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A Vaccine to Prevent Herpes Zoster and Postherpetic M.N. Oxman, M.D., M.J. Levin, M.D., G.R. Johnson, M.S., K.E. Schmader, M.D., S.E. Straus, M.D., L.D. Gelb, M.D., R.D. Arbeit, M.D., M.S. Simberkoff, M.D., A.A. Gershon, M.D., L.E. Davis, M.D., A. Weinberg, M.D., K.D. Boardman, R.Ph., H.M. Williams, R.N., M.S.N., J. Hongyuan Zhang, Ph.D., P.N. Peduzzi, Ph.D., C.E. Beisel, Ph.D., V.A. Morrison, M.D., J.C. Guatelli, M.D., P.A. Brooks, M.D., C.A. Kauffman, M.D., C.T. Pachucki, M.D., K.M. Neuzil, M.D., M.P.H., R.F. Betts, M.D., P.F. Wright, M.D., M.R. Griffin, M.D., M.P.H., P. Brunell, M.D., N.E. Soto, M.D., A.R. Marques, M.D., S.K. Keay, M.D., Ph.D., R.P. Goodman, M.D., D.J. Cotton, M.D., M.P.H., J.W. Gnann, Jr., M.D., J. Loutit, M.D., M. Holodniy, M.D., W.A. Keitel, M.D., G.E. Crawford, M.D., S.-S. Yeh, M.D., Ph.D., Z. Lobo, M.D., J.F. Toney, M.D., R.N. Greenberg, M.D., P.M. Keller, Ph.D., R. Harbecke, Ph.D., A.R. Hayward, M.D., Ph.D., M.R. Irwin, M.D., T.C. Kyriakides, Ph.D., C.Y. Chan, M.D., I.S.F. Chan, Ph.D., W.W.B. Wang, Ph.D., P.W. Annunziato, M.D., and J.L. Silber, M.D., for the Shingles Prevention Study Group* b a c k g r o u n d
The incidence and severity of herpes zoster and postherpetic neuralgia increase with The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr.
age in association with a progressive decline in cell-mediated immunity to varicella– Oxman at the Shingles Prevention Study zoster virus (VZV). We tested the hypothesis that vaccination against VZV would de- (Mail code 111F-1), VA San Diego Health-crease the incidence, severity, or both of herpes zoster and postherpetic neuralgia care System, 3350 La Jolla Village Dr., San Diego, CA 92161, or at mnoxman@ucsd.
*Other members of the Shingles Prevention We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, Study Group are listed in the Appendix.
placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine (“zoster vaccine”). Herpes zoster was diagnosed according to clinical and laboratory Copyright 2005 Massachusetts Medical Society. criteria. The pain and discomfort associated with herpes zoster were measured repeat-edly for six months. The primary end point was the burden of illness due to herpeszoster, a measure affected by the incidence, severity, and duration of the associated painand discomfort. The secondary end point was the incidence of postherpetic neuralgia.
More than 95 percent of the subjects continued in the study to its completion, with amedian of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases ofherpes zoster (315 among vaccine recipients and 642 among placebo recipients) and107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among place-bo recipients) were included in the efficacy analysis. The use of the zoster vaccine re-duced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced theincidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the inci-dence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site weremore frequent among vaccine recipients but were generally mild.
c o n c l u s i o n s
The zoster vaccine markedly reduced morbidity from herpes zoster and postherpeticneuralgia among older adults.
Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine gles Prevention Study (Department of Veterans characterized by unilateral radicular pain Affairs [VA] Cooperative Study No. 403) was con- hand a vesicular rash that is generally lim- ducted to determine whether vaccination with a live ited to a single dermatome.1,2 Herpes zoster results attenuated VZV vaccine would decrease the inci-from reactivation of latent varicella–zoster virus dence, severity, or both of herpes zoster and post-(VZV) within the sensory ganglia.3,4 The incidence herpetic neuralgia in adults 60 years of age or older.
and severity of herpes zoster increase with advanc-ing age; more than half of all persons in whom her- pes zoster develops are older than 60 years. Compli-
cations occur in almost 50 percent of older persons A detailed description of the methods used in this
with herpes zoster.3-5 The most frequent debilitat- study is provided in the Supplementary Appendix
ing complication is postherpetic neuralgia, a neuro- (available with the full text of this article at www.
pathic pain syndrome that persists or develops after nejm.org). A brief overview is presented here.
the dermatomal rash has healed.5-9 The frequency
and severity of postherpetic neuralgia also increase study design
with increasing age.9-11 The pain and discomfort as- We conducted a randomized, placebo-controlled,
sociated with herpes zoster can be prolonged and double-blind clinical trial at 22 sites, in which adults
disabling, diminishing the patient’s quality of life 60 years of age or older received either VZV vaccine
and ability to function to a degree comparable to that or placebo. The study was approved by a human
in diseases such as congestive heart failure, myocar- rights committee of the VA Cooperative Studies Pro-
dial infarction, diabetes mellitus type 2, and major gram (VACSP) and by the local institutional review
depression.12 Antiviral therapy reduces the severity boards at all study sites. An independent data and
and duration of herpes zoster but does not prevent safety monitoring board reviewed the safety data
the development of postherpetic neuralgia.2,11 and the interim results.
Postherpetic neuralgia may persist for years and is
often refractory to treatment.13
s t u d y p o p u l a t i o n
Forty years ago, Hope-Simpson proposed that Eligible subjects had a history of varicella or had re- immunity to VZV plays a pivotal role in the patho- sided in the continental United States for at least 30
genesis of herpes zoster,3 and subsequent observa- years. Immunocompromised persons and those
tions support the thesis that cell-mediated immu- unable to adhere to the study protocol were ex-
nity to VZV is a major determinant of the risk and cluded. All subjects provided written informed
severity of herpes zoster.3,7,11,14-17 Whereas levels consent.
