Dalbavancin Approval Issues: A Case of Much Ado About Nothing

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Dalbavancin has changed hands a few times in its development history, moving from Lilly to Vicuron, then Pfizer and ultimately Durata. The original NDA for dalbavancin was submitted to FDA on Dec. 21, 2004.  Pfizer acquired dalbavancin as a “Phase 3 completed” drug ready for world-wide marketing on June 15, 2005. The drug was eventually approved on May 23, 2014.  What a delay!  What an odyssey!

The main issues FDA brought up when it issued an ‘Approvable Letter’ on Dec 20, 2007 were related to (1) GMP issues, and (2) the lack of justification of the NI margin of 10% in pivotal trial VER001-8.

We are not told the details of the GMP / CMC issues but it is not something that would take 7 years to fix. It was the second issue, i.e., the NI margin justification, which held up the submission, made Pfizer throw in the towel, and forced Durata to conduct 2 new Phase 3 trials resulting in a much delayed approval.

FDA’s mandate is and remains to safeguard the public from the dangers of a thalidomide, ethylene glycol and medical quackery. Nowadays, new compounds that were poorly studied, poorly documented, without proper safety assessments, that lack GMP or GCP standards are appropriately being stopped by the FDA watchdogs. There is still the occasional case of egregious misconduct, by industry not living up to its sponsor responsibilities, and by investigators putting financial benefits ahead of patient concerns. This is a problem across the board and affects other therapeutic areas as well; we hear about them periodically from whistle blowers inside and outside the Agency.

However, even in a high-quality submission – one without major issues related to the Big 3: Efficacy, Safety, Quality – there is an inherent residual risk (call it beta) which is intrinsic to the development of any NCE; it is not reducible to Zero. Hence, regulators need to use judgement, or wisdom, based on precedent, based on in-house experience, based on the ancillary contextual information sometimes only available to FDA.

Every FDA reviewer’s nightmare is having given the green light to a drug like [insert your favorite example] that became a disaster. However, there really weren’t any in recent memory.  Would telithromycin (Ketek) have been a disaster if it had been unleashed on the US?  Unlikely. Already approved temafloxacin (Omniflox) was probably the most dangerous drug (it caused HUS) but surveillance measures were in place at the time and it was withdrawn from the market once this most unusual adverse event became known. Daptomycin (Cubicin), often cited for its failed pneumonia study, was found out about in the course of clinical investigation, not stopped by an astute FDA regulatory reviewer à la Dr. Kelly.

The last disasters we are aware of were those of FIAU (hepatic / mitochondrial toxicity) and TeGenero’s TGN-1412 (cytokine storm). In the former, early cases of mortality were overlooked that – with 20/20 hindsight – were (maybe) preventable. In the latter, there were no early warnings signs.

So, how much of a ‘risk’ represents a “non-justified NI margin of 10%”, a margin used by many other developers in the past?

When regulators want to ‘diversify risk’, they have several mechanisms to do so:  By calling an AIDAC (benign approach) or by delaying approval demanding new trials (the nuclear option).  Requesting a new set of clinical trials is tantamount to killing the drug: it usually makes industry lose interest in the project and give up on it.

In the case of Dalvance, the good folks at Durata chose to bite the bullet and redo the Phase 3 program. They did so with some safeguards, by obtaining an SPA, following the new thinking at FDA re: ABSSSI to a T, becoming Snodgrass [1,2] experts, and learning to love the FDA’s ABSSSI Guidance with its contrived NI justifications for M1, M2 and delta discounts.

Seven (7) years later we now have a new set of FDA-compliant Dalvance Phase 3 data. They show that not only at the EOT, the TOC visit and the 30-day f/u visit are clinical and bacteriologic responses between dalbavancin and comparator similar ,but also at the incredibly important Day 2-3 timepoint when lesion sizes are compared.

Obtaining this additional piece of information, of questionable clinical relevance at best and not endorsed by EMA, came at an incredible cost for industry. It also denied patients and caregivers access to a drug which had some really unique features. Unless there is more to the early rejection which did not make it into the public domain, the regulatory delay tactics in the case of dalbavancin are totally unjustified and incomprehensible.

Please take the time and vote below – your opinion matters.  Thank you!

Was FDA’s demand that studies be repeated following their new ABSSSI Guidance justified?

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P.S. #1:  On March 31, 2014 the FDA AIDAC voted 12:0 in favor of dalbavancin approval
P.S. #2:  There was no FDA AIDAC at the time of the 2007 dossier review prior to issue of the Approvable Letter
P.S. #3:  The Medical Review of the Dalvance dossier lists a total of 35 compounds currently approved for cSSSI / ABSSSI, most based on NI studies with a unjustified delta of 10%.

References:
For a review of studies comprising the original Dalbavancin submission see:
J. Bennett: Dalbavancin in the treatment of complicated skin and soft-tissue infections: a review. Therapeutics and Clinical Risk Management 2008;4: 31
[1]  Snodgrass W. 1937   BMJ, 2:101
[2]  Snodgrass W.  1937; BMJ, 2:1167

Abbreviations:
NI          non-inferiority
SPA      special protocol assessment
AIDAC  Anti-Infectives Drug Advisory Committee
HUS      hemolytic-uremic syndrome
EOT      End-of-Therapy
TOC      Test-of-Cure

 

 

 

 

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