Commentary
The Evergreening of Biopharmaceuticals:
Time to Defoliate
David F. Lehmann, PharmD, MD, FCP, and Sarabeth Wojnowicz, PharmD
Keywords
biopharmaceuticals, single enantiomer, value, racemic mixture, outcomes, cost
As a successful product approaches its date of patent
expiration, chiral switching, that is, the isolation,
testing, approval, and marketing of the pharmaco-
logically active stereoselective isomer (enantiomer),
termed “evergreening,” allows the manufacturer to
maintain market share via exclusivity.1 The market-
ing of one stereoisomer typically emphasizes a single
pharmacometric difference between the active and in-
active enantiomer via extrapolation to the bedside.2
On rare occasions, eg, S-albuterol in addition to its
inactivity may blunt access to the β 2 receptor by
racemic albuterol, given the longer half-life of S-
albuterol.3,4 However, such reductionism in the ap-
plication of clinical pharmacology and therapeutics
necessitates a high degree of scrutiny to determine
whether these differences are actualized in patient out-
comes (eg, prevention of hospital admissions, impact
on length of stay, and improvement in standard surro-
gate measures).5,6
Altered affinities for drug target receptors between
pairs of stereoisomers derive from the variability in
their mirror image presented to a 3-dimensional recep-
tor binding site.7 Indeed, pharmacometric variations
are the central cause of the differential affinities for
receptors that determine their therapeutics, toxicity,
and clearance.8
Suppositions derived from the extreme reductionist
approaches inherent in claims of enhanced effectiveness
or decreased toxicity in the use of enantiomeric com-
pounds must be challenged given the lack of a priori
knowledge of all confounders prior to the experimental
design.9 Such scrutiny takes on added importance be-
cause single-enantiomer products are uniformly more
expensive than their corresponding racemic mixtures.10
Furthermore, racemic mixtures typically are products
that have had extensive patient exposure correspond-
ing to well-defined margins of safety and clinical
effectiveness.11
The Journal of Clinical Pharmacology
2016, 56(4) 383–389

C 2015, The American College of
Clinical Pharmacology
DOI: 10.1002/jcph.642
This commentary assesses both the rationale for and
the value of preferring the use of single-enantiomer
products over their racemic counterparts in treat-
ing 3 prevalent conditions: major depressive disorder,
asthma, and acid-peptic disease. Standard tools of
clinical epidemiology applied to drug therapy (phar-
macoepidemiology) will assess claims that are made to
favor isolated pharmacometric characteristics for es-
citalopram, levalbuterol, and esomeprazole compared
with their racemic mixture counterparts.
Methodologies Used to Compare Health
Care Value
Application of Methods in Pharmacoepidemiology to
Compare Racemic and Single-Enantiomer Products
Health care value is defined as an outcome achieved
per dollar expended for that outcome to be realized.12
Although prior reports have assessed the comparative
efficacy and cost separately for pairs of racemic mix-
tures and single enantiomers, analyses derived from
pharmacoepidemiology have yet to be applied.9,13
Such techniques can provide a useful measure of
the ability of a drug product to achieve an outcome
(numerator) in the value equation in comparison to the
cost outlay for that specific outcome (denominator).
Therefore, this approach should yield clarity in evalu-
ating the comparative value for racemic mixtures and
single-enantiomer products available on the health care
market.
The pharmacoepidemiological parameters with
their derivations used for this analysis follow. The
SUNY Upstate Medical University, Syracuse, NY, USA
Submitted for publication 23 October 2015;
Corresponding Author:
David F. Lehmann, PharmD, MD, FCP, SUNY Upstate Medical University,
Syracuse, NY 13210
Email: lehmannd@upstate.edu
384
odds ratio (OR) was considered to be equivalent to
relative risk (risk ratio) because all 3 diseases under
consideration are highly prevalent.14 The method of
Hasselbad and Hedges was used to convert measures of
continuous variables into an OR for more meaningful
use by practicing clinicians deciding on a panoply
of available treatments.15 The active comparator
rate (ACR) for events in the groups in the racemic
(comparator) pool were defined as number of events
in the comparator pool divided by the number of
events in the total pool. The absolute risk reduction
(ARR) was determined by the formula: ARR = ACR
– (OR × ACR)/[1 – (ACR + {OR × ACR})]. The
number needed to treat (NNT) to determine the
number of patients required to be treated with the
single-enantiomer product for 1 patient to benefit
compared with the racemic product was 1/ARR.
