{"id":3297,"date":"2017-04-12T03:04:11","date_gmt":"2017-04-12T07:04:11","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=3297"},"modified":"2025-09-20T19:09:37","modified_gmt":"2025-09-21T01:09:37","slug":"fda-radical-reform","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2017\/04\/12\/3297\/fda-radical-reform\/","title":{"rendered":"FDA Needs Radical Reform"},"content":{"rendered":"

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

The nomination of Dr. Scott Gottlieb for\u00a0FDA commissioner, a political appointee, has created the usual bipartisan furor. He is called unqualified, a renegade, not committed enough to FDA orthodoxy, an industry darling by some and a maverick by others. All the while FDA lobbyists are singing the praises of an agency already highly efficient with speedy approvals and streamlined processes.<\/p>\n

Looking back at the last 15 years, the memories of FDA heavy-handedness with anti-infectives regulations and drug evaluations come back, and they still haunt us. We cannot forget the demands for new studies supposedly because \u201cthe science had changed\u201d when it had not, the occasions when minor deviations from guidelines became show-stoppers, when the Agency reneged on prior commitments, and when advertised \u2018flexibility\u2019 was absent when dealing with Phase 3 studies or a submission dossier.<\/p>\n

We cannot easily get over the demands for \u2018superiority\u2019 trials, still on the books but never attempted, which remain an oddity in the testing of antibiotics. Remember the FDA push for \u2018placebo\u2019 controlled studies not only for otitis\/ABOM, sinusitis\/ABS and bronchitis\/ABECB trials but also in CABP? How many sessions did FDA organize, how much time was wasted rationalizing an NI margin that in the end looked exactly like the one we had before?<\/p>\n

Poorly executed studies from the 1930’s were presented in support of the \u2018new science\u2019 – what a fine twist!<\/p>\n

We dare to challenge the usefulness of historical controls for quantitative analysis in general, but FDA\u2019s torture of historical data from Snodgrass publications dating back to1937 in order to derive M1 and M2 and then applying an arbitrary \u2018discount\u2019 was actually quite comical. A very entertaining exercise in contortionist thinking. No wonder the EMA did not go along with this.<\/p>\n

Antibiotics still have to\u00a0demonstrate efficacy over placebo, disregarding myriads of studies which have proven the concept. We choose to\u00a0ignore Bayesian concepts of statistics which would allow us to build on the rich experience from prior trials. A wasteful practice only rich countries can afford<\/span><\/p>\n<\/div>\n

Let us be clear: We don’t find fault with the agency\u2019s reviewers and the work they do. Their attention to quality, detailed reviews and rigorous data analysis are outstanding. What is less endearing to us are the onerous regulations that have reached a level of indescribable stupidity.<\/p>\n

Strong words?\u00a0 Not really. The new requirements made clinical studies almost impossible to execute for about a decade. Expert clinicians admonished FDA not to lose sight of the bigger picture, not to change what was not broken. Their advice went unheeded; zealots and statistical purists usurped the agenda and imposed their imprimatur on the regulations now in place.<\/p>\n

Today we want to highlight just one example of the \u201cgood work\u201d done by FDA philosophers which greatly impacts our ability to generate data in US patients.<\/p>\n

CABP Guidance \u2013 Fall-Out from the \u201cNo Prior Antibiotics\u201d Rule
\n<\/strong>In the US, it is rare for a pneumonia patient not to get antibiotics shortly after arrival in the ER. Analyses of large data sets have shown that delaying the administration of antibiotics negatively affects outcomes; hence, most hospitals strive to start them within the first 4 hours.<\/span><\/p>\n

It takes time in the ER to process patient intake data, do an H&P, obtain labs and the microbiology and imaging studies to establish a diagnosis of CABP. Obtaining a respiratory sample of decent quality is good practice in general, although required for registration studies. This step alone can be quite time-consuming as sampling of respiratory secretions may require the assistance of a respiratory therapist and inhalation treatment. Four hours go by fast in the best of settings.<\/p>\n

Then there is this thing called Informed Consent. Unless you ask your CAP patient to sign this document blindly, it takes time to go over all the pages with an acutely ill patient. How much time doctors really spend explaining study details, risks and benefits, and all the other yada, yada on the consent form is open to question, but withholding antibiotics while enrolling a patient into a CAP study becomes a race against time.<\/p>\n

