Results from expanded access programs: a review of academic literature 139 7♦ randomized trials would be ‘the only way to find effective and safe treatments for COVID-19’.83 Indeed, the results from the large-scale expanded access program of convalescent plasma in the US later failed to replicate in various randomized trials.88–91 Although we agree that the place for expanded access is in addition to clinical trials rather than instead of, there is a place for expanded access in facilitating serendipitous findings, especially in the field of rare diseases. Evidence of expanded access can be used in addition to clinical trials to explore the safety and effectiveness of medicines used in different populations, or in (slightly) different indications (for example, in the case of cancer therapies targeting the same genetic aberration in a different histology). The drawback of expanded access data collection does not imply that these data are worthless or that no data ought to be collected: we, together with other scholars,11,52 believe that the treatment of a patient with investigational medicine should always be used to further the understanding of the potential benefits and risks of investigational medicine.87 Limitations and future research First, we attempted to differentiate expanded access programs from other types of access to unregistered products, such as trials, compounded medication, or off-label usage. To label a paper as ‘expanded access’ or not, we primarily relied on the self-reported use of ‘expanded access’, i.e., if the authors (and editors, peer-reviewers) approved the term ‘expanded access’. Nonetheless, an exact definition of expanded access varies per jurisdiction. A strict interpretation of expanded access is ‘non-trial access to pre-approval medicine’– yet these programs can also be used after a product has been withdrawn from the market (post-withdrawal rather than pre-approval), or to bridge the gap between marketing authorization and reimbursement (post-approval, prereimbursement). In addition, the term expanded access is sometimes used to denote off-label usage or ‘compassionate use trials’. To prevent erroneous inclusion of (randomized) trials or offlabel usage, we used an independent review process and deliberated in case of doubt. Note that the interchangeable usage of expanded access and off-label is not wrong per se: some countries employ the same terminology and pathways for expanded access as for off-label usage. Most forms of off-label usage differ considerably from ‘expanded access’, in other instances, these concepts may be inherently related. Second, we only focused on peer-reviewed publications indexed in PubMed that were written in English and included ‘expanded access’ related terms. As such, we have missed both non-English publications and literature that did not incorporate these terms. Other ways of disseminating expanded access results, such as posters or oral presentations at scientific conferences have not been investigated in our work. The use of additional databases (e.g., Embase) could have resulted in more publications. Therefore, our work may underestimate the number of expanded access publications, drugs, and patients over the past two decades. Furthermore, not all expanded access
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