A systematic search for reports of site monitoring technique comparisons in clinical trials.

BACKGROUND: As part of a broader methodological programme of work around clinical trial monitoring, we wanted to evaluate the existing evidence for the effectiveness of different monitoring techniques. PURPOSE: To identify and evaluate prospective studies of the effectiveness of different monitoring strategies. METHODS: A systematic search of MEDLINE from 1950 onwards, using free-text terms to identify relevant published studies. We intended to extract data on details of comparative techniques, monitoring findings identified by different techniques, and recommendations or identification of areas in need of further research made by authors. RESULTS: A total of 1222 published abstracts were identified and reviewed. Of these, nine articles described methods for quality control (QC) of clinical trial activities, and one article was identified that compared the same monitoring technique at two timepoints. None included a direct comparison of different monitoring techniques and findings. LIMITATIONS: The search strategy was limited to MEDLINE. However, MEDLINE includes all the journals that tend to report trial methodological research. CONCLUSIONS: There is a lack of published empirical data that compare monitoring strategies prospectively. Assessment of the usefulness and cost-effectiveness of monitoring techniques in a variety of clinical trial settings and indications is needed.

The potential for central monitoring techniques to replace on-site monitoring: findings from an international multi-centre clinical trial.

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 centralised 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 randomised 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 database 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 database. 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 database 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 reviewed 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 prospective work is needed to compare monitoring practices in real time. CONCLUSIONS: While there may be some categories of findings that it is not possible to identify centrally, the very large majority of findings reviewed 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.

A randomised placebo-controlled safety and acceptability trial of PRO 2000 vaginal microbicide gel in sexually active women in Uganda.

OBJECTIVES: To determine the safety of 0.5% and 2% PRO 2000 gel in terms of local and systemic adverse events (AE) and the acceptability of gel use. DESIGN: A randomised placebo-controlled trial among healthy, sexually active African women aged 18-45 years. Between June 2003 and September 2004, 180 consenting women were randomly assigned to one of four groups: PRO 2000 gel (0.5% or 2%), placebo gel, or condom use only. Participants were screened for sexually transmitted infections, with HIV counselling and testing. Women randomly assigned to gel used this intravaginally twice a day for 28 days. Follow-up visits were fortnightly up to 6 weeks from enrolment, and comprised a physical examination including colposcopy, laboratory testing and questionnaire interviews. RESULTS: Ten women were lost to follow-up, none due to AE. Adherence with total gel doses was 69%. Observed rates of the primary toxicity endpoints, ulceration greater than 2 x 1 cm and clinically relevant coagulation abnormalities were, for PRO 2000 0.5%: 1.6% (95% CI 0.04% to 8.5%) and 0% (97.5% CI 0% to 5.7%), and for PRO 2000 2%: 0% and 0% (97.5% CI 0% to 5.9%). Women randomly assigned to active gels did not show an increased rate of AE. Gel use had no significant effect on haematology and biochemistry results. Women found gel use highly acceptable. CONCLUSIONS: Both concentrations of PRO 2000 gel were found to be safe and well tolerated. These data justified testing the gels in large-scale effectiveness trials.

A randomized controlled safety and acceptability trial of dextrin sulphate vaginal microbicide gel in sexually active women in Uganda.

OBJECTIVE: To assess the safety of dextrin sulphate (DS) gel compared to placebo gel in terms of local and systemic adverse events, and to determine the acceptability of dextrin sulphate gel. DESIGN: A 4-week randomized trial of DS intra-vaginal gel, partially blinded, with placebo and observation control arms. Participants were randomized to use DS gel twice daily, placebo gel twice daily, DS gel pre-sex, or into an observation only arm. METHODS: Sexually active women were recruited from post natal and HIV clinics at Nsambya Hospital, Kampala, Uganda. Screening, enrollment and follow-up visits took place every 1 or 2 weeks over an 8-week period and consisted of questionnaire interviews, colposcopy examinations, sexually transmitted infection screen and routine laboratory testing. RESULTS: Out of a total of 172 women screened, 109 were randomized to use DS gel twice daily (65 women), placebo gel twice daily (15 women), DS gel pre-sex (nine women) or into an observation only arm (20 women). Two individuals had abnormal colposcopy findings in the DS twice daily gel use arm. Vaginal bleeding was reported as frequently by participants in the active gel arm as by participants in the placebo and observation only arms. No clinically significant difference was observed between arms in terms of vaginal flora, Candida, haemoglobin, white cell count, platelets, thrombin time, activated partial thromboplastin time, creatinine and aspartate aminotransferase results after 4 weeks of gel use. DS gel appeared to be acceptable to over 95% of the users. CONCLUSIONS: Results show a satisfactory safety and acceptability profile of dextrin sulphate gel.