FDA insists that no more than 25% of patients receive even a single dose of non-study antibiotics prior to enrollment. Actually, this 25% figure was a hard-fought compromise as FDA did not want to accept any<\/u> patients receiving even a single dose of prior antibiotics.<\/p>\n

As a consequence of this \u201cNo Prior Antibiotics Rule\u201d, US centers are no longer able to contribute patients to international trials. Recent CABP studies make up for this by recruiting \u2018antibiotic-na\u00efve\u2019 patients in far-away places, preferably in Eastern European countries where health care standards seem to be more lenient and medicine is practiced in a way that makes it easier to comply with FDA wishes.<\/p>\n

In the recent Solithromycin CABP trial 301, only 11% of patients were from the US, and 5% were African-American. In the ceftaroline CABP program only 2% of patients came from the US. In another recently completed CABP trial, barely 5 US patients could be recruited.<\/p>\n

FDA\u2019s justification for not allowing even one prior dose of antibiotics was based on the analysis of the failed daptomycin CABP study[1]<\/a>. Since then we have newer data suggesting that a single prior dose of antibiotics does not affect outcomes. Contrary to some ideologues, FDA\u2019s \u2018purist\u2019 approach does not add much to the interpretability of the efficacy data.<\/p>\n

We argue that the loss of representative US data is a costly trade-off, with much lost for little gain. Currently, the demographics of CABP studies are certainly no longer representative of the US population, just the opposite.<\/p>\n

FDA seems to believe that the health care practices of the old Russian Satellite countries are similar enough to the US population. When one reviews the CRFs from these countries, one\u00a0comes away with a slightly different impression.<\/p>\n

As it stands right now, FDA will get used to seeing a lot more data from the Ukraine, Poland, Estonia, Latvia, or Russia \u2013 all countries of choice for CROs conducting CABP trials these days.\u00a0

In the Teflaro (ceftaroline program, only 1 pivotal CAP trial (Study 08) enrolled US patients amounting to 4% of study population.\u00a0Quoting the Medical Reviewer: “Of particular interest is the fact that the Applicant categorized Hungary and Poland as part of Western Europe”<\/span>\u00a0<\/p>\n<\/div><\/p>\n

This FDA \u2018No Prior Antibiotic Rule\u2019 has backfired because it diverged too much from clinical practice. It will take more than fine-tuning to get back to a realistic practicable approach for CABP trials. The same holds true for other indications.<\/p>\n

Our belief in evolutionary change is gone\u2026let\u2019s give the\u00a0new leadership a try, please!<\/p>\n

References:
\n<\/strong>[1]<\/a> P Pertel. Effects of Prior Effective Therapy on the Ef\ufb01cacy of Daptomycin and Ceftriaxone for the Treatment of Community-Acquired Pneumonia. CID 2008; 46:1142<\/p>\n","protected":false},"excerpt":{"rendered":"

