Clinical Equivalence of Generic and Brand-Name Drugs Used in Cardiovascular Disease A Systematic Review and Meta-analysis

Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02120, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 01/2009; 300(21):2514-26. DOI: 10.1001/jama.2008.758
Source: PubMed
ABSTRACT
Use of generic drugs, which are bioequivalent to brand-name drugs, can help contain prescription drug spending. However, there is concern among patients and physicians that brand-name drugs may be clinically superior to generic drugs.
To summarize clinical evidence comparing generic and brand-name drugs used in cardiovascular disease and to assess the perspectives of editorialists on this issue.
Systematic searches of peer-reviewed publications in MEDLINE, EMBASE, and International Pharmaceutical Abstracts from January 1984 to August 2008.
Studies compared generic and brand-name cardiovascular drugs using clinical efficacy and safety end points. We separately identified editorials addressing generic substitution.
We extracted variables related to the study design, setting, participants, clinical end points, and funding. Methodological quality of the trials was assessed by Jadad and Newcastle-Ottawa scores, and a meta-analysis was performed to determine an aggregate effect size. For editorials, we categorized authors' positions on generic substitution as negative, positive, or neutral.
We identified 47 articles covering 9 subclasses of cardiovascular medications, of which 38 (81%) were randomized controlled trials (RCTs). Clinical equivalence was noted in 7 of 7 RCTs (100%) of beta-blockers, 10 of 11 RCTs (91%) of diuretics, 5 of 7 RCTs (71%) of calcium channel blockers, 3 of 3 RCTs (100%) of antiplatelet agents, 2 of 2 RCTs (100%) of statins, 1 of 1 RCT (100%) of angiotensin-converting enzyme inhibitors, and 1 of 1 RCT (100%) of alpha-blockers. Among narrow therapeutic index drugs, clinical equivalence was reported in 1 of 1 RCT (100%) of class 1 antiarrhythmic agents and 5 of 5 RCTs (100%) of warfarin. Aggregate effect size (n = 837) was -0.03 (95% confidence interval, -0.15 to 0.08), indicating no evidence of superiority of brand-name to generic drugs. Among 43 editorials, 23 (53%) expressed a negative view of generic drug substitution.
Whereas evidence does not support the notion that brand-name drugs used in cardiovascular disease are superior to generic drugs, a substantial number of editorials counsel against the interchangeability of generic drugs.

Full-text

Available from: Alexander S Misono, Mar 05, 2015
REVIEW
Clinical Equivalence of Generic
and Brand-Name Drugs Used
in Cardiovascular Disease
A Systematic Review and Meta-analysis
Aaron S. Kesselheim, MD, JD, MPH
Alexander S. Misono, BA
Joy L. Lee, BA
Margaret R. Stedman, MPH
M. Alan Brookhart, PhD
Niteesh K. Choudhry, MD, PhD
William H. Shrank, MD, MSHS
T
HE PROBLEM OF RISING PRESCRIP-
tion drug costs has emerged as
a critical policy issue, strain-
ing the budgets of patients and
public/private insurers
1
and directly
contributing to adverse health out-
comes by reducing adherence to im-
portant medications.
2,3
The primary
drivers of elevated drug costs are brand-
name drugs, which are sold at high
prices during a period of patent pro-
tection and market exclusivity after ap-
proval by the Food and Drug Admin-
istration (FDA).
4
To control spending,
many payers and providers have en-
couraged substitution of inexpensive
bioequivalent generic versions of these
drugs, which can legally be marketed
by multiple manufacturers after the
brand-name manufacturer’s market ex-
clusivity period ends.
5
Generic drugs are chemically equiva-
lent to their brand-name counterparts
in terms of active ingredients but may
differ in peripheral features, such as pill
color or shape, inert binders and fill-
ers, and the specific manufacturing pro-
cess.
6
The 1984 Hatch-Waxman Act
first authorized the FDA to approve ge-
neric drugs demonstrated to be “bio-
equivalent,” which is defined as ab-
sence of a significant difference in the
availability of the active ingredient at
the site of drug action.
7
Bioequiva-
lency can be established on the basis of
the maximum serum concentration of
Author Affiliations: Division of Pharmacoepidemiol-
ogy and Pharmacoeconomics, Department of Medi-
cine, Brigham and Women’s Hospital, Harvard Medi-
cal School, Boston, Massachusetts.
Corresponding Author: Aaron S. Kesselheim, MD, JD,
MPH, Division of Pharmacoepidemiology and Phar-
macoeconomics, Brigham and Women’s Hospital, 1620
Tremont St, Ste 3030, Boston, MA 02120 (akesselheim
@partners.org).
Context Use of generic drugs, which are bioequivalent to brand-name drugs, can
help contain prescription drug spending. However, there is concern among patients
and physicians that brand-name drugs may be clinically superior to generic drugs.
Objectives To summarize clinical evidence comparing generic and brand-name drugs
used in cardiovascular disease and to assess the perspectives of editorialists on this
issue.
Data Sources Systematic searches of peer-reviewed publications in MEDLINE,
EMBASE, and International Pharmaceutical Abstracts from January 1984 to August
2008.
Study Selection Studies compared generic and brand-name cardiovascular drugs
using clinical efficacy and safety end points. We separately identified editorials ad-
dressing generic substitution.
Data Extraction We extracted variables related to the study design, setting, par-
ticipants, clinical end points, and funding. Methodological quality of the trials was as-
sessed by Jadad and Newcastle-Ottawa scores, and a meta-analysis was performed
to determine an aggregate effect size. For editorials, we categorized authors’ posi-
tions on generic substitution as negative, positive, or neutral.
Results We identified 47 articles covering 9 subclasses of cardiovascular medica-
tions, of which 38 (81%) were randomized controlled trials (RCTs). Clinical equiva-
lence was noted in 7 of 7 RCTs (100%) of -blockers, 10 of 11 RCTs (91%) of di-
uretics, 5 of 7 RCTs (71%) of calcium channel blockers, 3 of 3 RCTs (100%) of antiplatelet
agents, 2 of 2 RCTs (100%) of statins, 1 of 1 RCT (100%) of angiotensin-converting
enzyme inhibitors, and 1 of 1 RCT (100%) of -blockers. Among narrow therapeutic
index drugs, clinical equivalence was reported in 1 of 1 RCT (100%) of class 1 anti-
arrhythmic agents and 5 of 5 RCTs (100%) of warfarin. Aggregate effect size (n=837)
was −0.03 (95% confidence interval, −0.15 to 0.08), indicating no evidence of supe-
riority of brand-name to generic drugs. Among 43 editorials, 23 (53%) expressed a
negative view of generic drug substitution.
Conclusions Whereas evidence does not support the notion that brand-name drugs
used in cardiovascular disease are superior to generic drugs, a substantial number of
editorials counsel against the interchangeability of generic drugs.
JAMA. 2008;300(21):2514-2526 www.jama.com
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Page 1
the drug, the time until maximum con-
centration is reached, or the area un-
der the curve based on serum concen-
tration as a function of time.
Some physicians and patients have
expressed concern that bioequivalent
generic and brand-name drugs may not
be equivalent in their effects on vari-
ous clinical parameters, including
physiological measures such as heart
rate or blood pressure, important labo-
ratory measurements, and outcomes
such as health system utilization or
mortality.
8-10
Of particular concern are
narrow therapeutic index (NTI) drugs,
which are drugs whose effective doses
and toxic doses are separated by a small
difference in plasma concentration.
Brand-name manufacturers have sug-
gested that generic drugs may be less
effective and safe than their brand-
name counterparts.
11
Anecdotes have
appeared in the lay press raising doubts
about the efficacy and safety of certain
generic drugs.
12,13
Little empirical evidence has been
assembled to assess clinical differ-
ences resulting from the use of
generic medications, so we sought to
systematically evaluate comparisons
of generic and brand-name drugs on
these outcomes. We focused on drugs
used primarily to treat cardiovascular
disease, which as a group make up
the largest portion of outpatient
prescription drug spending.
