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Assessing bioequivalence of generic antiepilepsy drugs.

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ORIGINAL ARTICLE
Assessing Bioequivalence of Generic
Antiepilepsy Drugs
Gregory L. Krauss, MD,1 Brian Caffo, PhD,2 Yi-Ting Chang, MS,2
Craig W. Hendrix, MD,3 and Kelly Chuang1
Objective: Patients with epilepsy are often concerned that switching between brand-name and generic formulations
of antiepilepsy drugs (AEDs) may cause clinically significant changes in plasma drug concentrations. We assessed
bioequivalence (BE) studies for approved generic AEDs to evaluate US Food and Drug Administration claims that: (1)
generic AEDs are accurate copies of reference formulations; (2) delivery of reference formulations may be as variable
as generic AEDs and so provide no increased benefit; and (3) switches between generic AED formulations are safe
and effective.
Methods: We determined differences in 90% confidence interval limits for total drug exposure (AUC0-t) and peak
concentration (Cmax) ratios of generic and reference formulations during fasting and fed BE studies. We simulated
BE between generic formulations after adjusting for reference values.
Results: AUC0-t values of approved reference and generic formulations differed by <15% in 99% of BE studies;
Cmax differed by <15% in 89% of studies. Food affected variability of Cmax but not AUC0-t. Intersubject variability
in Cmax and AUC0-t was small and similar for reference and generic products. In simulated switches between 595
pairs of generic AED formulations, estimated AUC0-t differed by >15% for 17% of pairs; estimated Cmax differed by
>15% for 39%. AEDs with low bioavailability and solubility (eg, oxcarbazepine) had the greatest variability in BE.
Interpretation: Most generic AED products provide total drug delivery (AUC) similar to reference products;
differences in peak concentrations between formulations are more common. Switches between generic AED
products may cause greater changes in plasma drug concentrations than generic substitutions of reference products.
ANN NEUROL 2011;70:221–228
T
he Abbreviated New Drug Application (ANDA) process permits relatively inexpensive generic drug formulations to be marketed if they provide plasma concentrations similar to corresponding reference (brand-name)
formulations. This is established in small bioequivalence
(BE) studies—single-dose crossover studies in healthy
subjects comparing peak concentrations (Cmax) and total
drug exposure (concentration measured over time: AUC)
during treatment with either reference or generic test formulations.1 For generic drug approval, the distributions
of ratios of Cmax and AUC for reference to test formulations must be between 0.80 and 1.25 (defined by upper
and lower 90% confidence interval [CI]). More than 150
generic antiepilepsy drug (AED) formulations have been
approved through the ANDA process in the past several
years, reducing the cost per quarter (2008–2009) in the
United States for AEDs to treat epilepsy from approxi-
mately $800 million to $400 million.2 Some neurologists
and patients, however, report that conversion to generic
formulations is occasionally associated with seizures or
side effects and question the reliability of small BE studies.3–10 Consequently, it is important to determine how
accurately generic AEDs copy reference brand-name formulations.11 Furthermore, although generic-generic
switches are common, current regulations do not require
generic-to-generic BE comparisons, and there are few
data showing how similar generics are to each other.
We examined the accuracy of generic AED copies
in BE studies and evaluated several key issues: (1) Are
ratios of drug concentrations for generic and reference
AED formulations nearly identical (geometric mean
ratios [GMRs] for Cmax and AUC near 1.0 with distributions defined by upper and lower 90% CI limits) for
most subjects in the single-dose crossover BE studies, or
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22452
Received Nov 3, 2010, and in revised form Mar 22, 2011. Accepted for publication Apr 1, 2011.
Address correspondence to Dr Krauss, Meyer 2-147, 600 N. Wolfe St., Baltimore, MD 21287. E-mail: gkrauss@jhmi.edu
From the 1Department of Neurology, Johns Hopkins University; 2Johns Hopkins Bloomberg School of Public Health; and 3Department of Medicine (Clinical
Pharmacology), Johns Hopkins University, Baltimore, MD.
Additional Supporting Information can be found in the online version of this article.
