In addition to pharmaceutical industry (industry) funders, hundreds of global health clinical trials (CTs) are funded annually by private foundations, governments, and consortia. A meaningful number of these CTs end without being published or without trustworthy results [1,2,3]. A January 2024 query of ClinicalTrials.gov found 92 phase I–IV CTs currently active or enrolling participants that featured a majority of CT sites in sub-Saharan Africa. Industry—either alone or as leader of a funding group—funded 29.3% of the CTs; the US government funded 12.0% of CTs. The remaining 58.7% of CTs were funded by private foundations, with some contribution from other governments or organizations. These global health CTs had plans to enroll 91,200 participants (human research subjects). Before a CT begins, industry routinely performs scientific or methodological reviews on CT protocols to identify and address flaws in design. There is no direct evidence that other funders conduct such reviews. Because of this, it is imaginable that 70% of global health CT protocols do not receive a dedicated scientific review before enrolling their first study participants. This may account for the large difference in informativeness between industry and non-industry CTs found recently [4].
In its lifecycle, there are two phases prior to the CT’s start and participant recruitment. First is a phase when the CT has not procured a funding commitment (pre-funding), and then the second is a post-funding phase. The dominant approach used by government funders to decide if a research study will be funded is peer-review. While peer-review for pre-funding decisions is well established, it continues to evolve and not necessarily in a scientific direction. For example, a large fraction of stakeholders believe peer-review ought to change to only assess the investigator, not the proposed project, or include a lottery [5]. One systematic review found that, in pre-funding peer-review, comments on research design represented 2%, methodology 4%, and methodological details 5%, respectively, of total comments [6]. During pre-funding, these reviewers also needed to comment on dozens of other factors [6]. This dynamic—along with the sometimes-large time gap between pre-funding and CT inception and the design changes therein—makes peer review inadequate for scientific design review.
In the post-funding phase, there are two other types of review that focus on elements outside of CT design. These reviews and related concepts are described in Table 1. The two reviews that happen completely or primarily in post-funding and before participant recruitment begins are regulatory and ethical. The regulatory and ethics review domains are relatively mature and well-developed.
Ethical and regulatory reviews both overlap in limited ways with consideration of CT design methods. “It is clear that scientific assessments are a source of confusion for some ethics committees…ethics committee members revealed that they often had doubts about whether scientific validity is within their purview” [12]. Because the focus of an ethics review is not assessing optimal CT methods, “ethicists entering a review may be concerned about whether they have “the scientific literacy necessary to read and understand a protocol” [12]. Regulators and ethicists in low resource settings are often not trained in the scientific disciplines necessary to evaluate CT design risk—such as biostatistics and pharmacokinetics. Members of Institutional Review Boards seeking to deliver on their primary purpose—delivering an International Council for Harmonisation E6, E8, E9, and Good Clinical Practice guideline-supported participant protection review—and members of regulatory boards seeking to deliver on safety and participant protection may, justifiably, take only a secondary look at a CT’s statistical details. A cursory assessment of methods by an ethics committee may be necessary for them, but it may not be sufficient for funders. Likewise in the regulatory realm: the review of a protocol post-funding will include only targeted scientific assessment, since, for regulators, the focus on safety and similar matters crowds out efforts to identify more optimal approaches in CT design.
This state of affairs leaves an opportunity gap for scientific review of global health CT designs post-funding and prior to CT start. Industry performs scientific design reviews; it may or may not be coincidental that industry funded CTs were more likely to be informative during COVID than those CTs funded by others [17]. The US cancer academic CT community—funded by the US government—has created programs to comply with mandated post-funding scientific review of grantee CT designs. Multiple government and private CT funders, who to date have only performed pre-funding peer-reviews, are investigating the cost and effort involved with adding reviews of protocols. It is often only at the protocol stage of trial planning when a funder can see specifics such as whether the trial design is informed by systematic evidence; more advanced, pragmatic, or participant-centric design; or the presence of concrete recruitment plans, statistical analysis plans, or sample size simulations. As yet, standards do not exist.
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