14
We
reviewed studies published from 1984
to 2008 comparing clinical character-
istics of generic and brand-name
drugs in this field and pooled avail-
able results. To determine the concur-
rent expert opinion on the subject of
generic substitution, we also system-
atically reviewed the content of edito-
rials published during this time.
METHODS
Data Sources
We performed a systematic search of ar-
ticles published in peer-reviewed health
care–related journals between Janu-
ary 1984 and August 2008 using
MEDLINE, EMBASE, and Interna-
tional Pharmaceutical Abstracts (IPA)
with the help of a professional librarian.
We used 3 main subject heading do-
mains: terms relating to the type of
study (for example, clinical study, cross-
over, equivalen$, effect$, and out-
come$), terms relating to the products
of interest (for example, brand-name,
nonproprietary, generic$, innovator$,
patent$, and pharmaceutical drug), and
terms relating to cardiovascular medi-
cine. Cardiovascular disease was de-
fined as any condition affecting the
heart or blood vessels, including myo-
cardial infarction, hypertension, car-
diac arrhythmias, peripheral vascular
disease, and heart failure. Under the car-
diovascular category, we used search
terms addressing general terms (eg, car-
diovascular, heart, hematologic), cardio-
vascular disease (eg, atherosclerosis, hy-
perlipid, ischemia), and classes of
pertinent drugs (eg, β-agonist, antico-
agulant). Articles containing at least 1
search term in each of the 3 main cat-
egories met criteria for the title/
abstract review.
Search terms and parameters were
adjusted for each database while main-
taining a common overall architec-
ture. Search results from MEDLINE and
EMBASE were combined and screened
for duplicate entries. Search results from
IPA were handled separately because of
differences in output organization.
Study Selection
Studies were included if they reported
on a comparative evaluation of 1 brand-
name drug and at least 1 generic ver-
sion produced by a distinct manufac-
turer (biologic products, which are
regulated differently, were excluded).
The comparative evaluation had to in-
clude measurement of at least 1 clini-
cal efficacy or safety end point, includ-
ing a vital sign (eg, heart rate, blood
pressure, urine output), a clinical labo-
ratory study (eg, international normal-
ized ratio [INR], low-density lipopro-
tein, urine electrolytes), patient
morbidity or mortality, or health sys-
tem utilization. “Clinical laboratory
studies” did not include specialized as-
says of concentrations of the drug or its
metabolites used in pharmacokinetic
evaluation.
We included both randomized con-
trolled trials (RCTs) and observa-
tional studies. We excluded case stud-
ies as well as qualitative analyses of
effectiveness, pharmacoeconomic
evaluations, or surveys. For this part of
the study, we also excluded commen-
taries, essays, legal analyses, consen-
sus statements, and letters to the edi-
tor. Studies were excluded if they were
written in a language other than En-
glish or they were conducted in vitro
or in animals. Although the study could
take place in any location, the brand-
name drug used (or an identical for-
mulation of it) must have been ap-
proved by the FDA. Manual reference
mining of articles, letters, and com-
mentaries supplemented the search re-
sults.
Data Extraction and Synthesis
Data were extracted (A.S.K.) and
checked (W.H.S.), with disagree-
ments resolved by consensus. We as-
sessed a number of variables related to
the organization and outcome of the
studies: the study design, listed source
of funding, the setting (US vs non-
US), the characteristics of the popula-
tion studied, the number of partici-
pants, the mean age (or age range) of
the participants, the clinical end points,
and the self-identified source of fund-
ing (where listed). The methodologi-
cal quality of the randomized clinical
trials (RCTs) was assessed using the
5-point scale developed by Jadad et al.
15
The methodological quality of nonran-
domized trials was assessed using the
9-star Newcastle-Ottawa scale.
16
This
was done independently by 2 of us
(A.S.K. and W.H.S.), with differences
resolved by consensus.
Drugs were further subdivided based
on whether they had a wide therapeu-
tic index (WTI) or NTI. The federal
definition of an NTI drug follows: “(a)
There is less than a 2-fold difference in
median lethal dose (LD
50
) and median
effective dose (ED
50
) values, or (b)
There is less than a 2-fold difference in
the minimum toxic concentrations and
minimum effective concentrations in
the blood, and (c) Safe and effective use
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of the drug products require careful ti-
tration and patient monitoring.”
17,18
The
FDA does not formally designate the
therapeutic index of drugs, but accord-
ing to this definition (confirmed with
review of the cardiovascular litera-
ture), relevant drugs with an NTI in-
clude the anticoagulant warfarin (Cou-
madin; DuPont Pharmaceuticals,
Wilmington, Delaware) and antiar-
rhythmic drugs affecting the sodium
and potassium channels (class I and
class III).
To conduct a meta-analysis of in-
cluded studies, we identified those RCTs
where means and standard deviations for
clinical outcomes were presented or
could be derived from the published re-
sults. If the correlation was not re-
ported for a crossover design, we as-
sumed a coefficient of 0.5. We calculated
a Cohen D effect size for each study with
a 95% confidence interval (CI) accord-
ing to established methods from infor-
mation provided in the article.
19-22
The
effect sizes compare the difference in
effect between the study groups di-
vided by the standard deviation of this
difference. We considered an effect size
of less than 0.2 to be very small, an effect
size of 0.2 to 0.5 to be small, an effect
size of 0.5 to 0.8 to be medium, and an
effect size of greater than 0.8 to be large.
Since this measure is independent of the
measurement used, sample size, and
standard deviation of the outcome mea-
sure, we aggregated different end points
across studies to obtain effect sizes with
95% CIs for each cardiovascular drug
class as well as an aggregate effect size
for all studies included in the meta-
analysis.
23
Review of Editorials
We assessed the perspectives presented
in editorials about the appropriateness
of using generic drugs in treating car-
diovascular disease during the same time
period covered by our systematic re-
view of the data. We repeated the
MEDLINE and EMBASE searches using
the same criteria. Two of us (A.S.K. and
A.S.M.) then reviewed each title and ab-
stract. Editorials were defined as ar-
ticles expressing perspectives or view-
points that did not include direct
pharmacokinetic or clinical compari-
sons of generic and brand-name drugs.
We also excluded systematic literature
reviews, reports of surveys, case reports
without substantial additional discus-
sion, and letters to the editor.
Using content analysis,
24
2ofus
(A.S.K. and W.H.S.) then coded themes
in the commentaries. We focused on the
examples used (if any), sources cited (if
any), and ultimate conclusions reached
to categorize the editorial’s viewpoint
within 1 of 3 main categories: (1) those
presenting a generally negative opinion
discouraging generic drug substitution,
(2) those presenting a generally posi-
tive opinion encouraging generic drug
substitution, and (3) those presenting a
neutral analysis or that otherwise made
no recommendations on the issue. We
determined whether the editorial ad-
dressed generic and/or cardiovascular
drugs broadly or focused on a subset of
drugs, such as NTI drugs or drugs in a
particular class. Investigators recon-
ciled differences in coding by consensus.
RESULTS
The search done in September 2008
identified 8556 records, 3932 records
from EMBASE, 2848 records from
MEDLINE, and 1776 records from
IPA. After removing overlapping cita-
tions and applying our exclusion cri-
teria, 71 articles were prioritized from
those 3 sources. We added 2 studies
from evaluation of citations from pri-
oritized articles. A total of 26 citations
were excluded after full review. In
total, our review identified 47 articles
for detailed analysis (F
IGURE 1), cov-
ering 9 different subclasses of cardio-
vascular drugs.
Nearly half of included studies (23/47,
49%) were primarily bioequivalency stud-
ies, in which pharmacokinetic compari-
sons occurred along with clinical end
points, and more than a third (18/47, 38%)
involved only healthy, young subjects.
