No Such Thing as a Free Ride…

..when it comes to FDA review of antibiotic NDAs.  Some seem to have forgotten the dismal record of antibiotic approvals in the last 15 years, and the long list of failed submissions.  Many failed not because of lack of efficacy or a bad safety profile but because of changes in guidelines, changes in definitions and changes in regulatory demands.  This uncertainty drove many companies away from the field, choosing to rather pursue the more lucrative pickings in oncology.

Nobody should believe for a second that FDA lowered their standards for the 4 QIDP drugs approved in 2014

When it became clear – first to the public, eventually to regulators – that bacterial resistance was getting out of control, with no new drugs in sight, a few stop-gap measures were put in place in the hope that they would rekindle the flame.  QIDP status was created for drug candidates that addressed a medical need.  In return, a 5-year patent extension and accelerated review was granted (among other things).

Clearly, garnering the QIDP designation has helped many small companies justify their continued engagement in what was seen as a nonsensical investment by many big players.  With the notable exception of daptomycin/Cubicin and linezolid/Zyvox, no company had figured out yet how to make a profit with a narrow-spectrum, rare disease, formulary-restricted, limited-use antibacterial directed against MDR pathogens.  Not even QIDP enticed Big Pharma to return to the ID field (with a few exceptions).theBMJ

Now, in a recent “Feature” article, a junior BMJ editor proclaimed that QIDP drugs received ‘relaxed’ treatment at FDA [1].  According to his assessment several recently approved drugs did not warrant QIDP status at all as they were not sufficiently more active against problem pathogens than other drugs already on the market.

I like the BMJ because it does not shy away from controversy and often presents an unorthodox point of view.  However, here I find myself defending the FDA.  Nobody should believe for a second that FDA lowered their standards, and that review for the 4 QIDP drugs approved in 2014 was less exacting than for non-QIDP submissions.  The regulatory review process was certainly accelerated, but to call it ‘relaxed’ is a mischaracterization.  The SBAs for these drugs are available; could someone please point out to me where FDA made compromises for these QIDP drugs?BMJ - banner copy

Nor were more lenient development requirements applied.  Tedizolid (Sivextro) conducted a very standard Phase 3 program, no short-cuts there; dalbavancin (Dalvance) had to redo its entire Phase 3 program, thereby delaying approval by some 4 years while greatly enlarging the safety database in its oversized dossier; oritavancin (Orbactiv) had a somewhat tortuous development program which involved some early dose modification but was otherwise fairly typical; and the ceftolozane/tazobactam (Zerbaxa) program was as guideline-driven as they come.

All these drugs provided activity against problem organisms (either MRSA or ESBLs) and hence rightly qualified for QIDP status.

So, maybe the BMJ editor’s rub is that these QIDP drugs don’t improve ‘enough’ on existing drugs . The author feels that vanco/dalba/orita/telavancin are not differentiated except for PK differences.  His complaint that these drugs were tested in ABSSSI infections showing only non-inferiority to comparator drugs of which we already have “six other drugs already approved for MRSA infection” to choose from.

Here I agree, this is a valid argument: None of them showed superiority against existing drugs or faster killing of MRSA compared to vancomycin.  None showed clearly an add-on benefit over available drugs except for PK and convenience features.

Hence, it is fair to ask whether tedizolid is really better than linezolid, whether its lower dose translates into less bone-marrow toxicity.  How about coverage of ESBLs by ceftolozane/tazobactam?  Is it reliable against these MDR pathogens and is its clinical benefit proven?  Why did we not see that benefit in the cIAI trial?  These are reasonable questions to ask but impossible to answer in a Phase 3 development program. As most development experts already know from painful experience, finding those rare MDR pathogens for a prospective study is a daunting task which is likely to take more years than QIDP adds to the patent life.  Nonetheless, ceftolozane/tazobactam and ceftazidime/avibactam do have a differentiated spectrum.  There are many reasons why it is difficult to prove microbiologic differentiation in the clinical setting.  Suffice it to say that registration trials are not the tool to do it.

Still, there is a lingering feeling that QIDP status was occasionally conferred on drugs that really did not deserve it.  Although not mentioned in the BMJ article, there are some fairly egregious cases where industry pushed the envelope.  Like the recent string of inhaled antibiotics all riding high on the QIDP moniker (see earlier blog).  However, a few bad apples should not spoil the harvest: QIDP was most appropriately bestowed on Avycaz, on Zerbaxa and many other drugs.

While not perfect, I applaud the FDA for their QIDP drug label.  There are very few breaks ID drugs get during development, so this is one we gladly accept.  Our developer friends from the oncology department next door have a less daunting hurdle to prove efficacy.  Maybe, just maybe, we could learn from them and introduce progression-free survival (PFS) as a new efficacy standard for anti-infectives as well.

[1] BMJ 2015;350:h1453 doi: 10.1136/bmj.h1453 (Published 25 March 2015)

SBA     Summary Basis of Approval

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