Recruitment of Postmenopausal Women

in the PEP1 Trial

Susan Johnson, MD (Chair), Irma Mebane-Sims, PhD,

Patricia E. Hogan, MS, and Diane B. Stay, MA

INTRODUCTION

The paucity of research of women’s health issues has been blamed on many factors, including an unsubstantiated perception that women in general, and post- menopausal women in particular, are difficult to recruit into clinical trials (561. PEP1 was designed to compare the effects of various hormone regimens on cardio- vascular disease risk factors in women and was planned in 1988-1989 when there was virtually no information regarding recruitment of women into large multicen- ter cliical trials.

Given the lack of recruitment information in women, the PEP1 investigators drew on the experiences of trials in men and incorporated various recruitment activities recommended in the literature, including (1) extensive central and local planning prior to recruitment, (2) use of multiple recruitment strategies, and (3) regular monitoring of clinical center performance by the coordinating center [57- 601. Additionally, the investigatorsdeveloped several recruitment strategiesunique to PEPI. The purpose of this chapter is to describe the recruitment experience in PEPI. as this information may be us&! for future research efforts targe:ed at similar populations of women.

METHODS

Trial Design

The trial design was described in detail earlier [61]. Briefly, participants were postmenopausal women between the ages of 45 and 64 years who agreed to join the trial for three years and who provided informed consent for randomization to one of five trial regimens. Exclusion criteria were iimited and inciuded diagnoses such as recent heart attack, osteoporosis-related fracture, breast cancer, and endo- metrial hyperplasia or neoplasia. All users of hormones were required to discon- tinue such therapy two months prior to beginning the screening process. Eligibility status was determined at a series of three screening visits (SV1, SV2, and SW.) described in detail later in this chapter. In general, enrollment in PEP1 required that a woman be in good health, be willing to accept random assignment to a hormone regimen (or placebo), and be willing to undergo numerous, repeated and invasive medical procedures including endometrial biopsy.

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Recruitment of Postmenopausal Women 21s

Recruitment Goals, Planning, and Monitoring

Goals and Planning

The target sample size for the entire PEPI trial was 840 women (168 pertreatment arm). Each of the seven clinical centers was expected to recruit an equal number of participants (IV = 120). At the first protocol planning meeting, the PEPI investi- gators established a Recruitment Committee, which met regularly over the 2 years of planning of PEP1 and throughout the recruitment period. The Committee, which included PEP1 investigators and coordinating center staff, formulated recruitment strategies, developed recruitment materials for the use of the clinical centers, and provided oversight to the trialwide recruitment process.

Based on the experiences in men, the PEP1 investigators initially estimated that between 3 and 10 women would need to be screened for every woman randomized, i.e., it was projected that between 360 and 1200 women would need to be screened by each clinical center in order for that center to reach the target of 120 randomized women. Given this anticipated patient load, as well as other logistical considera- :ions, it was initially expected that recruitment and randomization could be com- pleted in a 12-month period, beginning in December 1989.

The coordinating center was responsible for training key clinical center staff concerning screening and recruitment procedures. Additionally, the coordinating center hosted annual meetings for these individuals that provided opportunities to share recruitment ideas, review study procedures, and improve trialwide com- munications.

By September 1990, within 10 months of initiating recruitment, it was apparent that the targeted numbers of participants in I’EPI could be enrolled within the general limits of the initial time frame. At this time, the coordinating center calcu- lated a projected enrollment for each clinical center based on that center’s recruit- ment performance and yield. These projections were used by the centers to deter- mine the data for stopping the screening process, i.e., the date when all needed participants were “in the pipeline.” Although all centers were encouraged to enroll 120 women, individual centers were allowed to modestly exceed that goal in order to ensure that the overall sample sire requirements would be met. By the end of November 1990, sufficient numbers of women had entered the screening process and recruitment activities were stopped. A decision was made to allow all women who had entered the screening process to continue and to be enrolled, if eligible. By February 1991. the last of these women was randomized.

Monitoring

After recruitment began, the coordinating center distributed biweekly reports to each clinical center on the trialwide recruitment status. These reports provided descriptive information concerning overall and center-specific recruitment and randomization results. Each clinical center was able to chart its progress in relation- ship to the other centers. This information also provided a stimulus to refocus recruitment activities as needed. For example, clinics with a less successful recruit- ment effort could contact those with a more successful strategy for advice. Like- wise, clinics that were relatively close to each other geographically could plan combined recruitment activities.

