RECRUITMENT, ADHERENCE, AND RETENTION STRATEGIES TALES FROM CLINICAL TRIALS

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RECRUITMENT, ADHERENCE, AND RETENTION
STRATEGIESTALES FROM CLINICAL TRIALS

• Kelley R. Branch, MD, MSc, FACC
• Associate Professor
• Associate Director, Clinical Trials Services Unit
• Director, Cardiovascular Clinical Trials
• University of Washington

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A Clinical Trial Story

• Once upon a time, there were 4 hypertension
  trials

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COMPARISON OF SHEP, STOP-H, MRC-92 AND SYST-EUR
CHARACTERISTICS
SHEP STOP-H MRC-92 Syst-Eur
Sample Size Sample Size 4736 1627 4396 4695
Mean Age Mean Age 71.5 75.6 70.3 70.3
BP Criteria SBP 160-219 180-230 160-209 160-219
DBP lt90 90 lt114 lt95
Primary Outcome Primary Outcome Total Stroke Total mortality Total stroke Total stroke
Design Design P R DB P R DB P R SB P R DB
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Sys-Eur Trial Accrual
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Trial Follow Up and Adherence
SHEP STOP-H MRC-92 Syst-Eur
Mean F/U Time 54 mo 25 mo 70 mo 30 mo
Mean Baseline BP 170/77 190/104 185/91 174/86
BP Differential 41247.00 19.5/8 14/6 11/5
Adherence Adherence Adherence Adherence Adherence
Lost to F/U 6 0 25 P 5 (116) A 5 (121)
Crossovers 33 23 31 23
Adherence 90/67 84/77 52D 37B 47P 85/72
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SYST - EURA WORST CASE ANALYSIS?
Late Recruitment Fewer Events High Lost to
Follow Up No Definitive Conclusions from the
Trial
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Major Trial Issues

• Recruitment - Timely Enrollment
• Adherence
• Complete Follow Up

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RECRUITMENT

• MANTRA Get Sufficient Population In a
  Reasonable Time

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RECRUITMENTFUNDAMENTAL 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
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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/)
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RECRUITMENTBASIC ISSUES

• Planning
• Entry criteria
• Sources and support
• Strategies
• Conduct - Implementation
• Monitoring - Short and long term goals
• Problems - Expect them to happen
• Solutions - Make them occur

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RECRUITMENT CAREFUL PLANNING

• BE CONSERVATIVE IN YOUR ESTIMATES
• Design easy recruitment
• Establish interim goals
• Have contingency plans
• 3 TO 6 MONTH PERIOD TO SEE RESULTS

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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

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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

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RECRUITMENT DATA Variable Success in 13 NHLBI
Studies
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Not Unusual Recruitment Graph
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Sys-Eur Trial Worst Case
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SELECT Trial AccrualProjected and Actual
Projected
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ACCORD Initial Trial
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ACCORD Main Trial Accrual
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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

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RECRUITMENT STRATEGIES (N3)How to Get Patients

• Chart Review Websites
• Media Efforts Registries
• Direct Mail Blood Bank Donors
• Mass Screening Occupational Screening
• Laboratory Lists Medical Referrals

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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

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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

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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

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POTENTIAL PROBLEMSExpect them-they will occur

• Inadequate funding for screening process
• Unwillingness to refer or allow participation
• Overestimation of prevalence
• Overly rigorous entry criteria

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RECRUITMENT PROBLEMS
MANTRA Get Sufficient Population In a
Reasonable Time

• RECRUITMENT FAILURE CAUSES
• Late start
• Inadequate planning
• Insufficient effort
• Overly optimistic expectations

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POSSIBLE RECRUITMENT SOLUTIONS

• EXTEND THE TIME FOR ENROLLMENT-X?
• RELAX INCLUSION/EXCLUSION CRITERIA-X
• ACCEPT A SMALLER SAMPLE SIZE-X
• RECYCLE PREVIOUS INELIGIBLES-O
• CHANGE THE DESIGN-XXX

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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 TrialsADHERENCE
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ADHERENCE DEFINITION

• Adherence is the extent to which a persons
  behavior coincides with medical or health advice
  in terms of taking medications, following diets,
  using devices, or executing life-style changes.

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TERMINOLOGY ADHERENCE VS. COMPLIANCE

• Adherence is preferred term
• Adherence Active, choice, interactive
• Compliance Passive, non-selective

NHLBI Workshop, Bethesda, MD 1987
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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

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BOTTOM LINEMINIMUM ACCEPTABLE ADHERENCE

• Know primary outcome status on every randomized
  participant.
• Human behavior will allow few to purposely harm a
  worthy scientific project.

