{"id":1301,"date":"2015-03-15T17:51:39","date_gmt":"2015-03-15T21:51:39","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1301"},"modified":"2016-07-14T15:02:20","modified_gmt":"2016-07-14T19:02:20","slug":"the-new-cuti-guideline-a-look-at-the-evolving-thinking-at-fda","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/03\/15\/1301\/the-new-cuti-guideline-a-look-at-the-evolving-thinking-at-fda\/","title":{"rendered":"The New cUTI Guideline: A Look at the \u2018Evolving Thinking\u2019 at FDA"},"content":{"rendered":"

Just to refresh everyone\u2019s memory: First, we had the Points-To-Consider document of 1993, then the 1998 Guidance, followed by the 2012 Guidance and now the 2015 Guidance for the conduct of registration studies in cUTI.\u00a0 They all have served us well and I cannot recall a situation when a drug was approved based on these guidelines but later found to be ineffective.\u00a0 Which begs the question: why is there this drive \u2013 almost obsession – to fine-tune a regulatory path that works just fine?<\/p>\n

Case in point: \u00a0the failed cUTI trial which recently ended the prospects of AN-3365 \/ GSK-052, a leucyl-transfer RNA synthetase inhibitor.\u00a0 The drug, rather surprisingly, was not active because resistance developed rather fast.\u00a0 In that case, inferiority to standard comparator was obvious and not a subtle finding; the drug would not have met the Points-to-Consider criteria for efficacy either.<\/p>\n

In what respect is the new cUTI Guidance different from earlier versions?\u00a0 Where is the impact of \u2018new science\u2019 that triggered a \u2018rethinking\u2019 of the regulatory approach to cUTI? \u00a0I can come up with several potential answers but they don\u2019t seem to amount to anything substantial.\u00a0 The changes in the 2015 Guidance are not unreasonable from a clinical point of view but are often of a \u201cC-III level of evidence\u201d which amounts to \u2018expert opinion\u2019 not hard facts.\u00a0 Many of the changes might get changed again in the next version(s).<\/p>\n

Does it really matter if efficacy now requires not just microbiologic cure but also clinical resolution of all core symptoms?\u00a0 Aren\u2019t these two things linked?\u00a0 And does it really matter if urgency persist on Day 12 (an incomplete response now considered a Failure) but then\u00a0resolves a few days later (making treatment outcome a Success)?\u00a0 Is a PRO tool really improving the evaluation of drug efficacy\u00a0in infectious diseases trials that already give us\u00a0the best of all possible surrogate markers of efficacy, i.e. bacterial response?<\/p>\n

I think the 2015 Guidance is a defensive document, incorporating some concepts which are important to regulators and statisticians, less so to clinicans (or patients):<\/p>\n

    \n
  1. An evidence-based justification for the 10% NI margin:

    Our assessment: MUCH ADO ABOUT NOTHING<\/span><\/p>\n<\/div>
    \nAs it turns out, only a single trial (from 1918) could be found that had a sizable population of cUTI patients from pre-antibiotic days.\u00a0 Despite its shortcomings, it became the basis of the HESDE justification, the \u2018historical evidence of sensitivity to drug effect\u2019.
    \nThis trial, like the Snodgrass publications from 1936\/1937 in cSSSI, is certainly of interest to historians but making it the basis of a statistical construct to derive M1 is really stretching the imagination.\u00a0 It is not often that regulators are credited with imaginative rulings but this is surely a prime example of \u2018data dredging\u2019.\u00a0 Or for the creative writing (A-I evidence)
    \nOur assessment: MUCH ADO ABOUT NOTHING<\/li>\n

  2. Incorporating the \u2018feel-function-survival\u2019 gospel into the cUTI Guidance:

    Our assessment: A GOOD THING TO IMPLEMENT<\/span><\/p>\n<\/div>
    \nThis \u2018holy trinity\u2019 of outcome criteria was conceived by FDA statisticians in an effort to make outcome determinations less biased, more objective (mortality!) and more patient-centric. While other disciplines had long worked with PROs for lack of better efficacy parameters, infectious diseases studies had always relied on microbiology results and investigator assessments.
    \nClearly, cUTI \u00a0patients can relate their symptoms and provide unfiltered feedback. \u00a0There is no reason to believe that patients could not provide information about their complaints and how they improved with treatment.
    \nOur assessment: A GOOD THING TO IMPLEMENT<\/li>\n