Further, ORs that crossed unity were included given
the small sample sizes that are typical for such direct
comparator studies (provided they had internal valid-
ity). The Cochrane database was used for all pooled
head-to-head comparator trials as a check on internal
validity.
Cost Comparisons Between Single-Enantiomer and
Racemic Mixture Products
All estimated drug expenditures were based on the
average wholesale price (AWP). Cost comparisons be-
tween daily doses of R/S-citalopram (20 mg) and
S-citalopram (10 mg) were based on outcomes at
12- and 24-week intervals.16–21 The expenditures for
levalbuterol 1.25 mg and albuterol 2.5 mg were com-
pared with assumptions of the average daily use of
8 nebulizer treatments over a 3.6-day period for the
inpatient treatment of acute asthma, with the cost of
acute length of stay derived from federal data sources.22
The cost of Nexium R
20 mg was compared with that
of omeprazole 40 mg per day for a 6-week course of
treatment for acid-peptic disease.
Annual drug revenues for the 3 pairs of racemic
mixtures and single-enantiomers were obtained from
publicly available data in www.drugs.com. For purposes
of comparison, if the last available full-year data for
a racemic product was more remote than that for its
trade-name single-enantiomer counterpart, the overall
trend for medication use in nonfederal hospitals was
applied to equilibrate the year for comparison.23
Evaluating the Rationale for the
Preferential Use of Single-Enantiomer
Products
Claims for Superiority of Benefit
The claim of greater benefit from a single-enantiomer
formulation can be restated into a simple narrative:
The Journal of Clinical Pharmacology / Vol 56 No 4 2016
“if one enantiomer of a pair does not contribute to
the therapeutic effect, the exclusive use of its active
counterpart must therefore confer advancement in ther-
apeutics.”
R
Escitalopram vs Citalopram. Celexa (R/S-citalopram)
was approved for marketing in the United States by
Forest Laboratories in 1998, with generic availability in
2004. In anticipation of the loss of patent protection,
R
Forest first marketed Lexapro (escitalopram) in 2002.
Six comparator studies in adults between the 2
products reached the level of internal validity to be
included in the analysis.16–21 Clinical outcome measure
was failure to respond at an endpoint of 6 to 12
weeks. The pooled OR was 0.67 (0.50, 0.89) favoring
escitalopram. However, it is possible that the observed
difference between the two products waned between
the 16- to 24-week period with an OR of 0.96 (0.56-
1.56).17 Alternatively, the severity of depression became
greater, requiring a selection from a different class of
compounds.
Given that all SSRIs are considered to be essentially
equivalent for the treatment of major depressive dis-
order, the pooled OR for those that were available as
generic products at the time of the initial marketing of
escitalopram were sertraline 1.06 (0.73, 1.53), favoring
sertraline24–26 ; paroxetine 0.89 (0.61, 1.32), favoring
escitalopram27,28 ; and fluoxetine 0.81 (0.60, 1.10), fa-
voring escitalopram.29–31
In summary, head-to-head comparisons for esci-
talopram vs citalopram show no clinical benefit at
considerable costs for escitalopram, particularly in the
long-term treatment of MDD. Furthermore, based on
the recognized equivalency of cheaper generic SSRIs
when compared to escitalopram, the discrepancies in
expense favoring generic paroxitine, sertraline, and
fluoxetine are even greater should 18- to 24-month
exposure be required to treat MDD.
