{"id":1234,"date":"2015-01-26T15:23:22","date_gmt":"2015-01-26T20:23:22","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1234"},"modified":"2015-01-27T07:34:00","modified_gmt":"2015-01-27T12:34:00","slug":"why-some-did-not-make-it","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/01\/26\/1234\/why-some-did-not-make-it\/","title":{"rendered":"Why Some Did Not Make It"},"content":{"rendered":"

There are numerous reasons why drugs get stuck in development.\u00a0 Certainly, problems with efficacy or problems with safety are main reasons but there are many other \u2018derailers\u2019 as well.\u00a0 For instance regulatory issues or manufacturing, difficulties can stop a program.\u00a0 Occasionally, a suboptimal dose was chosen because of (1) incomplete understanding of the PK\/PD relationship; (2) concerns about COGs; or (3) safety concerns which prevented higher and more effective dosing.\"toy<\/a><\/p>\n

Commercial re-evaluation because of a changed competitive landscape, patent concerns, or a strategic portfolio reassessment can sideline a drug which was yesterday\u2019s favorite.\u00a0 There are finite resources even in Big Pharma where few CEOs have a love affair with TA Anti-infectives.<\/p>\n

Unfortunately, companies rarely provide details in their press releases why a drug has hit a slick spot and no longer appears on the development roster.\u00a0 Sometimes it takes years to learn the full story.\u00a0 Below an incomplete list of antibiotics which ran into trouble in recent years. \u00a0Certainly, there are more examples that could have been included \u2013 feel free to add your favorite failed NDA or SNDA; the table is really just as a snapshot.<\/p>\n

Looking at the table, it may come as a surprise that so many drugs ran into trouble with Regulators.\u00a0 Proving efficacy usually requires demonstration of non-inferiority; clearly; some drugs did not pass this test.\u00a0 Sadly, adherence with GCP, i.e., issues with study execution and quality, were a major problem area as well. \u00a0\"toy<\/a><\/p>\n

The last decade was characterized by regulatory uncertainties that reached chaotic proportions.\u00a0 The never-ending changes in FDA guidances became a major stumbling block for drug developers. \u00a0Remember the drive for placebo studies in CABP and the contortions to define a NI margin for ABSSSI?\u00a0 In any event, some projects ran into trouble with Regulators when they\u00a0changed the rules in the middle of the game.\u00a0 FDA\u2019s justification that \u2018the science has changed\u2019 was never seriously challenged by PhRMA or the scientific community but that does not make it true. \u00a0When FDA speaks ‘ex cathedra’ are we supposed to say: ‘ipse dixit’?<\/p>\n

