Challenges in Generic Drug Safety and Surveillance – FDA Generic Drugs Forum 2018

Challenges in Generic Drug Safety and Surveillance – FDA Generic Drugs Forum 2018


director of the clinical safety
surveillance staff we call that the CS^3 or CSSS in CDER office of
generic drugs I’m gonna give you a little bit of an outline for what I’m
gonna talk to you about today first I’m gonna give you an example of what that I
mean by challenges in clinical safety for generic drugs I’m going to tell you
a little bit about how generic drugs are different from new drugs I’m gonna lead
this into why we care concern about generic drug safety and some of the
challenges we face and end with another example here on my slide you’ll see two
boxes a blue one and an orange one one’s a little bigger than the other this
example is about clonidine, This clonidine is also known as cata press it’s a blood
pressure drug and it’s put into a patch it’s indicated for the treatment of
hypertension. FDA received 89 reports of a lack of adhesion and efficacy on a new
generic product MedWatch the FDA system for receiving post-marketing safety from
consumers and from companies noted the large size of the generic patch for 0.3
mg per day the brand was ten point five centimeters squared and my
simple math has two centimeters by five cm to get about ten little
close to ten point five cm^2 and that is represented by the
blue rectangle on the slot for the generic it was thirty two point four
centimeters squared which is also represented as three centimeters by 10
cm on the slide so get you about thirty cm^2 so you
can see the relative difference in size FDA had an inspection that showed
significant manufacturing problems with the generic product a warning letter
shirt letter was issued to the generic manufacturer on May 21st 2010
the generic applicant voluntarily removed the generic patch in March 2011 so here the example was about the fact
that the patch was a different size and it didn’t stick very well it was allowed
to be different because generics can’t be exactly the same as their brand
counterparts sometimes there’s an issue like a patent or an issue that has to be
dealt with so in this case the generic patch was almost three times bigger than
the brand patch and of course sticking that on to your arm every day would fold
it would fall off and they caused those problems so in order to get to let me
call a foundation for the identity of generic drugs we have to look at what I
call here the magic triangle or magic pyramid we have to think about where do
we go but what it is makes up generic drugs evaluation and what brings us into
a concern about safety here you’ll see the building blocks basically for
generic drugs starts with chemistry moves up through something called
pharmaceutical equivalence luzon to buy equivalents and then takes clinical
relevance into can effect when the generic drug is placed into a clinical
situation so each of these I have to think about separately first chemistry
is your base chemical what is the drug made of when you get something called
pharmaceutical equivalence that gets to be about the active ingredient itself
the dosage form is it a tablet or capsule the route of administration do
you take it orally or is it a patch the strength quality purity and identity
pharmaceutical equivalence also known as PE is described more and what we call
the orange book cause it’s orange and this is er the approved drug products
that’s put out multiple times a year that updates all they approved you
drug products but in order like I said before the two different patches were
different because they were allowed to be different so we have something called
allowable differences in the regulations for generic drugs this is way generic
drugs can differ in shape the way the pad tablet might be scored the way it’s
released in the body packaging excipient switch are supposed to be in active
ingredients but sometimes aren’t an expiration time and labeling as well
within certain limits labels can be somewhat different that’s if that’s the
information that comes with the drug for patient information and for a physician
information here I’m going to show on the slide I just put up some different
capsules but factually they’re all the same the the brand-name prozac very well
known antidepressant is seen up at the top with an orange and green capsule
below that are four different generic forms of prozac or fluoxetine and there
are allowed to be different two colors like this blue white with orange stripes
for you know blue with blue and orange white blue this is because we allow the
capsule to be different but sometimes patients will receive this no they first
started on Prozac get the new tablet and think maybe the pharmacist made a
mistake why do I have these new different looking capsules sometimes the
dispensing might be every 30 days and you might get a different pill in your
bottle and therefore you would might might think that there might be a
problem with your tablets next I’m going to move into bioequivalence bioequivalence
is when we take a look at the product after it’s in the body and we see how
well it works basically the generic and brand drug should deliver the same
amount of the active drug at the same rate
the bioequivalence drug and the pharmaceutical equivalents generic drug
will should perform in the same way as the brand drug when it’s given in your
body here are two curves this is basically how much a drug is given with
the amount on the left side of the on the vertical and the time in hours on
the horizontal and when we try to decide whether something’s bioequivalent or not
equivalent we have to compare the time course we expect from the brand to the
generic so here the reference origin our brand drug is in green and we’re going
to look at two different generics as our test product on the left set of curves
the generic performs almost equally to the brand and the curves are almost
super imposable on the right however the generic doesn’t perform as well and it
doesn’t have as high a peak and it doesn’t have as much exposure or drug
released over time so the left generic would be bioequivalent and the right
generic would be would not be bioequivalent
so when we talk about the differences between generic drugs and brand drugs we
think about the new drug application or NDA versus the abbreviated new drug
application or anda requirements when you compare brand-name drug your generic
drug some of the things are actually the same FDA expects certain things in the
application the chemistry base is the same we talked about that the
manufacturing should be relatively the same the controls for those are the same
the labeling as we said except for some exceptions should be the same and
testing of product Lots should reveal that these are consistent but for a new
drug we allow and have to develop a new chemical we have to make sure it’s it’s
safe in animals before we more move into humans and then we do clinical studies
in new drugs and we do bioavailable studies for
good products but for generic drugs we use bioequivalence
to stand in for formal animal studies in clinical studies so with only using the
bio equivalents data comparing curves and expecting a product to work in the
body we are skipping some steps but of course we’re doing it on purpose we want
the best that’s why the and a stands for abbreviated new drug application
requirements if we required the same testing for a generic drug as a new drug
it would take years to get your narek dogs on the market so then we have to
think ok pharmaceutical equivalents and bio equivalents are fine but if you give
