Today the FDA
beat Europe on the antibiotics front for the first time in a long time.
There was another
advisory committee for anti-infectives at FDA today. This one focused n the presentation of
ceftazidime-avibactam for approval for use in patients with urinary tract
infection, intra-abdominal infection bacteremia and nosocomial pneumonia in patients with
limited or no other treatment options. As you may know from previous blogs,
avibactam is a novel beta-lactamase inhibitor (where beta-lactamase is the
major mechanism of resistance to beta-lactam antibiotics like the penicillins,
cephalosporins and carbapenems) that provides activity against key resistant
pathogens including carbapenem-resistant Enterobacteriacea (CRE) that kills
almost 2000 Americans every year according to the CDC. Ceftazidime was
developed initially by Novexel, which, in turn, was purchased by Astra-Zeneca
in 2009 but where Forest-Cerexa (now Actavis) retained the US rights to the
compound.
Incredibly, the
phase II data, completed in 2010 by Novexel, comprised the main data used for
approval. The PK/PD data were also
mainly, but not entirely, based on data from Novexel also available in 2010. The
complete microbiology surveillance dated from 2012 – but could have obviously
been done sooner. What accounts for the
delay? The evolution of FDA thinking on
providing rapid availability of new antibiotics active against key resistant
pathogens for patients who need them accounts for this delay.
Today’s meeting shows that in spite of all the arguments of yesterday (see that blog), the FDA is moving forward to carry out their mission of providing tools and options for American physicians and patients when needs arise and perhaps even ahead of time. Perhaps FDA is dumb like a fox. Yesterday’s disappointing meeting clearly prepared the advisory committee up for today’s approval of ceftazidime-avibactam for use in patients with unmet needs based on limited data.
Questions posed
to the committee and their votes –
1.
Has the applicant demonstrated
substantial evidence of safety and efficacy of ceftazidime/avibactam for the
proposed indication of complicated intra-abdominal infections, when limited or
no alternative treatments are available?
Yes = 11, No
= 1.
2.
Has the applicant demonstrated
substantial evidence of safety and efficacy of ceftazidime/avibactam for the
proposed indication of complicated urinary tract infections, including
pyelonephritis, when limited or no alternative treatments are available?
Yes = 9, No
= 3.
3.
Has the applicant demonstrated
substantial evidence of safety and efficacy of ceftazidime/avibactam for the
proposed indication of aerobic gram-negative infections (including
hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia
and bacteremia) when limited or no
alternative treatments are available?
Yes = 0, No
= 12
4.
Has the applicant demonstrated
substantial evidence of safety and efficacy of ceftazidime/avibactam for the
proposed indication of aerobic gram-negative infections (including
hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia
and bacteremia) when no alternative
treatments are available?
Yes =
1, No =11
Of course, for the last question – the committee
was basically voting on the use of ceftazidime in hospital-acquired pneumonia –
an indication for which it has been approved for almost 30 years. Why were they
so negative? They wanted data in humans that
were largely lacking in the NDA. One caveat – the FDA does not have to follow
the advice of its advisors. We await
further developments here.
Today’s meeting
also provides some optimism that Actavis is serious in their desire to enter
the antibiotics arena. Will they be
commercially successful? That remains to be seen.
AstraZeneca is
responsible for submitting the ceftazidime-avibactam dossier to the European
regulatory authorities. This is planned
for early 2015 and will be based on data that includes the phase III data according
to their recent press release – accounting for the delay compared to Actavis
and the FDA where the submission did not include recent phase III data. This
means that the drug will be available in Europe about one year after its release
in the US. Was this a result of EMA’s
guidance or the preferences of AstraZeneca or both? I don’t know the
answer. But it looks like we may be
going back to the normal situation of 20 years ago where antibiotics are
launched in the US well before they reach the market in Europe.
For now, today’s FDA
advisory committee sets an important precedent for the future and puts the FDA
well ahead of Europe in the speed with which it can move and in its willingness
to approve new antibiotics based on a more limited data set. In spite of remaining
issues with FDA guidance, required endpoints and other problems, today they
positioned themselves well ahead of Europe and the rest of the world in
responding to the needs of Americans. I
can only say – well done! Its about
time!
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