Levalbuterol vs Albuterol. Racemic albuterol has been
available in the United Kingdom since 1968 and in the
United States since 1982. It remains the standard treat-
ment of acute bronchospasm. Sepracor Laboratories
 R
achieved patent protection for Xopenex (levalbuterol)
in 2005. Five head-to-head studies (3 in children, 2 in
adults) between the 2 products comparing efficacy on
hospitalization rate: OR 0.76 (0.58, 0.98) and length of
hospital stay.32–35
Clinical outcome measures included the hospi-
tal admission rate—OR 0.76 (0.58, 0.98), favoring
levalbuterol32-35 —and length of hospital stay—OR
1.12 (1.09, 2.77), favoring albuterol.35
Careful analysis of this single isolated study in the
emergency setting that favored a decrease in admission
rate via the use of levalbuterol leads to the inescapable
conclusion the enantiomer is superior to racemic
albuterol. Were this so, the continued use of this
Lehmann and Wojnowicz
true advance in the treatment of asthma would have
produced a marked impact on the ALOS for patients
if used exclusively over racemic albuterol. This most
clearly was not the case, given the far greater expense
of the exclusive use of levalbuterol for admitted pa-
tients; and most telling, the ALOS for those patients
exclusively receiving levalbuterol was prolonged when
compared to those who received the racemic product.
Claims for Greater Safety
Enhanced safety from a single-enantiomer product is
claimed by eliminating the exposure to unwanted side
effects from the inactive stereoisomer.
Levalbuterol vs Albuterol. As it became apparent that
levalbuterol offered no clinical superiority to racemic
albuterol, in vitro pharmacokinetic investigations of
the inactive S-stereoisomer demonstrated a delayed
clearance from the alveoli as compared with the R-
stereoisomer (levalbuterol). Inferences were then pro-
moted by pharmaceutical manufacturers to extrapolate
by such PK deduction that bronchial smooth muscle
cells were prevented from recruiting β 2 receptor, given
the receptor blockade by the prolonged clearance of
the S-stereoisomer, which thereby antagonizes access to
the β 2 receptor by the R-stereoisomer.36,37 Despite the
paucity of this in vitro information, several reductionist
steps were promoted by industry to extrapolate this
meager in vitro evidence to the bedside.
The most profound effect of these unsubstantiated
claims is to add substantial costs of care without
improving the quality of healthcare (value) in clinical
medicine. Indeed, it is self-evident that rigorous head-
to-head clinical trials between levalbuterol and racemic
albuterol were widely promoted to practicing cardi-
ologists and pulmonologists as a means to influence
these providers to avoid even the most remote and
likely bogus differences in the induction of cardiac tach-
yarrhythmias. These claims derived from in vitro and
PK-alone studies seemed sufficient for the widespread
intensive pharmaceutical representative detailing that
took place in the aftermath of levalbuterol marketing.
These conjectures were singularly effective to increase
the market share of levalbuterol because they were
directed at a core principle of medicine, namely, primum
non nocere.
This issue has been definitively put to rest by the
lack of difference in cardiac risk between levalbuterol
and racemic albuterol in investigations in hospitalized
patients at the greatest risk for adverse cardiac events in
situations of similar degrees of bronchospasm requir-
ing comparable dose intensity of the 2 products.38
Thus, such a linear chain of deductions initiated
by in vitro studies of an increase in chronotropy due
to the S-enantiomer of racemic albuterol ultimately
led to a highly successful campaign of direct influence
385
on the prescribing of levalbuterol by cardiopulmonary
physicians, with significant indirect assistance by respi-
ratory therapists. The history of this large impact for
change in prescribing habits is the clearest example of
pharmacological reductionism.
Escitalopram vs Citalopram. In 2011 the FDA issued
a warning of a dose relationship between citalopram
and prolongation of the QTc interval.39 This warning
was based on ECG surveillance studies for groups of
SSRIs showing a dose relationship for citalopram and
QTc prolongation. Importantly, however, torsades de
points (TdP) only occurred with intentional overdose or
if used with significant confounding factors known to
cause TdP without drug exposure (eg, severe electrolyte
abnormalities).40
Furthermore, due to the market longevity of citalo-
pram, these studies did not include escitalopram.