C 2011 American Neurological Association
V
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do many generic formulations provide concentrations
near US Food and Drug Administration (FDA) 0.80 to
1.25 BE acceptance limits?12 (2) The FDA supports
generic drug use by noting that reference formulations
may provide no more uniform drug delivery than
approved generic formulations.13 We determined whether
variability in drug delivery was comparable in groups
receiving doses of reference and generic AED formulations in the BE studies. (3) Switches between generic
products are not currently limited in US pharmacies and
yet could potentially produce much larger shifts in drug
concentration than generic substitutions for reference
products.14 We used BE data from individual generic
products to model switches between >500 potential pairs
of generic AED formulations and estimated whether
generic-to-generic switches could produce shifts in drug
concentrations outside FDA acceptance ranges.
Patients and Methods
Bioequivalence Study Data
The FDA Center for Drug Evaluation and Research, Office of
Generic Drugs provided average bioequivalence and demographic data for approved generic AED formulations following
submission of Freedom of Information Act data requests. Separate fasting and fed BE studies were performed for most generic
formulations. Key data for test and reference formulations were
the GMRs and their 90% CIs for Cmax and for the area under
the plasma concentration time curve (AUC) calculated to the
last measured concentration (AUC0-t), and extrapolated to infinity (AUC0-inf ). The arithmetic means, associated coefficient
of variation, and within-subject variability for AUC0-t, Cmax,
and Tmax were tabulated. Demographic data assessed were: age
(mean and range), gender, ethnicity, and height and weight
(mean and range). Extended phenytoin and extended-release
carbamazepine formulations were not studied, because special
BE assessments are required to evaluate slow-release drug delivery technology. Limited demographic data were available for
several BE approval packets for older generic AEDs, particularly
carbamazepine, on which fed BE studies were not performed
prior to 2003.
Analysis of AUC and Cmax Ratios for Generic
and Reference AEDs
We indexed the variability of AUC and Cmax GMRs as the
maximum of the upper or lower 90% CI limit subtracted from
1.00, with absolute values and percentages displayed. For example, a BE study with upper and lower 90% CI limits for
AUC0-t GMR of 0.87 and 1.05 had a maximum deviation
(from 1.00) of 13%. These differences in AUC and Cmax were
tabulated by AEDs and doses for all studies in 5% bands (ie,
number of BE studies in which the differences were 0–5%;
>5% to 10%, etc). We also determined the number and proportions of generic and reference AED products for which the
90% CI of the AUC and Cmax GMRs did not include 1.00
222
(ie, the Cmax and AUC ratios met BE standards but differed
between reference and test formulations). These methods were
also used to compare results of fasting and fed BE studies to
assess food effects; fed and fasting BE studies were performed
on different populations.
Analysis of Variability of AUC and Cmax for
Generic and Reference Formulations
We determined intersubject standard deviations for AUC0-t and
Cmax for generic and reference products for each BE study. We
then compared standard deviations between generic and reference products and screened for major (>50%) differences in
standard deviations between generic and reference formulations.
Estimating AUC and Cmax with Switches
between Generic AED Formulations
We compared log relative pharmacokinetic (PK) measurements
of paired generic to reference formulations. Specifically, we
took the difference in the log ratio of the AUCs of generics to
the reference across generics, and repeated this exercise for
Cmax. To account for variation, we estimated changes via 90%
CIs for AUC and Cmax for switches between pairs of generic
AEDs tested at the same doses. GMRs of AUC and Cmax to
the reference formulation were compared across generics to normalize for study-specific variation. Because of the lack of individual data, standard errors for interstudy comparisons were calculated from CIs for the test to reference comparisons. For
example, if Lratio1 6 1.28 SE1 and Lratio2 6 1.28 SE2 are
90% test versus reference intervals on the natural log scale for
generics 1 and 2, our interval considered the exponentiated
endpoints of
Lratio2 Lratio161:28ðSE12 þ SE22 Þ1=2
The 90% CIs for AUC0-t and Cmax ratios for each pair
of generic AED formulations were determined and tabulated as
proportions of AED generic pairs in 5% bands for each AED.
To consider the possibility of spurious associations due to multiple comparisons, we conducted a brief simulation study, which
simulated log ratios from a normal distribution with variances
given by those in the study, and replicated the analysis. This
process was repeated 1,000.
