There are numerous reasons why drugs get stuck in development. Certainly, problems with efficacy or problems with safety are main reasons but there are many other ‘derailers’ as well. For instance regulatory issues or manufacturing, difficulties can stop a program. 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.
Commercial re-evaluation because of a changed competitive landscape, patent concerns, or a strategic portfolio reassessment can sideline a drug which was yesterday’s favorite. There are finite resources even in Big Pharma where few CEOs have a love affair with TA Anti-infectives.
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. Sometimes it takes years to learn the full story. Below an incomplete list of antibiotics which ran into trouble in recent years. Certainly, there are more examples that could have been included – feel free to add your favorite failed NDA or SNDA; the table is really just as a snapshot.
Looking at the table, it may come as a surprise that so many drugs ran into trouble with Regulators. Proving efficacy usually requires demonstration of non-inferiority; clearly; some drugs did not pass this test. Sadly, adherence with GCP, i.e., issues with study execution and quality, were a major problem area as well.
The last decade was characterized by regulatory uncertainties that reached chaotic proportions. The never-ending changes in FDA guidances became a major stumbling block for drug developers. Remember the drive for placebo studies in CABP and the contortions to define a NI margin for ABSSSI? In any event, some projects ran into trouble with Regulators when they changed the rules in the middle of the game. FDA’s justification that ‘the science has changed’ was never seriously challenged by PhRMA or the scientific community but that does not make it true. When FDA speaks ‘ex cathedra’ are we supposed to say: ‘ipse dixit’?
TA Therapeutic area
GCP Good Clinical Practice
ABSSSI Acute bacterial skin/skin structure infections
CABP Community-acquired bacterial pneumonia
PhRMA Pharmaceutical Research and Manufacturer of America
COGs Cost of goods
|Drug Name||Company||Abx Class||Efficacy Issue||Safety Issue||Quality Issue||Regx Issue||Description of Issues||Consequences|
|Ketek (telithromycin)||Sanofi||ketolide||S||Q||ΔR||hepatotoxicity, visual disturbances, QT prolongation, data manipulation||resticted label|
|Faropenem||Bayer/ Replidyne||penem||ΔR||FDA not accepting studies conducted following 1998 Guidances||FDA rejected NDA|
|Garenoxacin||Schering/Toyama||quinolone||ΔR||EMEA requested 'additional information'||company stopped dev|
|Exulett (Dalbavancin)||Pfizer / Vicuron||glycopeptide||Q||study quality concerns; new Phase 3 studies required by FDA||FDA rejected initial Pfizer application|
|Vibativ (Telavancin)||Astellas / Theravance||glycopeptide||E||S||ΔR||new 28-d mortality endpoint enforced - prior TOC endpoint not accepted; drug was NI at TOC but not at 28-d timepoint||FDA rejected NDA|
|Iclaprim||Arpida||DHFR-inhibitor||Q||ΔR||sponsor used NI criteria not suported by newer FDA Guidances||FDA rejected NDA|
|Zevtera (Ceftobiprole)||J&J / Basilea||cephalosporin||Q||Janssen / J&J botched some Phase 3 studies - details unknown but resulting in Basilea suing J&J||FDA rejected NDA|
|Tygacil (Tigecycline)||Wyeth||glycylcycline||E||did not meet NI criteria in VAP program (higher mortality)||SNDA failed|
|Doribax (Doripenem)||Shionogi / J&J||carbapenem||E||Q||VAP program: did not meet NI criteria (higher mortality); suboptimal dosing and treatment duration in VAP; data quality issues||SNDA failed|
|Restanza (Cethromycin)||Abbott / ALS||ketolide||R||Mission Impossible: FDA required proof of efficacy in MDR population|
|Tequin (gatifloxacin)||BMS||quinolone||S||cases of dysglycemia in post-marketing surveillance||lost market leadership to moxifloxacin|
|Cubicin daptomycin||Cubist||glycopeptide||E||ΔR||CAP trial showing inferiority to ceftriaxone 2/2 surfactant effect with daptomycin||no CAP pneumonia claim|
|Linezolid||Pfizer||oxazolidinone||S||thrombopenia with prolonged administration; superiority claim over vanco in VAP not granted despite clinically convincing data||no prostatitis claim; no superiority claim|
|GSK-052||GSK||leucyl tRNA synthetase||E||lack of efficacy in Phase 2 UTI PoC trial||company stopped dev|