Risk-proportionate clinical trial monitoring: an example approach from a non-commercial trials unit

Background Some level of monitoring is usually required during a clinical trial to protect the rights and safety of trial participants and to safeguard the quality and reliability of trial results. Although there is increasing support for the use of risk-proportionate approaches to achieve these aims, the variety of methods and lack of an empirical evidence base can present challenges for clinical trial practitioners. Methods This paper describes the monitoring methods and procedures that are utilised by a noncommercial clinical trials unit which coordinates a range of clinical trials across a variety of clinical areas with different associated risks. Results Monitoring activities and approaches should be selected to be proportionate to the risks identified within a trial. A risk-proportionate approach to monitoring is described giving details of methods that may be considered by clinical trial practitioners during the development of a trial monitoring plan. An example risk assessment and corresponding monitoring plan for a low risk (type A in the Medicines and Healthcare Products Regulatory Agency (MHRA) classification system) pediatric trial is provided for illustration. Conclusion We present ideas for developing a monitoring plan for a clinical trial of an investigational medicinal product based on our experience. Alternative approaches may be relevant or preferable in other settings based on inherent risk

Are Women Who Work in Bars, Guesthouses and Similar Facilities a Suitable Study Population for Vaginal Microbicide Trials in Africa?

BACKGROUND: A feasibility study was conducted to investigate whether an occupational at-risk cohort of women in Mwanza, Tanzania are a suitable study population for future phase III vaginal microbicide trials. METHODOLOGY/PRINCIPAL FINDINGS: 1573 women aged 16-54 y working in traditional and modern bars, restaurants, hotels, guesthouses or as local food-handlers were enrolled at community-based reproductive health clinics, provided specimens for HIV/STI and pregnancy testing, and asked to attend three-monthly clinical follow-up visits for 12-months. HIV positive and negative women were eligible to enter the feasibility study and to receive free reproductive health services at any time. HIV prevalence at baseline was 26.5% (417/1573). HIV incidence among 1156 sero-negative women attending at baseline was 2.9/100PYs. Among 1020 HIV sero-negative, non-pregnant women, HIV incidence was 2.0/100PYs, HSV-2 incidence 12.7/100PYs and pregnancy rate 17.8/100PYs. Retention at three-months was 76.3% (778/1020). Among 771 HIV sero-negative, non-pregnant women attending at three-months, subsequent follow-up at 6, 9 and 12-months was 83.7%, 79.6%, and 72.1% respectively. Older women, those who had not moved home or changed their place of work in the last year, and women working in traditional bars or as local food handlers had the highest re-attendance. CONCLUSIONS/SIGNIFICANCE: Women working in food outlets and recreational facilities in Tanzania and other parts of Africa may be a suitable study population for microbicide and other HIV prevention trials. Effective locally-appropriate strategies to address high pregnancy rates and early losses to follow-up are essential to minimise risk to clinical trials in these settings

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, enrolment 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

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