Efficiency and quality in conducting clinical trials in sub-Saharan Africa

Background The conduct of clinical trials is significantly regulated and requires substantial infrastructure and human resource investments and efforts. Clinical research centers in sub-Saharan Africa face particular constraints by the increasing trial related workload and administration, paired with capacity limitations. At the same time, trials are critically important for improving public health in these settings. We investigated the challenges in clinical trial conduct to optimize the efficiency of processes in sub- Saharan Africa while maintaining quality. Our working hypothesis was that the Good Clinical Practice guideline, is not adapted to these particular situations, and that its possibly overly strict interpretation was the main challenge. Methods We used an exploratory mixed methods design: First, we performed key informant interviews asking questions about quality, guidelines, challenges, and inefficiencies in clinical trials. We interviewed 60 clinical trial staff of different professional levels in two clinical research centers in Kenya, Ghana, Burkina Faso, and Senegal. The study covered English- and French-speaking, and Eastern and Western parts of sub-Saharan Africa. Content analysis was performed to identify themes across settings and positions, respectively. Emerging themes from data interrogation were tested in further interview analysis. We used MAXQDA software for the analysis. Second, we developed an online survey investigating trial protocol suitability based on the main interview themes. We distributed the survey by email to trial staff based in sub-Saharan Africa. We used the statistical software STATA for the analysis of categorical variables and to perform explorative factor analysis. Results We found various internal factors associated with constraining trial efficiency in sub-Saharan Africa. Internal factors are limited to those that exclusively relate to clinical trial teams and sponsors. These factors may be influenced independently of external conditions and may significantly increase trial efficiency if addressed by the respective teams. Identified internal factors were summarized in the two broad themes “planning” and “site organisation”. “Planning” factors related to budget feasibility, clear project ideas, realistic deadlines, understanding of trial processes, adaptation to the local context, and involvement of site staff in planning. “Site organisation” factors covered staff turnover, employment conditions, career paths, workload, delegation and management. Protocol suitability surfaced as another prominent internal topic in interviews with trial staff. By following the topic up in an online survey we found that the main constraints of protocol suitability were a lack of clarity, implementability, and adaptation to trial participants as well as to available workforce and infrastructure. In both, qualitative and quantitative investigations local site staff involvement in protocol development was identified as the most helpful measure to increase protocol suitability. Unexpectedly, the administrative burden resulting from the guidelines was not perceived as a difficulty; rather, researchers were grateful for having guidance by a globally accepted standard. Only in regards to informed consent did some clinical trial staff (one-third) perceive the guideline as insufficiently applicable. Conclusions Our data suggest that adequate and coherent planning, clear task allocation and strengthening of management capacity may help to overcome the identified internal factors and allow clinical trials to proceed more efficiently. In addition a careful assessment of the setting with a particular focus on available workforce and infrastructure as well as the needs and availability of trial participants was perceived to be beneficial. Trial protocol suitability is rarely addressed; however, we found this to be fundamental as it has a direct impact on the execution and outcomes of the work. Our results indicate that preliminary discussions and reviewing of the protocol with trial staff are most helpful in increasing protocol suitability. We concur with the interviewees and consider the involvement of operationally experienced staff to be most useful. To mitigate informed consent challenges we suggest making use of the flexibility that the GCP guideline offers as well as identifying and tackling challenges prospectively. We deem that clarifying guidance for informed consent issues in resource-limited settings would be helpful for trial staff. To allow for such measures, allocating enough time for trial preparation and enabling of the uptake of feedback and information on context at an early stage are a requisite. We found that such prospective planning would increase implementability, efficiency and quality in the long run. Due to a general lack of research on trial practices and our small sample size more research is needed in order to validate and strengthen some of these findings. Trial staff members proved to be a valuable source of information to investigate trial practices. We consider the incorporation of sponsors` perceptions and interests on top of investigations of the study site as important for future research

"You can save time if…" - a qualitative study on internal factors slowing down clinical trials in Sub-Saharan Africa

