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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