***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background 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 .The purpose of this project was to gain a better underst and ing 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 . Methods We review ed 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 abstract ed 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 , r and omisation , study intervention , patient compliance and data collection errors . Associations between PVs and study characteristics were investigated using logistic regression . Results Eighty clinical trials ( 20 from each journal ) were identified from 101 consecutive PubMed abstract s. 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 . 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 . 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 . Conclusions 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 Background Compliance with Good Clinical Practice ( GCP ) guidelines should ensure the safety of trial participants and the reliability of trial results . Over the last decade , increasing emphasis has been placed on the role of costly on-site monitoring and source data verification as processes to demonstrate that GCP is being followed , despite a lack of empirical evidence that these are effective . Purpose To assess whether findings from on-site monitoring of a recent international multi-centre clinical trial could have been identified using central data review and other central ised monitoring techniques . Methods Findings documented in a sample of site monitoring reports , and Programme Management Board Executive ( PMBe ) reports , from the Microbicides Development Programme ( MDP ) 301 trial – a r and omised placebo-controlled trial of a microbicide gel to prevent vaginally acquired HIV infection conducted in four countries in East and Southern Africa – were extracted and individually assessed to determine whether they could have been detected in the trial data base or through other central means . Results Four site visit reports contained 268 monitoring findings from a review of 104 participant files covering 324 study visits . Of the 268 findings , 76 ( 28.4 % ) were also identified in the study data base . Central checks , had these been in place ( such as central receipt and review of back-translated documents , enrolment and testing logs , informed consent , and more complex data base queries ) , could have identified a further 179 ( 66.8 % ) ; 13 ( 4.9 % ) other findings ( all minor ) could have been identified through a review of the participant folder at site . The four PMBe reports review ed included six major and three critical findings from a review of over 1000 participant files : only two of these ( both major ) were assessed as unlikely to be identified using central monitoring techniques . Limitations The study data used were not collected with this retrospective review in mind . It suggests that prospect i ve work is needed to compare monitoring practice s in real time . Conclusions While there may be some categories of findings that it is not possible to identify central ly , the very large majority of findings review ed in this analysis could be identified using central monitoring strategies . These data suggest that with better central and targeted on-site monitoring , it should be possible to identify and address most protocol and procedural compliance issues without performing intensive and costly routine on-site data monitoring Background Review ing clinical trial site performance identifies strategies to control outcomes . Performance across 5 geographical regions ( 36 sites across Asia , Australia , Europe , North America and Latin America ) was investigated in a study that r and omised 322 HIV-infected individuals . Methods Regional performance was compared using descriptive analysis for time to site opening , recruitment , quality of data and laboratory sample s. Follow-up consisted of 10 visits ( 96 weeks ) , electronic data collection ( EDC ) within 7 days of a visit and serious adverse events ( SAEs ) reported within 24 hours of site awareness . Results Median days to site opening was 250 ( 188 to 266 ) , ranging from 177 ( 158 to 200 ) ( Australia ) to 265 ( 205 to 270 ) ( Europe ) . Median days to ethics and regulatory approval was 182 ( 120 to 241 ) and 218 ( 182 to 341 ) days , respectively . Within regions , time to approval ranged from 187 ( 91 to 205 ) days ( Australia ) to 276 ( 175 to 384 ) days ( Europe ) . Time to first r and omisation ranged from 282 ( 250 to 313 ) days ( Australia ) to 426 ( 420 to 433 ) days ( North America).Recruitment was lower than forecasted in Asia , Australia , Europe and North America at 89 % , 77 % , 91 % and 43 % , respectively . The converse was true in Latin America where despite ethics , regulatory and contractual delays , recruitment was 104 % of predicted . Median days to EDC was 7 ( 3 to 16 ) , ranging from 3 ( 1 to 16 ) ( Asia ) to 13 ( 8 to 14 ) days ( North America ) . Median days for initial SAE su bmi ssion to sponsor was 6 ( 2 to 20 ) , ranging from 4 ( 2 to 18 ) ( Latin America ) to 24 ( 5 to 46 ) days ( Australia ) . Sites took longer to su bmi t final reports , overall median of 28 ( 7 to 91 ) days , ranging from 7 days ( Australia ) to 67 ( 23 to 103 ) days ( Europe ) . Conclusions Population availability and time to ethics and regulatory approvals influence recruitment ; therefore accurate feasibility assessment s are critical to site selection . Time to ethics and regulatory approval may not limit site inclusion if compensated by rapid recruitment . Identifying potential delays and methods for reduction can decrease time and costs for sponsors . Trial registration Clinical Trials . Gov identifier : NCT00335322 . Date of registration : 8 June Background Monitoring in r and omized trials is recommended as part of International Conference on Harmonisation Good Clinical Practice st and ards . On-site monitoring in multicentre trials is common but is costly and can be inefficient . Central statistical monitoring can be used to detect unusual data patterns , identify intentional or unintentional trial misconduct , and to prioritise on-site visits and additional training . Motivated by an ongoing international multicentre clinical trial of over 25,000 r and omized participants with electronic data capture , we developed key risk indicator ( KRI ) methods for central statistical monitoring in multicentre trials Large r and omized trials are required to provide reliable evidence of the typically moderate benefit of most interventions . To be affordable , such trials need to be simple ; to be widely applicable , they need to be close to normal clinical practice . However , current regulations and guidelines have hugely increased trial complexity , effectively becoming barriers to their design and conduct . Key barriers include inadequate funding , overly complex regulations producing needlessly complex trial procedures , excessive monitoring , over restrictive interpretation of privacy laws without evidence of subject benefit , and inadequate underst and ing of methodology . Complex regulations result in multiple ethics approvals for a multi-center study , unnecessary complexity in the study protocol , delays in securing regulatory approval , and cumbersome regulatory procedures , even for drugs widely used in clinical practice . The type of detailed safety monitoring currently needed in trials of new drugs is being applied indiscriminately to all studies including a simpler and basic level of monitoring that constitutes good practice in most trials could be agreed on , with that level being exceeded only in specific instances . More evidence about the pros and cons of alternative approaches to data quality monitoring would help inform this process . Complex procedures in the form of multiple-page consent forms , overzealous monitoring of side effects and adverse events , source data verification , and over-restrictive approaches to protocol amendments , can impede , rather than facilitate , trial objectives . Finally , further education on the nuances and functions of r and omisation would facilitate trial conduct , and reduce the need for burdensome complexity . A radical re-evaluation of existing trial guidelines is needed , based on a clear underst and ing of the important principles of r and omized trials , with the objective of eliminating unnecessary documentation and reporting without sacrificing validity or safety . Research ers should encourage public debate about how best to strike the balance between regulation and cost . Clinical Trials 2008 ; 5 : 40—48 . 
    Output:
    
Conclusions This review identifies a list of metrics to monitor site performance within multicentre r and omised trials .