Failure to report protocol violations in clinical trials: a threat to internal validity?

<p>Abstract</p> <p>Background</p> <p>Excessive protocol violations (PV), which can be defined as preventable mistakes in study conduct, may result in patient harm and introduce errors into a clinical trial's results leading to flawed trial conclusions.</p> <p>The purpose of this project was to gain a better understanding of reported PVs, to describe current practice with regards to the use of methods for the reduction of PVs and to investigate relationships between clinical trial characteristics and PVs.</p> <p>Methods</p> <p>We reviewed 80 clinical trials conducted across a broad range of medical specialties published in four major general medical journals (The Lancet, NEJM, JAMA, BMJ). Eligible papers were identified using a PubMed search. For each included trial, two authors independently abstracted information on trial characteristics, PV reporting and PV rates and interventions used to reduce PVs. PVs were categorised into one of five distinct types: enrolment, randomisation, study intervention, patient compliance and data collection errors. Associations between PVs and study characteristics were investigated using logistic regression.</p> <p>Results</p> <p>Eighty clinical trials (20 from each journal) were identified from 101 consecutive PubMed abstracts. The median number of participants was 701 (range: 20 to 162, 367) and the median number of participating sites was 15 (range: 1 to 701). Nineteen percent (15/80) of included trials were single centre trials. The median study duration was 24 months (range: 5.81 - 127 months) and 74% (59/80) of included trials were primarily academic funded.</p> <p>Thirty two percent (26/80) of included trials failed to provide explicit reporting of any type of PV and none (0/80) of the trials provided explicit reporting of all five types of PVs. Larger clinical trials (more patients, more sites, longer duration, more complex management structure) were more likely to have more complete reporting of PV's.</p> <p>Only 9% (7/80) of trials reported the use of a specific study method to prevent PVs. Use of a run-in phase was the only method reported.</p> <p>Conclusions</p> <p>PVs are under-reported. Although the CONSORT statement provides guidance on the reporting of PVs, reporting requirements are not explicit for all types of PVs. As a first step towards improved reporting by authors, we recommend the CONSORT statement highlight the importance of PVs by making reporting requirements more explicit.</p

A systematic review of techniques and interventions for improving adherence to inclusion and exclusion criteria during enrolment into randomised controlled trials

<p>Abstract</p> <p>Background</p> <p>Enrolment of patients into a randomised controlled trial (RCT) in violation of key inclusion or exclusion criteria, may lead to excess avoidable harm. The purpose of this paper was to systematically identify and review techniques and interventions proven to prevent or avoid inappropriate enrolment of patients into RCTs.</p> <p>Methods</p> <p>EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, online abstract repositories, and conference websites were searched. Experts were contacted and bibliographies of retrieved papers hand-searched. The search cut-off date was 31 August 2009.</p> <p>Results</p> <p>No primary publications were found. We identified one study in the grey literature (conference abstracts and presentations) reporting the results of an evaluation of the effectiveness of an intervention designed to prevent or avoid inappropriate enrolment of patients into an RCT. In the context of a multicentre trial, use of a dummy enrolment run-in phase was shown to reduce enrolment errors significantly (<it>P </it>< 0.001), from 16.1% during the run-in phase to < 1% after trial initiation.</p> <p>Conclusions</p> <p>Our systematic search yielded only one technique or intervention shown to improve adherence to eligibility criteria during enrolment into RCTs. Given the potential harm involved in recruiting patients into a clinical trial in violation of key eligibility criteria, future research is needed to better inform those conducting clinical trials of how best to prevent enrolment errors</p

In vitro evaluation of sustained released matrix tablets containing ibuprofen: a model poorly water-soluble drug

ABSTRACT A matrix system was developed that releases ibuprofen (IB) over a 12-hour period and the influence of the polymer type and concentration on the release rate of the drug was evaluated. Tablets containing different concentrations of Carbopol (CP), hydroxypropyl methylcellulose (HPMC), or ethyl cellulose (EC) were prepared using direct compression and the drug content, content uniformity, hardness, friability, dissolution performance, and in vitro release kinetics were examined. Formulated tablets were found to be within acceptable limits for physical and chemical parameters. The release kinetics of the Carbopol(r)971P 8% formulation showed the best linearity (r 2 =0.977) in fitting zero-order kinetics, suggesting the release rate was time independent. The drug release from tablets containing 8% CP was extended over approximately 18 hours and the release kinetics were nearly linear, suggesting that this system has the potential to maintain constant plasma drug concentrations over 12 hours, which could reduce the frequency of administration and the occurrence of adverse effects associated with repeated administration of conventional IB tablets