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

TA \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 Therapeutic area
\nGCP \u00a0 \u00a0 \u00a0 \u00a0Good Clinical Practice
\nABSSSI \u00a0 Acute bacterial skin\/skin structure infections
\nCABP \u00a0 \u00a0 \u00a0Community-acquired bacterial pneumonia
\nNI \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0Non-inferiority
\nPhRMA \u00a0 Pharmaceutical Research and Manufacturer\u00a0of America
\nCOGs \u00a0 \u00a0 Cost of goods
\nPK\/PD \u00a0 \u00a0Pharmacokinetic-pharmacodynamic<\/p>\n\n\n\n\n\t\n\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t\n\t
Drug Name<\/th>Company<\/th>Abx Class<\/th>Efficacy Issue<\/th>Safety Issue<\/th>Quality Issue<\/th>Regx Issue<\/th>Description of Issues<\/th>Consequences<\/th>\n<\/tr>\n<\/thead>\n
Ketek (telithromycin)<\/td>Sanofi<\/td>ketolide<\/td><\/td>S<\/td>Q<\/td>\u0394R<\/td>hepatotoxicity, visual disturbances, QT prolongation, data manipulation<\/td>resticted label<\/td>\n<\/tr>\n
Faropenem<\/td>Bayer\/ Replidyne<\/td>penem<\/td><\/td><\/td><\/td>\u0394R <\/td>FDA not accepting studies conducted following 1998 Guidances<\/td>FDA rejected NDA<\/td>\n<\/tr>\n
Garenoxacin<\/td>Schering\/Toyama<\/td>quinolone<\/td><\/td><\/td><\/td>\u0394R <\/td>EMEA requested 'additional information'<\/td>company stopped dev<\/td>\n<\/tr>\n
Exulett (Dalbavancin) <\/td>Pfizer \/ Vicuron<\/td>glycopeptide<\/td><\/td><\/td>Q<\/td><\/td>study quality concerns; new Phase 3 studies required by FDA<\/td>FDA rejected initial Pfizer application<\/td>\n<\/tr>\n
Vibativ (Telavancin)<\/td>Astellas \/ Theravance<\/td>glycopeptide<\/td>E<\/td>S<\/td><\/td>\u0394R <\/td>new 28-d mortality endpoint enforced - prior TOC endpoint not accepted; drug was NI at TOC but not at 28-d timepoint<\/td>FDA rejected NDA<\/td>\n<\/tr>\n
Iclaprim<\/td>Arpida<\/td>DHFR-inhibitor<\/td><\/td><\/td>Q<\/td>\u0394R <\/td>sponsor used NI criteria not suported by newer FDA Guidances<\/td>FDA rejected NDA<\/td>\n<\/tr>\n
Zevtera (Ceftobiprole)<\/td>J&J \/ Basilea<\/td>cephalosporin<\/td><\/td><\/td>Q<\/td><\/td>Janssen \/ J&J botched some Phase 3 studies - details unknown but resulting in Basilea suing J&J<\/td>FDA rejected NDA<\/td>\n<\/tr>\n
Tygacil (Tigecycline)<\/td>Wyeth<\/td>glycylcycline<\/td>E<\/td><\/td><\/td><\/td>did not meet NI criteria in VAP program (higher mortality)<\/td>SNDA failed<\/td>\n<\/tr>\n
Doribax (Doripenem)<\/td>Shionogi \/ J&J<\/td>carbapenem<\/td>E<\/td><\/td>Q<\/td><\/td>VAP program: did not meet NI criteria (higher mortality); suboptimal dosing and treatment duration in VAP; data quality issues<\/td>SNDA failed<\/td>\n<\/tr>\n
Restanza (Cethromycin)<\/td>Abbott \/ ALS<\/td>ketolide<\/td><\/td><\/td><\/td>R<\/td>Mission Impossible: FDA required proof of efficacy in MDR population <\/td><\/td>\n<\/tr>\n
Tequin (gatifloxacin)<\/td>BMS<\/td>quinolone<\/td><\/td>S<\/td><\/td><\/td>cases of dysglycemia in post-marketing surveillance<\/td>lost market leadership to moxifloxacin<\/td>\n<\/tr>\n
Cubicin daptomycin<\/td>Cubist<\/td>glycopeptide<\/td>E<\/td><\/td><\/td>\u0394R <\/td>CAP trial showing inferiority to ceftriaxone 2\/2 surfactant effect with daptomycin<\/td>no CAP pneumonia claim<\/td>\n<\/tr>\n
Linezolid<\/td>Pfizer<\/td>oxazolidinone<\/td><\/td>S<\/td><\/td><\/td>thrombopenia with prolonged administration; superiority claim over vanco in VAP not granted despite clinically convincing data <\/td>no prostatitis claim; no superiority claim<\/td>\n<\/tr>\n
GSK-052<\/td>GSK<\/td>leucyl tRNA synthetase <\/td>E<\/td><\/td><\/td><\/td>lack of efficacy in Phase 2 UTI PoC trial<\/td>company stopped dev<\/td>\n<\/tr>\n
<\/td><\/td><\/td><\/td><\/td><\/td><\/td><\/td><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n","protected":false},"excerpt":{"rendered":"

