{"id":2830,"date":"2016-10-27T09:54:27","date_gmt":"2016-10-27T13:54:27","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=2830"},"modified":"2025-09-20T19:18:36","modified_gmt":"2025-09-21T01:18:36","slug":"solithromycin-solitaire-iv-so-so-results-for-a-so-so-drug","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2016\/10\/27\/2830\/solithromycin-solitaire-iv-so-so-results-for-a-so-so-drug\/","title":{"rendered":"Solithromycin SOLITAIRE-IV: So-So Results for a So-So Drug"},"content":{"rendered":"

\"soli-iv-newer\"<\/a>Just before the November 4th AMDAC on solithromycin, we are being treated to a very fine piece of study write-up. Of course, we are speaking of the File paper on the SOLITAIRE-IV trial, and what a fine piece of crafty penmanship it is, if you haven\u2019t noticed.<\/p>\n

Just as a reminder: the SOLITAIRE-ORAL\u00a0study was like a walk in the park: equal efficacy (make this: non-inferiority) and safety were shown between oral solithromycin and moxifloxacin in this CABP study of mostly ambulatory patients.<\/p>\n

So far so good. In SOLITAIRE-IV, the File study, more sick CABP patients were enrolled in order to study\u00a0IV\/PO solithromycin and an IV to PO step-down concept. The study was conducted following the FDA CABP Guideline document to the letter, and the publication spares us none of the gruesome details. According to FDA wisdom, Early Clinical Response (ECR) around Day 3 is the primary efficacy parameter between test drug and control.<\/p>\n

Solithromycin did not disappoint us: the IV\/PO regimen showed very similar efficacy at that early time point to the comparator, moxifloxacin IV\/PO.\u00a0However, discordant results were seen at early f\/u, the key time point for the European Agency which requires that clinical evaluation at short-term f\/u (CE at SFU) be within a 10% NI delta.<\/p>\n

The SOLITAIRE-IV authors carefully avoided providing this data, instead presenting only their post-hoc analysis of a \u201cmodified CE population\u201d in Table 4 of the article. In this \u201cmodified CE population\u201d analysis, a favorable outcome was seen in 87.6% for solithromycin vs 92.5% for moxifloxacin, CI [-9.4, -0.5].

One\u00a0can bet the farm on this: without post-hoc data dredging, the CI would have been outside the -10% margin!<\/span><\/p>\n<\/div><\/p>\n

When a primary endpoint \u2013 prospectively specified in the protocol – is not detailed in the final article, when a post-hoc analysis is presented instead, one is dealing with obfuscation at the best, and with data manipulation at the worst.\u00a0Tom File, the main author, should not have let this happen, and neither should the reviewers of this paper and editors of the Clinical Infectious Diseases Journal.

Such selective reporting is appalling, even during this election season when one is getting used to half-truths and spin-doctoring<\/span>.<\/p>\n<\/div><\/p>\n

Of course, Tom File did not himself write this paper, ghost writers most likely wrote it who received their instructions, corrections and suggestions for \u2018proper wording\u2019 from company stakeholders. So much for the caliber of peer review and the publication process.<\/p>\n

Looking at the data as presented, it seemed that SOLITAIRE-IV had met FDA criteria for efficacy but failed to meet EMA criteria. Now the FDA has a dilemma: prior FDA Guidelines relied on clinical assessment of efficacy after treatment, just as the current EMA approach. This was called the Test-of-Cure (TOC) visit, usually done some 14 days after EOT just like the SFU. Will the FDA turn a blind eye and ignore the post-treatment\u00a0results?
\n

Admittedly, making a decision on drug efficacy on Day 3 and not at the end-of-therapy is an abstruse concept hard to comprehend. It is\u00a0a regulatory world, after all.<\/span><\/p>\n<\/div><\/p>\n

Will solithromycin become approved in the US but rejected in the EU? This is not likely but still possible. The drug passed the FDA litmus test of efficacy at the ECR timepoint; hence, we could predict that FDA approval is highly likely. EMA may have a tougher time with the data and not buy into Cempra\u2019s post-hoc analysis.<\/p>\n

Not always have US and EU regulators come to the same conclusions after looking at the same data. For instance, tigecycline\/Tygacil was approved for CABP in the US, but not in Europe. Xigris labeling was quite different in the US than in the EU.\u00a0