Less than half of the articles (21/47, 45%)
were published since 2000 and only 17
(36%) were conducted in the United
States. T
ABLE 1, TABLE 2, TABLE 3, and
Figure 1. Study Selection
47 Studies included in meta-analysis
38 Randomized controlled trials
9 Retrospective studies
34 Trials used WTI drugs
13 Trials used NTI drugs
71 Articles considered for inclusion
2 Articles added after evaluation of citations
from articles that were considered
26 Excluded
6 Did not compare brand-name with
generic drugs
5 Did not report clinical outcomes
8 Were not in English-language journals
1 Was a brief report of a trial
included in the final analysis
6 Used surveys or other qualitative
outcomes
8485 Excluded
7401 Did not meet inclusion
criteria for title and abstract
1084 Citations overlapped
8556 Articles found
3932 EMBASE
2848 MEDLINE
1776 International Pharmaceutical
Abstracts
NTI indicates narrow therapeutic index; WTI, wide therapeutic index.
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Page 3
TABLE 4 include all categories of WTI
cardiovascular drugs while TABLE 5 high-
lights the 2 NTI categories, warfarin
(Coumadin) and class I antiarrhythmic
drugs.
WTI Drugs
Nearly all trials (31/34, 91%) com-
paring generic and brand-name car-
diovascular drugs with a WTI were
RCTs with a crossover design. These
articles encompassed 7 different drug
classes, although more than three-
fourths (27/34, 79%) involved
-blockers, diuretics, or calcium
channel blockers.
Table 1. Studies Involving -Blockers
Source
Drugs
Studied
a
No. of Patients
(Age Mean
or Range, y)/
Duration Study Design
Population
(Setting)
Jadad or
Newcastle-
Ottawa
Score
b
Results
Listed Source
of Funding
Ahrens et al,
25
2007
Toprol XL vs 8
versions of
long-acting
metoprolol
49 673 (56)/4 y Retrospective
cohort
study
Patients
affiliated
with 3
German
health
insurers
(non-US)
8 No excess risk of
hospitalization for
cardiovascular events
after adjustment for
confounding (OR,
1.04-1.06; 95% CI,
0.89-1.21)
Generic
manufacturers
Portoles et al,
26
2005
Coreg vs
carvedilol
24 (22.8)/1 dose
of each with
washout
RCT with
crossover
Healthy
subjects
(non-US)
2 No significant differences
in HR, BP, PR length,
tolerability
Not listed
Mirfazaelian
et al,
27
2003
Tenormin vs
atenolol
12 (NA)/1 dose
of each with
washout
Bioequivalency
study:
double-
blind RCT
with
crossover
Healthy
subjects
(non-US)
2 No significant differences
in reductions of HR,
BP
Not listed
Bongers and
Sabin,
28
1999
Toprol XL vs
long-acting
metoprolol
52 (62)/4 wk
for each
product
Double-blind
RCT with
crossover
Outpatients
with stable
angina and
6 proven
ST-
segment
depres-
sions on
ambulatory
ECG
(non-US)
3 Both significantly reduced
ischemic events; no
significant difference in
reductions of HR or
BP, signs of ischemia
on telemetry (P = .21),
anginal attacks
(P = .34), nitrate use
(P = .13), or adverse
events (P = .08);
median HR slightly less
for brand-name
(P = .05)
Brand-name
manufacturer
Chiang et al,
29
1995
Tenormin vs
atenolol
23 (59)/4 wk
of each with
washout
Double-blind
RCT with
crossover
Outpatients
with hyper-
tension
(non-US)
3 No significant differences
in reductions of HR,
BP
Not listed
Sarkar et al,
30
1995
Tenormin vs
atenolol
31 (NA)/1 dose
of each with
washout
Bioequivalency
study: RCT
with
crossover
Healthy
subjects
(US)
2 No significant differences
in reductions of HR,
BP
Generic
manufacturer
Carter et al,
31
1989
Inderal vs
Inderal LA
(long-acting)
vs
propranolol
15 (46)/4 wk of
each with
washout
Single-blind
RCT with
crossover
Outpatients
with
hyperten-
sion (US)
3 No significant differences
in reductions of HR,
reductions of BP,
tolerability
National Institutes
of Health
el-Sayed and
Davies,
32
1989
Inderal vs
propranolol
vs placebo
12 (NA)/1 dose
of each with
washout
Double-blind
RCT with
crossover
Healthy
subjects
(non-US)
2 No significant differences
in change in resting
HR, SBP, postexercise
values
Not listed
Sanderson and
Lewis,
33
1986
Inderal vs
propranolol
1700 (68)/Half
switched to
Inderal LA
for 4 wk;
then all
switched for
4wk
Retrospective
cohort
study
Outpatients
with
multiple
indications
for -
blocker
(non-US)
3 Increased incidence of
self-reported adverse
effects among group
taking generic at
initiation of study
(P .001) (difference
extinguished after all
switched to Inderal LA,
P = .15)
Not listed
Abbreviations: BP, blood pressure; CI, confidence interval; ECG, electrocardiogram; HR, heart rate; NA, not available; OR, odds ratio; RCT, randomized controlled trial; SBP, systolic
blood pressure.
a
Toprol XL and Tenormin are manufactured by AstraZeneca, Wilmington, Delaware; Coreg, GlaxoSmithKline, London, England; and Inderal, Ayerst Laboratories, Radnor, Pennsylvania.
b
The Jadad score range is 1-5 for RCTs; the Newcastle-Ottawa score range, 1-9 stars for observational studies.
GENERIC DRUGS IN CARDIOVASCULAR MEDICINE
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Table 2. Studies Involving Diuretics
Source
Drugs
Studied
a
No. of Patients
(Age Mean or
Range, y) /
Duration Study Design
Population
(Setting)
Jadad or
Newcastle-
Ottawa
Score
b
Results
Source of
Funding
Murray et al,
34
1997
Lasix vs 3
versions of
furosemide
vs
intravenous
Lasix
17 (65)/1 wk of
each
product
Bioequivalency
study:
open-label
RCT with
crossover
Outpatients
with CHF
(US)
3 Statistically nonsignificant
differences in urine
electrolytes
(P = .37-.45) but wide
intraindividual variability
Brand-name
manufacturer
Awad et al,
35
1992
Lasix vs
furosemide
20 (21-32)/1
dose of
each with
washout
Bioequivalency
study: RCT
with
crossover
Healthy
subjects
(non-US)
0 Statistically nonsignificant
differences in urine
electrolytes, urine
volume (P .05)
Not listed
Kaojarern et al,
36
1990
Lasix vs 3
versions of
furosemide
8 (25-39)/1
dose of
each with
washout
Bioequivalency
study: RCT
with
crossover
Healthy
subjects
(non-US)
1 Statistically nonsignificant
differences in 6-h urine
output, urine
electrolytes (P .05)
Medical center,
brand-name
manufacturer
Sharoky et al,
37
1989
Dyazide vs
triamterene-
hydrochloro-
thiazide
30 (55)/3 wk of
brand and 3
wk of
generic
Bioequivalency
study:
RCT with
crossover
Outpatients
with
hyperten-
sion taking
brand-
name
Dyazide
(US)
4 Statistically nonsignificant
differences in
electrolytes, CBC, BP,
tolerability (P .05)
Generic
manufacturer
Singh et al,
38
1987
Intravenous
Lasix vs
intravenous
furosemide
5 (20-51)/1
dose of
each with
washout
Bioequivalency
study:
double-
blind RCT
Inpatients with
edema of
renal origin
(non-US)
2 Statistically nonsignificant
differences in urine
electrolytes, standing
and recumbent BP,
urine output,
tolerability
(P .05)
Not listed
Meyer et al,
39
1985
Lasix vs 3
versions of
furosemide
12 (NA)/1 dose
of each with
washout
Bioequivalency
study:
double-
blind RCT
with
crossover
Healthy
subjects
(non-US)
2 Statistically significant
differences in 6-h urine
output (P .05)
Not listed
Grahnen et al,
40
1984
Lasix vs
furosemide
vs
intravenous
furosemide
8 (26)/2 doses
of each with
washout
Bioequivalency
study:
double-
blind RCT
with
crossover
Healthy
subjects
(non-US)
2 Statistically nonsignificant
differences in urine
output (P .05)
Not listed
Garg et al,
41
1984
Lasix vs
furosemide
16 (NA)/1 dose
of each with
washout
Bioequivalency
study:
double-
blind RCT
with
crossover
Healthy
subjects
(non-US)
2 Statistically nonsignificant
differences in serum
and urine electrolytes,
HR, BP, urine output
(P .05)
Not listed
Pan et al
42
1984
Lasix vs
furosemide
5 (NA)/2 d of
each
Bioequivalency
study:
double-
blind RCT
with
crossover
Outpatients
with CHF
(non-US)
1 Statistically nonsignificant
differences in
electrolytes, urine
output, weight, urine
electrolytes (P .2)
Not listed
Maitai et al,
43
1984
Lasix vs 6
versions of
furosemide
6 (NA)/1 dose of
each with
washout
Bioequivalency
study: RCT
with
crossover
Healthy
subjects
(non-US)
0 “Acceptable level of
diuresis” in
self-reported urine
output (no statistical
tests done)
Government
Martin et al,
44
1984
Lasix vs
furosemide
12 (18-42)/1
dose of
each with
washout
Bioequivalency
study:
RCT with
crossover
Healthy
subjects
(non-US)
0 Statistically nonsignificant
trend of lower urine
output (P = .07-.08),
statistically
nonsignificant
differences in urine
electrolytes
Medical center
Abbreviations: BP, blood pressure; CBC, complete blood count; CHF, congestive heart failure; HR, heart rate; NA, not available; RCT, randomized controlled trial.
