Quality in Clinical Trials – A Resource-Limited Settings Perspective

Background: Clinical trials have to follow strict standards in order to assure participant safe-ty and data integrity. The development of these standards, however, did not include the per-spective from resource-limited settings, hence, leading to operational challenges when ap-plied in these settings. Over the past decades, the conduct of clinical trials was characterised by inefficiency and waste, questioning in how far adherence to the existing standards reflects "quality". A common and broadly accepted understanding of the concept of "quality" in clinical research has never been defined, potentially leading to wasteful, as well as undervalued clini-cal trial activities. An academic framework was developed to fill this gap; however, it did not consider the perspective of resource-limited settings. This thesis, therefore, sought to pro-vide insight about particular needs in clinical trial guidance encountered in resource-limited settings and to contribute to the perception of "clinical trial quality" from a resource-limited perspective.
Methods: We used a qualitative design, including semi-structured interviews with clinical trial stakeholders comprising investigators, sponsors, and monitors. 46 interviews were conduct-ed with stakeholders having experience in 27 countries in sub-Saharan Africa. Framework analysis was performed to identify themes with respect to the entire clinical trial scope and build a clinical trial quality concept. We used MAXQDA software for the analysis.
We additionally performed a systematic literature review to address the lack of guidance in the case of informed consent management for paediatric participants with minor parents. We searched PubMed/MEDLINE, Embase, CINAHL, and Google Scholar for arti-cles published up to March 2019. In total, 4382 articles were screened, and two analyses were performed based on these articles. In the first analysis, 16 articles met our inclusion criteria. Various study types addressing informed consent in clinical trials involving children with minor parents in sub-Saharan Africa were included. We performed descriptive and quali-tative framework analyses. In the second analysis, 44 articles met our inclusion criteria. We included publications of clinical trials that potentially included children with minor parents in sub-Saharan Africa and addressed informed consent. A descriptive analysis was performed.
Results: Clinical trial quality definitions resulted in 11 elements, summarised into a clinical trial quality concept, consisting of two components: clinical trial quality-building factors (Scientific factors and Moral factors) and -promoting factors (Context adaptation; Infrastructure; Part-nership; Operational excellence; Quality system). 12 resource-limited settings specific themes were identified, which could be categorised under the promoting factors "Context adaptation", "Infrastructure", and "Partnership".
The systematic review showed that informed consent approaches for children with minor parents were variable and could involve either the minor parent, another representative or both. When individual consent by minor parents based on emancipation or "mature minor" status was applied, it lacked an evidence base in the context of research and mostly followed national laws on medical care. When no laws or guidance existed, an interpretation of the local decision-making culture, including community engagement and collaboration with local ethics committees, defined the informed consent approach. In the secondary analysis, there was no robust evidence on whether any recruited children had minor parents and how con-sent was obtained for them. Explicit descriptions of proxy decision-makers were rare and were mostly provided in referenced clinical trial registrations or protocols. Also, terminology describing proxy decision-makers was often used inconsistently.
Conclusions: A comprehensive clinical trial quality concept should be multidimensional, in-cluding quality-promoting factors in addition to scientific and ethical components. Considera-tion of resource-limited setting-specific aspects led to three clinical trial quality-promoting as-pects as possible additions to the INQUIRE framework: 1) Clear communication of infrastruc-tural disadvantages to funders, sponsors, and auditors, 2) Prevention of exploitation of re-search populations and workforce in resource-limited countries by following existing ethical frameworks, and 3) Context adaptation as an additional clinical trial quality promoter. Amend-ing the INQUIRE framework by adding these aspects could be beneficial for proactive imple-mentation of quality into clinical trials.
The systematic literature review emphasised that the implementation of informed consent for children with minor parents may be context-dependent and hampered by absent or ambigu-ous clinical trial regulations, as well as divergent local realities. We recommended a set of questions to be considered in the development of an ethically acceptable informed consent approach and proposed information to be integrated into international clinical trial guidelines.
The review further highlighted that CT reporting guidelines should require clinical trial publica-tions to state or reference exceptional informed consent procedures applied for special popu-lation groups. Moreover, international clinical trial guidelines should provide harmonised defini-tions of proxy decision-maker types to facilitate correct and transparent informed consent for children and children with minor parents.
Overall, adopting practical guidance on exceptional, or context-dependent situations into general guiding documents or referencing such guidance in the respective area was consid-ered beneficial. This would, on the one hand, give more attention to these situations and, on the other hand, give more recognition to the related efforts.