Saturday, November 23, 2013

The FDA and Generic Antibiotics - Again

One of the general problems with generic drugs is that many have been developed long ago when our understanding of medicine was not the same as it is today.  Clinical trials were smaller making safety risks greater (since fewer patients are studied in a controlled manor). We had a lower appreciation for certain safety risks such as effects on the heart several decades ago. 

In addition, our understanding of how drugs work and how to estimate how well they work has also changed over the years.  In the case of antibiotics, the growth in importance of pharmacodynamics measures of activity has clearly been a major driver of our improved understanding of antibiotic efficacy and how to predict this in human trials.  It affects our choice of dose and regimen and may inform decisions to stop development if the doses predicted to be efficacious by pharmacodynamics are too close to doses where safety risks become high. 

How do these considerations impact the way we use generic antibiotics?  Until now – not at all. In terms of safety, a label change for a generic drug would have to wait for action by the brand manufacturer before it could be reviewed by FDA. Of course, some label changes are initiated by FDA – but are still carried out through negotiations with the brand manufacturer.  One wonders what happens when there is no such thing as a brand manufacturer anymore – like might be the case for penicillin (you remember penicillin, right?).  A recent proposal by the FDA would allow a generic manufacturer to initiate such safety label changes and presumably would allow the FDA to initiate this with generic manufacturers as well. This gets around the restriction of having to work with a brand manufacturer when none exists, and provides more speed and flexibility to get safety labeling out to physicians and patients.  All of this presumes that someone actually pays attention to these label changes of generic drugs – but that’s another problem.

I have already written several blogs on the problem of generic antibiotics in terms of relabeling for efficacy concerns (1,2).  Mostly this has been related to generic drugs that were approved many years ago for the treatment of infections like sinusitis and bronchitis where the trials that were performed to prove efficacy are no longer accepted by either FDA or EMA today.  These approvals are of greater concern today since a number of these drugs have had recent labeling changes (macrolides and fluoroquinolones) to highlight serious safety concerns.  At the same time, modern branded antibiotics studied for the same infections have been forced off the marketplace for the treatment of those same infections because their trial designs were no longer acceptable for proving efficacy plus there were some safety concerns (although the safety concerns do not seem more serious to me than those for generics). 

While I don’t see evidence of this changing, I do see the first crack in the door to relabeling for antibiotic efficacy at FDA. This is exemplified by the recent advisory committee meeting where relabeling of generic antibiotics (and new antibiotics for that matter) for susceptibility breakpoints was discussed.  The meeting was summarized nicely by John Rex in this blog last week. Here, the FDA is the regulatory body that decides susceptibility breakpoints.  As John notes – this is a very important decision directly impacting the efficacy of the antibiotic both in clinical trials and in the marketplace. The FDA is proposing to re-look at breakpoints through the lens of pharmacodynamics – a position supported generally by the advisory committee.

These efforts by FDA to reconsider generic labeling is an important step forward in that it will start to place modern, branded antibiotics and generics on a more level playing field.  We just need the FDA to execute on these plans.  The FDA also should reconsider the approval of generic antibiotics where the trial designs used to prove efficacy of those drugs are no longer considered valid.  Either branded drugs should be allowed to seek approval with the same trial designs used to approve the generics, or the generics should have their approval for treatment of these indications removed from the label.

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