a
Lasix is manufactured by Sanofi-Aventis, Paris, France; Dyazide is manufactured by GlaxoSmithKline, London, England.
b
The Jadad score range is 1-5 for RCTs; the Newcastle-Ottawa score range, 1-9 stars for observational studies.
GENERIC DRUGS IN CARDIOVASCULAR MEDICINE
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Page 5
We identified 9 articles that com-
pared clinical outcomes in generic and
brand-name -blockers.
25-33
These stud-
ies involved 4 different -blockers:
long-acting metoprolol (Toprol XL; As-
traZeneca, Wilmington, Delaware),
atenolol (Tenormin; AstraZeneca),
carvedilol (Coreg; GlaxoSmithKline,
London, England), and propranolol (In-
deral; Ayerst Laboratories, Radnor,
Pennsylvania). Long-acting metopro-
lol was evaluated in 1 double-blind RCT
in outpatients with stable angina and
1 retrospective cohort study involving
nearly 50 000 German patients over 4
years.
25
The cohort study identified us-
ers of -blockers from provincial ad-
ministrative data in Germany and found
no differences in clinical outcomes af-
ter controlling for patient sociodemo-
graphic characteristics and their co-
Table 3. Studies Involving Calcium Channel Blockers
Source
Drugs
Studied
a
No. of Patients
(Age Mean or
Range, y) /
Duration Study Design
Population
(Setting)
Jadad or
Newcastle-
Ottawa
Score
b
Results
Source of
Funding
Kim et al,
45
2007 Norvasc vs
amlodipine
camsylate
189 (53)/8 wk
with dose
increase
after 4 wk if
BP still
elevated
Multicenter
double-
blind
parallel
group RCT
Outpatients
with
uncompli-
cated
essential
hyper-
tension
(non-US)
3 Significant BP improvement
in both groups; statistically
nonsignificant differences
in tolerability (P .05)
Generic
manufacturer,
government
Mignini et al,
46
2007
Norvasc vs
amlodipine
maleate
24 (34.8)/1 dose
of each with
washout
Single-blind
RCT with
crossover
Healthy
subjects
(non-US)
2 Decrease in SBP, increase
in HR, decrease in PR
and QRS intervals,
with statistically
nonsignificant differences
between the 2 groups
Not listed
Park et al,
47
2004 Norvasc vs am-
lodipine
camsylate
18 (22)/1 dose
of each with
washout
Bioequivalency
study:
open-label
RCT with
crossover
Healthy sub-
jects (non-
US)
4 Significant improvements
in BP in both groups;
statistically nonsignificant
differences in
electrolytes, CBC, UA,
HR, ECG changes
(P .05)
Not listed
Saseen et al,
48
1997
Calan vs verap-
amil
8 (70)/2 wk of
each with
washout
Bioequivalency
study:
double-
blind RCT
with cross-
over
Elderly outpa-
tients with
hyper-
tension
(US)
3 Generics associated with
a marginally greater
BP reduction than
brand; statistically
nonsignificant differences
in HR, ECG changes
(P .05)
Not listed
Usha et al,
49
1997 Cardizem vs
long-acting
diltiazem
12 (27)/1 dose
of each with
washout
Bioequivalency
study:
double-
blind RCT
with cross-
over
Healthy sub-
jects (non-
US)
3 Statistically nonsignificant
differences in BP, HR,
ECG changes
(P .05)
Generic
manufacturer
Waldman and
Morganroth,
50
1995
Calan SR or
Isoptin SR
vs
sustained-
release ver-
apamil
24 (NA)/1 dose
of each with
washout
Bioequivalency
study (both
fasting and
after a
meal):
open-label
RCT
Healthy sub-
jects (US)
1 In fasting patients,
statistically nonsignificant
difference in BP, HR,
or ECG changes; in
fed patients, increased
PR interval on ECG
with generic (P .05)
Brand-name
manufacturer;
brand-name,
industry-
affiliated foun-
dation
Carter et al,
51
1993
Isoptin vs 1 of 2
versions of
verapamil
Youth cohort:
8 (27)/1 wk
of each with
washout;
elderly co-
hort:
8 (73)/3 wk
of each with
no washout
Double-blind
random-
ized 3-way
RCT with
crossover
Healthy sub-
jects and
elderly out-
patients
with hyper-
tension
(US)
2 Statistically nonsignificant
differences in HR, BP,
or PR intervals for
youth cohort;
statistically insignificant
differences in elderly
cohort also, except 1
generic associated
with increased PR
interval and
(paradoxically) higher
supine BP
American College
of Clinical
Pharmacy,
medical center
Abbreviations: BP, blood pressure; CBC, complete blood count; ECG, electrocardiogram; HR, heart rate; NA, not available; RCT, randomized controlled trial; SBP, systolic blood pres-
sure; UA, urinalysis.
a
Norvasc is manufactured by Pfizer, New York, New York; Calan, Searle Pharmaceuticals, Chicago, Illinois; Cardizem, Marion Merrell Dow Inc, Kansas City, Missouri; and Isoptin, Knoll
Pharmaceuticals, Whippany, New Jersey.
b
The Jadad score range is 1-5 for RCTs; the Newcastle-Ottawa score range, 1-9 stars for observational studies.
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Page 6
morbidities. In 1 RCT in outpatients
with hypertension and 2 bioequiva-
lency studies in healthy volunteers,
Tenormin was not found to be supe-
rior to the generic version in lowering
heart rate and blood pressure.
27,29,30
In
a retrospective cohort study of pa-
tients switching from short- to long-
acting -blocker preparations, self-
reported adverse effects occurred more
frequently at baseline in patients tak-
ing generic propranolol than in those
taking Inderal (34.6% vs 24.8%,
P.001), and the difference was noted
to be extinguished after all were
switched to Inderal LA (Long-Acting)
(20.5% vs 17.6%, P =.15).