S. Johnson et al.

Every 4-6 months, more extensive recruitment reports were prepared by the coordinating center. These provided details concerning the number of women excluded from PEP1 and the reasons for such exclusions. Based on these reports and information gathered at the clinical centers, exclusion criteria were closely examined by the PEP1 Steering Committee. Six months into the recruitment period it was observed that a significant number of hysterectomized women were being excluded from participation in PEP1 because of a hysterectomy prior to age 40. The PEP1 Steering Committee reviewed the rationale for this exclusion criterion; after considerable discussion, the age restriction for hysterectomy was considered to have been arbitrary. With the approval of the PEPI Data Safety and Monitoring Board in March 1990, the hysterectomy age restriction was eliminated.

Recruitment Strategies

The recruitment strategies used in PEP1 included a wide variety of media- and community-based approaches based on direct appeal to the target group of post- menopausal women. The initial racruitment activities for the PEP1 trial were launched with a national mass media campaign that included several mass marketing strate- gies. This campaign was designed both to increase general public awareness of the trial and to stimulate media and participant interest in PEP1 at the local sites.

Components of the initial trialwide campaign included identifying celebrity spokeswomen, releasing an informational letter to the national press, and estab- lishing a toll-free information line. Celebrity spokeswomen appeared in 30-set public service announcements (PSAs) promoting PEPI. The chair of the PEP1 Steering Committee sent a letter to all major national media sources (including major television stations) describing PEP1 and appealing for support. The toll-free telephone number had 10 lines operating ~4 hr a day and provided information about PEP1 to women who heard about the trial through mass media. Its 3-min message provided an overview of the trial and a listing of the Seven PEP1 centers, including their geographic locations and telephone numbers.

Local c Sinical Center Actiuities

Each clinical center was responsible for devising its own recruitment ap- proaches. Additionally, most clinical centers designated a single individual to be responsible for participant recruitment, although in practice most clinical staff, including the principal investigator, were significantly involved in recruitment activities. It wasconsidered imperative that the local medical community be aware of the aims of PEP1 and its recruitment effort; all centers sent letters of information to local physicians (gynecologists, internists, and family physicians) and made presentations to local medical groups.

A variety of media contacts was used by every clinical center: their university public relations offices wereoften a valuable resource for identifyingandestablish- ingmediacontacts. Newspaperswereasked to writenewsstoriesabout the trialand the PSA was offered to local television stations for use throughout the recruitment period (however, the stationscontrolled the timing and frequency of its broadcast). In some cases, paid television advertisements were used. Although expensive, they

Recruitment of Postmenopausal Women US

had the advantage of providing control over the time and location of airing. PEP1 investigators were available for interviews on local radio and television stations.

The PEP1 recruitment effort was also advanced locally through presentations to a variety of lay groups, including church groups and women’s groups. Educational information about menopause and the trial were integral aspects of the group pre~ntations. In seve:al communities, local newsletters and local community new+ papers carried stories about PEPI.

Mass mailings were also used as a recruitment tool in several clinical centers.

Sources of names and addresses included motor vehicle registration and magazine subscription lists. Clinical center staff also contacted women who had been re- cruited for and/or who had participated in prior medical research studies at their institutions. Finally, posters describing PEPI were used by several clinics: these were placed in a variety of public locations, including buses, hospital corridors,

and grocery stores.

Screening Process

The initial clinical contac: was usually made by telephone and a telephone

screening interview was conducted to make an initial assessment of eligibility.

This first assessment ascertained the age of the woman, whether she currently had menstrual periods, whether she was currently on hormone therapy, whether she had any medical conditions that would preclude her taking hormones, and whether she would be willing to accept random assignment to an active hormone therapy or placebo. Potentially eligible women were then invited to an orientation

session (usually in the evening) that generally included 5-15 other potential partici- pants. The content and form of this initial telephone contact was similar at all the clinical centers.

The PEPI orientation session included a slide presentation developed by the Recruitment Committee that described the trial in detail and provided general information on menopause and hormone replacement therapy. If a woman was

interested in participating in the trial after this presentation, she read and signed

an initial informed consent document agreeing to her participation in the trial screening visits.