of antibody to VZV remain relatively constant with
increasing age, the increased incidence and sever- intervention
ity of herpes zoster and postherpetic neuralgia Subjects received one subcutaneous injection of 0.5
among older adults are closely linked to a progres- ml of the investigational live attenuated Oka/Merck
sive age-related decline in cell-mediated immunity VZV vaccine (“zoster vaccine”) or placebo. The esti-
to VZV.4-8,14-21 Recurrences of herpes zoster are un- mated potency at vaccination of the 12 vaccine lots
common among immunocompetent persons, pre- used in the study ranged from 18,700 to 60,000
sumably because an episode of herpes zoster boosts plaque-forming units per dose. The median poten-
immunity to VZV, effectively “immunizing” against cy was 24,600 plaque-forming units, and more than
a subsequent episode.3,4,7,8,22
90 percent of vaccinated subjects received 32,300 Previous studies have shown that VZV vaccines plaque-forming units or less.
can elicit a significant increase in cell-mediated
immunity to VZV in immunocompetent older follow-up
adults21-25 and reduce the incidence and severity of Active follow-up and ascertainment of cases of
herpes zoster in recipients of bone marrow al-
herpes zoster were ensured by an interactive auto- lografts.26,27 These observations led us to hypothe- mated telephone-response system, which subjectssize that immunization of older persons with a VZV called monthly. If a subject’s responses to a stan-vaccine would boost their cell-mediated immunity dardized set of questions suggested a possible caseto VZV and thereby provide protection against her- of herpes zoster, the subject was instructed to con-pes zoster and postherpetic neuralgia.22 The Shin- tact the local study site immediately, and a fax con- Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. e f f i c a c y o f a v a r i c e l l a – z o s t e r v i r u s v a c c i n e taining the subject’s response was sent to the site. tool in the form of a questionnaire completed bySubjects who did not call the automated tele- the subject that was specifically designed to mea-phone-response system within a pre-established sure pain and discomfort in herpes zoster.28 Thislength of time were called by the automated tele- questionnaire and others29,30 were used to assessphone-response system. If this effort to reach the the effect of herpes zoster on the subjects’ activitiessubject failed, the local study site was notified by fax of daily living, quality of life, and general healthto contact the subject directly. At the end of the status. Characteristics of the rash, associatedstudy, subjects were asked to report any previously complications, and medication use were also re-unreported episodes of herpes zoster.
corded. Evaluations based on responses to thequestionnaires were repeated over a period of at s a f e t y e v a l u a t i o n
least 182 days, according to a schedule specified by All adverse events occurring within 42 days after the study protocol. Digital photographs and speci-
vaccination were recorded. Thereafter, only serious mens for laboratory diagnosis were obtained from
adverse events were recorded if reported by the sub- subjects with suspected cases of herpes zoster.
ject and considered by the study physician to be re-
lated to the vaccination. Deaths were identified on confirmation of cases
the basis of reports from family members and dur- Before unblinding, each suspected case of herpes
ing follow-up of missed monthly calls to the auto- zoster was classified as a confirmed case of herpes
mated telephone-response system.
zoster or as not a confirmed case with the use of a Approximately 300 subjects at each of the study hierarchical algorithm that incorporated the results sites were enrolled in a substudy that more closely of the polymerase-chain-reaction (PCR) assay per-monitored adverse events. These subjects main- formed at the central laboratory of the study, virustained a daily log of body temperature and a “report culture at the local virology laboratory, and the finalcard” of symptoms related to the injection site and clinical diagnosis of the study’s clinical evaluationother clinical symptoms during the 42 days after committee, consisting of five physicians with ex-vaccination. Thereafter, they were followed to iden- pertise in herpes zoster.
tify all hospitalizations.
The PCR assay, designed to detect and discrimi- nate among DNA from wild-type and vaccine strains i d e n t i f i c a t i o n a n d e v a l u a t i o n
of VZV and from herpes simplex virus (HSV), could o f s u s p e c t e d c a s e s o f h e r p e s z o s t e r
detect approximately 13 copies of DNA from wild- At enrollment, the subjects were educated with re- type or the vaccine strain of VZV. The PCR assaysgard to the signs and symptoms of herpes zoster. included primers and a probe for the human beta-Those who had a new rash or new unilateral pain globin gene to verify the presence of cellular DNAwere urged to contact their study site immediately. in the specimens from the lesions.
Study personnel attempted to evaluate all subjects If the PCR assay revealed VZV DNA, the suspect- with new rashes as soon as possible. Subjects with ed case of herpes zoster was classified as a con-unilateral rashes and no alternative clinical diag- firmed case; if the assay was positive for beta-globinnoses were classified as having “suspected cases of or HSV DNA and negative for VZV DNA, the caseherpes zoster” and were followed according to the was classified as not a case of herpes zoster. If thestudy protocol. The evaluating physician offered specimen obtained for the assay was inadequatesubjects with clinically diagnosed herpes zoster, (i.e., was negative for both viral and beta-globinwithout cost, the licensed antiviral drug famciclovir DNA) or was missing, the final diagnosis was de-(Famvir, SmithKline Beecham and Novartis Phar- termined by the isolation of VZV or HSV in the localmaceuticals), in accordance with the manufactur- virology laboratory. In the absence of a valid labo-er’s recommendations, and with standard-of-care ratory diagnosis, the case was classified on the ba-treatment for pain. Pain management was not spec- sis of the clinical diagnosis by the clinical evaluationified by the study protocol.
Herpes zoster–associated pain (including un- pleasant sensations such as allodynia and pruritus, efficacy end points
which are not always characterized as pain by per- The primary end point was the burden of illness
sons with herpes zoster) was measured with the use due to herpes zoster, a severity-by-duration measure
of the Zoster Brief Pain Inventory, an assessment of the total pain and discomfort associated with her-
Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine pes zoster in the population of study subjects.28,31,32 Vaccine efficacy with respect to the incidence of For each confirmed case of herpes zoster, responses postherpetic neuralgia (VEPHN) was defined as theto the “worst pain” question in the Zoster Brief Pain relative reduction in the incidence of postherpeticInventory were used to calculate a herpes-zoster se- neuralgia in the vaccine group as compared withverity-of-illness score, defined as the area under the that in the placebo group. The prespecified criteriacurve (AUC) of herpes-zoster pain plotted against for the success of the vaccine with respect to the in-time during the 182-day period after the onset of cidence of postherpetic neuralgia required a VEPHNrash. Subjects in whom herpes zoster developed had point estimate of 62 percent or more and a lowerseverity-of-illness scores ranging from 0 to 1813. bound of the 95 percent confidence interval greaterIncreasing mean scores are highly correlated with than 25 percent. The VEPHN was calculated witha decrease in the health-related quality of life and in the use of a conditional exact method weighted forfunctional status among older adults.28,33 A score age group.34-36 The VEPHN was also calculated withof 0 was recorded for subjects in whom herpes the use of alternative definitions of postherpeticzoster did not develop during the study period.