There are numerous reasons why drugs get stuck in development.\u00a0 Certainly, problems with efficacy or problems with safety are main reasons but there are many other \u2018derailers\u2019 as well.\u00a0 For instance regulatory issues or manufacturing, difficulties can stop a program.\u00a0 Occasionally, a suboptimal dose was chosen because of (1) incomplete Continue reading Why Some Did Not Make It<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1242,"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":[140,18],"tags":[809,81,810,792,403,791,804,595,220,796,783,114,808,229,92,66,85,228,741,432,597,803,798,782,781,788,5,790,795,779,799,246,482,787,523,785,72,780,745,67,800,655,784,789,807,801,793,200,811,74,786,797,480,805,43,479,802,426,86,659,440,806],"class_list":["post-1234","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-interesting_facts","category-the_viewpoint","tag-abbott","tag-absssi","tag-advanced-life-sciences","tag-als","tag-antibiotic-blog","tag-arpida","tag-astellas","tag-basilea","tag-bayer","tag-bms","tag-cabp","tag-ceftobiprole","tag-cethromycin","tag-cubicin","tag-cubist","tag-dalbavancin","tag-dalvance","tag-daptomycin","tag-doribax","tag-doripenem","tag-durata","tag-exulett","tag-factive","tag-failed-programs","tag-failed-studies","tag-faropenem","tag-fda","tag-garenoxacin","tag-gatifloxacin","tag-gcp","tag-gemifloxacin","tag-gsk","tag-gsk-052","tag-iclaprim","tag-jj","tag-ketek","tag-linezolid","tag-new-guidelines","tag-ni","tag-oritavancin","tag-oscient","tag-pfizer","tag-phrma","tag-replidyne","tag-restanza","tag-sanofi","tag-schering","tag-shionogi","tag-targanta","tag-telavancin","tag-telithromycin","tag-tequin","tag-the-medicines-company","tag-theravance","tag-tigecycline","tag-tmc","tag-toyama","tag-tygacil","tag-vibativ","tag-vicuron","tag-wyeth","tag-zevtera"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/01\/derailed-blog.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-jU","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":2911,"url":"https:\/\/allphasepharma.com\/dir\/2016\/11\/25\/2911\/prospecting-antibiotics\/","url_meta":{"origin":1234,"position":0},"title":"Prospecting for New Antibiotics","author":"Harald","date":"November 25, 2016","format":false,"excerpt":"The QIDP designation was introduced in 2012 to incentivize drug development in antiinfectives. QIDP came with several attractive features, such as prolongation of patent life, FDA\u00a0expedited review and more.\u00a0 In addition, FDA made it quite easy to garner the label.\u00a0 As you can see, there is really no downside to\u2026","rel":"","context":"In "Did you know...?"","block_context":{"text":"Did you know...?","link":"https:\/\/allphasepharma.com\/dir\/category\/interesting_facts\/"},"img":{"alt_text":"engine-qidp-blog","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/11\/Engine-QIDP-blog.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/11\/Engine-QIDP-blog.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/11\/Engine-QIDP-blog.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":751,"url":"https:\/\/allphasepharma.com\/dir\/2014\/08\/23\/751\/not-so-boring-boron-containing-antibiotics-create-a-stir\/","url_meta":{"origin":1234,"position":1},"title":"Not So Boring: \u00a0Boron-Containing Antibiotics Create a Stir","author":"Harald","date":"August 23, 2014","format":false,"excerpt":"Why are there so few boron-containing drugs on the market? \u00a0The cancer drug bortezumib (Velcade\u00ae) may be the only better-known drug on the market with a boron atom in its structure.[1]\u00a0 Among antibiotics, there is Kerydin\u2122 (tavaborole), an approved topical solution for the treatment of onychomycosis caused by Trichophyton but\u2026","rel":"","context":"In "The News"","block_context":{"text":"The News","link":"https:\/\/allphasepharma.com\/dir\/category\/the_news\/"},"img":{"alt_text":"Novel -lactamase inhibitors: a therapeutic hope against the scou","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/08\/fmicb-04-00392-g003-e1408842545171.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":1741,"url":"https:\/\/allphasepharma.com\/dir\/2015\/07\/17\/1741\/does-the-taxpayer-get-rewarded-for-funding-studies\/","url_meta":{"origin":1234,"position":2},"title":"Does The Taxpayer Get Rewarded For Funding Such Studies?","author":"Harald","date":"July 17, 2015","format":false,"excerpt":"Cabotegravir (S-1265744) is an integrase inhibitor similar to dolutegravir. \u00a0When formulated as a long-acting drug using crystalline nanoparticle technology it is called GSK'744 LAP.