Results
Subjects
A total of 141 generic AED products were evaluated in
258 BE studies. Demographic data were available for
251 studies enrolling 7,125 subjects. Subjects were predominantly male (78.7%), with a mean age of 31.9 years
(range, 19.6–82). No children (<18 years) were studied
and only 44 subjects (0.71%) were elderly (>65 years).
Ethnicities reflected locations of study sites and were:
Caucasian, 54.4%; Asian, 25.8%; black, 9.7%; Hispanic,
3.1%. Subject demographic factors were unequally distributed in many studies: 42.1% enrolled male subjects
Volume 70, No. 2
Krauss et al: Drug Bioequivalence
FIGURE 1: Differences in 90% confidence intervals for limits of total drug exposure (AUC0-t) geometric mean ratios for generic
and reference antiepilepsy drug (AED) formulations classified in 5% increments. Proportions of fasting and fed bioequivalence
(BE) study results are shown on the vertical axis. Nearly all AUC0-t values differ by <15%. AED abbreviations: CBZ 5 carbamazepine; VPA 5 divalproex; GBP 5 gabapentin; LTG 5 lamotrigine; LEV 5 levetiracetam; OXC 5 oxcarbazepine; TOP 5 topiramate; ZON 5 zonisamide.
only, 20.9% enrolled Asian subjects only, and 6.8% enrolled Caucasian subjects only.
Bioequivalence of Generic and Reference
Formulation AEDs
Total drug delivery (AUC0-t) for generic and reference
AED formulations was very similar: AUC0-t differed by
<15% for 255 of 258 (98.8%) BE studies.* In only 1
study (divalproex under a fasting condition) did the width
of the 90% CI exceed 15% (2 1-sided tests procedure).
Furthermore, 83.7% and 42.6% of studies differed by
<10% and <5%, respectively (Fig 1). Although AUC0-t
met BE standards, in 45 (18.6%) of BE studies, the 90%
CIs of the GMRs did not overlap (Supporting Information
Fig 1). Similar numbers of generic formulations were associated with small increases and decreases in AUC0-t compared
to reference formulations; these small differences were distributed across most of the tested AEDs and doses.
Peak drug concentrations (Cmax) differed more
between generic and reference formulations than AUC0-t
(Fig 2). In 28 BE studies (10.85%), the ratios of generic
and reference product Cmax differed by 15 to 25%. The
90% CIs for the Cmax GMRs for generic and reference
formulations did not overlap for 26% of generic formulations (see Supporting Information Fig 1).
*Percent differences in AUC and Cmax between generic and reference
products, between fasting and fed states and between generic product
pairs are determined as the maximum (upper or lower) limits of the
90% CI for the ratios of AUC and Cmax.
August 2011
Fasting versus Fed BE Studies
Both fasting and fed studies were performed for 111 AED
formulations. The GMRs for AUC0-t differed between fasting and fed states by <15% for 110 (91.8%) formulations
and by 15 to 25% for 9 (8.2%) formulations (Supporting
Information Table). For 4 (3.6%) of the 111 formulations,
the 90% CIs for the test/reference GMRs for AUC0-t did
not overlap when fasting and fed values were compared.
The test/reference GMRs for Cmax differed by 15 to 25%
between fasting and fed studies for 29 of 111 BE studies
(26%). The 90% CIs for Cmax GMRs, however, were generally wider than for AUC, reflecting the fact that Cmax
tends to be more variable than AUC. Consequently, the
90% CIs for the test/reference Cmax GMR ratios in the
fasting versus fed BE studies overlapped for 103 (92.3%) of
the 111 formulations. Cmax for 7 of 12 (58%) oxcarbazepine BE studies differed by 15 to 25% between fasting and
fed studies, a higher proportion than for other AEDs.
Gabapentin and divalproex also had slightly greater proportions of BE studies in which Cmax varied by 15 to 25%
compared to other AEDs.
Variability in PK Values for Reference
Compared to Generic AED Formulations
Variability in the distribution of AUC0-t for reference
and generic formulations in BE studies was very similar;
standard deviations differed markedly (>50%) between
reference and generic formulations for <1% (2 of 281) of
fasting and fed BE studies (Supporting Information Fig 2).