neuralgia as pain present for more than 30, 60, 120, The “herpes-zoster burden-of-illness score” rep- and 182 days after the onset of rash caused by herpes resented the average severity of illness among all zoster. Vaccine efficacy with respect to the incidencesubjects in the vaccine or placebo groups; it was of herpes zoster (VEHZ) was calculated similarly.
calculated as the sum of the herpes-zoster severity- Efficacy analyses were performed with the use of of-illness scores of all members of a group divided a follow-up period that excluded the first 30 days af-
by the total number of subjects in the group. The ter vaccination and excluded subjects who with-
secondary end point was the incidence of posther- drew and those in whom a confirmed case of herpes
petic neuralgia, defined as pain associated with her- zoster developed within the first 30 days after vacci-
pes zoster that was rated as 3 or more on a scale nation. The results were essentially unchanged
ranging from 0 (“no pain”) to 10 (“pain as bad as when subjects in whom herpes zoster developed
you can imagine”), persisting or appearing more during the first 30 days were included. All reported
than 90 days after the onset of rash. Scores lower P values are two-sided.
than 3 were not associated with significant decre-
ments in the quality of life or the ability to carry out conduct of the study
activities of daily living and were therefore not con- The study was designed by the planning and execu-
sidered to represent postherpetic neuralgia.10,28
tive committees of the Shingles Prevention StudyGroup, the members of which were selected for rel- s t a t i s t i c a l a n a l y s i s
evant expertise, with the support of a planning grant A data-analysis plan was completed before the from the VACSP to the study chairs (details aredata were unblinded for analysis.31,34-38 The analy- provided in the Supplementary Appendix). Mercksis was performed by the VACSP coordinating center contributed to the planning process through two(West Haven, Conn.), with review and approval by nonvoting members on these committees. The sta-the executive committee of the study. Vaccine effi- tistical methods for analyzing burden of illness werecacy with respect to the burden of illness due to developed and published by Merck statisticians be-herpes zoster (VE fore the initiation of the study. The study was ini- duction in the burden-of-illness score in the vaccine tiated and implemented as a VA Cooperative Studygroup as compared with that in the placebo group in collaboration with the National Institute of Al-and calculated as 1¡relative risk (i.e., 1¡the herpes- lergy and Infectious Diseases and Merck. Merck, thezoster burden-of-illness score in the vaccine group holder of the investigational new drug application,divided by the herpes-zoster burden-of-illness participated in the organization of oversight activi-score in the placebo group). The prespecified crite- ties and monitored the progress of the study. Theria for the success of the vaccine with respect to the Covalent Group, an independent company, wasburden of illness due to herpes zoster required a hired by Merck to monitor case report forms andVEBOI point estimate of 47 percent or more and a adherence to the study protocol and to report tolower bound of the 95 percent confidence interval Merck and the VACSP. The participating investiga-greater than 25 percent. A method of assessing the tors and their staff gathered the data. An unblindedcombined effect of disease incidence, severity, and statistician at the VACSP coordinating center, whoduration, weighted for age group, was used.31 was not involved in the operation of the study, pre- Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. e f f i c a c y o f a v a r i c e l l a – z o s t e r v i r u s v a c c i n e sented unblinded safety data to the data and safety viously unreported cases of herpes zoster. Of themonitoring board.
1308 suspected cases of herpes zoster, the final di- Management and consolidation of the data agnosis in 1156 cases (88.4 percent; 417 in the vac- were performed by the VACSP coordinating center. cine group and 739 in the placebo group) was basedData-analysis programs were developed and tested on the results of the PCR assay.
by biostatisticians and programmers at the coordi- Of the 1308 suspected cases, 984 (75.2 percent) nating center and at Merck. The data were analyzed were determined to be confirmed cases. In accor-at the coordinating center. The executive committee dance with the protocol, 24 cases were excludedreviewed and approved the data-analysis plan and from the efficacy analyses because they occurredall analyses of vaccine efficacy and safety and within 30 days of vaccination (6 in the vaccine groupvouches for the study’s results. The writing com- and 18 in the placebo group) and 3 because theymittee, all members of which were also members of were a subject’s second episode of herpes zosterthe executive committee, wrote the manuscript and (Fig. 1). The remaining 957 confirmed cases of her-takes responsibility for it.
pes zoster (315 in the vaccine group and 642 in theplacebo group) constituted the end points of the ef-ficacy analyses. The results of PCR testing were pos- itive for wild-type VZV DNA in more than 93 percent c h a r a c t e r i s t i c s o f t h e s t u d y s u b j e c t s
of the confirmed cases of herpes zoster in each A total of 38,546 subjects were enrolled in the study group (Fig. 1). Vaccine virus DNA was not de-study between November 1998 and September 2001 tected in any subjects with suspected herpes zoster.
(Fig. 1). The numbers enrolled at each study site The rate of use of antiviral medication among ranged from 1167 to 2508. Follow-up was complet- subjects with confirmed cases of herpes zoster was
ed in April 2004. The demographic characteristics similar in the two groups (87.3 percent in the vac-
of the two study groups were similar (Table 1). The cine group and 85.7 percent in the placebo group),
median age in both groups was 69 years; 6.6 per- as was the proportion in whom treatment was ini-
cent of the vaccine recipients and 6.9 percent of the tiated within 72 hours of the onset of rash — in
placebo recipients were 80 years of age or older. At 64.1 percent in the vaccine group and 65.9 percent
enrollment, most of the subjects had no health- in the placebo group. The frequency of use of vari-
related limitations on their activities (51.3 percent) ous medications to treat pain resulting from her-
or mild health-related limitations (38.6 percent). pes zoster was similar in the two groups, and the
More than 95 percent of the subjects were actively average duration of the use of opioids and the aver-
followed to the end of the study (Fig. 1) and com- age quantity of opioids used among subjects with
pleted a closeout interview. The mean duration of herpes zoster were greater in the placebo group
herpes zoster surveillance was 3.13 years (median, than in the vaccine group. Thus, differences in the
3.12 years; range, 1 day to 4.90 years) with no dif- use of pain medication did not inflate the estimates
ference in duration between the groups. Only 0.6 of VEBOI or VEPHN.
percent of the subjects withdrew from the study or
were lost to follow-up; 4.1 percent died during the burden of illness due to herpes zoster
study.
