treatment and prevention: clinical and preventive trials jeffrey l. probstfield, md, facp, facc,...
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TREATMENT AND PREVENTION: CLINICAL AND PREVENTIVE TRIALS
JEFFREY L. PROBSTFIELD, MD, FACP, FACC, FAHA, FESC, FSCT
DIRECTOR, CLINICAL TRIALS SERVICE UNIT
PROFESSOR OF MEDICINE (CARDIOLOGY)
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE
AD. PPROFESSOR OF EPIDEMIOLOGY
UNIVERSITY OF WASHINIGTON SCHOOL OF PUBLIC HEALTH AND COMMUNITY MEDICINE
SHORT COURSE: CLINICAL TRIALS OVERVIEW
• OVERIEW OF TRIALS METHODOLOGY
• BASIC ISSUES: CLINICAL TRIALS DESIGN
• RECRUITMENT AND ADHERENCE
• SUBGROUP ANALYSES
• EQUIVALENCE AND NON-INFERIORITY TRIALS, AND SURROGATE OUTCOMES
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: DEFINITION
A properly planned and executed clinical trial is a powerful experimental technique for assessing the effectiveness of an intervention.
“Ask a good question, get a clear answer!”
not
“Ask a good question, get a positive/negative answer!”
Study Question
In high risk people with IFG, IGT or early diabetes, does omega 3 PUFA supplementation reduce the risk of:
Primary• Cardiovascular death?
Secondary• MI, stroke or CV death?• Mortality?• Presumed arrhythmic death or cardiac arrest?
Years of Follow-up
Pro
po
rtio
n w
ith
eve
nts
0.0
0.0
50
.10
0.1
50
.20
0.2
50
.30
0 1 2 3 4 5 6 7
n-3 fatty acids
Placebo
# at Risk 1 2 3 4 5 6 7
n-3
P
6281 6161 6034 5882 5706 5503 3896 879
6255 6143 6017 5848 5685 5492 3893 837
Time to Adjudicated CV Death
Primary Outcome: CV Death
HR 0.98; 95% CI, 0.87-1.10;P=0.72
Years of Follow-up
Pro
po
rtio
n w
ith
eve
nts
0.0
0.0
50
.10
0.1
50
.20
0.2
50
.30
0 1 2 3 4 5 6 7
n-3 fatty acids
Placebo
# at Risk 1 2 3 4 5 6 7
n-3
P
6281 6161 6034 5882 5706 5503 3896 879
6255 6143 6017 5848 5685 5492 3893 837
Time to Adjudicated All Death
HR 0.98; 95% CI, 0.89-1.07
Death
Fatal arrhythmia
Years of Follow-up
Pro
po
rtio
n w
ith
eve
nts
0.0
0.0
50
.10
0.1
50
.20
0.2
50
.30
0 1 2 3 4 5 6 7
n-3 fatty acids
Placebo
# at Risk 1 2 3 4 5 6 7
n-3
P
6281 6161 6034 5882 5706 5503 3896 879
6255 6143 6017 5848 5685 5492 3893 837
Time to Adjudicated Arrhythmic Death
HR 1.10; 95% CI, 0.93-1.30
INTRODUCTION
Fredrickson - “The Indispensable Ordeal”
Phases - I-IV
Why Needed
Problems in Timing
Ethics
Protocol
References:
Friedman, Furberg & DeMets - Fundamentals of Clinical Trials
Peto, R et al - Br. J Cancer, 1976; 34:585-612 and 1977; 35:1-39
CLINICAL TRIALS OVERVIEW
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: WHAT IS THE QUESTION?
Each clinical trial must have a primary question. The primary question, as well as any secondary or subsidiary questions, should be carefully selected, clearly defined and stated in advance.
CLINICAL TRIALS OVERVIEW
WHAT IS THE QUESTION?
Primary Question Intervention
Secondary Question(s) Response Variable
Adverse Effects Surrogate Outcomes
Ancillary Questions, Substudies
Natural History
Large, Simple Clinical Trials
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: STUDY POPULATION The study population should be defined in advance, starting unambiguous inclusion (eligibility) criteria. The impact that these criteria will have on the study design, ability to generalize and participant recruitment must be considered.
