{ "docId": "019dd923-622c-750b-8b9a-21918ac10c17", "docSlug": "f3db2294dcf9", "documentTitle": "Harmony Biosciences (HRMY)", "authorId": "58_Scorpion_Capital", "authorName": "Scorpion Capital", "documentKindSlug": "research-note", "documentKindLabel": "Research note", "sourceTypeSlug": "short_seller", "sourceTypeLabel": "Short seller", "presentationDate": "2023-03-28 00:00:00", "orientation": "landscape", "aspectRatio": 1.3333334, "pageNumber": 229, "pageCount": 366, "prevPage": 228, "nextPage": 230, "slideType": "expose_contradiction", "function": "expose_contradiction", "density": "overcrowded", "nDataPoints": 6, "notes": "The slide highlights a specific regulatory failure/contradiction regarding the acceptance of post-hoc analysis in clinical trials.", "elementsJson": [ "paragraph", "callout_box", "footnote" ], "metadataConfidence": 1, "imagePath": null, "slideHref": "/slides/019dd923-622c-750b-8b9a-21918ac10c17/229", "deckHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17", "deckJsonHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17.json", "deckAnchorHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17#slide-229", "components": [ { "bbox": { "h": 0.04, "w": 0.86, "x": 0.07, "y": 0.57 }, "kind": "callout", "text": "FDA quotes the EMA’s criticism of HARMONY 1-bis post-hoc analysis as unplanned, but gave a free pass", "attrs": null, "subkind": "primary", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "30f147d9-11a4-4a1b-8342-7592fc7dad75", "frameworkName": null, "frameworkSlug": null }, { "bbox": null, "kind": "callout", "text": "FDA quotes the EMA's criticism of HARMONY 1-bis post-hoc analysis as unplanned, but gave a free pass", "attrs": null, "subkind": null, "toolName": "Visual emphasis", "toolSlug": "visual-emphasis", "confidence": null, "componentId": "019dd953-64d1-73a9-abb6-d90d310712b8", "frameworkName": null, "frameworkSlug": null }, { "bbox": null, "kind": "metric", "text": "p-value: 0.030", "attrs": null, "subkind": "primary", "toolName": "Quantification", "toolSlug": "quantification", "confidence": null, "componentId": "019dd953-64d1-73a9-abb6-e3701510e998", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.22, "w": 0.86, "x": 0.07, "y": 0.72 }, "kind": "paragraph", "text": "“According to EMA Public Assessment Report analysis of the primary efficacy data by “artificially clustering” small clinical study centers, the mean ESS decrease with pitolisant showed statistically significant improvement compared to placebo (-2.19; 95% CI (-4.17, -0.22); p = 0.03). The EMA report stated pooling of centers was not pre-planned. In contrast, the SAP which was issued a month (February 13, 2013) before the database lock (March 13, 2013) included an Appendix (see Figure 14 below) to display the random re-allocation of small centers into clusters. Analysis conducted without re-allocation of small study centers showed that pitolisant didn’t demonstrate statistically significant separation from placebo (-1.94; 95% CI (-4.05, 0.07); p = 0.065). In clarifying FDA request, the applicant made clear (April 25, 2019) that the SAP for the study was amended prior to unblinding of the study.”", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "25f1b76a-259f-427b-b589-228a7d954641", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.08, "w": 0.86, "x": 0.07, "y": 0.62 }, "kind": "paragraph", "text": "Of note, the EMA Public Assessment Report stated that clustering of small clinical study centers was not pre-planned and that results on the primary endpoint would not be significant without clustering of these centers. The Applicant clarified in a response to an information request that the clustering was in fact pre-planned. Further details, as provided in the biometrics review, are as follows:", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "a58496d3-0dba-41dd-9a1d-28753e5fac08", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.45, "w": 0.86, "x": 0.07, "y": 0.07 }, "kind": "paragraph", "text": "The next pivotal RCT after HARMONY 1 was HARMONY 1-bis. It was a flop and never published, but the EMA and FDA review documents contain telling details. The design was similar to HARMONY 1 – 8 weeks duration with pitolisant compared to placebo and modafinil with ESS again as the primary endpoint. Pitolisant showed an irrelevant -2.19 reduction in ESS vs. placebo, which Harmony claimed was statistically significant with p=0.030 – but only after an unplanned post-hoc clustering of “small clinical study centers,” without which the ESS reduction would have been -1.94 and not stat sig (p=0.065). And the daily cataplexy rate on pitolisant actually doubled from 0.84 at baseline to 1.69. Nonetheless, the FDA viewed the trial as evidence of efficacy, once again illustrating the glaring deficiencies of the accelerated approval pathway. The FDA summarized the EMA review which criticized the “artificial” clustering as unplanned, but then simply gave Harmony a free pass: “The Applicant clarified in a response to an information request that the clustering was in fact pre-planned.”", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "a5f7e457-39a6-4555-a2e6-06401cd55ca1", "frameworkName": null, "frameworkSlug": null }, { "bbox": null, "kind": "quote", "text": "The Applicant clarified in a response to an information request that the clustering was in fact pre-planned. — FDA", "attrs": null, "subkind": null, "toolName": "Authority citation", "toolSlug": "authority-citation", "confidence": null, "componentId": "019dd953-64d1-73a9-abb6-de7d91f2be58", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.02, "w": 0.45, "x": 0.07, "y": 0.95 }, "kind": "source-note", "text": "Source: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/211150Orig2s000MedR.pdf", "attrs": null, "subkind": null, "toolName": null, "toolSlug": null, "confidence": null, "componentId": "d3c91abf-38c4-4024-b16f-0fe630c6753b", "frameworkName": null, "frameworkSlug": null } ], "metrics": [], "tools": [], "frameworks": [], "arcBeats": [], "loops": [], "imagePathAlt": null, "thumbSrc": null, "thumbSrcAlt": null, "locked": true }