33
These pa-
tients were not randomly assigned to
Table 4. Studies Involving Other Non-NTI Cardiovascular Drugs Grouped by Drug Class
Source
Drugs
Studied
a
No. of Patients
(Age Mean or
Range, y)/
Duration Study Design
Population
(Setting)
Jadad or
Newcastle-
Ottawa
Score
b
Results
Source of
Funding
Antiplatelet Agents
Ashraf et al,
52
2005
Plavix vs
clopidogrel
30 (49)/1 dose
of each with
washout
Double-blind
RCT with
crossover
Patients with
suspected
ischemic
heart disease
(non-US)
3 Statistically nonsignificant
differences in
reduction in platelet
aggregation blood
tests (57.8% vs
60.7%, P = .72)
Generic
manufacturer,
government
Rao et al,
53
2003
Plavix vs
clopidogrel
20 (27)/10 d Bioequivalency
study:
open-label
parallel
group RCT
Healthy subjects
(non-US)
2 Statistically nonsignificant
differences in bleeding
time, tolerability
(P .05)
Not listed
Merali et al,
54
1996
Enteric-coated
aspirin vs 3
versions of
enteric-
coated
acetylsali-
cylic acid
12 (18-45)/1
dose of
each with
washout
Bioequivalency
study: RCT
with
crossover
Healthy subjects
(non-US)
2 Statistically nonsignificant
differences in platelet
function assay
(P .05)
Internal funding
Angiotensin-Converting Enzyme Inhibitors
Portoles et al,
55
2004
Vasotec vs
enalapril
24 (23)/1 dose
of each with
washout
Bioequivalency
study:
open-label
RCT with
crossover
Healthy subjects
(non-US)
3 Statistically nonsignificant
differences in BP
reductions, changes in
HR, effect on CBC, UA
(P .05)
Not listed
Statins
Assawawitoontip
and
Wiwanitkit,
56
2002
Zocor vs
simvastatin
48 (37)/8 wk
of each with
washout
Double-blind
RCT with
crossover
Outpatients with
hypercholes-
terolemia not
previously
treated
(non-US)
4 Reductions in LDL in both
groups; statistically
nonsignificant
differences in
cholesterol
measurements, LFTs,
creatine kinase levels
(unpaired t test,
= .05)
Generic
manufacturer
Wiwanitkit et al,
57
2002
Zocor vs
simvastatin
43 (49)/16 wk
of each with
washout
Double-blind
RCT with
crossover
Outpatients with
hypercholes-
terolemia not
previously
treated
(non-US)
4 Reductions in LDL in both
groups; statistically
nonsignificant
differences in
cholesterol
measurements, LFTs,
adverse effects
(P .05)
Generic
manufacturer
-Blockers
Tsai et al,
58
2007
Hytrin vs
terazosin
43 (63)/6 wk
of each with
washout
(dose
change
allowed
at week 2)
Open-label
RCT with
crossover
Outpatients with
BPH
(non-US)
3 Improvements in urine flow
and quality of life
indices in both;
statistically
nonsignificant
differences in effects
on BP, HR, CBC,
symptom scales
(P .05)
Generic
manufacturer
Abbreviations: BP, blood pressure; BPH, benign prostatic hypertrophy; CBC, complete blood count; HR, heart rate; LDL, low-density lipoprotein; LFTs, liver function test results; NTI,
narrow therapeutic index; RCT, randomized controlled trial; UA, urinalysis.
a
Plavix is manufactured by Bristol-Myers Squibb, New York, New York; Vasotec and Zocor by Merck, Whitehouse Station, New Jersey; and Hytrin by Abbott Laboratories, Abbott Park,
Illinois.
b
The Jadad score range is 1-5 for RCTs; the Newcastle-Ottawa score range, 1-9 stars for observational studies.
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Page 7
Table 5. Studies Involving Narrow Therapeutic Index Cardiovascular Drugs
Source
Drugs
Studied
a
No. of Patients
(Age Mean or
Range,
y)/Duration Study Design
Population
(Setting)
Jadad or
Newcastle-
Ottawa
Score
b
Results
Source of
Funding
Antiarrhythmic Agents
Amit et al,
59
2004
Rythmex vs
propafenone
119 (65)/18 mo Retrospective
cohort
study
(pre/post
design
without
concurrent
controls)
Patients with atrial
fibrillation
stable while
receiving brand
for 18 mo
switched to
generic
(non-US)
4 Generic use associated
with slight reduction in
total ED discharges
and ED visits for chest
pain (P .01); no
significant differences
in clinic visits,
admissions,
cardioversions, and
rate of use of other
cardiovascular
medications (P .05)
Generic
manufacturer
Kasmer et al,
60
1987
Pronestyl vs
procain-
amide
10 (62)/6 doses
of each
separated
by1wkof
prior therapy
Bioequivalence
study:
single-blind
RCT with
crossover
Patients with
ventricular
dysrhythmias
(US)
1 No significant change in
type or frequency of
VPBs on telemetry
(P .05)
Generic
manufacturer,
National
Institutes of
Health
Warfarin Anticoagulant
Handler et al,
61
1998
Coumadin vs
warfarin
57 (71)/4 wk of
Coumadin
and then 8
wk of
warfarin vs 4
wk of
warfarin and
then8wkof
Coumadin
Double-blind
RCT with
crossover
Outpatients with
arrhythmia (US)
5 No significant differences
in INR (P = .40), dose
adjustments, adverse
events (P .05)
Generic
manufacturer
Pereira et al,
62
2005
Coumadin vs
warfarin
7 (63)/Five 3-wk
periods of
each
Double-blind
RCT with
crossover
Outpatients with
indications for
anticoagulation
(US)
4 No significant differences
in INR measurements
or variation (P = .98)
Not listed
Paterson et al,
63
2006
Coumadin vs 1
of 2 versions
of warfarin
36 724 (66)/40
mo before,
1moof
transition,
and9mo
following
switch
Population-
based,
cross-
sectional
time-series
analysis
Elderly outpatients
with numerous
indications for
anticoagulation
taking
Coumadin
(non-US)
5 No significant differences
in INR testing (P = .93)
or hospitalization for
hemorrhage (P = .89)
or thromboembolism
(P = .97)
Government
Lee et al,
64
2005
Coumadin vs
warfarin
35 (52)/4 wk of
Coumadin
and then 8
wk of
warfarin vs 4
wk of
warfarin and
then8wkof
Coumadin
Single-blind
RCT with
crossover
Patients with
mechanical
heart valves
who received
Coumadin for
2mo
(non-US)
3 Dose changes were rare;
no significant
differences in pooled
INRs or frequency of
adverse effects
(P .05)
Unknown
Halkin et al,
65
2003
Coumadin vs
warfarin
975 (70)/6 mo
before and
6 mo after
switch
Retrospective
observa-
tional study
(pre/post
design)
Outpatients with
numerous
indications for
anticoagulation
taking
Coumadin
(non-US)
5 After the switch, INR
values were lower and
warfarin doses
prescribed were
higher, especially in
those who were
subtherapeutic when
receiving Coumadin
(P .01)
Not listed
Witt et al,
66
2003
Coumadin vs
warfarin
2299 (69)/3 mo
before and 3
mo after
switch
Retrospective
cohort
study
Outpatients with
numerous
indications for
anticoagulation
taking
Coumadin (US)
4 More INR values below
therapeutic range
with generic
(P .001); overall
average INR
decreased by 0.13
after switch; no
significant differences
in hospitalizations, ED
use, outcomes
(bleeding or
thromboembolism)
Not listed
(continued)
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Page 8
different preparations, and recipients of
the generic formulation may have been
different from recipients of the brand.
An RCT later conducted in hyperten-
sive patients found no clinical differ-
ences, including rates of observed ad-
verse effects, among these 3 versions of
propranolol.
31
Eleven articles compared outcomes
among patients using diuretics: 10 with
the loop diuretic furosemide (Lasix; Sa-
nofi-Aventis, Paris, France)
34-36,38-44
and
1 with the combination diuretic triam-
terene-hydrochlorothiazide (Dyazide;
GlaxoSmithKline).
