Wednesday, December 26, 2012

Antibiotics - Looking Backward and Forward.

This year, looking forward, I thought that looking back would be the best way to start.  I dug out the blog I wrote a year ago trying to predict what I thought would happen this last year and then going on from there.  I didn’t realize how humbling the experience would be.

The FDA –
In December, 2011, I said,  “the FDA has finally understood that they cannot continue to issue guidance documents requiring infeasible trial designs.  What is less clear is whether they understand what “feasible” means to clinical developers and to industry"  I was RIGHT here. But I was WRONG when I said, " I am going out on a limb in predicting that rather than issue design requirements that are unworkable for urinary tract and intraabdominal infections, the FDA will delay guidance documents on these indications until they have a more clear idea of what will and will not work.”   The FDA came out with guidance on complicated urinary tract infections prohibiting the use of prior antibiotics and with a margin, although feasible, is small for the size of the treatment effect (as always) and is simply impossible to achieve if all prior antibiotics are prohibited. On the other hand, their guidance on complicated intrabdominal infection changed our current practice very little and those trials are feasible.

In 2011 I said, “I also predict that the FDA will try and achieve some understanding of pharmacometrics and how these methods can be used in various ways including as methods to define treatment effect for clinically relevant endpoints in various infectious disease indications.”  WRONG!!!  Although the FDA has given lip service to this idea, I see no concrete evidence that they are moving forward in trying to understand how to use pharmacometrics either to set margins for clinically relevant endpoints or to use these methods to establish control levels of response.

I was RIGHT when I predicted that the FDA would not come forth with a re-evaluation of generic antibiotics in terms of their risk to benefit ratios in spite of their promise to do so in 2006.  

In 2013, I predict that the FDA will achieve a “reboot” but that it will focus on “unmet needs” or infections with highly resistant organisms for which other therapies are limited. I think they will remain stuck in providing feasible guidance for traditional indications – but I really hope I am wrong here.

Innovative clinical trial designs –

I was a little optimistic when I said, “I predict that the first truly innovative trial designs for antibiotics will be implemented in 2012 including superiority trials possibly even using adaptive Bayesian designs. “  But I was right on when I said that pharmacometrics will play an important role in the design of such approaches and that these novel designs will be negotiated first in Europe with the US playing a distant second fiddle to the European regulators.  This has actually happened in 2012.   As noted above, in 2013, I am hoping the FDA will catch up with Europe at least for the situation when we are talking about new therapies for patients with limited options.

The markets -

Another area where I believe I was correct was when I said, “2012 will be the year where the payor in mature markets begins to understand the value of antibiotics compared to high-priced drugs that only prolong lives weeks to months.  Whether this will result in price adjustments for antibiotics already on the market – I doubt it.  But prices for new drugs that offer clear advantages over generics or other marketed brand antibiotics will achieve higher prices.  If these are supported by superiority data, such value will be easier to justify.”  I know that such discussions have occurred and will continue to occur – so far mainly in Europe.

I hope I was wrong when I predicted that 2012 would also see continued if slowing growth of antibiotic revenues in the emerging markets.  Pressures from the global recession and internal economics will provide a braking of the rapid growth of the middle class in these economies and therefore will slow the growth in demand for branded antibiotics.  Unfortunately 2013 may be held hostage to the US “cliff” negotiations.  A worldwide recession will probably not be good for the antibiotic markets.

The pharmaceutical industry and antibiotics –

I was mostly on target when I said, “I predict that 2012 will see a continuing equilibrium at our current low point of only three large pharma companies truly engaged in antibiotics R&D. The three today are AZ, GSK and Sanofi (just getting back into the game).  Novartis will remain schizophrenic with their discovery group fully engaged and their pharma group not so sure.  Merck will continue with their slow, small program that is not large enough to really count.”  I am now convinced that Merck, even with its small effort, must be considered a player given their ongoing phase II trials of MK7655.   

I also predicted that we will see continued emergence of small pharma along the lines of the Cubist model.  Examples will be Trius and possibly Rib-X.   Was this right?

Biotechs developing antibiotics have continued to struggle.  Those that have novel compounds active against resistant Gram-negative pathogens are in the best position.  Those with newer versions of older antibiotics targeting mainly Gram-positive or even Gram-positive and respiratory pathogens are having a more difficult time providing an exit for their investors. I was right here and this will continue to be the case in 2013.

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