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FIGURE 2: Differences in 90% confidence intervals for peak concentration (Cmax) geometric mean ratios for generic and reference antiepilepsy drug (AED) formulations classified in 5% increments. Proportions of fasting and fed bioequivalence (BE)
study results are shown on the vertical axis. AED abbreviations: CBZ 5 carbamazepine; VPA 5 divalproex; GBP 5 gabapentin;
LTG 5 lamotrigine; LEV 5 levetiracetam; OXC 5 oxcarbazepine; TOP 5 topiramate; ZON 5 zonisamide.
Both of these BE studies were of generic formulations with
large variability in AUC0-t compared to reference formulations. Standard deviations (SD) for Cmax varied more than
for AUC; however, these varied markedly (>50%) between
only 4% (11 of 281) of generic and reference formulations
(2 reference formulations had higher SD; 9 generic formulations had higher SD) (Fig 3). This variability is similar to
standard benchmarks of variances and therefore is consistent
with the possibility of statistical equality.
Estimates of Effects of Generic-to-Generic
Formulation Switches
There were 595 potential pairs of generic AED products
tested at the same doses; 496 (83.4%) had an estimated
AUC0-t that differed by <15%, whereas 85 (14.3%) differed by 15 to 25%, and 14 (2.35%) differed by >25%
(Fig 4). AUC0-t for a large proportion (6 of 21) of pairs
of generic oxcarbazepine formulations differed by 25 to
30%. Pairs of generic formulations differed more in estimated Cmax than in AUC; 364 (61.2%) of generic pairs
had Cmax that differed by 0 to 15%, 209 (35.1%) differed by 15 to 25%, and 22 (3.7%) differed by >25%
(Fig 5). In a simulation study performed using variation
from comparisons of generics under specific dose conditions, the number of studies of anticipated spurious
results for AUC0-t and Cmax varied substantially by
drug/dose group. The study estimates that the probability
of seeing 14 or more changes of >25% in AUC0-t when
repeatedly simulating 595 comparisons was 51%. The
224
probability of seeing 25 or more changes of >25% in
Cmax in a similar simulation was 56%. That is, the
number of large (>25%) changes seen in the observed
data is not unexpected from a study with actual equivalence between all comparisons.
Discussion
Although BE studies are designed to evaluate whether
generic formulations meet ANDA standards, the small,
blinded crossover studies can also provide information
about how closely generic AEDs copy brand-name products. AUC values for generic and reference formulations
were very similar in nearly all BE studies; mean AUC0-t
values differed by <10% between generic and reference
products in 83% of BE studies and differed by >15% in
only 1 study. By contrast, mean Cmax values differed
between generic and reference products by 15 to 25% in
11% of studies. These findings are consistent with clinical series reporting that small subgroups of patients do
not tolerate conversion to generic formulations, most
commonly due to central nervous system (CNS)-related
side effects (eg, dizziness, drowsiness, imbalance, and
diplopia)3–5 and occasionally due to seizures.7 Many
patients in these clinical series were treated with relatively
high doses of AEDs and appeared to be near tolerability
thresholds, although some appeared sensitive to relatively
small (eg, 10%) changes in AED concentrations.3
The main effect of food on AED absorption overall
was to increase the variability of Cmax for both generic
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Krauss et al: Drug Bioequivalence
FIGURE 3: A comparison of standard deviations of peak concentration (Cmax) for generic (test) and reference antiepilepsy
drug (AED) formulations in bioequivalence (BE) studies. The standard deviations (presented in log scales) for the mean Cmax
for generic (test) and reference formulations are very similar across 8 AEDs. The symbols represent standard deviations of
Cmax for matched generic and reference formulations in the crossover BE studies.
and reference formulations. This variability resulted in
broad CIs in BE studies, which dominated specific patterns of food effects across generic and reference drugs.
Oxcarbazepine, probably due to low solubility, was
particularly variable; parent oxcarbazepine and its
10-monohydroxy metabolite met BE standards, but
Cmax and AUC ratios for the parent compound were
near acceptance limits. The FDA notes that that reference
formulations (including drugs with ‘‘narrow therapeutic
indices’’) may have variable absorption and offer no more
stable or uniform delivery than do generic formulations.13,15
Our analysis of BE studies generally supports this position;
only a small number of generic formulations had large
standard deviations in AUC or Cmax compared to reference drugs. Moreover, the overall variability in PK values
(Cmax and AUC) across subjects for most of the BE studies was <30%. Together, these findings suggest that most
patients could initiate therapy with either generic or reference AED formulations and achieve comparable AED concentrations. Repeated dosing with reference and generic
formulations in 4-way individual BE studies would be
needed to see whether reference drugs provide the same or
decreased intrasubject variability compared to generics.