The herpes-zoster burden-of-illness score was sig-nificantly reduced in the vaccine group as compared c o n f i r m e d c a s e s f o r t h e e f f i c a c y a n a l y s e s
with the placebo group (P<0.001) (Table 2). Over- More than 3500 rashes that developed in subjects all, VEBOI was 61.1 percent (95 percent confidence
in each treatment group were evaluated clinically but interval, 51.1 to 69.1), a result that met the prespec-
were not considered to be suspected cases of her- ified criteria for success. There were no significant
pes zoster. A total of 1308 subjects with suspected differences in the VEBOI when the results were
herpes zoster were evaluated according to the pro- stratified according to sex or age (Table 2).
tocol (Fig. 1). Among these subjects, 317 (156 in the
vaccine group and 161 in the placebo group) were incidence of postherpetic neuralgia
determined not to have herpes zoster. Of these 317 There were 107 cases of postherpetic neuralgia, 27
subjects, 49 had rashes that were caused by HSV in the vaccine group and 80 in the placebo group
(24 in the vaccine group and 25 in the placebo (0.46 case vs. 1.38 cases per 1000 person-years, re-
group). Closeout interviews did not identify any pre- spectively; P<0.001) (Table 3). Overall, the VEPHN
Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Randomization
Disposition
Confirmation of Cases
Suspected cases of herpes zoster (n=1308) Not herpes zoster (n=156 [24 HSV-positive]) Confirmed cases of herpes zoster in intention-to-treat population (n=322) in intention-to-treat population (n=662) Excluded from modified intention-to-treat Excluded from modified intention-to-treat Cases of herpes zoster within 30 days of Cases of herpes zoster within 30 days of Confirmed cases of herpes zoster in modified Confirmed cases of herpes zoster in modified Positive for VZV on PCR testing (n=294 [93.3%]) Positive for VZV on PCR testing (n=600 [93.5%]) Positive for VZV on culture by local virology Positive for VZV on culture by local virology Diagnosis of herpes zoster by clinical evaluation Diagnosis of herpes zoster by clinical evaluation Figure 1. Diagram of the Study Design and Results.
The intention-to-treat population included all subjects who underwent randomization. Efficacy analyses were performed with the use of a follow-up interval that excluded the first 30 days after vaccination and the modified intention-to-treat population, which excluded subjects who withdrew or in whom a confirmed case of herpes zoster developed within the first 30 days after vaccination. For three subjects in whom more than one confirmed case of herpes zoster developed, only the first case was in-cluded in the modified intention-to-treat analyses. HSV denotes herpes simplex virus, and VZV varicella–zoster virus.
Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. e f f i c a c y o f a v a r i c e l l a – z o s t e r v i r u s v a c c i n e was 66.5 percent (95 percent confidence interval,47.5 to 79.2), a result that met the prespecified cri- Table 1. Baseline Characteristics of the Study Participants.*
teria for success. There were no significant differ- Vaccine Group
Placebo Group
Characteristic
(N=19,270)
(N=19,276)
Demographic
The VEPHN did not change appreciably when postherpetic neuralgia was defined with the use of alternative cutoff times for the duration (persis-tence) of pain (Table 3). In a time-to-event analysis, the cumulative incidence of postherpetic neuralgia was significantly lower in the vaccine group than in the placebo group (P<0.001) (Fig. 2A).
i n c i d e n c e o f h e r p e s z o s t e r
The overall incidence of herpes zoster per 1000 per- son-years was significantly reduced by the zoster vaccine, from 11.12 per 1000 person-years in theplacebo group to 5.42 per 1000 person-years in the vaccine group (P<0.001) (Table 2). The VE General health status
51.3 percent (95 percent confidence interval, 44.2 to 57.6). In a time-to-event analysis, the cumulative incidence of herpes zoster was significantly lower in the vaccine group than in the placebo group (P<0.001) (Fig. 2B). The VEHZ was 37.6 percent among subjects 70 years of age or older and 63.9percent among younger subjects (P<0.001). There d u r a t i o n a n d s e v e r i t y o f h e r p e s z o s t e r
The median duration of pain and discomfort among subjects with confirmed cases of herpes zoster was significantly shorter in the vaccine group than in the placebo group (21 days vs. 24 days, P=0.03). Simi-larly, the mean herpes-zoster severity-of-illness score (AUC) among subjects with confirmed cases of herpes zoster was significantly lower in the vac- cine group than in the placebo group (141.2 vs.
180.5, P=0.008). For almost every level of the severi- Health-related limitations on activities ty-of-illness score, there were fewer cases of herpes zoster in the vaccine group than in the placebo group. The effect of the zoster vaccine on the se- verity of illness was greater among older subjects; thus, the VEBOI, the primary end point of the study, * Not all subjects responded to every question in the questionnaires. Percentag- v a c c i n e s a f e t y i n t h e t o t a l s t u d y
p o p u l a t i o n
† One subject was 59 years of age.
Over the entire study period, the numbers and per- ‡ Race was self-reported on a questionnaire administered at enrollment.
