{"id":2641,"date":"2016-07-20T22:37:07","date_gmt":"2016-07-21T02:37:07","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=2641"},"modified":"2025-09-20T19:20:46","modified_gmt":"2025-09-21T01:20:46","slug":"choose-your-outcome-how-design-minutiae-affect-trial-results","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2016\/07\/20\/2641\/choose-your-outcome-how-design-minutiae-affect-trial-results\/","title":{"rendered":"Choose your Outcome: How Design Minutiae Affect Trial Results"},"content":{"rendered":"

\"Tag<\/a><\/p>\n

When you search for \u2018ceftidoren\u2019 on Wikipedia, you will get a surprise: there is no entry. However, a search on the web tells us that Spectracef (ceftidoren pivoxil) still exists. Gee, now the drug is spelled \u2018cefditoren\u2019 and \u2013 looking through the list of retrieved articles \u2013 it seems that the spelling for this cephalosporin seems to go both ways: both the \u201cd-t\u201d and the \u201ct-d\u201d versions are in widespread use. Clinicaltrials.gov lists a trial in AECB of ceftidoren (\u201ct-d\u201d) vs levofloxacin [1]<\/a>, the latter also often misspelled as levafloxacin. With a brand name of Levaquin, this is understandable.\u00a0 Fortunately, Wikipedia has an article on cefditoren (“d-t”). Let\u2019s hope this beta-lactam never comes up at a spelling bee.<\/p>\n

The reason this blog is about ceft*d\u2026(ah, forget it, let\u2019s just call it Spectracef here) has to do with an interesting analysis provided by an FDA reviewer some 15 years ago. By applying small modifications to eligibility, validity and evaluation criteria, he was able to show just how much results in an\u00a0AECB trial were affected. In this case, results varied by as much as\u00a030% (see Table).<\/p>\n

\"cefditoren<\/a>
modified from FDA Medical Review Spectracef 2001 [2]<\/figcaption><\/figure>This is more variability than most of us would have predicted. How can one\u00a0justify lumping\u00a0study results across various AECB studies when outcomes are so sensitive to even\u00a0minor differences in design? Can we\u00a0trust assessments from a meta-analysis of trials when there is no way of standardizing criteria across trials or compensating for their effects on\u00a0outcome?\u00a0The FDA Medical Officer commented on small differences between the Avelox and Spectracef trials despite seemingly very similar guideline-driven designs.<\/p>\n

Small changes to study design may have unintended consequences but study design elements can also be tweaked \/ manipulated to produce desired results. Marketing, ever concerned about impressions, would probably not be happy to see any trial with efficacy rates in the 50% range – even if non-inferiority was demonstrated \u2013 when other competitors have published success rates for the same indication of say, 80%. The Spectracef CEF 97-003 study was a high-quality registration trial; even in the context of a well-controlled prospective blinded trial (comparing 2 doses of Spectracef with cefuroxime) with rigorously defined design features a favorable numerical outcome can be pre-programmed.<\/p>\n

Publications cannot provide such fine details; only a diligent FDA reviewer can do such detailed\u00a0confirmatory subset analyses. If raw data sets were available to the public for reanalysis, it would be easier\u00a0to perform independent sensitivity tests and ‘level the playing field’ for a meta-analysis. But we are not there yet. Fortunately, in the case of the Spectracef AECB trial, a\u00a0comparator arm of\u00a0patients subjected to identical conditions of analysis and treatment \u00a0provided an internal reference point to\u00a0validate the results.<\/p>\n

This was not the case in many LAIV studies we discussed recently [3]. Historical controls just cannot make up for the lack of a randomized contemporaneous cohort whatever fancy statistical footwork is done. Studies using historical controls are tantamount to comparing the performance of a shiny new car on a freshly paved road to that of old gas guzzlers, bikes and trucks, all from a different era and on different road conditions. Nothing more.<\/p>\n

The regulatory agencies are currently facing a dilemma: They recognize that RCT cannot be done to study drug efficacy in pure\u00a0MDR infections.\u00a0Trials using historical control of patients with CRE, ESBL, or with\u00a0rare infections, like Pseudomonas or Acinetobacter, have been suggested as feasible alternatives\u00a0and we may discuss the topic in another blog. It is well known that\u00a0historical\u00a0‘control’ trials always favor the new drug; from a regulatory perspective, results from such ‘trials’ are almost impossible to interpret.<\/p>\n

 <\/p>\n

References:<\/strong><\/p>\n

[1]<\/a> https:\/\/clinicaltrials.gov\/ct2\/results?term=ceftidoren&Search=Search
\n<\/a>[2]<\/a> http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2001\/21-222_Spectracef.cfm
\n<\/a>[3]\u00a0https:\/\/allphasepharma.com\/dir\/2016\/07\/07\/2596\/is-laiv-dead-or-just-on-laiv-support\/<\/a><\/p>\n

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

When you search for \u2018ceftidoren\u2019 on Wikipedia, you will get a surprise: there is no entry. However, a search on the web tells us that Spectracef (ceftidoren pivoxil) still exists. Gee, now the drug is spelled \u2018cefditoren\u2019 and \u2013 looking through the list of retrieved articles \u2013 it seems that Continue reading Choose your Outcome: How Design Minutiae Affect Trial Results<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":2643,"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":false,"_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":[19,3,18],"tags":[1271,403,215,1699,1000,1702,1707,1701,1583,1709,1704,1703,1686,516,213,1708,1706,47,1371,38,1700,1705],"class_list":["post-2641","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-qidp_antibiotic","category-the_news","category-the_viewpoint","tag-allphase-pharma-consulting","tag-antibiotic-blog","tag-avelox","tag-cefditoren","tag-cefuroxime","tag-control-group","tag-cross-study-design-differences","tag-fda-review","tag-harald-reinhart","tag-historical-comparison-studies","tag-impact-of-evaluation-criteria","tag-impact-of-selection-criteria","tag-laiv","tag-levaquin","tag-levofloxacin","tag-medical-officer","tag-meta-analysis","tag-moxifloxacin","tag-qidp","tag-rct","tag-spectracef","tag-study-design"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/07\/Tag-Cloud-3-slider.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-GB","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":3211,"url":"https:\/\/allphasepharma.com\/dir\/2017\/03\/05\/3211\/qidp-liberal-hand-out-fda\/","url_meta":{"origin":2641,"position":0},"title":"QIDP, a Liberal Hand-Out from FDA","author":"Harald","date":"March 5, 2017","format":false,"excerpt":"On our blog site, \u2018QIDP\u2019 stands for \u201cQualified Infectious Diseases Product\u201d but when you look up \u2018QIDP\u2019 on the internet, you will find that it also stands for \u201cQualified Intellectual Disabilities Professional\u201d. 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