Expanded access as a source of real-world data: An overview of FDA and EMA approvals 87 5♦ As some of the FDA documents are scanned files, we first performed optical character recognition (OCR) using Google’s Tesseract engine,19 to extract text from the scans, and subsequently process the extracted text . To find candidate documents, i.e., documents that mention ‘expanded access’, we searched for the related terms: ‘compassionate use’, ‘expanded access’, ‘early access’, ‘pre-approval access’, ‘namedpatient’ and ‘managed access’. We expected these terms to appear if the data from an associated expanded access program were used in the submission package. When at least one of these terms appeared in the document, the associated submission package possibly included expanded access data for the approval. Therefore, we assessed these ‘candidates’ manually to determine whether data from expanded access were used in a supportive/pivotal manner, or whether the mention of EA-related terms was not in support of efficacy. The manual assessment was performed by T.B.P. and in case of doubt discussed with C.A.U.-d.G. As all (pre-approval) data concerning patient safety are reported for purposes of pharmacovigilance, we focused on data from efficacy. Patients in expanded access programs are never randomized, and the absence of a direct control group makes it challenging to draw sound conclusions on efficacy. Nonetheless, this makes it even more attractive to understand the reasons that led to acceptance of expanded access programs as source of evidence. Duplicates are removed from our data set. Duplication in this sense occurs when an approved treatment consists of multiple (recurring) compounds and the underlying data is duplicated. If no new data from expanded access were used, we removed such duplicates. To determine whether expanded access data were included in the clinical efficacy profile, we followed two criteria. First, the data from the expanded access program must have been mentioned under the section ‘clinical efficacy’ in the medical/summary review (FDA) or scientific discussion/public assessment report (EMA). In addition, we studied the impact of the evidence. If the expanded access data were mentioned under the ‘pivotal/main’ studies, we considered the data to have a ‘pivotal’ (P) level of evidence. If not, we labeled the evidence as ‘supportive’ (S). For all candidate documents, we considered related approved treatment. Figure 2 illustrates our review procedure.
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