§ The EuroQol thermometer is a visual-analogue scale for patients to use to rate centages of deaths were similar in both study their overall status from 0 (worst imaginable health) to 100 (best imaginable groups (Table 4). During the first 42 days after vac- health). The thermometer is included in the EuroQol questionnaire regarding cination, the number and types of serious adverse the quality of life, on which patients graded their general health status in the categories shown.
events were similar in the two groups (Table 4), as Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 2. Effect of Zoster Vaccine on the Burden of Illness in Herpes Zoster in the Modified Intention-to-Treat Population.*
Subjects
Vaccine Group
Placebo Group
(95% CI)§
* Efficacy analyses were performed with the use of a follow-up interval that excluded the first 30 days after vaccination and in a modified intention-to-treat population, which excluded subjects who either withdrew from the study or in whom a confirmed case of herpes zoster developed within the first 30 days after vaccination. Of three subjects in whom more than one case of herpes zoster developed, only the first case was included. VEBOI denotes vaccine efficacy for the burden of illness due to herpes zoster (BOI), and CI confidence interval.
† For the total population and the subgroups stratified according to sex, the BOI score in each treatment group (vaccine or placebo) was the weighted average of the observed BOI stratified according to age, with weights proportional to the total number of subjects within each age group; subjects in whom herpes zoster did not develop were assigned a score of 0 for severity of illness due to herpes zoster on the basis of the Zoster Brief Pain Inventory, a questionnaire developed for the Shingles Prevention Study.
‡ For the total population and for subgroups stratified according to sex, the incidence of herpes zoster in each treatment group was the weighted average of the observed incidence of herpes zoster stratified according to age group, with weights proportional to the total number of person-years of follow-up in each age group.
§ VEBOI for all subjects was the protocol-specified primary end point.
was the distribution of serious adverse events ac- 30 minutes after eating peanuts); the second was
cording to body system (data not shown). During 69 years of age and received a diagnosis of polymy-
this period, varicella-like rashes at the injection site algia rheumatica on day 15; and the third was 78
occurred more frequently among those in the vac- years of age and received a diagnosis of Goodpas-
cine group than among those in the placebo group, ture’s syndrome on day 52.
but varicella-like rashes at other sites occurred at
similar rates in the two groups (Table 4). There adverse-events substudy
were 7 confirmed cases of herpes zoster in the vac- In the adverse-events substudy, a significantly great-
cine group and 24 in the placebo group during the er number of subjects in the vaccine group had one
first 42 days after vaccination.
or more adverse events than in the placebo group, Five subjects had serious adverse events that reflecting a greater frequency of adverse events at were assessed by site investigators as possibly vac- the injection site among subjects in the vaccinecine-related. Two subjects had received vaccine: a group (Table 4). In the vaccine group, the most fre-64-year-old woman who had an exacerbation of quent adverse events at the injection site wereasthma two days after receiving the vaccination, and erythema (in 35.8 percent of the vaccine group),an 80-year-old man in whom symptoms of polymy- pain or tenderness (in 34.5 percent), swelling (inalgia rheumatica developed on day 3. The remain- 26.2 percent), and pruritus (in 7.1 percent). No oth-ing three subjects, all men, who had serious ad- er adverse event at the injection site was observed inverse events had received placebo: the first subject more than 2 percent of the vaccine recipients. Over-was 65 years of age and had an anaphylactoid reac- all, the proportion of subjects with one or more sys-tion 90 minutes after receiving the vaccination (and temic adverse events was similar in the two groups; Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. e f f i c a c y o f a v a r i c e l l a – z o s t e r v i r u s v a c c i n e Table 3. Effect of Zoster Vaccine on the Incidence of Postherpetic Neuralgia in the Modified Intention-to-Treat Population.*
Variable
Vaccine Group
Placebo Group
VEPHN (95% CI)
* For the secondary end point, postherpetic neuralgia (PHN) was defined as the pain and discomfort associated with her- pes zoster rated as 3 or more, on a scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine), persisting or appearing more than 90 days after the onset of herpes zoster rash. Efficacy analyses were performed with the use of a fol-low-up interval that excluded the first 30 days after vaccination and the modified intention-to-treat population, which ex-cluded subjects who withdrew or in whom a confirmed case of herpes zoster developed within the first 30 days after vac-cination. Of three subjects in whom more than one confirmed case of herpes zoster developed, only the first case was included. VEPHN denotes vaccine efficacy for the incidence of PHN, and CI confidence interval.
† For the total population and the subgroups stratified according to sex, the incidence of PHN in each treatment group (vaccine or placebo) was the weighted average of the observed incidence of PHN stratified according to age group, with weights proportional to the total number of person-years of follow-up in each age group.
‡ VEPHN for all subjects was the protocol-specified secondary end point.
§ PHN was defined as the pain and discomfort associated with herpes zoster that was rated as 3 or more persisting or ap- pearing more than 30, 60, 90, 120, and 182 days after the onset of herpes zoster rash.
however, systemic adverse events assessed as vac- The number of subjects who had one or more cine-related occurred more frequently among vac- hospitalizations was similar in the two groups. Nocine recipients (Table 4).
hospitalization among subjects in either group was In the substudy, during the 42 days after vacci- considered to be related to the vaccine.
nation, significantly more subjects in the vaccinegroup had serious adverse events than in the placebo group (1.9 percent vs. 1.3 percent, respectively;P=0.03); there were no significant differences in The pain and discomfort of herpes zoster andthe distribution of serious adverse events accord- postherpetic neuralgia cause substantial morbid-ing to body system or type of event (data not ity among older adults.9-12,15,28 Although herpesshown). A post hoc, subject-by-subject review of zoster is not a reportable disease, we estimate thatserious adverse events conducted by the writing 1 million or more cases occur each year in the Unitedcommittee revealed no clinically meaningful dif- States, a number that is likely to increase as the pop-ferences between the groups in the pathophysiol- ulation ages. Thus, a means of prevention would of-ogy, nature, timing, intensity, or outcome of these fer important medical and economic benefits.
events.
The zoster vaccine reduced the burden of illness Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Cumulative Incidence of PHN (%)
Cumulative Incidence of HZ (%)
Years of Follow-up
Years of Follow-up
No. at Risk
No. at Risk
Figure 2. Kaplan–Meier Estimates of the Effect of Zoster Vaccine on the Cumulative Incidence of Postherpetic Neuralgia (Panel A) and Herpes
Zoster (Panel B) in the Modified Intention-to-Treat Population.