A number of drugs, including AEDs, have recently
been categorized by their solubility and permeability into
the Biopharmaceutics Classification System (BCS).16 Some
newer AEDs are BCS I drugs that are highly soluble and
permeable, and dissolve rapidly (eg, levetiracetam and lamoAugust 2011
trigine). Several AEDs are BCS II drugs, which are poorly
soluble, but highly permeable (oxcarbazepine, carbamazepine, phenytoin); gabapentin is BCS III (highly soluble and
rapidly dissolving with poor permeability). Absorption for
BCS I AEDs was generally more uniform (ie, narrowed
90% CI and point estimates near 1.00) compared to
BCSII/III drugs in the BE studies. This supports the possibility that BE standards might best be scaled according to
solubility and dissolution characteristics of AEDs.17
Due to the large number of possible generic-togeneric formulation switches (n ¼ 595) and differences
in their PK distributions, we modeled differences in
AUC and Cmax, which could occur upon generic-togeneric switches. In our model, 17% of generic product
switches were estimated to produce differences of >15%
in estimated AUC, whereas 39% of generic pair switches
had >15% differences in estimated Cmax (based on the
maximum of the upper and lower 90% CI). These estimates require confirmation but nonetheless suggest that
some generic-to-generic product switches could potentially produce larger differences in PK than reference-togeneric product substitutions.
Although this study confirms equivalent total exposure of generics relative to reference formulations and
demonstrates potential novel findings on generic-togeneric switches, the analysis had several methodological
limitations. First, no subject-level information was available to refine the BE study analyses. There was also no
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FIGURE 4: Estimated differences in limits of total drug exposure (AUC0-t) between 595 pairs of generic antiepilepsy drug
(AED) formulations: maximum limits of 90% confidence intervals (upper limit 2 100%, 100% 2 lower limit) for AUC ratios
are plotted for 8 AEDs by doses. AUC0-t is estimated to differ
by >15% between many pairs of the same doses of generic
AED formulations. AED abbreviations: CBZ 5 carbamazepine;
VPA 5 divalproex; GBP 5 gabapentin; LTG 5 lamotrigine; LEV
5 levetiracetam; OXC 5 oxcarbazepine; TOP 5 topiramate;
ZON 5 zonisamide. [Color figure can be viewed in the online
issue, which is available at annalsofneurology.org.]
number of patients in the large epilepsy treatment population are likely to experience greater shifts.
This is consistent with larger clinical series identifying small subgroups of patients who do not tolerate or
develop seizures with generic conversion. In a Canadian
survey, 10% of patients with epilepsy switched back from
generic to reference lamotrigine due to unspecified clinical problems,19 a proportion much higher than the 2%
switchback for other common drug classes. Another
study found that a large proportion of patients seen in
an emergency department for seizures or drug toxicity
had recently been switched to generic AED formulations.5,20 The FDA, however, emphasizes that no large
objective studies have demonstrated increased seizures or
side effects with generic switches.15,21 It cites 2 small,
blinded crossover studies that showed no significant
increase in seizures or side effects in patients treated with
several different carbamazepine formulations (though carbamazepine concentrations varied up to 40% for individual patients).22,23 A more recent study, however, showed
that conversion to generic carbamazepine formulations
caused both side effects and increases in Cmax in some
patients.24 A recent pilot study verified that some
patients with seizures or side effects during conversion to
generic lamotrigine have concentration changes that are
outside the BE limits.25
crossover information between generics, as generic-togeneric switches were not part of any study. Consequently,
all information is compared across study populations, and
generic-to-generic formulation comparisons and fasting-fed
comparisons may be influenced by differences in study populations and in manufacturing pill lots. Our comparison of
generic formulations potentially accounts for this source of
bias by adjusting for relative absorption rates of reference
drugs; however, this correction depends heavily on log-linearity assumptions and adds substantial variability to the
analysis. Our simulation study also suggests caution in overinterpreting results, as many spurious associations are likely
when studying so many possible generic combinations.