Three screening visits (SVl. SV2. SV3) were required to determine trial eligibil- ity. At SVl no invasive tests were done and eligibility was met if the woman was within defined limits of body size, blood pressure, age, and menopausal status.

V2 included a blood drawing for determinations of lipid levels and other clinical chemistries, and eligibility was met if the woman was within defined Iimitsof these clinical chemistries. At V3 the participant had a physical examination, including a mammogram and endometrial biopsy (if needed). Run-in medication (discussed below) was also dispensed at V3.

The three screening visits had windows, i.e., O-6 weeks separating SVl and

SV2 and 2-6 weeks separating SV2 and SV3. (Note that SVl and SV2 could occur on the same day.1 The randomization visit occurred 4-12 weeks following SV3. The interval from SVl to randomization ranged from 2 to 6 months. The timing of the various tests for eligibility determination was planned to maximize efficiency, minimize expenditure of financial resources, and miniie discomfort for the woman.

For example, assessment of serum FSH level was used to determine menopausal status and thus eligibility. It also is relatively inexpensive and confers minimal

S. Johnson et al.

Gml: 840 .- l

:

o 720 1 ’ -2’

d

1540

2 E

Figure i Cumulative distribution of the875 PEP1 participants randomized from December 27,19&9 through February 8, 1992.

patient discomfort, and thus was done at SVZ. An endometrial biopsy, however, is an expensive and slightly uncomfortable procedure whose results were unlikely to make a woman ineligible; therefore, this was performed at SK+.

The final step prior to randomization was a 4- to 12-week run-In period during which the potential participant took placebo trial medication. The run-in period allowed the woman to experience the daily pill-taking requirements of the trial and provided the investigators with an obJJve opportunity to -that woman’s potentialadherencetotrialmedication. Acomplhmcelevelof 80% orgreaterforeach trial medication (three different pill packs) was a requirement for randomization.

FINDINGS

A total of 1463 women began the screening process between September 1989 and December 1990. However, there were a total of 1557 SVl visits as the PEPI protocol permit:ed women who were Initially ineligible at SVl due to age or current hormone use to be rescheduled for a second SVZ. Of these, 875 women were randomized into the PEPI trial between December 27, I989 and February 8, 1991(56 weeks). This represents 104% of the recruitment goal of 840 participants, achieved with an 8% increase in duration of the initially projected recruitment period of 52 weeks. Weekly projected and observed cumulative randomization results trialwide are depicted In Figure 1.

A measure of the overall efficiency of recruitment (the summary statistic R) was calculated 1591. This statistic represents the ratio between the observed and the expected numbers of person-weeks accrued during the planned recruitment period. An I? value of 1 means that recruitment proceeded on schedule whereas an R value of less than 1 means either that fewer subjects were recruited or that the time period was longer than expected. The overall efficiency of recruitment. as measured by R, was 0.81 for the planned 52 weeks (781 randomized out of

xuitment of Postmenopausal Women 2.554

Table 1 Initial Sources of Information about PEP1 Reported by Screenees at Screenine Visit 1

Item

Clinical Center -- UCSD IHU UCLA GWU UTSA IOWA STAN Total Yield

News article 65 32 90 31 90 92 127 527 (34%) 303(57%) Mass mailing 21 104 12 13 4 lb 3 173 (11%) 108 (62%)

Newspaper ad 6 20 37 43 22 13 21 162 (10%) 80(49%) Friend 34 10 12 19 15 20 30 140 (9%) asKa%) Radio 4 3 4 2 5 2 30 50 (3%) 31(62%) PSA* 13 0 2 12 6 2 4 39 (3%) UC46981 Poster 11 2 4 0 8 3 3 31 (2%) 25@1%) Physician 8 2 4 0 2 3 1 20 (1%) 11(55%) Other 92 8 69 136 30 30 51 414 (27%) Zll(Sl%b)

Total 254 181 23C 254 182 181 270 1556 flOO%b) 875 (56%)

'Oneresponsemissing.

b Public service announcements

840). (With the recruitment period extended by 4 weeks to allow women who had started the screening process a chance to be randomized, R equaled 0.89 for the S&week period.)

Over 50% of the SVl visits were women who indicated they first heard about PEP1 from the mass media (Table 1). The most commonly cited medium was newspaper, with 44’% of all women entering the screening process reporting this as their initial source. Over a quarter of all SVl visits were from women who heard of the trial through “other” sources, which included various local and na- tional television programs.

