% were graded as strongly justified in the context of the specific RCT. Exclusion criteria were not reported in 12.0% of trials. Multivariable analyses revealed independent associations between the total number of exclusion criteria and drug intervention trials (risk ratio, 1.35; 95% confidence interval, 1.11-1.65; P = .003) and between the total number of exclusion criteria and multicenter trials (risk ratio, 1.26; 95% confidence interval, 1.06-1.52; P = .009). Industry-sponsored trials were more likely to exclude individuals due to concomitant medication use, medical comorbidities, and age. Drug intervention trials were more likely to exclude individuals due to concomitant medication use, medical comorbidities, female sex, and socioeconomic status. Among such trials, justification for exclusions related to concomitant medication use and comorbidities were more likely to be poorly justified. The RCTs published in major medical journals do not always clearly report exclusion criteria. Women, children, the elderly, and those with common medical conditions are frequently excluded from RCTs. Trials with multiple centers and those involving drug interventions are most likely to have extensive exclusions. Such exclusions may impair the generalizability of RCT results. These findings highlight a need for careful consideration and transparent reporting and justification of exclusion criteria in clinical trials.
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              Practical statistics for medical research

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                Author and article information

                Contributors
                +47 92 29 32 38 , +47 22 85 92 02 , ambraend@medisin.uio.no
                jorund.straand@medisin.uio.no
                atle.klovning@medisin.uio.no
                Journal
                BMC Fam Pract
                BMC Fam Pract
                BMC Family Practice
                BioMed Central (London )
                1471-2296
                29 December 2017
                29 December 2017
                2017
                : 18
                Affiliations
                ISNI 0000 0004 1936 8921, GRID grid.5510.1, Department of General Practice, Institute of Health and Society, Faculty of Medicine, , University of Oslo, ; Postbox 1130 Blindern, N-0318 Oslo, Norway
                Article
                680
                10.1186/s12875-017-0680-7
                5746953
                29284407
                189a30b0-dac6-4513-9c9c-d34e0b9612ae
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: The Norwegian Research Fund for General Practice
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Medicine
                general practice,clinical trials,external validity,applicability,generalizability,eligibility determination

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