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Adherence is bad in clinical trials. Get over it.
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SAMPLE SIZE ADJUSTMENT FOR REDUCED ADHERENCE

• Key Point - Adherence correction term-sample size
  formula, a squared function.
• 2N ?2(z? z?)2 ? (?1 - ?2)2(1-p)2
• p Reduction in Adherence

• p SS Increase
• .01 1.02
• .05 1.11
• .10 1.23
• .20 1.56
• .30 2.04
• .50 4.00

Sample size 2000
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SAMPLE SIZE ADJUSTMENT FOR REDUCED ADHERENCE

• Key Point - Adherence correction 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

• p SS Increase
• .01 1.02
• .05 1.11
• .10 1.23
• .20 1.56
• .30 2.04
• .50 4.00

SHEP
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SAMPLE SIZE ADJUSTMENT FOR REDUCED ADHERENCE

• Key Point - Adherence correction 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

• p SS Increase
• .01 1.02
• .05 1.11
• .10 1.23
• .20 1.56
• .30 2.04
• .50 4.00

MRC
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ALTERATION OF NATURAL HISTORY TRIAL

• Enrolled group must do the intervention
• Looking for efficacy on clinical outcomes
• Adherence is crucial
• e.g., Phase IV trials

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PREDICTORS OF ADHERENCELRC 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

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FACTORS AFFECTING ADHERENCE TO INTERVENTIONS
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RUN-IN PERIOD

• Pre-randomization procedure
• Single blind
• Placebo used for intervention
• Stress test for "pill-taking behavior

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CONCLUSIONS ABOUT PLACEBO RUN-IN PERIOD
What does it do

• Identifies individuals who dont adhere well
  during run-in
• Successful repeat run-in performers (6.9) adhere
  less well during trial
• Those identified representative of those enrolled

What doesnt it do

• Identify all who will adhere poorly to
  intervention

Uncertainties

• If those who fail would all be poor adherers
• Cost/Benefit - advantageous

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TEST-DOSING PERIOD

• Pre-randomization procedure
• Single blind
• Active drug used
• Identify those with severe adverse effects

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Non-Adherence
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SIGNS OF POTENTIAL NON-ADHERENCE 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

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SIGNS OF POTENTIAL NON-ADHERENCE RED FLAGS

1. Sarcasm about trial or study medication
2. Any expression by participant that he/she may
   discontinue study medication
3. Unusual or unexplained change in adherence to
   study medication
4. Unconcern by participant about adherence rate
5. Reassignment to new primary-care manager
6. Reassignment to other new clinic personnel
7. Illness with increased attention to trial
   related disease
8. Hospitalization for any reason
9. Any major change in life style which is imminent

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DISTRIBUTION OF ADHERENCE PROBLEMS IN A CADRE OF
DROPOUTS AND OTHERS IN AN RCT
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MECHANISMS INVOLVED IN PARTICIPANT NON-ADHERENCE

• Lack motivation
• Lack of knowledge (disease, intervention)
• Rejects medical diagnosis
• Denies significance of disease process
• Self-debate over intervention regimen
• Rejects intervention regimen

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MEDICAL THERAPEUTICS TEAM
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WORST CASE ANALYSIS HYPERTENSION IN
ELDERLYSTROKE PREVENTION 5,000 PARTICIPANTS, 5
YRS FOLLOW-UP
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PRINCIPLES AND GOALS PARTICIPANT COUNSELING IN
DROPOUT RECOVERY
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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

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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

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AdherenceContingency Plans
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Contingency Plans

• Identify cause for non-adherence
• Motivation
• Negotiation
• Withdrawl of consent

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DROPOUTSHOW 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.

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DROPOUTSHOW 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.

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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.

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PARTICIPANT MOTIVATIONHow staff can contribute
to it

• Must know continuing importance of the trial.
• Information from other studies.
• Be proactive-dont 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.

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NEGOTIATION

• YOU DONT GET IN LIFE WHAT YOU DESERVE--
• YOU GET WHAT YOU NEGOTIATE!
• Ronald Karass-in Flight Add

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NEGOTIATED ADHERENCE REGIMENS(Informal Contracts)

• Reduced Dose
• Drug Holiday
• Follow-up only
• Final assessment at trial end

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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

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WITHDRAWAL OF CONSENTHOW 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?

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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

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Summary

• Complete Follow Up
• Dropouts can drop back in
• Know primary outcome status on every randomized
  participant