Incidence rates of postherpetic neuralgia (PHN) and herpes zoster (HZ) were significantly lower in the vaccine group than in the placebo group (P<0.001, by a stratified log-rank test that pooled the results of the log-rank test from the two age groups). Cumulative incidence, ex-pressed as a percentage of the subjects at risk, is the probability of the development of the disease during the period from 30 days after vac-cination to the follow-up time.
due to herpes zoster among people 60 years of age We believe that the observed efficacy of the or older by 61.1 percent and reduced the incidence zoster vaccine reflects its ability to boost immunityof postherpetic neuralgia by 66.5 percent. Signifi- to VZV in vaccinated subjects — an issue that willcant efficacy with respect to the incidence of post- require further study. The investigational zosterherpetic neuralgia was demonstrated, regardless of vaccine had low rates of serious adverse events, sys- how postherpetic neuralgia was defined, with a temic adverse events, hospitalization, and death.
trend toward greater efficacy for postherpetic neu- Results were similar in the two study groups, andralgia of longer duration. The vaccine also showed local reactions at the vaccination site were general-significant efficacy for these end points even when ly mild. The greater number of early cases of herpesthe results were stratified according to age and sex. zoster in the placebo group, as compared with theZoster vaccine also reduced the overall incidence of vaccine group, and the fact that no vaccine virusherpes zoster by 51.3 percent and significantly re- DNA was detected, indicate that the vaccine did notduced the pain and discomfort among subjects in cause or induce herpes zoster.
whom herpes zoster developed. Although the ef- The minimum potency of the zoster vaccine ad- fect of zoster vaccine on the incidence of herpes ministered to subjects in the study was at least 14zoster was less among older subjects than among times greater than the minimum potency of Varivaxyounger subjects, the effect of the vaccine on the (Merck), the vaccine currently licensed to preventseverity of illness was greater among older sub- varicella. A preliminary study indicated that poten-jects, so that the VE , the primary end point of cies of this magnitude are required to elicit a signif- the study, was maintained at 55.4 percent.
icant increase in the cell-mediated immunity to Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. e f f i c a c y o f a v a r i c e l l a – z o s t e r v i r u s v a c c i n e Table 4. Adverse Events among All Subjects and among Those in the Adverse-Events Substudy.*
Vaccine Group Placebo Group
Difference in Risk (95% CI)
All subjects
Varicella-like rash not at injection site Subjects in the adverse event substudy
One or more vaccine-related systemic adverse events‡ Self-reports of feeling abnormal temperature¶ One or more adverse events at injection site¿ * The rates of death and of hospitalization are percentages of subjects in each treatment group. Otherwise, percentages are rates weighted in proportion to the number of subjects with safety follow-up in each age group. NC denotes not cal-culated. Three subjects who had withdrawn from the study because of worsening health and subsequently died were in-cluded in the safety analysis.
† The difference in risk (vaccine group¡placebo group) and the 95 percent confidence intervals for deaths and hospitaliza- tions are based on the rates per 1000 subject-years of follow-up to account for differential follow-up among the study par-ticipants as a result of staggered enrollment. Otherwise, the differences in risk and 95 percent confidence intervals are based on an asymptotic method for the difference of two binomial proportions where the proportions are weighted ac-cording to the number of subjects with safety follow-up in each age group. Negative values for the difference in risk result when the rate in the placebo group is larger than that in the vaccine group.
‡ Events classified as possibly related to vaccination were assessed by a blinded investigator at each site.
§ P<0.05 for the comparison with the placebo group.
¶ A temperature of 38.3°C or higher was not documented.
¿ None of the adverse events related to the injection site were considered to be serious adverse events.
Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine VZV among older adults — hence, the need to for- plied by Merck; famciclovir was supplied by SmithKline Beechammulate a high-potency vaccine for this study. We and Novartis Pharmaceuticals.
Drs. Crawford, Gershon, Griffin, Levin, Schmader, and Wright know of no data to suggest that the licensed vari- report having received consultation fees, lecture fees, or honoraria cella vaccine would be efficacious in protecting from Merck; Drs. Betts, Greenberg, Kauffman, Levin, Weinberg,older adults from herpes zoster or postherpetic and Wright report having received grant support from Merck; Drs.
Annunziato, C.Y. Chan, I.S.F. Chan, Crawford, Harbecke, Keller, Sil- neuralgia. Thus, we do not recommend the use of ber, Simberkoff, and Wang and Ms. Williams report holding equity the current varicella vaccine in an attempt to pro- in Merck; Drs. Annunziato and Levin report having partial intereststect against herpes zoster and postherpetic neural- in relevant patents; and Drs. Annunziato, C.Y. Chan, I.S.F. Chan, Keller, Silber, and Wang are employees of Merck.
gia. The results of our study show that vaccination This article is dedicated to the memory of the late Edgar Hope- of immunocompetent persons 60 years of age and Simpson, whose seminal observations and prescient hypotheses onolder with live attenuated zoster vaccine (Oka/ herpes zoster provided our inspiration and rationale, and to the lateMerck) markedly decreases the morbidity associat- John Franklin Enders, who taught us what really matters.
ed with herpes zoster and the incidence of posther- We are indebted to the members of the data safety and monitor- ing board for ensuring the safety and integrity of the study for a peri- od of six years; to the more than 38,000 subjects whose participation Supported by the Cooperative Studies Program, Department of has been the key to the study’s success; to Dr. Robert H. Friedman Veterans Affairs, Office of Research and Development; by a grant for expert advice regarding the automated telephone-response sys- from Merck (to the Cooperative Studies Program); and by a grant tem; and to Professors Michiaki Takahashi and J. Edwin Seegmiller from the James R. and Jesse V. Scott Fund for Shingles Research (to and the late Richard T. Perkin, founding president of the Varicella– Dr. Oxman). The vaccine and placebo used for the study were sup- Zoster Virus Research Foundation, for their encouragement.