Intravenous amino acid therapy for kidney function in critically ill patients: a randomized controlled trial

Importance: Acute kidney injury (AKI) is characterized by severe loss of glomerular filtration rate (GFR) and is associated with a prolonged intensive care unit (ICU) stay and increased risk of death. No interventions have yet been shown to prevent AKI or preserve GFR in critically ill patients. Evidence from mammalian physiology and small clinical trials suggests higher amino acid intake may protect the kidney from ischemic insults and thus may preserve GFR during critical illness. Objective: To determine whether amino acid therapy, achieved through daily intravenous (IV) supplementation with standard amino acids, preserves kidney function in critically ill patients. Design, setting, and participants: Multicenter, phase II, randomized clinical trial conducted between December 2010 and February 2013 in the ICUs of 16 community and tertiary hospitals in Australia and New Zealand. Participants were adult critically ill patients expected to remain in the study ICU for longer than 2\ua0days. Interventions: Random allocation to receive a daily supplement of up to 100\ua0g of IV amino acids or standard care. Main outcomes and measures: Duration of renal dysfunction (primary outcome); estimated GFR (eGFR) derived from creatinine; eGFR derived from cystatin\ua0C; urinary output; renal replacement therapy (RRT) use; fluid balance and other measures of renal function. Results: 474 patients were enrolled and randomized (235 to standard care, 239 to IV amino acid therapy). At time of enrollment, patients allocated to receive amino acid therapy had higher APACHE\ua0II scores (20.2\ua0±\ua06.8 vs. 21.7\ua0±\ua07.6, P\ua0=\ua00.02) and more patients had pre-existing renal dysfunction (29/235 vs. 44/239, P\ua0=\ua00.07). Duration of renal dysfunction after enrollment did not differ between groups (mean difference 0.21\ua0AKI days per 10\ua0patient ICU days, 95\ua0% CI −0.27 to 1.04, P\ua0=\ua00.45). Amino acid therapy significantly improved eGFR (treatment group\ua0×\ua0time interaction, P\ua0=\ua00.004), with an early peak difference of 7.7\ua0mL/min/1.73\ua0m (95\ua0% CI 1.0–14.5\ua0mL/min/1.73\ua0m, P\ua0=\ua00.02) on study day\ua04. Daily urine output was also significantly increased (+300\ua0mL/day, 95\ua0% CI 145–455\ua0mL, P\ua0=\ua00.0002). There was a trend towards increased RRT use in patients receiving amino acid therapy (13/235 vs. 25/239, P\ua0=\ua00.062); however, this trend was not present after controlling for baseline imbalance (P\ua0=\ua00.21). Conclusion and relevance: Treatment with a daily IV supplement of standard amino acids did not alter our primary outcome, duration of renal dysfunction. Trial registration: anzctr.org.au Identifier: ACTRN12609001015235

Scouting for girls? Gender and the Scout Movement in Britain

This article was published in the journal, Gender, Place and Culture [© Taylor & Francis (Routledge)] and the definitive version is available at: http://dx.doi.org/10.1080/0966369X.2011.583342This article brings a feminist geopolitics to bear upon an analysis of the Boy Scout Movement in Britain in order to illustrate how an emphasis upon seemingly banal, embodied practices such as dressing, writing and crafting can provide a counter-view to prevailing notions of the elite, organisational `scripting' of individualised, geopolitical identities. Here, these practices undertaken by girls are understood not as subversive, or even transgressive, in the face of broader-scale constructions of the self and the collective body, but rather as related moments in the emergence of a complex, tension-ridden `movement' that exceed specific attempts at fixity along the lines of gender. Using archival data, this article examines various embodied practices by `girl scouts' that were made possible by such attempts at fixity but which also, in turn, opened up new spaces of engagement and negotiation. A cumulative shift from a determinedly masculine to a co-educational organisation over the course of the twentieth century thus reflects complex geographies of gender, national identity and citizenship and offers a historical contribution to the feminist geopolitics literature

Gender and rural livelihoods in Kenya

This article considers the implications for gender relations of different rural livelihoods. While many rural areas in Kenya have been drawn into intensive commercial production, others, formerly dependent on remittances from migrant labour, have seen these diminish. Recent empirical studies of gender and livelihoods in Kenya are compared. Commercial production and the drying up of remittances set up quite different processes in rural households. These may lead to greater corporateness, to conflict or even to fragmentation. The outcome depends on the potential rewards of co-operation, but also on domestic authority relations and on ideologies of common or divided interest.