Now it appears that FDA’s new efficacy criteria have become less stringent than the older ones<\/span><\/p>\n<\/div><\/p>\n

Just think, what if SOLITAIRE-IV had failed to show NI at the Day 3 timepoint but, nevertheless, shown NI at early follow-up? What happens if a study meets EMA criteria for efficacy but not FDA? \u00a0There is no need to speculate; FDA will likely tell us this was a review issue. Good answer!<\/p>\n

There is another wrinkle in the SOLITAIRE-IV trial, and this one has to do with the inordinately high incidence of IV site reactions. A whopping 31.3% of patients on solithromycin IV had infusion site reactions! How fast did they infuse this otherwise well-tolerated 4th generation macrolide to create such a mess? Was it over 60 or 90 minutes? The article does not mention this. We have to dig deeper \u2013 a topic for another blog.<\/p>\n

There was yet another peculiar aspect to this study, also related to dosing. As patients were switched from IV to PO solithromycin, the first oral dose was a loading dose of 800 mg. Folks, we need your help with this: Since when is a loading dose required in the middle of a treatment course? Is this also necessary with other antibiotics that have a long half-life? Have we missed that lecture \u2013 where have we\u00a0been all this time? Please, enlighten us!<\/p>\n

NOTE added in Proof (11\/12\/16):<\/span><\/strong>
\nThankfully, the FDA AMDAC\u00a0on 11\/4\/16 provided the missing data; the delta for the CE population at the SFU timepoint was 12.4%. This is not much off the mark and – as a single aberration – was not a big issue for FDA. \u00a0We predict it will not be a big issue for EMA, either. Quite an\u00a0unnecessary attempt to cover up in the File publication, we feel.<\/span><\/p>\n

Reference:<\/strong>
\nT File. SOLITAIRE-IV. IV Solithromycin vs Moxifloxacin in CABP. Clin Infect Dis 2016; 63: 1007<\/p>\n

Abbreviations:<\/strong>
\nAMDAC \u00a0Antimicrobial Drug Advisory Committee
\nECR \u00a0Early Clinical Response (Day 3 of Therapy)
\nSFU \u00a0Short-term Follow-Up (Day 12-17 after EOT in this trial)
\nEOT \u00a0End-of-therapy timepoint
\nTOC \u00a0Test-of-Cure (usually 14 days after EOT)
\nCE \u00a0population clinically evaluable for efficacy assessment<\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

Just before the November 4th AMDAC on solithromycin, we are being treated to a very fine piece of study write-up. Of course, we are speaking of the File paper on the SOLITAIRE-IV trial, and what a fine piece of crafty penmanship it is, if you haven\u2019t noticed. Just as a Continue reading Solithromycin SOLITAIRE-IV: So-So Results for a So-So Drug<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":2847,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":true,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[19,227,3,18],"tags":[778,1271,1404,403,215,1780,819,1056,682,1781,1782,5,1783,1784,1583,1779,253,924,977,223,47,745,153,1785,1778,1626,43,426,683],"class_list":["post-2830","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-recent_literature","category-the_news","category-the_viewpoint","tag-aidac","tag-allphase-pharma-consulting","tag-amdac","tag-antibiotic-blog","tag-avelox","tag-cabp-guidance","tag-cempra","tag-delta","tag-drotrecogin","tag-efficacy-criteria","tag-efficacy-margins","tag-fda","tag-fda-vs-eu-guidelines","tag-file","tag-harald-reinhart","tag-iv-site-reactions","tag-ivpo","tag-ketolide","tag-loading-dose","tag-macrolide","tag-moxifloxacin","tag-ni","tag-non-inferiority","tag-port-score","tag-solitaire-iv","tag-solitaire-oral","tag-tigecycline","tag-tygacil","tag-xigris"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/10\/SOLI-IV-newer.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-JE","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":2862,"url":"https:\/\/allphasepharma.com\/dir\/2016\/11\/07\/2862\/profiling-solithromycin-fda-amdac-on-solithera\/","url_meta":{"origin":2830,"position":0},"title":"Profiling Solithromycin: FDA AMDAC on Solithera","author":"Harald","date":"November 7, 2016","format":false,"excerpt":"Police profiling based on race, sex or gender is a highly controversial practice. 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