At the completion of recruitment, each clinical center was asked to indicate which single strategy had been most effective (Table 2) and to assess the effective- ness of each method employed. Newspaper stories were rated as the most effective method to reach potential participants in five of the seven centers. In the two remaining centers, television interviews with trial personnel and mass mailing were rated as most effective. Overall. those methods felt to berelatively ineffective by the majority of clinical centers included radio PSAs and interviews, posters, presentations to lay and professional audiences, community newsletters, andrefer- rals from physicians or other PEP1 centers.

One center (JHUJ relied primarily on a mass mail campaign with names and addresses derived from a state drivers’ license list; 57% of participants at this center were recruited from this one source. A total of 27,650 letters were sent over the first 7 months of the recruitment period and 4% of the recipients contacted the center for further information: of these, about 10% were eligible to attend SVl. Based on their early results this clinic calculated the number of mailings needed to achieve one SVl visit (i.e., 2SO:l). They were then able to “titrate” the number of weekly mailings in order to (1: :ecrui: :he targeted number of women in the time frame specified and (2) provide a steady and balanced dmic workload. Four other centers used mailings to a lesser extent.

Information about telephone contacts prior to SV1 was not centrally coded and maintained. However, the total number of telephone contacts was estimated

S. Johnson et al.

Table 2 PEP1 Clinical Center Use and Evaluation of Recruiting Strategies

Number of Clinics

Judged To Be Judged To Be Some-wiia: the Most

strateav Used Effective Effective

Mass screening Newspaper stories TV interviews w/study personnel Radio public service announcements rosters TV public service announcements Presentations to lay groups Mass mailings Community~group newsletters Radio interviews w/study personnel Paid print advertisements

Referral Subjects from previous stud& Presentations to medical groups Direct referrals from physician Referrals from other PEP1 centers

7 7 7 7 6 6 5 5 5 4

6 6 5 3

7 5 2 2 3

Cl

from logs kept at six of the seven PEP1 centers. The average number of calls per clinical center was about 1200 (approximately 8400 calls total). This suggests that about 17% of women making an initial telephone contact eventually came to a screening visit (based on the estimated telephone calls and the actual number of women attending SW IN = 146311. The estimated ratio of telephone contacts (N = 84001 to the number of women eventually randomized (N = 8751 was approximately 1O:l.

Table 3 summarizes the overall monthly recruitment experience in PEPI, includ- ing the number remaining eligible after each screening visit. A total of 1463 women attended 1557 SW visits yielding 875 trial participants (a ratio of X.7:1). Figure 2 presents this ratio for each clinical center. Of note is the consistently high yield from all centers.

Center-specific information regarding yield after SVl is provided in Table 4. The reasons for exclusion at each screening visit and the compliance assessment are shown in Tables 5-8. Overall, only 12% of the women were ineligible for participation (Tables S-81 at the completion of SVl. As indicated, reasons for exclusion at SVl were diverse. At the completion of SV2, 81% of the attenders were eligible to continue the screening process (Tables 2-61. The most frequent reasons for exclusion at SV2 were (11 low values for FSH -32% of exclusions; (21 high values for LDL-cholesterol-20% of exclusions; and (3) abnormal values for thyroid-stimulating hormone (TSHI - 18% of exclusions.

A high proportion!84%! of the wornen continued to beeligible after SV3 (Table 71. The most frequent reasonsforexclusionat thisvisit were (1) suspicious findings on mammography - 21% of exclusions: (21 elevated mean LDL-cholesterol based on the average of two visits- 15% of exclusions; and (31 withdrawal of consent - 15% of exclusions.

Recruitment of Po;tmenopaiisal Womea 27s

Table 3 PEP1 Cumulative Recruitment: Frequencies and Yields for Each Visit Type

All Clinics

kern Screening visit 1

Number ( %) eligible Screening visit 2

Number (% ) eligible Screening visit 3

Number (% ) eligible Compliance assessment

Number (%) eligible Randomization

With uterus (%) Without uterus (%I

Figure 2

SEPT 89 JAN 90

234 178 (76) 146 127. (84) 76 65 (86) 22 21 196) 21 1.3 (86) 3 (14)

FEB

99 a5 (86) 89 74 (83) 50 47 (94) 23 23 (1001 23 20 (87) 3 (13)

MAR

96 $6 (90) 81 n (88) 61 53 (87) 41 41 mo) 4iJ 30 (75) 10 (25)

APR MAY JUN

89 163 154 81 (91) 156 (96) 139&W 92 153 139 78 (85) 134 (88) 109 (78) 70 90 124 61 (87) SO (89) 1O9w 58 52 67 58(100) 52 (100) 66 (99) 57 54 64 44 (77) 43 (80) 45 (70) 13 (23) 11 (20) 1900)

250 _- - / !

