Acta Clinica Belgica

International Journal of Clinical and Laboratory Medicine

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BIOEQUIVALENCE, THERAPEUTIC EQUIVALENCE

AND GENERIC DRUGS

R.K. Verbeeck

To cite this article: R.K. Verbeeck (2009) BIOEQUIVALENCE, THERAPEUTIC EQUIVALENCE AND
GENERIC DRUGS, Acta Clinica Belgica, 64:5, 379-383, DOI: 10.1179/acb.2009.063

To link to this article: https://doi.org/10.1179/acb.2009.063

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 BIOEQUIVALENCE, THERAPEUTIC EQUIVALENCE AND GENERIC DRUGS
Editorial
BIOEQUIVALENCE,
THERAPEUTIC EQUIVALENCE
AND GENERIC DRUGS
R.K. Verbeeck
Between 1995 and 2002 I served as an external
expert to the Belgian Medicines Evaluation Board and
during those 8 years I assessed most, if not all, dos-
siers in which one or more bioequivalence studies
were described as part of the application for marketing
authorization of a medicinal product. During that pe-
riod I evaluated more than 400 bioequivalence studies
submitted for marketing authorization of generic drug
products in Belgium via the National Procedure or via
the Mutual Recognition Procedure of the EMEA (Euro-
pean Medicines Agency). I therefore read with much
interest the articles on generic drugs by Dupont and
Heller and Heller and Dupont which appear in this is-
sue of Acta Clinica Belgica (1,2).
Clinical experts generally agree that a bioequiva-
lence study is the most appropriate approach for de-
monstrating therapeutic equivalence between two
drug products and the value of bioequivalence as a sur-
rogate for therapeutic equivalence is not questioned
(3,4). Consequently, bioequivalence studies have been
for many years an essential part of registration dos-
siers not only for generic drug products but also for
innovator drug products (4,5). For example, registra-
tion of the majority of orally administered innovator
drug products is based on one or more bioequivalence
studies for the simple reason that in most cases the
formulation that will be marketed is not the same as
the formulation that was used in the clinical efficacy/
safety studies during the clinical phases of drug deve-
lopment (5). A bioequivalence study, a so-called “brid-
ging study”, is in those cases necessary to demonstra-
–––––––––––––––
Ecole de Pharmacie
Université Catholique de Louvain
Bruxelles
Belgique
379
te therapeutic equivalence between the “clinical” and
the final “market image” formulation of the innovator
drug product. Thus for the majority of new drugs ad-
ministered orally, clinical studies were not carried out
on the final “market image” formulation, just as is the
case for generic drugs.
Although the general principle that bioequivalence
is a surrogate marker of therapeutic equivalence is not
questioned, the discussion regarding the therapeu-
tic equivalence between generic drugs and innovator
drugs continues unabatedly. The pharmaceutical com-
panies see their sometimes huge profits plummet as
soon as the patent protection on their drug products
expires and the market is taken over by much cheaper,
but therapeutically equivalent, generic drugs. From a
pure marketing standpoint, discrediting the principle
that generic drugs are therapeutically equivalent to
their innovator counterparts, therefore, may seem to
be an effective approach to try to ensure that these
high profits continue even after patent protection
has expired. Health professionals, however, should be
objectively and correctly informed about the quality
and therapeutic equivalence of generic drugs and their
prescription behaviour should be guided by a correct
understanding of the real important issues regarding
the use of generic drugs.
In their articles, Dupont and Heller do not really
provide a clear explanation and balanced view of the
important issues regarding bioequivalence and the-
rapeutic equivalence (1,2). Both articles are a collec-
tion of incompletely explained principles and (mostly)
anecdotal reports regarding bioequivalence assessment
and the notion of therapeutic equivalence. Indeed, alt-
hough the authors recognize that “there are very few
well-conducted prospective studies that enable one
to analyse whether generics meet pharmaceutical and
clinical quality criteria“, they nevertheless continue to
Acta Clinica Belgica, 2009; 64-5
380 BIOEQUIVALENCE, THERAPEUTIC EQUIVALENCE AND GENERIC DRUGS
describe a number of case reports on the basis of which
it is extremely dangerous to draw any conclusions. To
cite a few examples, Heller and Dupont refer to a case
report that describes an increase in valproate serum
levels when two patients in India were switched from
a generic sodium valproate formulation to a branded
formulation of sodium valproate (2,6). However, how
can this observation be interpreted and what is its re-
levance for the EU market if all information regarding
the quality of the generic drug in question as well as