Indeed, later analyses that did include the single-
enantiomer product showed a similar risk for QTc
prolongation as for the racemic compound.41 This
observation is entirely consistent with and explained by
the nearly identical IC50 for the hERG channel of both
citalopram (3.2 μM) and escitalopram (2.6 μM).42
Therefore, the FDA warning for the racemic com-
pound and not the single enantiomer likely reflects the
greater reporting bias due to the larger patient exposure
in the 4 years prior to the marketing of escitalopram.
Hence, in contrast to calls for a moratorium on the pre-
scribing of citalopram in light of the FDA warning43
(because both drugs are equivalent in their ability to
inhibit hERG), such a recommendation exposes a lack
of appreciation of the pharmacological principle of
competition for receptor occupancy between 2 antag-
onist compounds.44
Pharmacokinetic Alterations to Enhance Thera-
peutic Response: Esomeprazole vs Omeprazole
AstraZeneca lost patent protection for the exclusive

R
marketing of Prilosec (R/S-omeprazole) in September
 R
2011, followed by FDA approval for Nexium (S-
omeprazole) in August 2012.
The rationale for developing esomeprazole was en-
tirely based on pharmacokinetic differences between
it and racemic omeprazole. Because of the differential
variability between the 2 products in substrate affinity
for CYPs, particularly CYP2C19, superimposed on the
polymorphic variability of this isoform, esomeprazole
was more bioavailable than omeprazole. This, in turn,
resulted in a greater AUC as associated with a persis-
tence of gastric pH above 4.0.45
Similar to the prior discussion of the β-agonists,
such pharmacological reductionism involving surro-
gate markers does not equate with either clinical out-
come superiority or greater safety.46 Indeed, simple
adjustments in the dose regimens of omeprazole can
386
Table 1. Relative Value Between 2 Product Pairs of Stereoisomers for Selected Clinical Outcomes
Stereoisomer
Pairs Clinical Outcome Odds Ratio
Escitalopram vs Failure to respond at 6–12 0.67
Citalopram weeks endpoint
Failure to respond at 16–24 0.96
weeks endpoint
Levalbuterol vs Hospital admission rate 0.76
Albuterol
ALOS 1.12
ALOS, acute length of stay; ARR, absolute risk reduction; NNT, Number needed to treat.
See References 14–21,23 (escitalopram vs citalopram); 32-35 (levalbuterol vs albuterol).
approximate or exceed the optimal goal for gastric pH
in gastroesophageal reflux disease (GERD).47
Further, because the clinical studies evaluating either
esomeprazole or racemic omeprazole in the treatment
of GERD did not genotype for CYP2C19 as part of
their design strategy, their external validity is called into
serious question. This characteristic is typically cou-
pled with a lack of rigorous patient outcomes despite
reaching internally valid conclusions (vis-à-vis pH).
Last, inexpensive PPIs such as racemic omeprazole
may indeed be more cost-effective than more expensive
alternatives for acid-peptic disease should genotyping
be used to guide therapy.47,48
Assessment of the Relative Health Care
Value
Table 1 summarizes the application of standard meth-
ods used in pharmacoepidemiology to comparative
studies between 2 pairs of racemic mixture–enantiomer
products (escitalopram vs citalopram; levalbuterol vs
albuterol) for a quantitative assessment of healthcare
value (outcomes/cost).14,15
Based on the literature for the treatment of an
episode of MDD, treatment failure was defined at
12 and 24 weeks as the clinical endpoints.16–21 Costs
were then determined by estimating the expenditures
necessary to treat a defined number of patients (NNT)
with depression in order that one patient could achieve
a superior benefit of escitalopram over citalopram.15,23
Given an NNT of 4 for the 12-week endpoint, an
additional $1939 would be required for superior benefit
to be realized for one patient. Moreover, given an NNT
of 37 for the 24-week endpoint, an additional $35 899
would be required for superior benefit to be realized
for one patient.17 Further, given the overall equivalency
between SSRIs in the treatment of MDD, combined
with the generic availability of SSRIs at the time of
the initial marketing of escitalopram, these same results
between escitalopram and generic SSRIs with minor
variability can reasonably be expected.24–31
The Journal of Clinical Pharmacology / Vol 56 No 4 2016
$ Spent or (Saved)
From Exclusive Use of
95% CI ARR NNT Enantiomer per Patient
[0.50, 0.89] 0.28 4 $1939
[0.56, 1.56] 0.027 37 $35 899
[0.58, 0.98] 0.138 8 ($2696)
[1.090, 2.77] 0.04 25 ($4490)
In the treatment of asthma, a cost savings of $2696
could be achieved if levalbuterol was used to abort an
attack for the patient to be subsequently discharged to
home. However, should any patient require hospitaliza-
tion, this savings would be eliminated by the equiva-
lence in response to racemic albuterol and levalbuterol
at an additional expense of $4490.
