RECRUITMENT AND ADHERENCE STRATEGIESEXPERIENCE FROM CLINICAL TRIALS

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RECRUITMENT AND ADHERENCE STRATEGIES/EXPERIENCE
FROM CLINICAL TRIALS

• Jeffrey L. Probstfield, MD
• University of Washington Schools of Medicine and
  Public Health
• Fred Hutchinson Cancer Research Center

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COMPARISON OF SHEP, STOP-H, MRC-92 AND SYST-EUR
CHARACTERISTICS
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COMPARISON OF SHEP, STOP-H, MRC-92 AND SYST-EUR
CHARACTERISTICS
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COMPARISON OF SHEP, STOP-H, MRC-92 AND
SYST-EUROUTCOMES PERCENT REDUCTION
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SYST - EURA WORST CASE ANALYSIS?
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RECRUITMENT

• Successful recruitment has been documented in
  many trials Government and Industry.
• Clinical SitesPast performance predicts future
• Your centers carefully selected past performance
• (http//www.fhcrc.org/science/phs/swog/recrcct/)

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RECRUITMENTFUNDAMENTAL POINT

Friedman, Furberg and DeMets Successful
recruitment depends on developing a careful plan
with multiple strategies, maintaining
flexibility, establishing interim goals and
preparing to devote the necessary effort.
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RECRUITMENT OF STUDY POPULATION

• GET SUFFICIENT POPULATION,
• IN REASONABLE TIME
• RECRUITMENT FAILURE OCCURS
• LATE START
• INADEQUATE PLANNING
• INSUFFICIENT EFFORT
• OVERLY OPTIMISTIC EXPECTATIONS

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RECRUITMENTBASIC ISSUES

• Planning-sources and support
• Strategies and sources
• Conduct-implementation
• Monitoring-short and long term goals
• Problems-expect them to happen
• Solutions-make them occur
• Reasons for Participation

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ADVANTAGESWIDE ENTRY CRITERIA

• Easier screening and recruitment
• More feasible and affordable
• Broader range of variables and larger study size
• More reliable overall result
• Greater public health Impact
• Better opportunity to test subgroup hypotheses

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PLANNING

• Likelihood of getting sufficient participants
• Statistical power-assumes constant enrollment
• Staff-organized and experience
• Institutional support-proper facilities
• Publicity- start before trial
• Multiple strategies- at least 3
• Pilot test strategies
• Contingency plans

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RECRUITMENT DATA13 NHLBI STUDIES
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PATIENTS RANDOMIZED
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SELECT ACCRUAL Projected and Actual
Projected
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ACCORD VANGUARD
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• ACCORD
• MAIN TRIAL

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STRATEGIES AND SOURCES

• POINTS OF EMPHASIS
• Strategies are unpredictable
• Good relationship with medical community
• Respect families and significant others
• Do not be overly aggressive
• run-in period
• Combinations of approaches

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RECRUITMENT STRATEGIES IN CONTROLLED TRIALS

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

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NEW STRATEGY

• WEB-SITE SCREENING TOOL
• LIMITED INFORMED CONSENT
• ENDORSED BY IG OF USA
• QUALIFIED SCREENEES TO GEOGRAPHICALLY CLOSEST
  CLINIC
• CCC AGREED TO WORK OUT PROGRAMMING
• RETAIN DATA WITHOUT IDENTIFIERS AT CCC

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LESSONS LEARNED FROM MASS MAILING

• Integrate into overall recruitment program
• Targeted population-e.g. age, ethnicity
• Post card prompt
• Return
• Phone
• Telephone follow-up
• Repeat mailing same list

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RECRUITMENT OF MINORITIES

• SELECT SITES WITH MINORITIES
• MUST BE INVITED
• MAY NEED HELP WITH APPLICATION
• ADDITIONAL TRAINING MAY BE REQUIRED
• NON- MINORITY SITES MINORITY STAFF
• INVOLVEMENT LOCAL MINORITY PHYSICIANS
• COMMUNITY APPROACHES DIFFERENT
• CHURCHES, FAMILY EVENTS
• INCENTIVES MAY BE DIFFERENT

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CONDUCT

• Successful implementation
• Logging activities recruitment source
• Respect participant privacy
• Prescreening helps workload
• Smooth clinic operation essential
• Regular staff meetings
• Record keeping crucial

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CROSS-TRAINING STAFF

• STAFF ALWAYS ABLE TO DO ALL THINGS
• STAFFING LIMITATIONS-NOT ALL CAN
• DURING RECRUITMENT-IT MUST CONTINUE
• WE HAVENT DONE IT WELL ENOUGH
• WE MUST DO BETTER
• STAFF ABSENCES FOR ANY REASON

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MONITORING

• Establish long and short term goals
• overall and by clinical center
• Tables, graphs and charts
• overall and by clinical center
• Identify reasons if lagging
• overall and by clinical center
• Establish role models-use as a resource

