Chapter 7 138 program is prohibited (or discouraged), in part over fears of data quality or companies attempting to bypass trial regulations,65,83,84 seems to be at odds with the numbers of publications from those countries (n=13, n=5, n=56, respectively). The number of expanded access publications show that the treatment of patients with investigational medicine is, in itself, being used as a means to support (ongoing) investigations. Nonetheless, the analyses of expanded access data should be interpreted with caution. Expanded access data are non-blinded, non-randomized data, and as such may be inherently confounded. These ‘real-world’ data may harbor serious data quality issues. Furthermore, expanded access data may suffer even more quality loss as 50.9 % of the reports in our sample collected data retrospectively. This may severely impact data quality, although main parameters (such as survival) should be straightforward to gather. In our analysis of endpoints used in EAPs for COVID-19, we found that data is collected beyond mandatory safety reporting. Endpoints included various clinical improvement ratings/scales, respiratory or oxygen support status, duration of hospitalization, viral load, and patient-reported outcomes among others. The heterogeneity of research methods and endpoints makes it difficult to compare studies. Ideally, an EAP should include a pre-specified, prospective data collection to ensure highest data quality that is fit-for-purpose. Although the inclusion of expanded access data (and other sources of real-world data) in regulatory decision-making is increasing,50,85,86 the lack of oversight could contribute to suboptimal data quality and hesitance of regulatory bodies to include said data in decision-making processes. To expand the application of expanded access data beyond peerreviewed publications, it is important to develop minimal data quality standards for expanded access studies in the future.87 Harmonization of publications may be an area of potential development. Some expanded access programs harbor ‘salami-tactics’: i.e., there are different publications per center, then per region, then per country, and subsequently, a synthesized international publication.73–77 Additionally, the basis of a new publication may not be a different geographic location, but rather a different (sub) topic: publishing separately on safety,78 efficacy, and/or quality-of-life.79 Although we acknowledge that the lack of observational research harmonization across countries impedes international collaboration, we question the incremental added value of each of these single publications as opposed to several large, overarching, international publications. As local investigators may not be aware of all scientific endeavors worldwide, drug manufacturers should better coordinate local efforts by connecting researchers across regions. The impact of COVID-19 on the expanded access landscape is remarkable. Early in the pandemic, various authors cautioned against the widespread use of medication outside of clinical trials as
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