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  "documentTitle": "Harmony Biosciences (HRMY)",
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  "presentationDate": "2023-03-28 00:00:00",
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  "notes": "The slide uses direct quotes from FDA clinical reviews to highlight the discrepancy between pre-approval assumptions and post-approval safety signals.",
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      "text": "FDA review clearly indicates its reliance on the lack of reported serious adverse events at the time of approval in 2019 – now contradicted by the facts (FDA CDER Clinical Review (Solages, Sep 28, 2020)",
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      "text": "Throughout the FDA’s discussion of the fatalities, the deference afforded Harmony via the rare drug/accelerated approval pathway is evident. Despite the number of suspicious deaths, it concluded that “no clear signal for serious dysrhythmias or QT prolongation emerged in the clinical development program.” However, few patients had been exposed to pitolisant at the time and the FDA clearly relied upon the small number of serious adverse event reports. With those numbers now spiking and individual case narratives clearly indicating a safety signal, we think the FDA will be less forgiving. We note numerous statements by the FDA reviewer that are now flatly contradicted by post-approval reports.",
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      "text": "(e.g., electrocardiogram abnormalities, increased risk of cardiovascular or respiratory events). Of note, cardiac, vascular, and pulmonary adverse events have not been reported frequently in the postmarketing period (see Postmarketing Data), either in the United States or in Europe (where pitolisant has been available for more than 4 years). A thorough QT (TQT) study submitted to the association with pitolisant exposure has not been established. Cardiovascular and pulmonary adverse reactions were infrequently reported in the postmarketing period, both in the United States and in Europe (where pitolisant has been available since 2016). In patients with",
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      "text": "Reviewer comment: Based on the clinical information presented, the reported TEAE of prolonged QT may have been spurious. No clear signal for serious dysrhythmias or QT prolongation emerged in the clinical development program. Patients in the dementia and Parkinson's disease trials reported cardiovascular adverse events including cardiac failure, myocardial infarction, hypertension, and angina. Most of these patients had underlying risk factors for cardiovascular disease and most of these events occurred in the open-label phase of the clinical trials. Therefore, whether there is a correlation between pitolisant and these other cardiovascular events is unclear.",
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      "text": "No clear signal for serious dysrhythmias or QT prolongation emerged in the clinical development program. — FDA CDER Clinical Review (Solages, Sep 28, 2020)",
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      "text": "Source: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/211150Orig2s000MedR.pdf",
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