BE studies are not clinical efficacy or safety studies
and cannot be used to evaluate whether changes in AED
concentrations might be associated with side effects or
seizures in individual patients. The FDA, however,
describes approved generic formulations as being ‘‘bioequivalent’’ and ‘‘therapeutically equivalent’’ to brand
name drugs, and BE studies are the current standard for
approving generic formulations.18 Drug concentration
ratios differed significantly between many generic and
reference formulations (with nonoverlapping CIs) despite
meeting BE standards, suggesting that many patients are
likely to have small to moderate (5–15%) changes in
drug concentrations with generic conversion; a small
FIGURE 5: Estimated differences in peak concentration
(Cmax) between 595 pairs of generic antiepilepsy drug (AED)
formulations: maximum limits of 90% confidence intervals
(upper limit 2 100%, 100% 2 lower limit) for ratios of Cmax
are plotted for 8 AEDs by doses. Cmax is estimated to differ
by >20% between many pairs of the same doses of generic
AED formulations. AED abbreviations: CBZ 5 carbamazepine;
VPA 5 divalproex; GBP 5 gabapentin; LTG 5 lamotrigine; LEV
5 levetiracetam; OXC 5 oxcarbazepine; TOP 5 topiramate;
ZON 5 zonisamide. [Color figure can be viewed in the online
issue, which is available at annalsofneurology.org.]
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Krauss et al: Drug Bioequivalence
Partially due to limited safety data regarding generic
drug conversion, there has been a good deal of caution
and controversy regarding the use of AED generic products; neurology societies recommend physicians be permitted to continue brand-name medications for individual patients, for example, for patients requiring high
AED doses with plasma concentrations near tolerability
thresholds, for patients sensitive to CNS-related side
effects of AEDs, and for patients whose seizures were initially difficult to control.26–28 BE studies are also
criticized for not evaluating AED absorption in young or
elderly subjects and in patients receiving polytherapy.1,29
In the absence of gastric disorders, there has been no
clear evidence, however, that absorption of AEDs varies
in special populations.16 The limited number of objective
studies and publications on generic AEDs may be related
to differing marketing and advocacy positions of drug
manufacturers, regulators, and clinical groups.
Finally, although our simulations suggesting that
switches between generics could potentially be associated
with greater changes in AED concentrations than reference-to-generic switches, this possibility should be
explored further in clinical PK studies. It is not market
practice to maintain patients on single generic formulations, and such studies could help interpret findings,
such as those of a recent survey showing increased seizures and injuries in patients switched between multiple
generic topiramate formulations.30 In Denmark, AEDs
other than benzodiazepines are designated as ‘‘narrow
therapeutic index’’ drugs, and generic formulations must
meet a 90 to 111% BE acceptance standard.31 This
standard would have been met for AUC0-t by 81.4% of
BE studies in our analysis and for Cmax by 63.6% of
studies. The FDA’s Pharmaceutical Sciences Advisory
Committee discussed designating ‘‘Critical Dose’’ drugs
that must meet this narrower standard for AUC0-t.32
This and other approaches to improve bioavailability,
such as maintaining stable AED concentrations using
slow-release formulations for BCS II drugs, require additional evaluation.33,34
vision of Bioequivalence II, Office of Generic Drugs,
CDER at the FDA for assisting with data collection.
Authorship
Statistical analysis was performed by B.C. and Y.-T.C.
Potential Conflicts of Interest
G.L.K.: consultancy, UCB Pharma, Eisai Laboratories;
expert testimony, Rischmiller and Knippel; grants/grants
pending, UCB Pharma, Eisai Laboratories, Icagen Pharmaceuticals, Epilepsy Research Foundation, Epilepsy Study
Consortium, National Institute of Neurological Disorders
and Stroke, Sepracor; speaking fees, German League
against Epilepsy. Y.-T.C.: fees for participation in review
activities, Johns Hopkins Biostatistics Center. C.W.H.:
grants/grants pending, Gilead.
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Acknowledgment
The project described was partially supported by grant
number UL1 RR 025005 from the National Center for
Research Resources (NCRR), a component of the NIH
and NIH Roadmap for Medical Research. Its contents
are solely the responsibility of the authors and do not
necessarily represent the official view of NCRR or NIH.
Dr S. Wright collected the BE study data.
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