.’ I i

UCSD JHU UCLA GWU UTSAlOWASTAN

Number of women seen at the first screening visit and the number randomized at each clinical center. The clinical centers are the Llniversitv of California-San Diego !UCSD): Johns Hopkins University (JHU); Universit; of California-Los An&s KlCLA): George Washington University (GWU); University of Texas Health Science Center-San Antonio (UTSA); University of Iowa (IOWA): and Stanford University (STAN).

28s S. Johnson et al.

Table 3 Continued

nn. AUG SEP QCT NOV DEC JAN91

iii PO) 129 100 (78) 108 87 (81) 94 92 (98)

Z (73) 24 (27)

133 118 (891 123 100 (81) 113 95 (84)

101 96 (97) 104 b9W 35 (34)

129 115 (89) 105 77 (73)

LO, 82 79 (96) 76 40 (53) 36 (47)

175 148 (85) 149 116 (78) 93 77 (83) 94 93w

$64) 33 (3b)

133 120 (90) 120 88 (73) 94 78 (83) 74 73K9) 73 41 (56) 32&l)

10 9w 21 19 (91) 101

76 (751 56 52 (93) 53 33 (62) 20 (38)

0 0 (0) 0 0 (0) 5 5 (loo)

119 119 (100) 120 81 (68) 39 (33)

All Clinics

FEB

: (0)

: (0) 0 0 (0)

10 8 w 10 9tw l(10)

Total

1557 1363 (88) 1347 1088 (51) 1069 900 (84) 893 87s (98) 875 59bva 279 (321

A total of 893 women participated in the drug compliance assessment and 98% qualified for randomization (Table 8). Only eight women were excluded due to noncompliance during the run-in period.

The relationship between three medical/demographic factors and eventual ran- domization status was examined among the women who attended SVl. Overall, 60% of the women with a uterus were randomized, compared with 52% of those without a uterus. Although the PEP1 cohort is a highly educated group, the rate of randomization after SVl did not vary substantially by educational. attainment: 55% of women with high school or less education were eventually randomized, compared to 57% with some college, and 56% of those with college or greater education. Age appeared to be slightly associated with eventual randomization, with the youngest age-eligible group of women (45-49) the least likely to go on to be randomized (40%) and the oldest age-eligible women (55-64 years) the most likely to be ultimately randomized (61%).

DISCUSSION

The PEP1 trial recruited in excess of its original goal, on schedule, and with greater efficiency than initially anticipated. For every 10 telephone contacts and for every 2 women seen at the initial screening visit, one woman was randomized. Of the total number of women seen at SVl (N = 1466). only 5% (N = 80) later chose to withdraw consent and drop out of the screening process.

Three factors may have influenced this success but cannot be directly measured. First is the level of interest in the research on the part of potential participants, a factor over which investigators have no control. This factor is critical when large numbers of healthy volunteers are required for a trial, and PEP1 was fortunate to have started at a time when public interest in menopause, hormone replacement therapy, and women’s health research was increasing.

Second, the investigators wereexperienced recruiters. Five of the seven principal investigators had previous recruitment experience in the Lipid Research Clinics Program. Several of the clinical centers had previous successful experiences in recruiting postmenopausal women for hormone and lipid studies. With prior rele- vant experience, recruitment staff may be more efficient as well as more familiar

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kpo

int.

in

z

Tab

le

6 R

easo

ns

for

lnu

ligib

ility

a

t Sc

ree

nin

g V

isit

2”

- -

.-

Clin

ical

C

ente

r

km

Num

ber

of S

V2’

s co

nduc

ted

Num

ber

(%)

excl

uded

at

sequ

enti

al c

heck

poin

ts:

