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RECRUITMENT, ADHERENCE, AND
RETENTION STRATEGIES
TALES FROM CLINICAL TRIALS
Kelley R. Branch, MD, MSc, FACC
Associate Professor
Associate Director, Clinical Trials Services Unit
Director, Cardiovascular Clinical Trials
University of Washington
A Clinical Trial Story…
Once upon a time, there were 4
hypertension trials…
COMPARISON OF SHEP, STOP-H,
MRC-92 AND SYST-EUR CHARACTERISTICS
SHEP
STOP-H
MRC-92
Syst-Eur
Sample Size
4736
1627
4396
4695
Mean Age
71.5
75.6
70.3
70.3
160-219
180-230
160-209
160-219
BP
SBP
Criteria
DBP
Primary
Outcome
Design
<90
90+
<114
<95
Total Stroke Total mortality Total stroke Total stroke
P R DB
P R DB
P R SB
P R DB
Sys-Eur Trial: Accrual
Trial Follow Up and Adherence
Mean F/U Time
SHEP
54 mo
STOP-H
25 mo
MRC-92
70 mo
Syst-Eur
30 mo
Mean Baseline BP
170/77
190/104
185/91
174/86
14/6
11/5
BP Differential
41247.00
19.5/8
Adherence
Lost to F/U
6%
0%
25%
% Crossovers
33%
23%
31%
52%D
37%B
47%P
% Adherence
90%/67% 84%/77%
P 5% (116)
A 5% (121)
23%
85%/72%
SYST - EUR
A WORST CASE ANALYSIS?
600
500
STROKE
507
CHD
TOTAL EVENTS
Number
400
Late
Recruitment
= Fewer Events
LOST TO
FOLLOW-UP
300
262
237
High Lost to Follow
Up = No 245
Definitive
200
Conclusions
from the Trial
131
255
124
100
10
0
SYST-EUR
SHEP
6
Major Trial Issues
• Recruitment - Timely Enrollment
• Adherence
• Complete Follow Up
RECRUITMENT
MANTRA: “Get Sufficient
Population In a Reasonable Time”
RECRUITMENT
FUNDAMENTAL POINT
Successful recruitment depends on
developing a careful plan with multiple
strategies, maintaining flexibility,
establishing interim goals and preparing to
devote the necessary effort.
Friedman, Furberg and DeMets
RECRUITMENT
• Successful recruitment has been
documented in many trials
• Clinical Sites: Past performance predicts
future
• Centers carefully selected by past
performance
(http://www.fhcrc.org/science/phs/swog/recrcct/)
RECRUITMENT:BASIC ISSUES
• Planning
– Entry criteria
– Sources and support
– Strategies
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•
•
•
Conduct - Implementation
Monitoring - Short and long term goals
Problems - Expect them to happen
Solutions - Make them occur
RECRUITMENT: CAREFUL
PLANNING
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•
•
•
BE CONSERVATIVE IN YOUR ESTIMATES
Design easy recruitment
Establish interim goals
Have contingency plans
• 3 TO 6 MONTH PERIOD TO SEE RESULTS
TRIAL PLANNING
• Correct entry criteria - Increase likelihood of
•
•
•
•
•
•
•
getting sufficient participants
Staff – Organized, experienced
Institutional support - proper facilities
Publicity - start before trial
Multiple recruitment strategies - at least 3
Pilot test strategies
Contingency plans
Statistical power - assumes constant enrollment
ADVANTAGES: WIDE ENTRY
CRITERIA
• Easier screening and recruitment
• More feasible and affordable
• Broader range of variables and larger study size
• Reliable overall result
• Greater public health impact
• Testing subgroup hypotheses
14
Not Unusual Recruitment Graph
16
Sys-Eur Trial: Worst Case
SELECT Trial Accrual
Projected and Actual
SELECT Accrual
Actual and Projected Accrual vs. Estimated Accrual
40000
35000
30000
Actual accrual as of
March 31, 2004: 24,166
Reach accrual goal of 32,400 at
end of April 2004
25000
Actua
Proje
20000
Estim
15000
10000
5000
0
Projected
ACCORD Initial Trial
ACCORD Main Trial Accrual
10000
80
9000
70
Number Randomized
60
7000
50
6000
5000
40
4000
30
3000
