David's New Book

Friday, December 5, 2014

FDA Beats Europe!




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!