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RECRUITMENT CAREFUL PLANNING

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

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PROBLEMS

• Expect 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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SOLUTIONS

• Accept a smaller sample size
• Relax inclusion/exclusion criteria
• Extend enrollment time
• Change the design
• Recycle previous ineligibles

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AVOIDING SLUMPS PRACTICAL APPROACHES

• WE MUST AVOID FUTURE SLUMPS
• CROSS TRAINING
• STAFF-VACATIONS NOT AT SAME TIME
• HOLIDAYS-THANKSGIVING, CHRISTMAS/NEWYEARS
• PRELOAD
• POSTLOAD

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REASONS FOR PARTICIPATION

• Answer scientific question accurately
• Benefit other patients-current and future
• Benefit to themselves-quality of care
• additional monitoring
• second opinion of their condition
• reassurance regarding diagnosis

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OVERALL RECRUITMENT PROGRAM (1)

• 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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OVERALL RECRUITMENT PROGRAM (2)

• 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 (3)

• Identify excellent staff
• Calendar for ENTIRE recruitment period
• Pretest your recruitment strategies
• Regular review and evaluation of program
• Develop contingency plans
• Flexible clinic hours

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FOR YOUR APPLICATION

• RECRUITMENT MOST IMPORTANT CRITERIA
• DOCUMENT RECRUITMENT CAREFULLY
• DETAILS FROM EACH CLINICAL SITE
• CONSIDER INCLUSION/EXCLUSION CRITERIA
• NOT ON PAPER, IT DOESNT EXIST
• SCREENEES 6 TO 8X PARTICIPANT GOAL
• DESCRIBE TIME TABLE FOR RECRUITMENT
• DESCRIBE POTENTIAL STRATEGIES
• WHICH ONES, WHY

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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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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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CLINICAL TRIALS OVERVIEW

• FUNDAMENTAL POINT PARTICIPANT ADHERENCE
• Many potential adherence problems can be
  prevented or minimized before participant
  enrollment. Once a participant is enrolled,
  taking measures to enhance and monitor
  participant adherence is essential.

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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 k Increase in Sample Size
p k .01 1.02 .05 1.11 .10 1.23 .20 1.56 .30
2.04 .50 4.00
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OVERALL ADHERENCE PLAN (1)

• Develop a bottom line - cannot be
  transgressed(Minimum amount of data which is
  essential)
• Set goals depending on protocol
• Acceptability trial
• Alteration of natural history trial
• Recruitment
• Dont randomize all number eligibles
• Do use run-in and test dosing procedures

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OVERALL ADHERENCE PLAN (2)

• Pay attention to signs and symptoms of potential
  poor adherence
• Adherence team approach
• Constant care taker model
• Optimization of dosing regimen
• Teach adherence techniques
• Use behavioral counseling approach(Interviewing
  and counseling skills)
• Have an intervention plan for poor adherers
• 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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EQUIPOSE AND THE ETHICS OF CLINICAL RESEARCH
Benjamin Freedman, PhD
EQUIPOISE
- a state of genuine uncertainty on the part of
the (all) clinical investigator(s) regarding the
comparative therapeutic merits of each arm in a
trial.
NEJM 1987 317141-145
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ALTERATION OF NATURAL HISTORY TRIAL

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

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PHYSICIANS ABILITY TO PREDICT ADHERENCE (1)

• Dirks and Kinsman least accurate and
  reliable of the assessment procedures
• Antacid regimen - 525 patients - 3-4 wks.
• 27 physicians
• Evaluation by private interview of physician
• Estimate compliance
• Estimate confidence in assessment
• Results Distribution not symmetrical.

• 22 of 27 physicians overestimated. Only 5
  underestimated.
• Estimate 41-86 (med. 70) Measured 36-78
  (med. 46)
• Caron and Roth JAMA, 1968

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PHYSICIANS ABILITY TO PREDICT ADHERENCE (2)

• ATR - 2 years 116 patients/3 physicians
• Stated intake patients 89 Actual measured
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• Those claiming 100 intake (range 2-130),
  mean59
• Physicians estimates 50 higher than actual
• Patients low intake median 13 Estimated 55
  (400)
• Correlation physicians estimate and actual
  0.48
• No improvement with familiarity
• Demographic data - no help. Including race
  matched
• Monthly intake could be mean 80 of daily intake
• Roth and Caron 1978
• Davis, JME 1966 Senior physicians no better than
  junior