20
2000
1000
ACTUAL
GOAL
0
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
Weeks
0
Number of Sites Active
8000
Checklist: OVERALL
RECRUITMENT PROGRAM
Start recruitment on target date
Choose physically accessible location
Use at least three recruitment strategies
Recruitment Coordinator - overall responsibility
Trial-wide recruitment coordinator network
Accurate tracking system
Match staff and screenees
RECRUITMENT STRATEGIES (N=3)
How to Get Patients
Chart Review
Websites
Media Efforts
Registries
Direct Mail
Blood Bank Donors
Mass Screening
Screening
Occupational
Laboratory Lists
Medical Referrals
22
OVERALL RECRUITMENT
PROGRAM
Identify excellent, experienced staff
Provide staff back-up
Be aware and anticipate staff burnout
Inform medical and lay communities
Recruits - Solicit in simple language
Medical associations and hospital staffs contacted by the Principal Investigator
OVERALL RECRUITMENT
PROGRAM
Calendar for ENTIRE recruitment period
Pretest your recruitment strategies
Regular review and evaluation of program
Develop contingency plans
Flexible clinic hours
Patient reasons for participation clear
PATIENT REASONS FOR
PARTICIPATION
• Answer scientific question accurately
• Altrusim: Benefit other patients - current and
future
• Benefit to themselves
– additional monitoring
– second opinion of their condition
– reassurance regarding diagnosis
25
POTENTIAL PROBLEMS
Expect them-they will occur
• Inadequate funding for screening process
• Unwillingness to refer or allow participation
• Overestimation of prevalence
• Overly rigorous entry criteria
RECRUITMENT PROBLEMS
MANTRA: “Get Sufficient Population
In a Reasonable Time”
RECRUITMENT FAILURE CAUSES:
• Late start
• Inadequate planning
• Insufficient effort
• Overly optimistic expectations
POSSIBLE RECRUITMENT SOLUTIONS
• EXTEND THE TIME FOR ENROLLMENTX?
• RELAX INCLUSION/EXCLUSION
CRITERIA-X
• ACCEPT A SMALLER SAMPLE SIZE-X
• RECYCLE PREVIOUS INELIGIBLES-O
• CHANGE THE DESIGN-XXX
Recruitment: Summary
•
•
•
•
Plan, plan, plan
Design for success with recruitment program
At least 3 recruitment strategies
Problems happen, make solutions
• Sufficient population in reasonable time
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Clinical Trials
ADHERENCE
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ADHERENCE DEFINITION
Adherence is the extent to which a
person’s behavior coincides with medical
or health advice in terms of taking
medications, following diets, using
devices, or executing life-style changes.
TERMINOLOGY:
ADHERENCE VS. COMPLIANCE
• Adherence is preferred term
• Adherence: Active, choice, interactive
• Compliance: Passive, non-selective
NHLBI Workshop, Bethesda, MD 1987
OVERALL ADHERENCE PLAN
• Develop a bottom line - cannot be transgressed
– Minimum amount of data which is essential
• Set adherence goals depending on protocol
– “Acceptability” trial
– “Alteration of natural history” trial
• Teach adherence techniques, plan for poor
adherence
– Run-in and test dosing procedures
– Have a maintenance plan for everyone
BOTTOM LINE:
MINIMUM ACCEPTABLE ADHERENCE
• Know primary outcome status on every
randomized participant.
• Human behavior will allow few to purposely
harm a worthy scientific project.
Adherence is bad in clinical trials.
Get over it.
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SAMPLE SIZE ADJUSTMENT FOR
REDUCED ADHERENCE
• Key Point - Adherence correction p
term-sample size formula, a
squared function.
