Transcript VA Cooperative Study #504 Risperidone Treatment for

Subject
Recruitment
& Retention
Joyce A. Cramer
Associate Research Scientist, Yale Univ School of Medicine
President, Epilepsy Therapy Project
Former National Project Director, VA Cooperative Studies Program
Patient Recruitment in Clinical Trials
Written from personal experience
Published in 1992
My first RCT 1977
My last RCT 2007
Little change over 30
years, except web-based
methods
Take Away Points
• Have a plan
• Review it regularly
• Revise as needed to reach
targets
3 PLAGUES:
Endemic to clinical trials
Baseline
Retention
Recruitment
Appropriate BL assessments (reduce placebo responders)
Finding appropriate patients
Keeping them active for the duration of the study
RECRUITMENT IS A
SCIENCE
How do
I do it?
• Like Sisyphus,
Researchers are
doomed to start at the
bottom if they do not
learn how to develop
and implement a
recruitment strategy
• Recruitment problems can
severely affect a clinical trial
if not well managed
ELEMENTS OF A
RECRUITMENT STRATEGY
• Methods
•
•
•
•
•
•
Chart review
posters
Letters to pt & MD
calls
direct advertising
internet
The Strategy
• Sources
• your own patients
• referrals from within your
center
• referrals from outside
your center
• direct contacts with
patients
•Develop a recruitment strategy
NOW
–Start screening quickly and
continue to screen until the
study closes
Study Sponsor / Principal Investigator
• Need personal ‘ownership” of the study
• Need to connect with every Investigator
& Coordinator
• Need to train all site staff
– Learn at start which sites have
weaknesses; monitor closely
RECRUITMENT CONSIDERATIONS for Sites
 Current non-response to
another med for this dx
 Willing to try another
type of medication
 Able to describe events
 Able to attend follow-up
for 6 months
Ⅹ Inadequate trials of
other meds for this dx
Ⅹ Multiple other medical
issues
Ⅹ Cannot describe
traumatic events
Ⅹ Frequent admissions
Ⅹ Unable to complete
assessments
independently
Ⅹ Cognitive ability
Ⅹ Depression
Avoiding high placebo responses
• Avoid inappropriate baseline data
– If patients are having an exacerbation of
symptoms/events when enrolled, all will improve.
• Insist on stability before enrollment (e.g., sev months)
– If recruiters explain too much about eligibility
criteria, patients may endorse what they think you
want to hear
• Overstate number of symptoms/events
SET TARGETS
• Target: 400 patients
• Timetable: 24
Months
• Sites: 20
• Site Goal:
– 20 patients total
– 10 patients per year
• Low enrollment means the
site never learns the
protocol!
• Every site must enroll 1
patient every month for
the next 2 years
– Sites unable to meet these
requirements will be placed
on probation.
– Rapid improvement will be
necessary to demonstrate
capacity to remain a study
site.
– Non-performing sites will be
replaced.
Example of a Study That Enrolled “On-Target”
and “On-Time”
Exceed Target of 600 (627)
randomized patients on
schedule
700
VA CSP #425
600

500
400
300
200
Randomized an average of 25
patients per month for 24 months,
final month = 46
100
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Cumulative Total
Monthly Total
Monitored compliance to
assure studying drug
Re-Engage Sites in Your Study
160
Reach Target (120)
three months after
probation
140
120

100
80
Very low recruitment
for >12 months; Study
“on probation” at month
12.
60
40

Re-engage Sites
20
at Month 14 (N=60)
ENROLLED
18
16
14
12
10
8
6
4
2
0
0
Yes, it is a “battle” to the end, with many
headaches and casualties
Case Report Forms
• If site staff do not
keep pace with case
report forms every
day, they pile up.
• This impedes
recruitment because
they don’t have time
to be searching
Conference Calls &
Problem Calls
• Schedule monthly
conference calls to
continue training, inform
everyone about updates.
• Urge sites to call with any
questions.
– If you cannot find an answer
in the Operations Manual
within 5 minutes, call the
monitor
Site Progress Review
The funnel effect…
• Site progress is monitored
monthly
– # pre-screened
– # full screening
– # evaluated for eligibility
–
# randomized
–
# assessments completed
–
# completed
– Dropouts
Site Progress Review
The funnel effect of Lasagna’s Law for Tx studies
• Monitor progress monthly
– 10 pre-screened
– 5 full screening
– 4 evaluated for eligibility
–
3 randomized
–
2 assessments completed
–
1 completed
– Minus dropouts
Site Progress Review
The funnel effect of Cramer’s Corollary for non-Tx studies
• Monitor progress monthly
– 40 pre-screened
– 5 full screening
– 4 evaluated for eligibility
–
3 randomized
–
2 assessments completed
–
1 completed
– Minus dropouts
Set Targets and Timelines
• Example:
• Have 24 months to
enroll 400 patients.
• 20 sites=20
Every month costs $$
patients/site
• 10 patients/yr/site
There should be no extensions !
• Every site needs 1
enrollment every
month for the next 2
years
Mistakes
Happen…
• Subjects erroneously
considered not eligible
• Subjects erroneously
considered eligible
• Subjects complete screen and
decline randomization
• Subjects enroll, attend one visit
(or take one dose of study
medication) and withdraw
• Subjects complete part, but not
all of the study before
withdrawing
• BUT..analyses must
consider every
person.
Consider patient
burden to
enhance
recruitment
• Schedule appointments at the
convenience of the patient not you!
• Don’t overwhelm patients with
too much at one time.
• Give patients a coffee/lunch
break as needed
– Provide vouchers for food,
parking
– Place for family to wait
• Check self-report forms for
completion BEFORE the
patient leaves for the day.
Recommendations:
• INCLUDE RECRUITMENT MATERIALS IN
INITIAL IRB SUBMISSION
– Update immediately when plan changes
– Consider national and local needs
• All sponsor and site staff should perform a full
“mock” evaluation with all CRFs
• This will give everyone the “look and feel” of
issues for sites and patients.
Take Away Points
• Have a plan
• Review it regularly
• Revise as needed to reach
targets