The costs, complexity, legal requirements and number of amendments associated with clinical trials are rising constantly, which negatively affects the efficient conduct of trials. In Sub-Saharan Africa, this situation is exacerbated by capacity and funding limitations, which further increase the workload of clinical trialists. At the same time, trials are critically important for improving public health in these settings. The aim of this study was to identify the internal factors that slow down clinical trials in Sub-Saharan Africa. Here, factors are limited to those that exclusively relate to clinical trial teams and sponsors. These factors may be influenced independently of external conditions and may significantly increase trial efficiency if addressed by the respective teams.; We conducted sixty key informant interviews with clinical trial staff working in different positions in two clinical research centres in Kenya, Ghana, Burkina Faso and Senegal. The study covered English- and French-speaking, and Eastern and Western parts of Sub-Saharan Africa. We performed thematic analysis of the interview transcripts.; We found various internal factors associated with slowing down clinical trials; these were summarised into two broad themes, "planning" and "site organisation". These themes were consistently mentioned across positions and countries. "Planning" factors related to budget feasibility, clear project ideas, realistic deadlines, understanding of trial processes, adaptation to the local context and involvement of site staff in planning. "Site organisation" factors covered staff turnover, employment conditions, career paths, workload, delegation and management.; We found that internal factors slowing down clinical trials are of high importance to trial staff. Our data suggest that adequate and coherent planning, careful assessment of the setting, clear task allocation and management capacity strengthening may help to overcome the identified internal factors and allow clinical trials to proceed more efficiently

Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4–methylenedioxy­methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence

Characteristics of participants.

<p>Characteristics of participants.</p

Sampling procedure.

<p>Sampling procedure.</p

Participants` experience of working in clinical trials.

<p>Participants` experience of working in clinical trials.</p

Duloxetine increased MDMA exposure.

<p>Pharmacokinetics of MDMA, MDA, HMMA, and duloxetine (<b>a–d</b>). Duloxetine was administered 16 h and 4 h before MDMA, which was administered at the 0 h time point. Duloxetine increased the C_max and AUC_0–6 of MDMA (<b>a</b>), had no significant effect on MDA exposure (<b>b</b>), and decreased the C_max and AUC_0–6 of HMMA (<b>c</b>). Plasma duloxetine concentrations were similar in the duloxetine-placebo and duloxetine-MDMA groups before MDMA administration (at –4 h and 0 h). Duloxetine concentrations increased 1 h after MDMA administration in the duloxetine-MDMA <i>vs</i>. duloxetine-placebo group (<b>d</b>). Values are expressed as mean±SEM of 16 subjects. MDMA, 3,4-methylenedioxymethamphetamine; MDA, 3,4-methylenedioxyamphetamine; HMMA, 4-hydroxy-3-methoxymethamphetamine.</p

Duloxetine blocked MDMA- and MDA-induced 5-HT and NE efflux.

<p>Duloxetine inhibited SERT-mediated 5-HT release by MDMA (<b>a</b>) and MDA (<b>b</b>). Duloxetine also inhibited NET-mediated NE release by MDMA (<b>c</b>) and MDA (<b>d</b>). Values are expressed as mean ± SEM (<i>n</i>  = 3–6) of retained radiolabeled substrate following incubation with various concentrations of MDMA and MDA.</p

Duloxetine prevented the acute effects of MDMA in the Altered States of Consciousness (ASC) scale.

<p>MDMA significantly increased the ASC sum score, Oceanic Boundlessness (OB), Anxious Ego Dissolution (AED), and Visionary Restructuralization (VR) dimensions, and most of the subscales (*p<0.05, **p<0.01, ***p<0.001, placebo-placebo vs. placebo-MDMA). Duloxetine significantly reduced the effect of MDMA in all dimensions and subscales (^#p<0.05, ^##p<0.01, ^###p<0.001, placebo-MDMA vs. duloxetine-MDMA). Values are expressed as mean+SEM (n  = 16).</p

Inhibition of MDMA-induced 5-HT or NE release by different inhibitors.

<p>95% CI, 95% confidence interval; na, not assessed.</p