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  "documentTitle": "Harmony Biosciences (HRMY)",
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  "presentationDate": "2023-03-28 00:00:00",
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      "text": "However, FDA reviewer missed the forest for the trees and viewed it as evidence of efficacy",
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      "text": "EMA rejects HARMONY 1-bis EDS score reduction as clinically immaterial",
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      "text": "The FDA’s reviewer’s conclusion – shown below – exhibits no awareness that a 2 point reduction in ESS is a failure: “HARMONY 1-bis provides confirmatory evidence of pitolisant’s effect on EDS.”",
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      "text": "The EMA noted that the clustering was ultimately irrelevant, as even after using it the ESS reduction barely improved from -1.94 to -2.19. Although this drove the p-value from non-stat sig (p=.07) to stat sig (p=.03), the reduction “was clinically not relevant in both analyses.” In contrast, the FDA missed the forest for the trees and used the 1-bis trial along with HARMONY 1 as sufficient to show efficacy in EDS. Even the HARMONY 1 paper as well as the protocol for HARMONY 1-bis stated that the clinically relevant threshold is 3 points, as the EMA repeats: “This difference was not clinically relevant as it was lower than the pre-defined threshold of 3 points.” The FDA’s reviewer’s conclusion – shown below – exhibits no awareness that a 2 point reduction in ESS is a failure:” “HARMONY 1-bis provides confirmatory evidence of pitolisant’s effect on EDS.”",
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      "text": "According to the pre-specified minimal clinically relevant difference in both pivotal studies, pitolisant showed an improvement on the ESS final score compared to placebo only in Harmony I study (-3.3 points), but not in Harmony Ibis (-2.19 points, with small centres re-allocation and -1.94 points with original centres). The effect of clustering did not improve the modest effect of pitolisant on ESS changes (-1.94 versus 2.19) in Harmony Ibis as it was clinically not relevant in both analysis. However, the clustering artificially improved the p value, from non-significant (p=0.07) to significant (p=0.03).",
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      "text": "Reviewer comment: HARMONY 1-bis provides confirmatory evidence of pitolisant’s effect on EDS. This study demonstrated efficacy on the primary endpoint, the ESS. However, when results of the MWT, an objective measure of EDS, were analyzed using the statistical test that was prespecified in the analysis plan, the results were not significant. The CGI-C results suggest that pitolisant had a clinically meaningful effect on EDS, though the study did not detect a difference in quality of life scores or overall opinion on treatment in pitolisant-treated patients. No effect on daily rates of cataplexy was found in this study. The lack of effect on cataplexy events could have been related to the lower maximum dose (20 mg) as compared with the dose in HARMONY I and HARMONY CTP (40 mg).",
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      "text": "“This difference was not clinically relevant as it was lower than the pre-defined threshold of 3 points.” — EMA. “HARMONY 1-bis provides confirmatory evidence of pitolisant’s effect on EDS.” — FDA Reviewer.",
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      "text": "Source: https://www.ema.europa.eu/en/documents/assessment-report/wakix-epar-public-assessment-report_en.pdf; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/211150Orig2s000MedR.pdf",
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