Generic Drugs and Bioequivalence
Are Brand Name Drugs Worth the Extra Cost?
Marketers work hard to create "brand loyalty." We all have our favorite brands of
cars, clothing, or breakfast cereal. Whether brand loyalty is really in the
consumer's interest is another matter. It may not matter much for most consumer
choices, because these are mostly low-risk decisions where the main hazard is
whether the consumer gets the best value for the money.
This is not the case with brand loyalty to medications. Brand-name medications
almost always are more expensive. A major cause of skyrocketing health care
costs is prescribing more expensive medications when cheaper ones would be just
as effective. And this is an arena where prescribers and patients can make
individual choices to insist on better value for the money.
But how do we know that generic versions of a drug are just as good as the brand
name? Much marketing, and extensive past discussion in the literature, has
focused on this very question. This Newsletter describes the facts behind generic
medications, and why choosing generic forms of a drug is usually a very cost-
effectiveness decision for prescribers and patients.
Generic Drugs - Guaranteed Bioequivalence
A very rigorous, successful program has been established by the US Food and
Drug Administration (FDA) and its European and Canadian counterparts to insure
that every marketed form of the same medication has the same biological effect.
That means that generic drugs are for all practical purposes the same as the
brand name drug -- no better and no worse.
In general, new medications are eligible for a 20-year patent. Because drugs are
usually patented long before the manufacturer's New Drug Application (NDA)
goes to the FDA, the manufacturer can often extend the patent for up to 5 years.
But, with few exceptions, under current US law no drug's patent lasts longer than
14 years after its FDA approval.
Once the patent on a drug expires, generic manufacturers are free to try to
develop a generic equivalent. The approval process for generics does not require
repeating all of the animal and clinical efficacy studies already done and filed by
the original manufacturer. Rather, the generic developer must prove that the new
generic drug has exactly the same active ingredients at exactly the same strength
in exactly the same dosage strengths as the original brand name version. FDA
inspects the facilities used to manufacture each new generic drug to make sure
that all the raw materials, manufacturing steps, and quality control measures are
the same as those used for the brand name drug.
This is the first way that the FDA guarantees that generic and branded versions of
the same drug are, for all clinical purposes, identical. In addition, as the FDA
states (http://www.fda.gov), "the generic version must deliver the same amount
of active ingredients into a patient's bloodstream in the same amount of time as
the pioneer drug." This means that the generic drug must be bioequivalent to the
brand-name version.
Understanding Bioequivalence
The key to marketing brand name drugs after the patent expires is to challenge the
validity of the generic's bioequivalence. This can involve misrepresenting the
scientific process used by the FDA to assess bioequivalence.
To prove bioequivalence to the FDA, the generic manufacturer performs a study in
which around 12 to 36 healthy, normal volunteers are each given a single dose of
one version of the drug, followed a few hours later by a single dose of the other
version (the studies are designed that half the group takes the brand-name first,
then the generic while the other half takes the medications in reverse order). This is
called a single-dose, two-way crossover study, and for immediate release drugs is
usually done under fasting conditions. (A third arm is usually added for extended
release medications in which the effects of food on drug concentration are also
determined.)
The concentration of each version of the drug in the blood is then measured at
regular intervals and pharmacokinetic (PK) methods are used to quantify how much
drug is absorbed into the circulation; the peak concentration of the drug; and the
time needed to reach that peak. The values for the generic and brand name drugs
are then compared.
The FDA uses a statistical test to determine bioequivalence. In technical terms,
bioequivalence exists only when the 90% confidence interval for the percentage
ratio of generic to brand drug formulations falls within the interval of 0.80 to 1.25,
based on log-transformed data.
This has been represented as meaning that generic drugs are anywhere from 20%
less potent to 25% more powerful (and therefore more likely to cause adverse side
effects) than the original drug. And there are clinical anecdotes of patients who
experienced clinical deterioration or toxic side effects when they were switched
from a brand to a generic drug.
But that is not valid. First, it is well known that if anyone takes a medication on two
different days, the pharmacokinetic data-the blood levels- will be different. This is
intra-individual variation, a well-known biological phenomenon, and is caused by a
host of factors including differences in gastrointestinal motility, level of hydration and
even, in the case of psychoactive medication, emotional state. There is normal
variation in biological measures, such as heart rate, temperature, respiratory rate, or
blood pressure, from day to day and even hour to hour. Similarly, the biology of
drug concentrations, which is affected by how the GI tract and liver are working at
a particular time, is subject to normal biological fluctuations.
This is why the FDA -- and Canadian and European regulatory agencies --have
adopted the bioequivalence tests described above. This means that a person
switching from brand name drug to a generic drug should experience about the
same difference in blood levels as he or she will taking the same brand-name drug
on two different days because of normal biological fluctuation.
Second, patients may clinically deteriorate or experience side-effects when
switched from one form of a drug to another. That can also happen when they
have not been switched, as part of the clinical course of the underlying disease.
While clinicians are strongly influenced by their particular experience, when well
controlled studies have been done, the anecdotes turn out to be just that. The
data tell us that bioequivalence means clinical equivalence.
Some Considerations To Keep in Mind
There are a few exceptions to the above discussion. More stringent requirements are
in place for drugs with a Narrow Therapeutic Index (NTI), meaning there is a very
small difference between the plasma concentration of effective and toxic doses.
Examples of NTI drugs are amikacin, gentamicin, digoxin, theophylline, phenytoin,
and quinidine. (Note that none of these are behavioral pharmacy medications.)
Similar requirements are in place for Critical Dose Drugs, which have special dosing
requirements, often requiring blood level monitoring or dosing based on weight. This
can make establishing bioequivalence of a generic version problematic (e.g.
cyclosporine and tacrolimus), digoxin, phenytoin, procainamide and quinidine.
Although lithium requires blood level monitoring, bioequivalence has never been an
issue among the various generic versions of lithium that have been available since
lithium was first approved by the FDA in 1970.
Finally, the FDA grades generic drugs for bioequivalence with either an A or B. B
grades are given generic drugs that were approved before FDA started requiring
that bioequivalence be established by actual human, in vivo testing. Only three
psychiatric drugs are on the B list-amitriptyline hydrochloride/perphenazine tablets,
chlorpromazine hydrochloride tablets, and nortriptyline hydrochloride capsules. (You
can access the complete list of A and B-rated generic drugs at
http://www.fda.gov/cder/orange/default.htm)
The FDA's Therapeutic Inequivalency Action Coordinating Committee (TIACC).
Investigates reports that a generic drug isn't as good as its brand name originator.
According to TIACC, it has often been unable to find any scientific support even for
some published cases of supposed lack of bioequivalence.
Take Home Message - and CMT's Commitment
In the overwhelming number of cases - and for all psychotropic medications -
generic drugs are bioequivalent and clinically equivalent to the brand name
version. As a prescriber, you can often help your patient's ability to afford medical
care by prescribing generic versions of medications whose patents have expired
without sacrificing clinical effectiveness.
CMT recognizes the importance of bringing scientific information to the clinician so
that cost-effective prescribing decisions are based on empirical evidence. Before
recommending any generic version of a drug, CMT queries the FDA database to
insure that the generic version has received an A rating and that no special
considerations have been attached to generic form. In this way, we can be sure
that a specific chemical entity, whether it comes with a brand or generic name,
works the same.
And, all other things being equal, we are all better off if we can spend less money to
achieve the same clinical effect.