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DROPOUTS () AT FIRST AND LAST VISIT
POSTRANDOMIZATION IN LONG-TERM STUDIES
TRIAL DROPOUTS TIME OF VISITS BHAT 3.5, 15 1
mo, 36 mos AMIS 3, 6 1 mo, 36 mos UKP 18, 30 6
mos, 77 mos CAPS 4, 9 3 mos, 12 mos LRC-CPPT 1,
1.8, 6.1 2 wks, 4 wks, 86 mos B-MC 2, 4, 0.6 2
wks, 4 wks, 86 mos
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EQUIPOSE AND THE ETHICS OF CLINICAL RESEARCH
Benjamin Freedman, PhD
EQUIPOISE
- a state of genuine uncertainty on the part of
the (all) clinical investigator(s) regarding the
comparative therapeutic merits of each arm in a
trial.
NEJM 1987 317141-145
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LRC ANALYSIS FOR PREDICTORS OF ADHERENCE

• Adherence after first month associated with
  plt0.01
• Adherence in first month most powerful predictor
• Smoking status
• Age
• Extent of Psychological Distress
• Multiple regression analysis adherence in first
  month is best predictor of subsequent (r.59 or
  r².34)
• r².36 with smoking and other factors added.
• No statistical association with adherence in
  first year of
• Exercise -Overall risk status
• Weight -Motivational level
• Vitamin consumption

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RUN-IN PERIOD

• Pre-randomization procedure
• Single blind
• Placebo used
• Test for "pill-taking behavior

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ACCORD RUN-IN

• Main Issue - Delta in Glycemic Control
• Focus - The overall regimen
• Demonstration of willingness to monitor
• Multiple visits not likely to help
• Already doing multiple medications
• Recycle

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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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ADHERENCE PERFORMANCE TEST-DOSING AND RUN-IN
(NUMBERS EXCLUDED)
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CONCLUSIONS ABOUT PLACEBO RUN-IN PERIOD
What does it do

• Identifies a group of individuals who dont
  adhere well during designated 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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GENERALIZIBILITY
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MECHANISMS INVOLVED IN DEVELOPMENT OF 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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COMPARISON OF DURATION DROPOUT STATUS AND
RECOVERY FROM DROPOUT STATUS 6 MONTHS AND 55
MONTHS
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DISTRIBUTION OF ADHERENCE PROBLEMS IN A CADRE OF
DROPOUTS AND OTHERS IN AN RCT
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RESULTS OF PROGRAM FOR RECOVERY OF DROPOUTS AT
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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FACTORS AFFECTING ADHERENCE TO INTERVENTIONS
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SIGNS AND SYMPTOMS POTENTIAL NON-ADHERENCE
RED FLAGS (1)

• 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 AND SYMPTOMS POTENTIAL NON-ADHERENCE
RED FLAGS (2)

• 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

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ADHERENCE CHECK SHEET FOR RED FLAGS

• Participant behavioral changes from
• previously consistent behavior - 5
• Participant behavioral signs - 7
• Medical Signs - 2
• Clinic environmental changes - 4

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HEALTH BEHAVIOR COUNSELING AND ADHERENCE
MANAGEMENT

• Systematic - Approach to problem identification
• Targeted - Identify and resolve problems
• Data Based - Collect information on behaviors
• Adaptable - Approaches and solutions, tailored
• Generic - Useful for clinical trials and practice

Russell et al, AJM 198578277-282
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NEGOTIATION!!!!

• IN BUSINESS AS IN LIFE--
• YOU DONT GET WHAT YOU DESERVE--
• YOU GET WHAT YOU NEGOTIATE!
• CHESTER KARRASS-IN-FLIGHT ADD

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INFORMAL CONTRACTSTHE ART OF THE DEAL

• Implied circumstance between two people.
• Trust level is critical.
• Professional (staff)Person(participant)
• Trust equation is not equal.
• Will be seen as binding on you by participant.
• Cant just discuss contract-must ask permission.
• Refusal to discuss means identification of old.
• Frequency of contract discussion- an issue.

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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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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 describe 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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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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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.
• 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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INTENTION TO TREAT, ONCE IN, ALWAYS COUNTED
(1)

• Issue Avoid bias
• Fundamental Point
• Excluding randomize subjects from analysis and
• sub-grouping on the basis of the outcome or
• response variables and lead to biased results.
• This bias can be of unknown magnitude and
  direction.

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INTENTION TO TREAT, ONCE IN, ALWAYS COUNTED
(2)

• Preserves the benefits of randomization by
  including
• all randomized patients based on their original
• allocation.
• Safeguards against
• Erroneous claims of efficacy by exclusion of
  those
• who do not adhere to the protocol

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WHAT IS A PI?

• Principal Investigator
• orPractically Invisible
• Clinical sites most successful where the PI is
  engaged and actively involved.
• Coordinators-- be proactive and identify
  activities where PI can help you!

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PRINCIPAL INVESTIGATOR DUTIES

• Select appropriate staff
• Give Coordinators authority
• Develop recruitment plan (with RC)
• Selection of R and A strategies (with C)
• Utilize appropriate monitoring system
• Be flexible and receptive to change in plans
• Inform medical and lay community

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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.