the criteria used for its marketing authorization are
lacking? Similarly, they state the following: “Generic
substitution of itraconazole resulted in subtherapeutic
levels and resistance in 3 patients” and without further
explanation refer to a Letter to the Editor published in
the International Journal of Antimicrobial Agents (7).
Although the reduction in itraconazole plasma concen-
trations observed in these 3 patients may have been
caused by switching from the brand-name to the ge-
neric drug product, other possible causes such as lack
of compliance or drug interactions cannot be not ruled
out. In addition, a literature search using the MEDLI-
NE database with “itraconazole” and “generic” as key
words not only shows this Letter to the Editor on ge-
neric substitution of itraconazole mentioned by Heller
and Dupont, but also shows a full publication reporting
the results of a double-blind randomized controlled
trial in 133 patients with tinea pedis demonstrating
equivalent efficacy of the original and generic itraco-
nazole (8). To provide the reader with a balanced view
of the therapeutic equivalence or inequivalence of ge-
neric drugs, the authors should also have mentioned
the results of this clinical trial comparing the original
and generic itraconazole formulations.
An interesting paper was recently publis-
hed in the Journal of the American Medical Associa-
tion (JAMA) describing the results of a comprehensive
search in peer-reviewed publications from January
1984 to August 2008 to systematically evaluate com-
parisons of generic and brand-name cardiovascular
drugs (9). Unfortunately, this paper was not referred
to by Dupont and Heller (perhaps because their ma-
nuscripts were submitted before this JAMA paper was
published on December 3, 2008?). Because in my opi-
nion this publication is important when discussing the
therapeutic equivalence of generic and brand-name
drugs, I will briefly summarize its main findings. The
study was carried out by researchers from the Division
of Pharmacoepidemiology and Pharmacoeconomics
of the Harvard Medical School in Boston (USA). The
authors identified 47 articles for detailed analysis, co-
Acta Clinica Belgica, 2009; 64-5
vering 9 different subclasses of cardiovascular drugs,
of which 38 were randomized controlled trials (RCTs).
According to the results, therapeutic equivalence was
noted in 7 of 7 RCTs of beta-blockers, 10 of 11 RCTs of
diuretics, 5 of 7 RCTs of antiplatelet agents, 2 of 2 RCTs
of ACE inhibitors, and 1 of 1 RCT on alpha-blockers. To
determine the expert opinion on the subject of generic
substitution, the authors also reviewed the content of
editorials published during the same period. Of the 43
editorials and commentaries identified as meeting the
study criteria, 23 (53%) expressed a negative view of
the interchangeability of generic drugs with innovator
drugs, 12 (28%) encouraged substitution between ge-
neric and innovator drugs, and the remaining 8 (17%)
did not reach a conclusion on this issue. According to
the authors of this paper, one explanation for this dis-
cordance between the results of the studies on the one
hand and editorial opinion on the other hand is that
commentaries may be more likely to highlight physici-
ans’ concerns based on anecdotal experience or other
nonclinical trial settings. Another possible explanation
is that the conclusions may be skewed by financial re-
lationships of editorialists with innovator pharmaceu-
tical companies, which are not always disclosed. In fact,
nearly half of the trials in the study sample and nearly
all the editorials and commentaries did not identify
sources of funding, according to the Harvard resear-
chers. The authors conclude the following: “Whereas
evidence does not support the notion that brand-na-
me drugs used in cardiovascular disease are superior to
generic drugs, a substantial number of editorials coun-
sel against the interchangeability of generic drugs”.
I would also like to point out that describing the
methodology used to assess bioequivalence between
two oral formulations with a systemic effect is not
simple if the reader does not have the necessary ba-
sic pharmacokinetic and statistical knowledge (5). In
my opinion, on the basis of the papers of Dupont and
Heller the average reader of Acta Clinica Belgica will
not have a good understanding of how therapeutic
equivalence is established between two oral medici-
nal products containing the same amount of the same
active substance. Both papers not only contain a lot of
sketchy information regarding bioequivalence assess-
ment but also inaccurate statements which may con-
fuse the reader. For example, the following sentence
can be found in one of their articles: “At the moment,
demonstration of equivalent absorption rates between
generics and the original product is not mandatory …”
(1). This statement implies that two oral formulations