37
The furosemide
studies were of lower quality, and 7
were bioequivalency studies per-
formed in a total of 82 generally young,
healthy subjects who received only 1
dose of each brand-name or generic for-
mulation.
35,36,39-41,43,44
The clinical end
points for these studies were primar-
ily urine output and urine electro-
lytes. However, only 1 study, con-
ducted in South Africa in 1985, found
significant differences.
39
Three studies of furosemide involved
patients with volume overload. In these
studies, generic and brand-name formu-
lations of furosemide showed no signifi-
cant clinical differences.
34,38,42
A 1997
open-label RCT with crossover in 17 out-
patients with congestive heart failure who
received Lasix, 3 versions of generic fu-
rosemide, and intravenous furosemide for
a week’s time noted wide intraindividual
variability in patients’ urine electrolytes
that the authors hypothesized might over-
whelm any minor differences in bio-
availability.
34
The study of triamterene-
hydrochlorothiazide was a prospective
RCT in 30 patients with hypertension.
37
It demonstrated no statistically significant
differences on blood pressure and serum
electrolytes in patients using the medica-
tion for 3-week blocks.
Seven articles evaluated generic and
brand-name versions of calcium chan-
nel blockers.
45-51
The largest, a multi-
center, double-blind, parallel-group RCT
in 189 patients with hypertension, found
Table 5. Studies Involving Narrow Therapeutic Index Cardiovascular Drugs (continued)
Source
Drugs
Studied
a
No. of Patients
(Age Mean or
Range, y) /
Duration Study Design
Population
(Setting)
Jadad or
Newcastle-
Ottawa
Score
b
Results
Source of
Funding
Warfarin Anticoagulant
Milligan et al,
67
2002
Coumadin vs
warfarin
182 (75)/8 mo
before and
10 mo after
switch
Retrospective
cohort
study
Outpatients with
numerous
indications for
anticoagulation
taking
Coumadin (US)
5 No significant differences
in INR (P = .3), dose
adjustments (P = .41),
adverse events
Insurance
company
Weibert et al,
68
2000
Coumadin vs
warfarin
113 (70)/4 wk
before and
10 wk after
switch
Multicenter
double-
blind RCT
with
crossover
Outpatients with
atrial fibrillation
who received
Coumadin for
1 mo (US)
4 No significant differences
in daily dose (0.5
mg/d), average INR
difference (P .08),
adverse events
(P = .24 for
hemorrhagic)
Generic
manufacturer
Swenson and
Fundak,
69
2000
Coumadin vs
warfarin
210 (78)/8 wk Prospective
observa-
tional
cohort
study
Outpatients with
indications for
anticoagulation
receiving
Coumadin for
3mo
switched to
warfarin (US)
6 No significant differences
in INR between groups
(P = .15); changes in
INR of 1.0 were rare;
no adverse effects or
adverse events
Not listed
Neutel and
Smith,
70
1998
Coumadin vs
warfarin
39 (70)/3 wk of
Coumadin
and then 6
wk of
warfarin vs 3
wk of
warfarin and
then6wkof
Coumadin
Single-blind
RCT with
crossover
Outpatients with
arrhythmia
stably treated
with Coumadin
for 6 wk (US)
2 Changes in INR after
switching were small
and not significant
(P .05); no
differences in adverse
effect profiles between
drugs
Not listed
Richton-Hewett
et al,
71
1988
c
Coumadin vs
warfarin
55 (57)/3 mo of
warfarin and
then4moof
Coumadin
Retrospective
cohort
study
Outpatients with
indications for
anticoagulation
switched to
warfarin in a
single hospital
(US)
5 Higher rate of INR out of
range (P .001), dose
changes (P .05),
clinic utilization
(P .03) with generic
group; no significant
differences in
morbidity/mortality
Not listed
Abbreviations: ED, emergency department; INR, international normalized ratio; RCT, randomized controlled trial; VPBs, ventricular premature beats.
a
Rythmex is manufactured by Knoll Pharmaceuticals, Delkenheim, Germany; Pronestyl, E. R. Squibb & Sons, New Brunswick, New Jersey; and Coumadin, DuPont Pharmaceuticals,
Wilmington, Delaware.
b
The Jadad score range is 1-5 for RCTs; the Newcastle-Ottawa score range, 1-9 stars for observational studies.
c
Although conducted in the United States, this study did not involve a bioequivalent generic.
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Page 9
improvements in blood pressure and no
significant differences between brand-
name and generic versions of amlo-
dipine (Norvasc; Pfizer, New York, New
York) over 8 weeks.
45
Two studies re-
ported slight, but statistically signifi-
cant, differences in 1 measured clinical
outcome (the PR interval on electro-
cardiogram), although there were no as-
sociated changes in heart rate or other
clinical outcomes in either of those
studies.
50,51
The remaining 7 studies evaluated an-
tiplatelet agents (clopidogrel; [Plavix;
Bristol-Myers Squibb, New York, New
York] and enteric-coated aspirin [ace-
tylsalicylic acid]),
52-54
the angiotensin-
converting enzyme (ACE) inhibitor
enalapril (Vasotec; Merck, Whitehouse
Station, New Jersey),
55
the statin simva-
statin (Zocor; Merck),
56,57
and the -
blocker terazosin (Hytrin; Abbott Labo-
ratories, Abbott Park, Illinois).
58
None of
these studies reported significant clini-
cal differences between the generic and
brand-name versions. Two longer-term
RCTs of simvastatin were conducted in
Thailand. Both of these studies, of high
methodological quality, showed no sta-
tistically significant differences in low-
ering low-density lipoprotein levels.
56,57
However, there were a number of im-
portant limitations in the studies. The 2
studies of clopidogrel used clinical out-
comes related to platelet aggregation and
bleeding time, not incidence of cardio-
vascular disease such as myocardial in-
farction.
52,53
The study involving enala-
pril was well designed but measured
bioequivalency in 24 healthy subjects
who received only 1 dose of the generic
and brand-name forms.
55
The terazosin
study, which was conducted in outpa-
tients with benign prostatic hypertro-
phy, found no significant differences in
heart rate and blood pressure and was of
relatively high quality.
58
NTI Drugs
Thirteen articles analyzed generic and
brand-name versions of cardiovascular
drugs with an NTI. Two addressed clini-
cal end points in treatment with class I
antiarrhythmic drugs (propafenone
[Rythmex; Knoll Pharmaceuticals,
Delkenheim, Germany] and procain-
amide [Pronestyl; E. R. Squibb & Sons,
New Brunswick, New Jersey]).
59,60
The
study of propafenone used a pre/post de-
sign of 114 patients with atrial fibrilla-
tion receiving stable doses of brand-
name propafenone for at least 18 months
who were required by their insurer to
switch to a generic version of the drug.
This study, which included no concur-
rent controls, found no differences in
rates of health system utilization such as
clinic visits, coprescription with other
medications, or rates of cardioversion in
the 18 months after switching to a ge-
neric drug and a slight reduction in emer-
gency department visits with the ge-
neric version (P.01).
59
Procainamide
was studied in a bioequivalency study of
patients with ventricular dysrhythmias;
no differences in telemetry output were
found between the generic and brand-
name versions.
60
The remaining 11 articles studied
warfarin (Coumadin).
61-71
In 6 RCTs or
prospective studies, generic and brand-
name warfarin performed similarly with
respect to clinical end points such as
INR, frequency of adverse events, and
number of required dose adjust-
ments.
61,62,64,68-70
Five retrospective ob-
servational studies evaluated patient
INRs and clinical outcomes in pa-
tients who were required to switch from
Coumadin to warfarin because of
changes in coverage in diverse set-
tings: nationwide in Israel, a Cana-
dian province, a staff model health
maintenance organization (HMO), a
commercial HMO, and a municipal hos-
pital in the United States. All of these
studies used pre/post designs and found
results similar to the RCTs; no signifi-
cant differences were seen in clinical
outcomes, including hemorrhagic ad-
verse events or thromboembolic dis-
ease.