a p p e n d i x
The authors’ affiliations are as follows: the Department of Veterans Affairs (VA) San Diego Healthcare System and the Departments of Med-icine and Pathology, University of California, San Diego (M.N.O., H.M.W., J.C.G., P.A.B., R.H.); University of Colorado Health Sciences Cen-ter, Denver (M.J.L., A.W., A.R.H.); VA Cooperative Studies Program Coordinating Center, West Haven, Conn. (G.R.J., J.H.Z., P.N.P., T.C.K.);Geriatric Research, Education and Clinical Center, Durham VA Medical Center and Center for Aging, and the Department of Medicine,Duke University Medical Center, Durham, N.C. (K.E.S.); Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infec-tious Diseases, National Institutes of Health, Bethesda, Md. (S.E.S., P.B., N.E.S., A.R.M.); St. Louis VA Medical Center and the Departmentof Medicine, Washington University, St. Louis (L.D.G.); VA Boston Healthcare System, Boston (R.D.A., R.P.G., D.J.C.); VA New York HarborHealthcare System and the Department of Medicine, New York University School of Medicine, New York (M.S.S.); Columbia University,New York (A.A.G.); New Mexico VA Healthcare System, Albuquerque (L.E.D.); VA Cooperative Studies Program Clinical Research PharmacyCoordinating Center, Albuquerque (K.D.B.); National Institute of Allergy and Infectious Diseases, Bethesda, Md. (C.E.B.); Minneapolis VAMedical Center, Minneapolis (V.A.M.); VA Ann Arbor Healthcare System, Ann Arbor, Mich. (C.A.K.); Edward Hines Jr. VA Hospital, Chicago(C.T.P.); VA Puget Sound Healthcare System, Seattle (K.M.N.); University of Rochester Medical Center, Rochester, N.Y. (R.F.B.); VanderbiltUniversity Medical Center, Nashville (P.F.W., M.R.G.); Baltimore VA Medical Center, Baltimore (S.K.K.); Birmingham VA Medical Center,Birmingham, Ala. (J.W.G.); VA Palo Alto Healthcare System, Palo Alto, Calif. (J.L., M.H.); Baylor College of Medicine, Houston (W.A.K.);University of Texas Health Science Center San Antonio, San Antonio (G.E.C.); Northport VA Medical Center, Northport, N.Y. (S.S.Y., Z.L.);James A. Haley Veterans Hospital, Tampa, Fla. (J.F.T.); Lexington VA Medical Center, Lexington, Ky. (R.N.G.); Merck Research Laboratories,West Point, Pa. (P.M.K., C.Y.C., I.S.F.C., W.W.B.W., P.W.A., J.L.S.); University of California, Los Angeles, Neuropsychiatric Institute, Los An-geles (M.R.I.).
The members of the Shingles Prevention Study Group were as follows: Writing committee — M.N. Oxman (chair), R.D. Arbeit, L.D. Gelb, G.R. Johnson, M.J. Levin, K.E. Schmader, S.E. Straus, M.S. Simberkoff; Planning and executive committees — M.N. Oxman (chair), R.D. Arbeit,P. Barry, C.E. Beisel, K.D. Boardman, C.L. Colling, L.E. Davis, L.D. Gelb, A.A. Gershon, A.R. Hayward, M.R. Irwin, G.R. Johnson, M.J.
Levin, P.N. Peduzzi, K.E. Schmader, M.S. Simberkoff, S.E. Straus, A. Weinberg, H.M. Williams, P.W. Annunziato, C.Y. Chan, I.S.F. Chan, S.
Manoff, C.J. White; Clinical evaluation committee — L.D. Gelb, M.J. Levin, M.N. Oxman, K.E. Schmader, S.E. Straus, G.R. Johnson, H.M. Wil-liams; Data and safety monitoring board — R. Whitley (chair), N. Blacklow, C. Crumpacker, R.H. Dworkin, J.D. Neaton, S.G. Self, J. Zaia; VACSPhuman rights committee, West Haven, Conn. — R. Marottoli (chair), J.C. Niederman, W. Pritchett, F. Randall, D.G. Beckwith, R.C. Feldman, W.
Farrell, S. Kasl, M. Zeman, R. Mehta, H. Allore, E.B. Perry, B. Kathe, M. Coral, D. Marshall, J. Solomon; Clinical study sites (listed in descend-ing order of the number of subjects enrolled) — Minneapolis VA Medical Center, Minneapolis: V.A. Morrison (principal investigator), D.L. Con-don, G.J. Kayser, T. Knutson, E. Lorenz, R. Mahlum, S. St. Marie; VA San Diego Healthcare System, San Diego, Calif.: J.C. Guatelli, P.A. Brooks(principal investigators), D.J. Beck, B.J. Blood, R. Bourne, J. Hutsell, S. Johns, A.D. Lucko, P. McCook, D. Ram, S.L. Smith; Durham VA Med-ical Center, Durham, N.C.: K.E. Schmader (principal investigator), T. Alexander-Howard, L. Folsom, N. Hampshire, J. Smith, V. Willi; Univer-sity of Colorado Health Sciences Center, Denver: M.J. Levin (principal investigator), D. Barber, J. Block, N. Lang, L. Murray, S. Narro; VA Ann ArborHealthcare System, Ann Arbor, Mich.: C.A. Kauffman (principal investigator), M. Ford, D. Hammer, M. Pesti, J.P. Thompson; Edward Hines Jr. VAHospital, Chicago: C.T. Pachucki (principal investigator), J. Leal, M. Poly Samuel, D. Terry, N. Villanueva, S. Wood; VA Puget Sound HealthcareSystem, Seattle: K.M. Neuzil (principal investigator), P. Cleary, K. Greer, J. M. Laguire, K. Margulies, M. Moroz, J.A. Zuydhoek Nicholas; St.
Louis VA Medical Center, St. Louis: L. Gelb (principal investigator), C. Bodicky, E.A. Clark, L. Conwill, R.E. Davis, C. Goessling; New Mexico VAHealthcare System, Albuquerque: L.E. Davis, M.K. King (principal investigators), M. Bowles, M. Estrada, K. Falkenberg, A. Garduno, J.E. Jones;University of Rochester Medical Center, Rochester, N.Y.: R.F. Betts (principal investigator), E. Barker, B. Fernaays, B. Mahoney, J. Marianacci;Vanderbilt University Medical Center, Nashville: P.F. Wright, M.R. Griffin (principal investigators), P. Chapin, L. Craddock, T. McMinn, C.