can be considered to be bioequivalent even though
 BIOEQUIVALENCE, THERAPEUTIC EQUIVALENCE AND GENERIC DRUGS
the rate of absorption of the active substance follo-
wing oral administration of the two formulations may
be different, which is not really the case. The primary
metrics used to assess bioequivalence are AUCt (the
area under the plasma concentration-time profile of
the active substance), Cmax (the maximum plasma con-
centration of the active substance) and tmax (the time
at which Cmax is reached). AUCt is the bioequivalence
metric describing the extent of absorption, tmax is the
metric which characterizes the rate of absorption, and
Cmax is influenced by both extent and rate of absorp-
tion (4,10). To demonstrate bioequivalence between
two oral formulations the EMEA Note for Guidance on
the Investigation of Bioavailability and Bioequivalence
recommends to calculate the 90% confidence interval
around the geometric mean ratios of both AUCt and
Cmax for Test (generic) and Reference (innovator) (11).
These 90% confidence intervals should, in most cases,
be located within the 0.80 – 1.25 acceptance limits.
(To fully understand why this particular statistical test
is used in bioequivalence assessment and how to inter-
pret the results, the interested reader should consult
one of several excellent books recently written on this
subject (e.g. 4,10)). A statistical evaluation of tmax, the
metric characterizing rate of absorption, is indeed not
generally required according to the EMEA guidelines:
“Statistical evaluation of tmax only makes sense if there
is a clinically relevant claim for rapid release or action
or signs related to adverse effects. The non-parametric
90% confidence interval for this measure of relative
bioavailability should lie within a clinically determined
range” (11). I would like to make the following brief
remarks regarding Dupont and Heller’s statement (see
above) on rate of absorption. First, the EMEA Note for
Guidance clearly states that the confidence interval
for tmax should lie within a clinically determined range
if there is a clinically relevant claim for rapid release
or action or signs related to adverse effects. This me-
ans that for medicinal products which act acutely - e.g.
hypnotics, hypoglycemics, analgesics for acute pain -
rate of absorption is a critical factor as far as activity
and safety is concerned and, therefore, tmax has to be
similar between two medicinal products in order to
be bioequivalent. Second, although Cmax is affected by
both rate and extent of absorption, in the context of
bioequivalence studies Cmax is often referred to as the
metric characterizing rate of absorption. Indeed, when
two plasma concentration-time profiles show bioequi-
valence for both AUCt and Cmax, not only the extent of
absorption but also the rate of absorption between the
two medicinal products will normally be very similar.
381
Although Cmax is the standard regulatory measure of
rate of absorption, it should be mentioned that it has
several drawbacks (4). Therefore, in the revised EMEA
bioequivalence guidelines the partial AUC, truncated
at the population median of tmax for the reference for-
mulation, is recommended as a measure of early ex-
posure for products where rapid absorption is of im-
portance (12). Third, most drugs are administered as a
multiple dose regimen and efficacy and safety depend
on steady state plasma concentrations of the active
substance. Unlike extent of absorption, rate of absorp-
tion is in most cases not a critical determinant of drug
efficacy and safety under steady state conditions, es-
pecially considering the fact that Cmax values have to
be in all cases very similar between two bioequivalent
medicinal products. It is in this context that the re-
commendations of authorities such as the FDA (US
Food and Drug Administration) and EMEA concerning
bioequivalence assessment should be interpreted. But
it is also clear from my brief comments that the prin-
ciples underlying the methods for bioequivalence as-
sessment are not simple and, it is fair to say, not well
known to most health professionals.
On the issue of therapeutic equivalence between
oral medicinal products containing active substances
with a narrow therapeutic index, the major authori-
ties issuing bioequivalence guidelines do not share
the same opinion. On the one hand, the FDA does not
recommend stricter norms for narrow therapeutic in-
dex drugs (13). Their standpoint is very clear: “FDA re-
cognizes the scientific concept that drugs differ in their
therapeutic range. However, because of FDA’s strict bio-
equivalence criteria, we believe that drugs do not fall
into discrete groups that would allow one to consider
NTI (Narrow Therapeutic Index) drugs as being clearly
different from other drugs for purposes of therapeutic
substitution” (13). This means that for narrow thera-