63,65-67
One of the cohort studies
found a small but significant decrease
in INR in patients using the generic
drug, although it did not translate into
differences in morbidity or mortal-
ity.
66
A fourth retrospective cohort study
found increased health care system uti-
lization in patients not taking Couma-
din (although no differences in mor-
bidity/mortality), but the drug used as
a comparator in that study was not rated
as bioequivalent by the FDA.
71
Aggregate Effect Sizes
Data from 30 studies contributed to the
effect sizes of the outcomes. As seen in
F
IGURE 2, when data were pooled by
drug class, in each case, the 95% CI
crossed zero, and the effect size was
“very small” (except for statins and an-
tiplatelet agents, where the effect size
was “small”). The aggregate effect size
(n=837) was −0.03 (95% CI, −0.15
to 0.08), which indicates nearly com-
plete overlap of the generic and brand-
name distributions. These data sug-
gest no evidence of superiority of
brand-name to generic drugs in mea-
sured clinical outcomes among these
studies.
Figure 2. Drug Class and Aggregate Meta-analyses of Trials Comparing Generic and
Brand-Name Drugs Used in Cardiovascular Disease
–1.0 –0.5 0 0.5 1.0
Effect Size (95% CI)
No.
Favors
Brand Name
Favors
Generic
Drug Class
Effect Size
(95% CI)
Studies
30
Subjects
ACE inhibitors –0.09 (–0.68 to 0.50)123
Warfarin –0.09 (–0.33 to 0.15)4 138
Diuretics –0.03 (–0.28 to 0.22)10 135
β-Blockers 0.00 (–0.24 to 0.25)6 135
Calcium channel blockers 0.00 (–0.53 to 0.53)4 242
α-Blockers 0.06 (–0.37 to 0.50)143
Statins –0.25 (–0.62 to 0.12)271
Antiplatelet agents 0.21 (–0.19 to 0.61)250
837Overall –0.03 (–0.15 to 0.08)
ACE indicates angiotensin-converting enzyme; CI, confidence interval.
GENERIC DRUGS IN CARDIOVASCULAR MEDICINE
©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, December 3, 2008—Vol 300, No. 21 2523
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Page 10
Editorials Addressing
Generic Substitution
Forty-three editorials and commentar-
ies met our criteria during the study pe-
riod. The greatest number (19, 44%)
were published from 1993 to 1999
9,72-89
while 14 (33%) were published from
2000 to 2008.
90-103
Twenty-five (58%)
discussed cardiovascular and generic
drugs broadly* while 18 (42%) focused
only on cardiovascular NTI drugs.†
Of these editorials, 23 (53%) ex-
pressed a negative view of the inter-
changeability of generic drugs com-
pared with 12 (28%) that encouraged
substitution of generic drugs (the re-
maining 8 did not reach a conclusion
on interchangeability). Among edito-
rials addressing NTI drugs specifi-
cally, 12 (67%) expressed a negative
view while only 4 (22%) supported ge-
neric drug substitution.
COMMENT
To our knowledge, our analysis is the
first comprehensive review of the em-
pirical evidence comparing clinical
characteristics of generic and brand-
name drugs used in cardiovascular dis-
ease. The 47 studies in our sample
covered 8 different subclasses of car-
diovascular drugs, including 2 types of
NTI drugs. Measured clinical out-
comes included vital signs; clinical labo-
ratory values such as INR and urine
electrolytes; adverse effects or other
morbidity; and health care system uti-
lization, including clinic and emer-
gency department visits.
The studies in our sample con-
cluded that generic and brand-name
cardiovascular drugs are similar in
nearly all clinical outcomes. Among
WTI drugs, the best evidence for clini-
cal equivalence emerged from high-
quality prospective RCTs in patients
with cardiovascular disease involving
-blockers, calcium channel blockers,
and statins. Fewer trials compared ge-
neric and brand-name diuretics, anti-
platelet agents, ACE inhibitors, and -
blockers, limiting our ability to reach
similar conclusions in these drug
classes.
Among NTI drugs, warfarin was the
subject of the most studies addressing
therapeutic equivalence. The 6 studies
with a prospective design (461 patients)
demonstrated similar clinical outcomes
with brand-name and generic versions of
the drug for multiple different outcomes,
includingINR, required dose adjustments,
and adverse events. Among the retrospec-
tive reviews, 2 revealed transient differ-
ences in INR after changes from brand-
name to generic warfarin without any
differences in clinical outcomes. The only
study showing specific differences in use
of health care resources compared Cou-
madin with a version of warfarin that was
not rated as bioequivalent by the FDA.
Takenas a whole,these results suggest that
switching from brand-name to generic
warfarin products rated as bioequivalent
by the FDA is safe, although it may be use-
ful to monitor the INR of higher-risk pa-
tients more closely during a switch period.
Even though there is little evidence of
important clinical differences between ge-
neric and brand-name drugs in cardiovas-
cular disease, many editorials expressed
a negative view of generic drug inter-
changeability and urged heightened con-
cern on the part of physicians and patients.
Thisopinion has not changed substantially
over time; among the most recent edito-
rials(published 2000-2008), 6 of 14 (43%)
expressed a negative view of substitution.
One explanation for this discordance be-
tween the data and editorial opinion is that
commentaries may be more likely to high-
light physicians’ concerns based on an-
ecdotal experience or other nonclinical
trial settings. Another possible explana-
tion is that the conclusions may be skewed
by financial relationships of editorialists
with brand-name pharmaceutical com-
panies, which are not always disclosed.
114
Approximately half of the trials in our
sample (23/47, 49%), and nearly all of the
editorials and commentaries, did not iden-
tify sources of funding.
Our study has several limitations that
reflect the underlying literature. The ma-
jority of the studies we identified were
bioequivalence studies, which included
small populations and were powered to
assess differences in pharmacokinetic
parameters rather than clinical out-
comes. For the smaller studies, only large
differences in clinical outcomes would
have been statistically significant, al-
though our meta-analysis addresses the
limitation of small sample size by pool-
ing results across studies. Most clinical
outcomes were evaluated by testing a su-
periority hypothesis rather than nonin-
feriority hypothesis. Statistical insignifi-
cance in the context of a superiority study
does not allow one to conclude that
agents are equivalent, only that there is
insufficient evidence available to con-
clude that the agents are different. In ad-
dition, many of the bioequivalence stud-
ies included disproportionately young
and healthy subjects, and there were lim-
ited data comparing generic and brand-
name medications in patients with mul-
tiple morbidities and taking numerous
medications. Such patients may be at
greater risk of adverse events if modest
clinical differences in medication for-
mulations exist.
Most of the studies were conducted in
4 medication classes: -blockers, cal-
cium channel blockers, diuretics, and
warfarin. The small numbers of studies
in other classes limited our ability to draw
class-specific conclusions about com-
parative safety or efficacy. Finally, most
studies were short-term evaluations and
did not collect the data necessary to com-
pare long-term outcomes associated with
generic drug use such as rates of myo-
cardial infarction or death. The lack of
studies evaluating clinical outcomes in
generic drug use is not altogether sur-
prising, as neither generic drug makers
nor brand-name manufacturers are likely
to make large financial investments over
many years to pursue a research initia-
tive that could adversely affect their busi-
ness model if their hypotheses are not
confirmed.
Despite these limitations, we identi-
fied numerous studies that evaluated dif-
ferences in clinical outcomes with ge-
neric and brand-name medications. Our
results suggest that it is reasonable for
physicians and patients to rely on FDA
bioequivalence rating as a proxy for clini-
*References 72, 76, 77, 80-84, 86, 87, 90, 93-95, 97,
101-110.
†References 9, 73-75, 78, 79, 85, 88, 89, 91, 92, 96,
98-100, 111-113.