Meisch, B. Redd, C. Robbins, J.Sanders; National Institutes of Health, Bethesda, Md.: P. Brunell, N.E. Soto, A.R. Marques (principal investiga-tors), C. Groden, P. Hohman, C. Jones, M. Kelly, R. McCown, E. Meshesha, M. Raj, V. Koneti Rao; Baltimore VA Medical Center, Baltimore: S.K.
Keay (principal investigator), C. Boyce, T. Bremer, K.B. Haymart, N.D. Lamb, J. Murray; VA Boston Healthcare System, Boston: R.D. Arbeit, R.P.
Downloaded from www.nejm.org at INSERM DISC DOC on April 15, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved. e f f i c a c y o f a v a r i c e l l a – z o s t e r v i r u s v a c c i n e Goodman, D.J. Cotton (principal investigators), J. Ambrosino, M. Campasano, I. Cook, D.J. Cowan, S.A. Davis, Jr., B. Dionian, C. Flem-ming, R.Serrao, J. Strymish, D. Syat; Birmingham VA Medical Center, Birmingham, Ala.: J.W. Gnann, Jr. (principal investigator), L. Davis, M.S.
Holloway, J. Moody, P. Pappas, T. Reynolds, M. Salvaggio, N. Story, L.J. Williams; VA Palo Alto Healthcare System, Palo Alto, Calif.: J. Loutit, M.
Holodniy (principal investigators), D. Cowley, S.C. Ezeji-Okoye, V.L. Faria, K.F. Kodair, S.M. Rios; Baylor College of Medicine, Houston: W.A.
Keitel (principal investigator), C.B. Dyer, H. El-Sahli, R.J. Hamill, P. Holder, K. Humphrey, I. Leonard, C. Tajonera, J. Wells; VA New York Har-bor Healthcare System (New York campus), New York: M.S. Simberkoff (principal investigator), J.P. Adams, S. Diaz, D. Head, M.M. Lacher; Univer-sity of Texas Health Science Center San Antonio, San Antonio: G.E. Crawford (principal investigator), S. Andrews, S. Campbell, D. Hicks, C. Reva-do, P. Shope, K. Summers; Northport VA Medical Center, Northport, N.Y.: S. Yeh, V.E. Jimenez, Z. Lobo (principal investigators), S. Chien, L.
Donnelly, B. Lorenzo, S. Lovitt, J.M. Schanfeld, M.C. Stanganelli, A. Zias; James A. Haley Veterans Hospital, Tampa, Fla.: J.F. Toney (principal in-vestigator), J. Kirk, D. Kuziel, R. Morales, J.H. Stocks, M. Walker; Lexington VA Medical Center, Lexington, Ky.: R.N. Greenberg (principal inves-tigator), J. Cox, K. Damron, L. Danko, N. Johnson, D. Meade, T.R. Mucci, J. Peake; VA Cooperative Studies Program Coordinating Center, VA Con-necticut Healthcare System, West Haven: G.R. Johnson (study biostatistician), M. Antonelli, D. Collins, P. Collins, R. Concepcion, C. Cushing,K. Dellert, K. DiBenedetto, A. Hudson, B.J. Huff, T.C. Kyriakides, K. Newvine, P. O’Brien, V. McBride, S. O’Neil, P.N. Peduzzi, J. Vitale, T.
Warholak, D. Wood, J.H. Zhang; VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, N.M.: K.D. Boardman,C.L. Colling, B. Del Curto, R.W. Fetter, J. Peterson, M.R. Sather; VA Office of Research and Development, Washington, D.C.: D. Deykin, J. Feussner,S. Fihn, B. Schuster, P. Lavori, S. Berkowitz, J. Gough, G. Huang; Study chair’s office, VA San Diego Healthcare System, San Diego, Calif.: M.N. Ox-man (study chair), H.M. Williams (national study coordinator), A.E. Kendall, S. Markum, J. Pettiford; Central Diagnostic Laboratory VA San Di-ego Healthcare System, San Diego, Calif.: R. Harbecke, Y. Naidu, L.J. Wopschall; Central Cell-Mediated Immunity Laboratory, University of ColoradoHealth Sciences Center, Denver: A.R. Hayward, A. Weinberg, D. Elizabeth, L. Enomoto, M. Jones; Central Cell-Mediated Immunity Laboratory, San Di-ego VA Healthcare System, San Diego, Calif.: H.A. Stanley, P. Jordan; Merck Research Laboratories, West Point, Pa.: K. Abraham, K. Adair, L. Amorn-wichet, P. Annunziato, D. Anzalone, B. Arnold, N. Brown, P. Brownell, M. Bulotsky, M. Caulfield, C.Y. Chan, I.S.F. Chan, F. Chen, C. Cheney,K. Chirgwin, J. Chodakewitz, S. Ci, J. Clair, K. Coll, S. Cook, P. Coplan, D. Cromley, C. Durkan, L. Eaton, J. Field, T. Fitzgerald, J. Ginanni,E. Giuliani, C. Gracin, D. Gutsch, A. Harmon, K. Hencken, J. Heyse, L. Hostelley, C. Ip, H. Joseph, J. Kang, R. Kaufhold, P.M. Keller, B.
Lang, L. Levit, S. Lewis, S. Li, J. Liu, J. Lou, R. Lowry, S. Manoff, R. Marchese, H. Matthews, T. Morley, K. Murray, A. Ngai, A. Nikas, C.
O’Brien, G. Pannicke, N. Patel, K. Perrin, L. Petruhkin, S. Ptyza, J. Rafter, V. Rednar, B. Rich, L. Rubinstein, K. Russell, R. Rutledge, J. Ryan,P. Saddier, J. Sadoff, K. Schlienger, F. Schödel, S. Senior, A. Shaw, T. Sheehan, J. Silber, J. Smith, Y. Su, T. Sterling, D. Stinson, S. Sutradhar,M.E. Thompson, R. Vessey, H. Wang, J. Wang, W. Wang, R. Wasserman, M. Waters, D. Weiss, C.J. White, M. Wooters, J. Xu; Study monitoring— Covalent Group, Wayne, Pa; VACSP Good Clinical Practice Monitoring (SMART), Albuquerque, N.M.: C. Haakenson, C. Colling, D.
Krueger, and L. Taylor.
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