CLINICAL TRIALS OVERVIEW
STUDY POPULATION Definition of Study Population: The study population is the subset of the Population with the condition or characteristics of interest defined by the eligibility criteria:
GeneralizabilityRecruitment
KEY INCLUSION/EXCLUSION CRITERIA (HOPE)
Inclusion CriteriaPatients (age 55) at high risk for cardiovascular
events because of:• any evidence of vascular disease (CHD, stroke,
PVD)
• diabetes + one other coronary risk factor
Exclusion CriteriaHeart failure or low EF
On ACE-I or Vitamin E
KEY HOPE BASELINE CHARACTERISTICS/DRUGS
Mean age 65.9
Female 26.7%
Any CAD 80.6%
MI 52.8%
PVD+AABP 43.4%
Stroke + TIA 10.8%
Any Diabetes 38.3%
Hypertension 46.5%
High Cholesterol 65.8%
ASA/antiplatelet 76.3%
Lipid Lowering 28.9%
Beta-Blockers 39.5%
Diuretics 15.1%
CCB 47.0%
Any anti-ischemicagents
74.4%
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: BASIC STUDY DESIGN
Sound scientific clinical investigation almost always demands that a control group be used against which the new intervention can be compared. Randomization is the preferred way of assigning participants to control and intervention groups.
CLINICAL TRIALS OVERVIEW
BASIC STUDY DESIGN
• Randomized control studies• Nonrandomized concurrent control studies• Historical controls/databases• Cross-over designs• Withdrawal designs• Factorial designs• Hybrid designs• Studies of equivalency• Large simple clinical trials
CROSSOVER DESIGNS
• Each person serves as own control.
• Two period crossover.– 1/2 receive A first and 1/2 B.– Order of interventions excluded.
• Multiple Period crossover.– Order and sequence effects eliminated by design.
• Insertion of “Washout Period”.
FACTORIAL DESIGN
• Motive: to ask two or more questions in same trial in an efficient manner.
• Types:
– 2x2
– 2x2x2 etc.
– Incomplete/Partial
Ramipril + Rosiglitazone
DREAM: 2 x 2 factorial design-main effects analysis
DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
N = 5269 with IFG and/or IGT
Ramipril
Rosiglitazone Placebo
Ramipril + Placebo
PlaceboRosiglitazone +
PlaceboPlacebo +Placebo
FACTORIAL DESIGN
Indications• Interaction - small chance• Interaction - important• Interaction - must estimate
Contraindications• Design too complex - adherence• Power of simple comparison greater• Interaction - large change
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: THE RANDOMIZATION PROCESS
Randomization tends to produce study groups comparable with respect to known and unknown risk factors, removes investigator bias in the allocation of participants, and guarantees that statistical tests will have a valid significance levels.
CLINICAL TRIALS OVERVIEW
THE RANDOMIZATION PROCESS
“Your most powerful ally - preserve at all costs”
• Fixed AllocationsSimpleBlockedStratified
• Adaptive RandomizationBaseline AdaptiveResponse Adaptive
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: BLINDNESS
A clinical trial, ideally, should have a double-blind design to avoid potential problems of bias during data collection and assessment . In studies where such a design is impossible, a single- blind approach and other measures to reduce potential bias are favored.
CLINICAL TRIALS OVERVIEW
BLINDNESS
• Types of TrialsUnblindedSingle-blindDouble-blindTriple-blind
• Special ProblemsMatching of
drugsCoding of drugsUnblinding of
trialsAssessment of
the blind
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: SAMPLE SIZE
Clinical trials should have sufficient statistical power to detect differences between groups considered to be of clinical interest. Therefore calculation of sample size with provision for adequate levels of significance and power is an essential part of planning
CLINICAL TRIALS OVERVIEW
SAMPLE SIZE
Power Level of Significance AdherenceEvent Rate Effect Size Variability
Dichotomous Response VariablesContinuous Response VariablesRepeated Measures“Time to Failure”Equivalency of InterventionsCluster RandomizationMultiple Response Variables
CLINICAL TRIAL RESULTS: TYPE 1 AND 2 ERRORS
TYPE 1 ERROR-FALSE POSITIVE-
‘YOU THINK IT IS THERE, BUT IT ISN’T.”