peutic index drugs to be bioequivalent the FDA guide-
lines require the 90% confidence interval around the
geometric mean ratio of Cmax and AUCt to be located
within the usual acceptance range of 0.80 to 1.25. For
narrow therapeutic index drugs, the Health Product and
Food Branch (Health Canada) and the EMEA, on the
contrary, recommend to apply stricter bioequivalence
criteria. In 2006 Health Canada, published a short do-
cument entitled “Bioequivalence Requirements: Criti-
cal Dose Drugs” (14). In this document a list of 9 drugs
is given, i.e. cyclosporine, digoxin, flecainide, lithium,
phenytoin, sirolimus, tacrolimus and theophylline, for
which Health Canada recommends that the 90% con-
fidence interval for AUCt be located within the 0.90 to
Acta Clinica Belgica, 2009; 64-5
382 BIOEQUIVALENCE, THERAPEUTIC EQUIVALENCE AND GENERIC DRUGS
1.12 acceptance range. According to the EMEA guide-
lines the normal acceptance range for the 90% confi-
dence interval for AUCt and Cmax is 0.80 to 1.25, which
is the same as the “strict bioequivalence criteria” refer-
red to in the above quoted FDA statement. Regarding
narrow therapeutic index drugs, the EMEA guidelines
state the following: “In specific cases of a narrow the-
rapeutic range the acceptance interval may need to be
tightened” (11). These recommendations of the EMEA
are rather vague: 1) they do not specify exactly which
substances are concerned, and 2) they do not specify
how much tighter the usual acceptance range should
be. The “prescribability” of a generic drug containing
an active substance with a narrow therapeutic index
and which has been shown to be bioequivalent to the
innovator drug is generally not questioned. This means
that the generic can be prescribed when the patient is
first diagnosed with an ailment for which treatment
with an active substance having a narrow therapeu-
tic index is recommended. With narrow therapeutic
index drugs, irrespective of whether therapy is star-
ted with the innovator or with the generic drug, the
correct dosage will be determined in each individual
patient by careful dose titration possibly in combina-
tion with therapeutic drug monitoring. The scientific
and clinical community, however, is divided about the
issue of therapeutic equivalence and “switchability”
between generic and innovator drugs with a narrow
therapeutic index. Indeed, many experts believe that
switching from innovator to generic, or vice versa, in a
patient stabilized on a narrow therapeutic index drug
is not recommended. For example, the advice of expert
bodies such as the American Academy of Neurology,
the Epilepsy Society of Australia, the National Institute
for Clinical Excellence (NICE), the German section of
the International League Against Epilepsy, the Scottish
Intercollegiate Guidelines Network, is that a patient
with well controlled epilepsy should not have the epi-
leptic medicinal product, whether generic or innova-
tor, substituted. If substitution is undertaken, however,
then appropriate clinical monitoring is required (15).
In my opinion this advice should be followed for the
limited number of therapeutic agents which fall under
the category of narrow therapeutic index drugs or cri-
tical dose drugs.
In conclusion, the general principle that bioequi-
valence assessment is a surrogate for therapeutic
equivalence is not questioned by influential clinici-
ans and pharmacologists. In Western countries, such
as the European Union and the USA, registration and
marketing of both innovator and generic drugs are
Acta Clinica Belgica, 2009; 64-5
subject to the same, strict regulations. Correct and
objective reporting on the quality, i.e. efficacy and
safety, of generic drugs is very important for health
professionals who are prescribing these medicinal pro-
ducts. In the European Union experts from the natio-
nal and/or European Drug Evaluation Agencies assess
the chemical-pharmaceutical quality and the clinical
efficacy/safety of innovator drugs and generic drugs
according to exactly the same standards and norms
as those used for the registration of innovator medici-
nal products. Contract Research Organisations (CROs)
specialized in bioequivalence studies and other phase
I clinical trials are audited by expert inspection teams
to make sure these studies are carried out according
to good clinical practice (GCP) rules. Similarly, produc-
tion sites are approved only when they manufacture
medicinal products according to good manufacturing
practices (GMP). Despite all these measures unexpec-
ted problems may occur from time to time not only
with generic drugs but also with innovator drugs, as il-
lustrated by the recent contamination of heparin with
oversulfated chondroitin sulfate, mentioned by Heller
and Dupont, which caused serious allergic reactions
leading to dozens of deaths (2,16).
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