The nomination of Dr. Scott Gottlieb for\u00a0FDA commissioner, a political appointee, has created the usual bipartisan furor. He is called unqualified, a renegade, not committed enough to FDA orthodoxy, an industry darling by some and a maverick by others. All the while FDA lobbyists are singing the praises of an Continue reading FDA Needs Radical Reform<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":3298,"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":[3,18],"tags":[1410,2057,1411,520,1271,403,2058,1407,783,1780,2055,1056,625,2052,2056,5,2060,1583,2053,2062,2063,1055,2061,2054,2059,1405],"class_list":["post-3297","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-the_news","category-the_viewpoint","tag-abecb","tag-abom","tag-abs","tag-acute-otitis-media","tag-allphase-pharma-consulting","tag-antibiotic-blog","tag-bayesian-statistics","tag-bronchitis","tag-cabp","tag-cabp-guidance","tag-cro","tag-delta","tag-ema","tag-enrollment-criteria-for-cabp","tag-enrollment-x-us","tag-fda","tag-fda-commissioner","tag-harald-reinhart","tag-koseisho","tag-m1","tag-m2","tag-non-inferiority-margin","tag-placebo-controlled-trials","tag-pmda","tag-scott-gottlieb","tag-sinusitis"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/04\/FDA-change-slider.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-Rb","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":4745,"url":"https:\/\/allphasepharma.com\/dir\/2025\/07\/18\/4745\/cabp-trial-enrollment-but-not-in-the-usa\/","url_meta":{"origin":3297,"position":0},"title":"CABP TRIAL ENROLLMENT \u2013 BUT NOT IN THE USA","author":"Harald","date":"July 18, 2025","format":false,"excerpt":"Today\u2019s topic is about the lackluster recruitment of US centers in recent CABP trials. We noticed that Eastern European (EE) centers, specifically from Ukraine, Bulgaria, and Serbia, contribute patients in large numbers, actually making these trials feasible.\u00a0 When sponsors and CROs needed to enroll CABP patients, they could not rely\u2026","rel":"","context":"In "Did you know...?"","block_context":{"text":"Did you know...?","link":"https:\/\/allphasepharma.com\/dir\/category\/interesting_facts\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/07\/image.png?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/07\/image.png?resize=350%2C200&ssl=1 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/07\/image.png?resize=525%2C300&ssl=1 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/07\/image.png?resize=700%2C400&ssl=1 2x"},"classes":[]},{"id":2466,"url":"https:\/\/allphasepharma.com\/dir\/2016\/05\/03\/2466\/solithromycin-cap-study-cap-the-details-in-the-publication\/","url_meta":{"origin":3297,"position":1},"title":"Solithromycin CAP Study: \u00a0Cap the Details (in the Publication)","author":"Harald","date":"May 3, 2016","format":false,"excerpt":"In a recent publication, the results of a large Phase 3 trial comparing solithromycin with moxifloxacin in the treatment of CAP are presented\u00a0[1]. As this was a global registration trial, we should refer to the indication as CABP, the current FDA acronym for a very defined entity which has some\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"Solitair ORAL - slider copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/04\/Solitair-ORAL-slider-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/04\/Solitair-ORAL-slider-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/04\/Solitair-ORAL-slider-copy.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":2830,"url":"https:\/\/allphasepharma.com\/dir\/2016\/10\/27\/2830\/solithromycin-solitaire-iv-so-so-results-for-a-so-so-drug\/","url_meta":{"origin":3297,"position":2},"title":"Solithromycin SOLITAIRE-IV: So-So Results for a So-So Drug","author":"Harald","date":"October 27, 2016","format":false,"excerpt":"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\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"soli-iv-newer","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/10\/SOLI-IV-newer.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/10\/SOLI-IV-newer.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/10\/SOLI-IV-newer.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1265,"url":"https:\/\/allphasepharma.com\/dir\/2015\/02\/11\/1265\/commenting-on-comments-the-ceftaroline-trial-program-in-cabp\/","url_meta":{"origin":3297,"position":3},"title":"Commenting on Comments:\u00a0 The Ceftaroline Trial Program in CABP","author":"Harald","date":"February 11, 2015","format":false,"excerpt":"The ceftaroline (Teflaro\u00ae) program was executed at a time when FDA was debating a new CABP Guidance with new outcome measures: no longer was the time-honored TOC assessment acceptable, instead improvement on Day 3-5 was to become the new primary endpoint.\u00a0 FDA made other significant changes to the old 1998\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"Teflaro Ad CAP","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/02\/Teflaro-Ad-CAP.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/02\/Teflaro-Ad-CAP.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/02\/Teflaro-Ad-CAP.jpg?resize=525%2C300 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/02\/Teflaro-Ad-CAP.jpg?resize=700%2C400 2x"},"classes":[]},{"id":2998,"url":"https:\/\/allphasepharma.com\/dir\/2017\/01\/12\/2998\/omissions-commissions-errors-blunders-solithromycin\/","url_meta":{"origin":3297,"position":4},"title":"Omissions \u2013 Commissions \u2013 Errors \u2013 Blunders – Solithromycin","author":"Harald","date":"January 12, 2017","format":false,"excerpt":"Cempra received a complete response letter (CRL) as a X-mas present from FDA, and the news was pretty bad for company investors. 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