Syst

olic

blo

od p

ress

ure

z 20

0 m

m H

g D

iast

olic

bl

ood

pres

sure

2

105

mm

H

g P

hysi

cal

exam

T

SH

LD

L-c

hole

ster

ol

2 21

0 m

g/dl

T

rigl

ycer

ides

2

500

mg/

dl

Glu

cose

z

140

mgl

dl

FSH

> 4

0 &

f/m

l H

emog

lobi

n <

9.5

g/d

1 H

emat

ocri

t <

30%

C

hem

istr

y pr

ofile

A

ppro

pria

tene

ss

Wit

hdra

wal

of

cons

mt

Oth

er

Tot

al n

umbe

r in

elig

ible

UC

SD

IH

U

UC

LA

G

WU

223

170

216

164

2 (5

) 2

(10)

9

(20)

1

(5)

17 (

29)

6 (1

4)

4 (1

9)

7 (1

2)

1 (2

) 1

(2)

1 (2

) 1

(5)

3 (5

) 7

(16)

6

(291

23

(40

1 1

(2)

1 (2

)

4 (Q

) 1

(5)

12 (

27)

2 (1

01

6 llD

) 4

(19)

1

(2)

44

21

58

7 (2

2)

10 (

31)

2 (6

) 3

(9)

1 (3

)

32

UT

SA

1OW

A

STA

N

Tot

al

177

157

240

1347

4 (2

) 8

(25)

6

021

46 (

18)

10 (

31)

12 (

55)

10 (

20)

53 (

20)

1 (3

1 3

(1)

3 (9

1 2

(41

17

(71

9 (2

8)

6 (2

7)

21 (

421

82 (

321

2 (ii

2 (9

) 9

(31

1 (5

) 24

(9

) 1

(5)

10 U

OI

16

(6)

1 (3

1 1

(21

3 (1

) 32

2.

2 50

25

9 --

Tab

le

7 R

easo

ns

for

Inel

igib

ilit

y at

Scr

eeni

ng

Vis

it 3“

-

Clin

ical

C

ente

r

Item

U

CSD

JH

U

UC

Lk

cwu

UT

SA

IOW

A

STA

N

Tot

al

Num

ber

of S

VJ’

s co

nduc

ted

179

147

148

132

138

135

190

1069

N

umbe

r (%

I ex

clud

ed

at s

eque

ntia

l ch

eckp

oint

s:

Syst

olic

bl

ood

pres

sure

a

2o[r

mm

H

g D

iast

olic

bl

ood

pre

ssu

re

L

105

mm

H

g 1

(4)

1 8

2 (1

) M

ean

syst

olic

blo

od

pres

sure

a

160

mm

Hg

2 (5

) 4

(17)

I

(5)

2 (5

) 9

(5)

Mea

n di

asto

lic

bloo

d p

resu

re

2 95

mm

Hg

1 (4

) 2

(14)

2

(5)

5 (3

) Pe

lvic

ex

am

1 (3

) 1

(1)

Ent

ry

into

ute

rus

4 (1

1)

2 (8

) 5

(33)

4

(21)

3

(8)

18 (

11)

End

cmet

rial

bi

opsy

2

(5)

1 (4

) 3

(2)

Mam

mog

raph

y 7

(19)

4

(19)

4

(16)

1

(7)

2 (1

1)

6 (4

3)

11 (

29)

35 (

21)

LD

L-c

bole

ster

oal

a 21

0 m

g/dl

2

(5)

4 (1

9)

1 (4

1 1

(7)

1 (5

) 2

(14)

11

(7

) T

rigl

ycer

ides

h

500

mgl

dl

1 (7

) 1

(5)

1 (7

) 3

(2)

Mea

n L

DL

-cho

lest

erol

2

190

mg/

dl

4 (1

1)

3 (1

4)

5 (2

0)

2 (1

3)

3 (1

6)

1 (7

) 8

(21)

26

(15

) M

ean

trig

lyce

ride

s 2

400

mg/

dl

kpra

wal

of

con

sent

7

09)

3 (1

4)

3 (1

2)

3 (2

0)

2 (1

1)

6 (2

1)

26 (

15)

8 (2

2)

7 (3

3)

3 (1

2)

2 (1

3)

5 (2

6)

2 (1

4)

3 12

9)

30 (

18)

Tot

al n

umbe

r in

elig

ible

37

21

25

15

19

14

38

16

9

* T

he fr

eque

ncie

s lis

ted

for e

ach

elig

ibili

ty c

heck

poin

t per

tain

to w

omen

who

fail

that

che

ckpo

int a

fter s

uc

ce

ssfu

lly m

ee

ting

the

elig

ibili

ty c

rite

ria o

f a

ll pr

eced

ing

chec

kpoi

nts.