2N = 2(z + z)2  (1 - 2)2(1-p)2
p = Reduction in Adherence
Sample size: 2000
.01
.05
.10
.20
.30
.50
SS Increase
1.02
1.11
1.23
1.56
2.04
4.00
SAMPLE SIZE ADJUSTMENT FOR
REDUCED ADHERENCE
• Key Point - Adherence correction p
term-sample size formula, a
squared function.
2N = 2(z + z)2  (1 - 2)2(1-p)2
p = Reduction in Adherence
Sample size: 2230
.01
.05
.10
.20
.30
.50
SS Increase
1.02
1.11
1.23 SHEP
1.56
2.04
4.00
SAMPLE SIZE ADJUSTMENT FOR
REDUCED ADHERENCE
• Key Point - Adherence correction p
term-sample size formula, a
squared function.
2N = 2(z + z)2  (1 - 2)2(1-p)2
p = Reduction in Adherence
Sample size:
8000
.01
.05
.10
.20
.30
.50
SS Increase
1.02
1.11
1.23
1.56
2.04
4.00 MRC
PREDICTORS OF ADHERENCE
LRC Study
Adherence after first month associated with:
•Adherence in first month- most powerful predictor (r=.59 or
r²=.34)
– r²=.36 with smoking and other factors added
•Smoking status
•Age
•Extent of Psychological Distress
•No statistical association with:
– Exercise
-Overall risk status
– Weight
-Motivational level
– Vitamin consumption
FACTORS AFFECTING
ADHERENCE TO INTERVENTIONS
Effect on Adherence
Positive
Negative
Patient
Education
Low social class
“Blue collar:
occupation
Social isolation
Regimen Supervised
Therapy duration
Parental
Number of drugs
administration
Dosing frequency
Cardiac drugs
Symptomatic drugs
Respiratory drugs
Diabetic drugs
Illness
Disability
Severity of
symptoms
Severity of illness
Psychiatric illness
No Effect
Age
Sex
Race
Adverse effect
Disease duration
Clinical
improvement
Concurrent illness
“RUN-IN” PERIOD
• Pre-randomization procedure
• Single blind
• Placebo used for intervention
• Stress test for "pill-taking behavior”
CONCLUSIONS ABOUT
“PLACEBO RUN-IN PERIOD”
What does it do
• Identifies individuals who don’t adhere well during run-in
• Successful repeat run-in performers (6.9%) adhere less well
during trial
• Those identified representative of those enrolled
What doesn’t it do
• Identify all who will adhere poorly to intervention
Uncertainties
• If those who “fail” would all be poor adherers
• Cost/Benefit - advantageous
“TEST-DOSING” PERIOD
• Pre-randomization procedure
• Single blind
• Active drug used
• Identify those with severe adverse effects
Non-Adherence
SIGNS OF POTENTIAL NONADHERENCE: “RED FLAGS”
1. Missed visits
2. Difficulty in reaching by phone or failure to return calls
3. Rescheduling appointment twice (change in behavior)
4. Complaints about office visits
5. Impatience during clinic visit
6. Length of time (mandatory) at each visit
7. “Distance” during interview
8. Length of time since participation in study was discussed
between physician and participant
9. Humor dealing with negative aspects of trial medication
SIGNS OF POTENTIAL NONADHERENCE: “RED FLAGS”
10. Sarcasm about trial or study medication
11. Any expression by participant that he/she may discontinue study
medication
12. Unusual or unexplained change in adherence to study medication
13. Unconcern by participant about adherence rate
14. Reassignment to new primary-care manager
15. Reassignment to other new clinic personnel
16. Illness with increased attention to “trial related disease”
17. Hospitalization for any reason
18. Any major change in life style which is imminent
DISTRIBUTION OF ADHERENCE PROBLEMS IN A
CADRE OF DROPOUTS AND OTHERS IN AN RCT
Type of Problem
Adverse effects
Percent
Dropouts Others*
19
22
Medical problems
11
20
Psychosocial problems
69
58
* Those who experienced either a 10% drop in medication adherence or a 10 day delay from their