TYPE 2 ERROR-FALSE NEGATIVE-
“YOU THINK IT ISN’T THERE, BUT IT IS.”
ACE INHIBITORS, NOT THE SAME? HOPE vs. QUIET
HOPE• Effects of ACE Inhibition
(Ramipril 10 mg/day), CVD Morbidity and Mortality in 9297 High-risk CVD Participants
• Primary Outcome: MI/Stroke/CV Death
QUIET• Effects of ACE Inhibition
(Quinapril 20 mg/day) in 1750 Participants with CAD
• Primary Outcome: (MI/CV
Death/VT/VF
QUIET = Quinapril Ischemic Events TrialQUIET = Quinapril Ischemic Events Trial
Lees R, et al. Lees R, et al. Am J Cardiol.Am J Cardiol. 1996;78:1011-1016. 1996;78:1011-1016.The HOPE Study Investigators. The HOPE Study Investigators. N Engl J MedN Engl J Med. 2000;342:145-153.. 2000;342:145-153.
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Days of Follow-up
Kap
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ates
Ramipril Placebo
Primary Outcome - Ramipril vs Placebo
RR=078(0.70-0.86) P=0.000002
Dagenais GR, et al. Lancet. 2006;368:581-88.
Dagenais GR, et al. Lancet. 2006;368:581-88.
Dagenais GR, et al. Lancet. 2006;368:581-88.
Dagenais GR, et al. Lancet. 2006;368:581-88.
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: BASELINE ASSESSMENT
Relevant baseline data should be measured in all study participants before the start of intervention.
CLINICAL TRIALS OVERVIEW
BASELINE ASSESSMENT
• Use of Baseline Comparability at baseline Stratification and subgrouping Evaluation of change Natural history analysis• What Is True Baseline Measurement?• Balance and Imbalance
FAR TOO MUCH DATA IS COLLECTED
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: Recruitment of Study Participants
Successful recruitment depends on developing a careful plan with multiple strategies maintaining flexibility, establishing interim goals, and preparing to devote the necessary effort.
CLINICAL TRIALS OVERVIEW
RECRUITMENT OF STUDY PARTICIPANTS
PLAN, PLAN, PLAN, PLAN
Strategies and SourcesConductMonitoringProblemsSolutionsReasons for Participation
http://depts.washington.edu/cardweb/fellowship/educational-resources.shtml
RECRUITMENT:13 NHLBI STUDIESRECRUITMENT:13 NHLBI STUDIESNumber of Participants
RecruitedRecruitment
Time
Person-Years inPlanned Recruitment
PeriodStudy Actual Actual/Planned Actual/Planned Actual/Planned (R)
AMIS 4,524 1.06 1.00 0.83BHAT 3,837 0.95 1.21 0.82CAPS 502 1.00 1.08 0.82CARDIA 5,182 1.02 1.00 0.86CDP 8,345 1.00 1.22 0.55CSSCD 3,241 1.01 1.13† 1.16HDFP 10,940 1.04 1.50 1.02LRC 3,843 1.08 1.54 0.34MILIS 985 0.82 2.71 0.35MRFIT 12,886 1.07 1.13† 0.81POSCH 838 0.84 1.58† 0.25SHEP Pilot 551 1.10 1.17 0.71TIMI-1* 316 0.93 0.96 0.98*TIM-1 was stopped on the recommendation of Data and Safety MonitoringCommittee; the treatment showed strong evidence of efficacy.† The ‘projected’ time was revised after additional clinics joined the study.
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: DATA COLLECTION AND QUALITY CONTROL
During all phases of a study, sufficient effort should be spent to ensure that all key data critical to the interpretation of the trial are high quality.
CLINICAL TRIALS OVERVIEW
DATA COLLECTION AND QUALITY CONTROL
Problems
DO WE CHECK ALL DATA---IF NOT, WHICH?
• Variability• Minimize Poor Quality
Protocol/Manual Training Reduce VariabilityForms Pretesting Data Entry
• Quality Control Monitoring-Source Documentation• Audits
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: ASSESSING AND REPORTING ADVERSE EFFECTS
Adequate attention needs to be given to the assessment, analysis and reporting of adverse effects to permit valid assessment of potential risk of interventions.