Pe

rce

nta

ge

r Ale

ct

the

nu

mb

er

of

wo

me

n s

cre

en

ed

ou

t b

y e

ac

h c

he

ckp

oin

t re

lativ

e t

o t

he

to

tal

nu

mb

er

of

wo

me

n f

aili

ng

an

y c

bK

kpo

,int.

v,

Recruitment of Postmenopausal Women 33s

Table 8 Reasons for ineligibility at Compliance Assessment”

CIii~ical Center

kern UCSD IHU UCLA GWU UTSA IOWA STAN Total

Number of compliance assessments c&ducted 142 125 122 117 116 119 152 893

Number excluded due to: Pill compliance

below 80% 1 2 2 1 0 0 2 8 Difficulties with

venipuncture 2 0 0 0 1 0 1 4 Withdrawal of consent 0 0 0 0 1 0 2 4 Other 3 0 0 0 0 0 0 2 Total number ineliaible 6 2 2 1 2 0 5 18

’ The frequencies listed for each eligibility chKkpoint pertain to women who fail that checkpoint after successfully meeting the eligibility criteria of all preceding checkpoints. Percentages reflect the number of women screened out by each checkpoint relative to the total number of women failing any checkpoint.

with effective strategies for their community. However, even centers with no similar experience were able to meet their targeted enrollment.

Third, there is a direct relationship between the “richness” of the subject pool (the proportion of ti:e population meeting eligibility requirements) and the rate of recruitment (621. In PEPI, most women in the target age group (45-64 years) would be expected to meet the primary criterion of menopause, so that the preva- lence of the “target condition” was unusually high. Further, in order to increase generalizability of the findings from PEPI, relatively broad eligibility criteria were set and exclusions were based on severe health problems or extreme laboratory abnormalities. This resulted in a small number of exclusions and therefore a rich subject pool. PEP1 staff utilized many of the recommendations made in the recruit- ment literature (57,58,60,62,63l. Prerecmitment phnning took place at both the national and local level during the 2 years of protocol development. A specific recruitment coordinator was designated at each center, and these individuals com- municated with each other throughout the recruitment period. In addition, recruit- ment responsibilities were assumed by virtually all staff (including the investigators) at each dmic. Multiple recruitment strategies were used simuhaneously throughout the recruitment period by each clinical center because no single one was sufficient to reach recruitment goals.

Adata-basedmanagementsystemformonitoringrecruitmenteffortswasdevel- opedbythecoordinatingcenter, andfrequentfeedbackwasprovidedto theclinical centers throughout the recruitment period. Based on the biweekly monitoring, individual clinical centers lagging behind were offered consultation with staff from the coordinating center and/or from members of the Recruitment Committee.

Because of the close monitoring of recruitment patterns, two trialwide changes were made early in the recruitment. First, one eligibility criterion was altered to allow women who had undergone hysterectomy before the age of 40 to enter. Twelve percent (N = 104) of the women ultimately randomized were eligible because of this change. Second, based on randomization projections, the period for recruitment was extended by 4 weeks. This slit increase in recruitment time resulted in the targeted sample size being exceeded.

34s S. Johnson et al.

Altering eligibility criteria to increase participation rates shouid be viewed very cautiously J58.6OJ. A better strategy is to define initially only exclusion criteria for which there is a strong scienbfic rationale. The PEPI Data and Safety Monitor- ing Board concurred with the PEPI investigators that the original exclusion c&e- rion for age at hysterectomy had been arbitrary and that the alteration would not adversely impact the outcome variables or trial design.

The national publicity campaign provided initial visibility for the trial. Al- though the direct yield from the public service announcements was low, the use of celebrity spokeswomen (from the “Golden Girls” television show) was helpful in stimulating media interest. The costs involved in developing such sponsorship were modest; the celebrities donated their time and the production costs were minimal. However, because the assignment of time slots for PSAa is at the discre- tion of television stations, there were variations among the centers in local media use of this option. When used, they were often shown during non-prime time hours.