Given the lack of adequate clinical outcome mea-
sures for the treatment of acid-peptic disease, their
insignificant drug interaction differences, and that any
superiority of esomeprazole is based on a pharma-
codynamic measure of gastric pH sustainability, costs
alone are a better method to compare esomeprazole vs
omeprazole (ie, no difference in outcome).43,45 The cost
difference for an equipotent dose of the 2 products to
maintain a gastric pH ࣙ 4.0 for a standard duration
of treatment of 6 weeks was $111 per patient more for
esomeprazole than for omeprazole (www.drugs.com).
Figure 1 shows the difference in annual revenues to
the manufacturer for each of the 3 product pairs. For
the years selected, the differential in annual revenues
for escitalopram vs citalopram was $1 933 816 (2011);
esomeprazole vs omeprazole, $1 572 564 (2013); and
for levalbuterol vs albuterol, $22 614 309 (2011). The
individual year selected for comparison was either the
last year that data were publicly available for a single-
enantiomer product that still retains patent protection
 R
(Nexium ) or the last full year that a single-enantiomer
product enjoyed such exclusivity.
Because the most robust data regarding pairs of
racemates and their corresponding stereoisomers orig-
inate from February 2001 (esomeprazole), February
2002 (levalbuterol), and August 2002 (escitalopram),
it is these that provide the greatest statistical analytic
power. However, the “evergreening” of pharmaceuti-
cals is flourishing. To support this claim, here is a list
of additional racemic and stereoisomer pairs that are
currently marketed:
r lansoprazole (Prevacid)
r dexlansoprazole (Dexilant); date of approval:
Jan 30, 2009
Lehmann and Wojnowicz 387

Figure 1. Annual revenues for 3 pairs of racemic-mixture/single-enantiomer products for selected years.

r loratadine (Claritin) tee of significant return on investment is substantial, to

r desloratadine (Clarinex); date of approval: Dec pursue development of single-enantiomer products is
21, 2001 alluring.
r venlafaxine (Effexor, Effexor XR, Lanvexin, The practice of developing single-enantiomer prod-
Trevilor) ucts on the heels of patent protection loss is simul-
r desvenlafaxine (Pristiq, Desfax); date of ap- taneously an exercise in diversion of resources away
proval: Feb 29, 2008 from pursuit of novel compounds that have a signif-
r cetirizine (Zyrtec) icantly greater potential to improve healthcare value.
r levocetirizine (Xyzal); date of approval: May Unfortunately, greater margins in the short term create
25, 2007 the temptation for the pursuit of enantiomer products,
r methylphenidate (Ritalin, Ritalin LA, Meta- thereby ensuring an immediate financial margin for
date, Concerta, etc) isolated stakeholders.
r dexmethylphenidate (Focalin XR); date of ap- Although the development of enantiomers is obvi-
proval: May 26, 2005 ously advantageous for the bottom line, resources are
r dextroamphetamine and amphetamine diverted from investment in the pursuit of novel com-
(Adderall, Adderall XR) pounds, which is at odds with manufacturers’ claims
r lisdexamphetamine (Vyvanse); date of ap- for their commitment to the service of society. This
proval: Feb 23, 2007 diminution creates the milieu for a perverse relationship
that maintains financial security at the expense of
innovation.
Final Comments
Marked improvements in basic and clinical research in
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