GENERIC DRUGS IN CARDIOVASCULAR MEDICINE
2524 JAMA, December 3, 2008—Vol 300, No. 21 (Reprinted) ©2008 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ on 02/25/2013
Page 11
cal equivalence among a number of im-
portant cardiovascular drugs, even in
higher-risk contexts such as the NTI drug
warfarin. These findings also support the
use of formulary designs aimed at stimu-
lating appropriate generic drug use. To
limit unfounded distrust of generic medi-
cations, popular media and scientific
journals could choose to be more selec-
tive about publishing perspective pieces
based on anecdotal evidence of dimin-
ished clinical efficacy or greater risk of
adverse effects with generic medica-
tions. Such publications may enhance
barriers to appropriate generic drug use
that increase unnecessary spending with-
out improving clinical outcomes.
Author Contributions: Dr Kesselheim had full access to
all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Study concept and design: Kesselheim, Misono, Shrank.
Acquisition of data: Kesselheim, Misono, Lee, Shrank.
Analysis and interpretation of data: Kesselheim,
Misono, Stedman, Brookhart, Choudhry, Shrank.
Drafting of the manuscript: Kesselheim, Misono, Lee,
Shrank.
Critical revision of the manuscript for important in-
tellectual content: Kesselheim, Misono, Stedman,
Brookhart, Choudhry, Shrank.
Statistical analysis: Stedman, Brookhart, Choudhry.
Obtained funding: Kesselheim, Shrank.
Administrative, technical, or material support:
Kesselheim, Misono, Lee, Shrank.
Study supervision: Kesselheim, Shrank.
Financial Disclosures: None reported.
Funding/Support: The study was supported in part by
a grant from the Attorney General Prescriber and Con-
sumer Education Grant Program. Dr Kesselheim’s work
was supported by an Agency for Healthcare Re-
search and Quality Post-Doctoral Fellowship in Health
Services Research at the Harvard School of Public
Health. Dr Brookhart is supported by a career devel-
opment award from the National Institute on Aging
(AG027400). Dr Shrank is supported by a career de-
velopment award from the National Heart, Lung, and
Blood Institute (K23HL090505-01).
Role of the Sponsor: These funding organizations had
no role in the design and conduct of the study; in the
collection, management, analysis, and interpretation
of the data; or in the preparation, review, or ap-
proval of the manuscript.
Additional Contributions: Paul Shekelle, MD, PhD (Vet-
erans Affairs Greater Los Angeles Health Care System
and RAND Corp), provided comments on an earlier ver-
sion of the manuscript. Jerry Avorn, MD (Brigham and
Women’s Hospital and Harvard Medical School), helped
conceive the study and provided comments on the de-
sign and manuscript. Neither received compensation.
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GENERIC DRUGS IN CARDIOVASCULAR MEDICINE
2526 JAMA, December 3, 2008—Vol 300, No. 21 (Reprinted) ©2008 American Medical Association. All rights reserved.
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    • "Many countries are pursuing policies of encouraging the utilization of less costly generic medicines to cut spending and ensure efficient resource distribution. It is generally believed that generic medicines are less expensive copies of originators with the same therapeutic effects and the potential for appreciable savings [1][2][3][4][5][6][7][8][9][10][11] . Considerable resources can also be saved without compromising patient care by encouraging the prescribing of low costs generics versus more expensive patented products in classes where all products are seen as essentially similar at therapeutic doses. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: There have been concerns in Korea that the availability of cheaper generics can appreciably increase prescribed volumes thereby negating their beneficial effects on overall pharmaceutical expenditure. Consequently, this study aimed to explore market changes after newly entered generics including market expansion and substitution effects, and to examine factors contributing to the prescribing of newly entered generics using atorvastatin as an exemplar. This is because previous studies have shown market expansion had occurred following generic atorvastatin. Methods: Explore market expansion effects by extracting all statins users from July 2008 to June 2010 from the nationally representative dataset of 2008, combined with the National Health Insurance Claims data, with atorvastatin's patent expiring in July 2008. The data consisted of medical visit episodes of patients who had been prescribed statins at least once during the observational period. Patients who had been prescribed any statin before the observation period were classified as the previously treated group and those who had not as the newly treated group. Descriptive time series analysis was conducted and the mixed logit model applied to understand factors contributing to generic atorvastatin prescriptions. Results: Market expansion was observed after generic atorvastatin availability with an appreciable increase in number of newly treated patients, whereas substitution effect was found among previously treated patients. Newly treated patients tended to get significantly lower daily doses (p < 0.0001). According to the mixed logistic analysis, newly treated patients were more likely to be prescribed generic atorvastatin (OR = 2.58; 95 % CI, 2.05-3.26) than their counterparts. Clinicians and secondary hospitals were also key drivers of generic atorvastatin (ORs were 10.41 and 9.81, respectively). Conclusions: Newly marketed generic statins in Korea resulted in an expanding market by substantially increasing the number of new patients with clinics and hospitals appreciably using newly marketed generics. However lower doses of statins were prescribed. Policy makers do recognize that generic availability can save costs so should be encouraged. However, this is a concern when generic availability appreciably expands the market, potentially increasing the financial burden. This needs to be addressed. Additionally in Korea, the quality of prescribing should be monitored, especially focusing on clinics and secondary hospitals.
    Preview · Article · Dec 2016 · BMC Health Services Research
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    • "According to meta-analysis that evaluated many articles for clinical equivalence in cardiovascular therapies, it has been reported that there was an equivalence among all cardiovascular therapies except for thiazides. It has been found that one out of 12 products was not equivalent, and two out of 7 products of calcium channel blockers were not equivalent in clinical response [1]. On the other hand, there is evidence that shows even with generic products having the same active ingredient; there are differences in their therapeutic outcome. "
    Full-text · Article · Mar 2016
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    • "Addressing this would help to improve understanding and provide clarity to healthcare professionals (whose opinions may be negatively affected by conflicting and confusing information), and may, in turn, help to increase trust and confidence in generic medicines within this cohort. A considerable amount of research in the area of equivalence of generic medicines has shown that generics can be used safely with no negative clinical impact2324252627 92] . However, some discrepancies remain between patient and professional experiences and the stated equivalence by regulators [43] . "
    [Show abstract] [Hide abstract] ABSTRACT: Considerable emphasis is presently being placed on usage of generic medicines by governments focussed on the potential economic benefits associated with their use. Concurrently, there is increasing discussion in the lay media of perceived doubts regarding the quality and equivalence of generic medicines. The objective of this paper is to report the outcomes of a systematic search for peer-reviewed, published studies that focus on physician, pharmacist and patient/consumer perspectives of generic medicines. Literature published between January 2003 and November 2014, which is indexed in PubMed and Scopus, on the topic of opinions of physicians, pharmacists and patients with respect to generic medicines was searched, and articles within the scope of this review were appraised. Search keywords used included perception, opinion, attitude and view, along with keywords specific to each cohort. Following review of titles and abstracts to identify publications relevant to the scope, 16 papers on physician opinions, 11 papers on pharmacist opinions and 31 papers on patient/consumer opinions were included in this review. Quantitative studies (n = 37) were the most common approach adopted by researchers, generally in the form of self-administered questionnaires/surveys. Qualitative methodologies (n = 15) were also reported, albeit in fewer cases. In all three cohorts, opinions of generic medicines have improved but some mistrust remains, most particularly in the patient group where there appears to be a strongly held belief that less expensive equals lower quality. Acceptance of generics appears to be higher in consumers with higher levels of education while patients from lower socioeconomic demographic groups, hence generally having lower levels of education, tend to have greater mistrust of generics. A key factor in improving confidence in generic products is the provision of information and education, particularly in the areas of equivalency, regulation and dispelling myths about generic medicines (such as the belief that they are counterfeits). Further, as patient trust in their physician often overrules their personal mistrust of generic medicines, enhancing the opinions of physicians regarding generics may have particular importance in strategies to promote usage and acceptance of generic medicines in the future.
    Full-text · Article · Jul 2015 · BMC Medicine
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