clinic visit window
MECHANISMS INVOLVED IN PARTICIPANT
NON-ADHERENCE
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Lack motivation
Lack of knowledge (disease, intervention)
Rejects medical diagnosis
Denies significance of disease process
Self-debate over intervention regimen
Rejects intervention regimen
MEDICAL THERAPEUTICS TEAM
Psychologist-Behaviorist
Nurse-Clinician
Therapeutic Plan
Physician
Participant
(Patient)
Intervention Schedule
Dietitian-Nutritionist
Physician
Assistant
RECOVERY OF DROPOUTS
BAYLOR-METHODIST CLINIC OF CPPT
• 94 % were recovered for some regular visit
with clinic personnel (90% within 6 months )
• Remaining participant was contacted
regularly by telephone
• 3% recidivism
• 70% reinstituted study medication
• Average adherence: study medication 35 %
55
Adherence: Key Points
• Adherence is key to knowing the magnitude of
effect
– Withdrawal may be an outcome
– Good trial = Good Adherence
• Plan, set goals, make contingencies
• Enhancing and actively monitoring participant
adherence essential through trial
• KNOW FINAL OUTCOME FOR EACH SUBJECT
Adherence:
Contingency Plans
Contingency Plans
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Identify cause for non-adherence
Motivation
Negotiation
Withdrawl of consent
DROPOUTS:
HOW TO DEAL WITH THEM
• “Sense it coming”- use the “red flags”
• A lesson in using your “Pause Button”
• “Seek first to understand, then be
understood.”
• Issues frequently complex.
– May not be solvable at the first interaction.
DROPOUTS:
HOW TO DEAL WITH THEM
• You are playing for- “Win, Win!”
– Forcing resolution-may lead to “No.”
• Get agreement to talk again.
• Maintaining contact is your first principle.
MOTIVATION
• Waning motivation is a common element for
trial participants with adherence difficulties,
e.g. clinical trial fatigue.
• Strong resolve is critical, if one is to cope
with problems of life and continue trial
participation.
PARTICIPANT MOTIVATION
How staff can contribute to it
• Must know continuing importance of the trial.
• Information from other studies.
– Be proactive-don’t wait for them to ask/tell you.
• Remind them that the DSMB meets
regularly.
– Considers potential benefit and harm.
– Last meeting ended-vote for continuation.
• Reassure participant of your position.
NEGOTIATION
“YOU DON’T GET IN LIFE WHAT YOU
DESERVE-YOU GET WHAT YOU NEGOTIATE!”
Ronald Karass-in Flight Add
NEGOTIATED ADHERENCE REGIMENS
(Informal Contracts)
• Reduced Dose
• “Drug Holiday”
• Follow-up only
• Final assessment at trial end
RECHALLANGE: RESTARTING
STUDY MEDICATION
• INFORMAL CONTRACT - BE CAUTIOUS.
• What was the reason for stopping?
– Has that reason gone away?
• Can you make small steps to your goal?
• Part of a “Win, Win” is participant success
WITHDRAWAL OF CONSENT:
HOW TO DEAL WITH IT
• Use your “Pause Button” immediately.
• Few will want to harm what is worthwhile.
• You get what you negotiate.
– “Seek first to understand, then be understood.”
•
•
•
•
Know EXACTLY what your participant means.
Make it clear you understand their position.
Make clear your goal of minimum adherence.
“Is there a way both can achieve goals?”
Summary
• Recruitment
– Plan, design for success
– Timely Enrollment
– 3 Recruitment Strategies
• Adherence
– Develop a bottom line
– Set adherence goals depending on protocol
– Non-adherence adds to sample size by p2
– Teach adherence techniques, plan for poor adherence
Summary
• Complete Follow Up
– Dropouts can drop back in
– Know primary outcome status on every
randomized participant