National media coverage had both positive and negative effects. On the positive side, national coverage increased the public’s awareness of PEP1 and prompted large numbers of telephone referrals. The number of calls received on the informa- tion line (over 16,000) reaffirmed that many postmenopausal women were inter- ested in participating in a clinical trial like PEPI. However, there were two major disadvantages to the national media exposure. First, the timing of promotional effort was controlled by the media and unfortunately these uncoordinated and multiple publicity efforts stimulated large numbers of contacts or calls within a relatively narrow time period. Clinical center staff were unable to return some calls within a reasonable period of time [62J.

Second, and more importantly, is the difficulty inherent in stimulating national interest in a trial that is conducted at a relatively small number of geographic sites. The national promotions for PEP1 elicited large numbers of calls from women living in virtually every state in the United States. Although many women were willing to travel to the nearest PEP1 center at their own expense. the investigators wereconcernedabout theimpactof distanceonadherenceandthemedicalmanage- ment of such participants. The decision regarding the acceptability of these long- distance candidates was left to the individual clinical centers, although the general policy was to discourage longdistance participation. Nonetheless, an unintended advantage of the national campaign yvas that PEPI participants were able to feel a part of a nationwide effort; clinic staff used these articles and ads appearing in national magazines to bolster morale and to reinforce the perception of a national endeavor.

Print and broadcast messages were the best sources for potential participants in PEP1 as over half of the women at SVl claimed to have heard of the trial through a media source. This is much higher than the experience in Lipid Research Clinics’ Coronary Primary Prevention Trial, where only 11% of the men had been recruited from a media source 1641. In several large clinical trials, referral sources have been the most productive source of participants (571, although relatively few participants in the PEP1 trial came from referral sources. The most productive referral sources were lists of participants in other studies and the PEPI participants themselves, who referred their friends and occasionally family members to the trial.

Reauihnent of Postmenopausal Women 35s

Telephone screening of initial contacts was an effective initial screening tool. Inaddition toprovidiiginforrnation to thepotentiafparticipant, thephonecontact served to identify grossly ineligible callers. Thus, once a woman came to her first screening visit, the likelihood of ultimate randomization was relatively high.

The frequency of exclusion based on abnormal test results was as expected. Of note, however, was the low rate of exclusion due to endometrial biopsy abnor- malities (N = 3). Also of note was the low occurrence of failure to obtain a biopsy. Of the biopsies attempted, only i8 could not be performed, primarily due to cervical stenosis.

Retention rates at each screening visit were high and comparable among the clinical centers. It is notable that the same high retention rate was achieved even after the visit at which the endometrial biopsy was performed. Almost all ineligibil- ity determinations were due to laboratory and test results rather than personal factors. Of the 1463 women screened, few withdrew their consent (N = 80) or were considered inappropriate by the clinical center staff (N = 42). Only 18 of the 893 women eligible after SV3 had unsatisfactory pill compliance: in retrospect, it may not have been necessary to commit time and resources to this activity.

Hysterectomy status and education did not affect randomization rates among women who came to SVI. Younger women were less likely to be eventually ran- domized, in part because a higher proportion were not menopausal by trial defini- tion. The investigators originally felt that women without a uterus would be more likely to volunteer for the trial, in part because the endometrial biopsy would not be necessary. This did not turn out to be the case.

Theethniccompositionof therandomizedcohort wasg9% white: 5% Hispanic; 4% black; and 2% Asian [48]. Reported total family income tended to be high; at baseline nearly half (46%) of randomized participants reported annual incomes of $50,000 or more and only 11% reported incomes below $20,000 [48j. Thus, the general recruitment strategies used in PEP! appear to be predominantly effective in reaching a white, higher socioeconomic group of women. It should be noted that PEP1 had no specific expectations to recruit minority women, and thus minority women were not specifically targeted in the overall recruitment plan.

In conclusion, the PEP1 experience has demonstrated that large numbers of healthy postmenopausal women can be efficiently recruited with direct appeals delivered through broadcast and print mass media as well as direct mailings. Success in meeting recruitment goals is dependent on utilization of a variety of community-based strategies. Central monitoring of recruitment aIlowsearlydete~- tion of recruitment lags and general troubleshooting, and can foster both healthy competition and camaraderie among clinical centers. The PEPI recruitment experi- ence suggests that women are highly motivated to volunteer for clinical trials even in the presence of multiple screening visits and uncomfortable invasive procedures.