\u00a0 When injected intramuscularly, '744 LAP it has a half-life of >1 month which makes it ideally suited for PrEP\u00a0of HIV for high-risk patients who nowadays are\u2026","rel":"","context":"In "Did you know...?"","block_context":{"text":"Did you know...?","link":"https:\/\/allphasepharma.com\/dir\/category\/interesting_facts\/"},"img":{"alt_text":"LAP HIV Drugs - slider copy","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/LAP-HIV-Drugs-slider-copy.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/LAP-HIV-Drugs-slider-copy.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/07\/LAP-HIV-Drugs-slider-copy.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1168,"url":"https:\/\/allphasepharma.com\/dir\/2014\/12\/15\/1168\/the-circuitous-route-to-phase-3-another-chapter-in-the-fitful-development-of-ptk-0796\/","url_meta":{"origin":1234,"position":3},"title":"The Circuitous Route to Phase 3:\u00a0 Another Chapter in the Fitful Development of PTK-0796","author":"Harald","date":"December 15, 2014","format":false,"excerpt":"When antibiotics change hands, it can be a good thing.\u00a0 Small companies are often desperate to attract a partner with \u2018deep pockets\u2019 to help them finance an expensive late phase development but often have to give up control once\u00a0the honeymoon period is over.\u00a0 Such transitions can bring delays because new\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/12\/PTK-slider-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/12\/PTK-slider-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/12\/PTK-slider-copy.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":2271,"url":"https:\/\/allphasepharma.com\/dir\/2016\/01\/31\/2271\/moving-towards-greater-transparency-one-step-at-a-time-inexorably\/","url_meta":{"origin":1234,"position":4},"title":"Moving Towards Greater Transparency \u2013 One Step At A Time, Inexorably","author":"Harald","date":"January 31, 2016","format":false,"excerpt":"Sharing trial data has been a controversial topic for quite a while. Recently the editors of major medical journals decided to take a stand. They will\u00a0make access to trial source data a requirement, as a condition of publication, arguing that patients and the scientific community have a right to this\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"Cleaning Up - slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/01\/Cleaning-Up-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/01\/Cleaning-Up-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/01\/Cleaning-Up-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":3238,"url":"https:\/\/allphasepharma.com\/dir\/2017\/03\/21\/3238\/gc-therapy-shooting-stars\/","url_meta":{"origin":1234,"position":5},"title":"GC Therapy – \u00a0Shooting for the Stars","author":"Harald","date":"March 21, 2017","format":false,"excerpt":"Besides ceftriaxone (CTRIAX), cefixime and spectinomycin we have no other highly effective single-dose treatment regimens for urogenital GC. Failures of all 3 drugs have been described but remain rare, can be overcome with higher doses of CTRIAX (1 g instead of 250 mg IM) or with azithromycin combination therapy. Worse\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/GC-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/GC-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/GC-slider.jpg?resize=525%2C300 1.5x"},"classes":[]}],"jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1234","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/comments?post=1234"}],"version-history":[{"count":11,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1234\/revisions"}],"predecessor-version":[{"id":1252,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/posts\/1234\/revisions\/1252"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media\/1242"}],"wp:attachment":[{"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/media?parent=1234"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/categories?post=1234"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/allphasepharma.com\/dir\/wp-json\/wp\/v2\/tags?post=1234"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}