  3. Beating a path back to reality regarding prior antibiotic use:
    \nEnrolling patients into cUTI trials should really not be that difficult: the condition is not rare, the symptoms are tell-tale, and there are rapid diagnostics in the form of Gram-stain and diptick tests. What makes these studies hard to execute in the real world is the inelligibility\u00a0of patients who received systemic antibiotics prior to enrollment.
    \nIn the past, treatment <24 hours with non-study antibiotics was acceptable; given a total treatment duration of 7-14 days this 1 day of \u201ccontamination\u201d would not seem very consequential.\u00a0 However, the FDA is correct in their thinking that such early antibiotic use can have a substantial impact on outcome.\u00a0 At least, it is a significant confounder in the context of NI studies as it tends to blunt any true difference between study meds and controls.
    \nIn addition, some of these non-study antibiotics have long half-lives, or prolonged urinary excretion times, or accumulate in the urine, thereby resulting in treatment effects past 24 hrs.
    \nSo, the scientifically correct approach is to demand that study patients be free of such exposure. However, here is the rub: \u00a0in the real world,\u00a0patients will have started antibiotic therapy before coming to an\u00a0ER with cUTI to be admitted.\u00a0 A good FMD who has a patient with known structural abnormalities or indwelling catheter will not hesitate to start therapy as he sends the patient on his way to the hospital.
    \nFDA wants our clinical studies to reflect reality, otherwise we would not have an ITT approach but a per-protocol approach\u00a0in our\u00a0studies.
    \nIn an effort to\u00a0find middle ground: FDA now\u00a0allows up to 24 hrs of prior antibiotic use in up to 25% of patients.\u00a0 They encourage sponsors to reduce the amount to a single-dose of prior antibiotics, if possible. \u00a0But then they still demand that >75% of all cUTI study patients should not have any prior antibiotics.
    \nOur assessment: \u00a0IT SHOULD HAVE READ:\u00a0\u201cUP TO 75% OF PATIENTS CAN HAVE A SINGLE DOSE OF NON-STUDY DRUG PRIOR TO RANDOMIZATION\u201d.<\/li>\n<\/ol>\n

     <\/p>\n

    Reference:<\/p>\n

    Complicated Urinary Tract Infections: Developing Drugs for Treatment. \u00a0Guidance for Industry. \u00a0http:\/\/www.fda.gov\/downloads\/Drugs\/Guidances\/ucm070981.pdf<\/p>\n

     <\/p>\n

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

    Just to refresh everyone\u2019s memory: First, we had the Points-To-Consider document of 1993, then the 1998 Guidance, followed by the 2012 Guidance and now the 2015 Guidance for the conduct of registration studies in cUTI.\u00a0 They all have served us well and I cannot recall a situation when a drug Continue reading The New cUTI Guideline: A Look at the \u2018Evolving Thinking\u2019 at FDA<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1303,"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":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[3,18],"tags":[403,879,355,99,884,883,882,881,880],"class_list":["post-1301","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-the_news","category-the_viewpoint","tag-antibiotic-blog","tag-complicated-uti","tag-cuti","tag-fda-guidance","tag-intent-to-treat","tag-itt","tag-patient-reported-outcomes","tag-pro","tag-urinary-tract-infection"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/03\/UTI-Guidance-Slider.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-kZ","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":4964,"url":"https:\/\/allphasepharma.com\/dir\/2025\/08\/15\/4964\/new-idsa-cuti-guideline\/","url_meta":{"origin":1301,"position":0},"title":"NEW IDSA cUTI GUIDELINE","author":"Harald","date":"August 15, 2025","format":false,"excerpt":"A new Guideline for the treatment of cUTI just arrived.[1] First, we are glad that this somewhat mundane topic receives the attention it deserves.\u00a0 UTIs are often downplayed as minor infections, but the cUTI variety should not be taken lightly.\u00a0 Many patients still are admitted with life-threatening infections, so prompt\u2026","rel":"","context":"In "The News"","block_context":{"text":"The News","link":"https:\/\/allphasepharma.com\/dir\/category\/the_news\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/cUTI-classification.jpg?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/cUTI-classification.jpg?resize=350%2C200&ssl=1 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/cUTI-classification.jpg?resize=525%2C300&ssl=1 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/cUTI-classification.jpg?resize=700%2C400&ssl=1 2x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/08\/cUTI-classification.jpg?resize=1050%2C600&ssl=1 3x"},"classes":[]},{"id":3144,"url":"https:\/\/allphasepharma.com\/dir\/2017\/02\/09\/3144\/smiles-press-conference-plazomicin-delivers\/","url_meta":{"origin":1301,"position":1},"title":"All Smiles at the Press Conference: Plazo+Levo Delivers","author":"Harald","date":"February 9, 2017","format":false,"excerpt":"This December, Achaogen released much data on 2 plazomicin trials[1]: the pivotal EPIC study comparing plazomicin \/ levofloxacin with meropenem\u00a0\/ levofloxacin in cUTI is the one we want to look at today because it is interpretable, while the other trial called CARE is not. 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