the product you have to make sure it’s due it’s given the same clinically
relevant way what do I mean by that I mean that the clinical effect and the
safety profile when administered to patients under conditions in labeling
how it’s supposed to be given should be the same so I if I give you a brand
Prozac or a generic Prozac no matter you know how the capsules look they should
be the same they should be they should be what’s called substitutable and that
includes how long the drug should act so if I give you a drug that’s supposed to
act in 12 hours the generic should work in 12 hours as well the indication
should be the same meaning that they again the brand when you get the generic
it should be properly used in the same set of patients and the same kind of
target populations this is for adults as is for geriatrics is this for pediatrics
so all these thought processes get involved in generic drug development so
when you think about all the things I just went through very quickly since
this is not a long talk this is a summary of what we say is why worry
about generic drug safety it’s a good question we’ve tried to cover
bioequivalence pharmaceutical equivalents clinical relevance in our
assessment of generic drugs before we approve them but sometimes unexpected
safety considerations and concerns happen over time
why does this happen sometimes generic drug uses warmind more widespread
because the brand is tested in patients it gets out into the population and then
some people get it and then once it becomes a generic and more affordable a
lot more people get it in a lot more diverse population sometimes when
patients are switched from a branch of generic they get the generic for the
first time they’re used to the brand and sometimes they feel that the generic
feels different it sometimes a patient gets one generic to
another generic like the prozac example they’ll walk in they’ll say these pills
look different and they feel that they’re maybe acting different but that
may not be true so when I talk about post marketing surveillance of generic
drugs I’m trying to say that we are concerned about unexpected safety
considerations in generic products examples could include that the generic
drug set itself with and with its allowable differences has caused some
adverse events some problems for example an excipient an inactive ingredient
could have an independent effect that was not foreseen when the drug is put
together there could be quality problems with the
product where the tablets are falling apart or the packaging is not working or
the injectors not working sometimes and this is very common is that patients
perceive that the generic drug gets selfs inferior the chemistry is the same
it should work the same we know it’s approved to work the same yet people say
this generic doesn’t work so well sometimes there’s contamination and
sometimes we get concerns for a difference in a safety profile
especially when drugs are being used off-label or in a in an indication or in
a population we know it has never been tested in before there are many quality
issues and complaints that come in sometimes to our group sometimes tablets
are breaking apart sometimes the tablets don’t break evenly when split
sometimes the tablets might be a different size and stick in the throat
there might be an unusual odor or taste or smell or texture in oral liquids and
injectables there might be something that’s not dissolved
it’s a precipitate as we saw my first example patches don’t stick right
sometimes there’s a container closure issue or a dropper issue an issue within
injectors such as a device issue and sometimes like I said earlier a large
size tablet or capsule looks different and feels different here you’ll see a
little picture of some beige colored tablets on a green background if you
look very carefully you’ll see three larger looking caplets to the right of
that picture this was sent in to us for an evaluation of concern about safety
during the manufacture of these particular products the press that was
making and compressing the tablets was got overfilled and a lot of the products
a lot not many but a certain lot or a number of these caplets became large or
slightly larger than the ones you see on the left and above and we were asked is
there a safety concern for this should we take these off should we pull these
off the market and after assessment we said yes for several reasons one they
look different someone might think they’re a different drug two they might
not break evenly when they get scored or they might stick in the throat the fact
is they they are the same per se but they look different and if you received
a bottle of these in there were 30 and there were three that look different you
might think to yourself again there’s something wrong with these so we ask
that these be removed from the market to avoid any future safety issues we get
information from a lot of different sources
you know people contact us directly from the public they’ll send letters right in
and emails right into our office director the MedWatch which I spoke
about before is FDA’s formal way for consumers and companies
report problems with products write to FDA directly and that’s on the web
FDA has its own internal databases to assess drug safety other regulatory
agencies like the VA might might contact us if they’re having an issue with the
product and manufacturers themselves send in reports of safety concerns that
they themselves have generated or have come to them through outside sources
sometimes we see this in the scientific literature as well and here’s my little
plug for the FDA MedWatch if you yourself have had ever had a problem
with the product I encourage you to report it to FDA MedWatch well as I’m
closing down this talk I have one more example for you before I go
and this may again illustrate some of the issues we see this example is about
lorazepam or will concentrate lorazepam is a sedative and in this particular one
is a liquid and you can see a picture of the vial there it’s given with a dropper
mostly to young children it’s indicated for the treatment of anxiety it’s used
with a calibrated dropper as I said already and using children and other
seniors and all or anyone who has trouble swallowing tablets because
typically this is given as a tablet we received a report that there were some
Mis printed droppers on my picture here you’ll see the correctly printed dropper
on your left ah the next three droppers you’ll see were incorrectly printed one
was printed upside down one was printed only partially or shifted and one had no
print at all and FDA was asked would this be a problem well yes it would be a
problem because this has to be measured very carefully and if it wasn’t measured
carefully people would get either under dosed or overdosed
since the dropper comes with the bottle so fortunately the company recalled
these droppers and products and last August 13
lots were drawn and recalled and put the drivers out with a correct print and all
was well so that’s my talk and I hope this gives you an idea of some of the
reasons why we would have some challenges with generic drug safety I
like to acknowledge ceders offices of generic drugs our deputy office director
John Peters our clinical safety surveillance staff including Debbie
Caterson our lead safety coordinator our data team consisting of Jim austere hot
young Leonid Kim and our clinical team Karen fibers and then divorcee I also
want to thank Cedars Office of surveillance and epidemiology and seders
office of pharmaceutical quality for their help in getting me some of the
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