CLINICAL TRIALS OVERVIEW
ASSESSING AND REPORTING ADVERSE EFFECTS
• Determinants of Adverse EffectsDefinitionAscertainmentFrequencyLength of Follow-upIndividual SusceptibilityAnalysis of Non-adherent Participants
• Reporting - FDA Format
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: ASSESSMENT OF HEALTH-RELATED QUALITY OF LIFE
Assessment of the effects of interventions of participants’ HRQL may be an important component of clinical trials, especially those that involve interventions directed at primary or secondary prevention of chronic disease.
CLINICAL TRIALS OVERVIEW
ASSESSMENT OF HEALTH-RELATED QUALITY OF LIFE• Definitions• Primary HRQL Dimensions
Physical FunctioningPsychological FunctioningSocial FunctioningOverall Life Satisfaction/Well BeingPerceptions of Health Stages
•Additional DimensionsNeuropsychological FunctioningPersonal ProductivityIntimacy and Sexual FunctionsSleep DisturbancePainSymptoms
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.
CLINICAL TRIALS OVERVIEW
PARTICIPANT ADHERENCE
“Prevention is the key issue”
Considerations before participant enrollmentMaintaining good participant adherenceSpecial InterventionsAdherence monitoringSpecial populations
EQUIPOSE AND THE ETHICS OF EQUIPOSE AND THE ETHICS OF CLINICAL RESEARCHCLINICAL RESEARCH
Benjamin Freedman, PhD
EQUIPOSE
“ - 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; 317:141-145
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 Adherencek = Increase in Sample Size
SAMPLE SIZE ADJUSTMENT FOR SAMPLE SIZE ADJUSTMENT FOR REDUCED ADHERENCEREDUCED ADHERENCE
p k.01 1.02.05 1.11.10 1.23.20 1.56.30 2.04.50 4.00
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: SURVIVAL ANALYSIS
Survival analysis methods are important in trials where participants are entered over a period of time and have various lengths of follow-up. These methods permit the comparisons of the entire survival experience during the follow-up and may be used for the analysis of time to any dichotomous response variable such as a nonfatal event or an adverse effect.
CLINICAL TRIALS OVERVIEW
SURVIVAL ANALYSIS
•Estimation of the Survival Curveeg. Kaplan - Meier
•Comparison of Two Survival CurvesPoint-by-point comparisonComparison of median survival timeeg. Mantel - Haenszel - Gehan
•Generalizations•Covariate Adjustment
0
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Days of Follow-up
Kap
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ates
Ramipril Placebo
Primary Outcome - Ramipril vs Placebo
RR=078(0.70-0.86) P=0.000002
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: MONITORING RESPONSE VARIABLES
During the trial, response variables need to be monitored for early dramatic benefits or potential harmful effects. Preferably, monitoring should be done by a person or group independent of the investigators. Although many techniques are available to assist in monitoring, none of them should be used as the sole basis for the decision to stop or continue the trial.
CLINICAL TRIALS OVERVIEW
MONITORING RESPONSE VARIABLES
Data and Safety Monitoring Committee (Board)
•Repeated Testing for Significance•Decisions for Early Termination•Statistical Methods Used in Monitoring
Classical Sequential MethodsGroup Sequential MethodsFlexible Group Sequential Methods
“Spending the Alpha”Boundaries - Setting them A-priori
Asymmetrical
MONITORING BOUNDARIIESOVER TIMERamipril versus Placebo
1.51
2.322.75
4.54.31
4.76
-1
0
1
2
3
4
5
Z
O
ct. 9
5
Aug
. 96
Nov
. 97
Nov
. 98
Mar
. 99
Jan.
94
Nov
. 99
Ben
efit
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: ISSUES IN DATA ANALYSIS
Excluding randomized participants or observed outcomes from analysis and sub-grouping on the basis of outcome or response variables can lead to biased results of unknown magnitude or direction.
CLINICAL TRIALS OVERVIEW
ISSUES IN DATA ANALYSIS
•Which Participants Should Be Analyzed?Intention to treatBy treatment analysis - Non-
adherence•Withdrawals•Ineligibility•Poor quality or missing data•Competing events •Covariate adjustment - Baseline, surrogates•Subgroup analysis•Not counting some outcomes•Comparison and multiple variables•“Cutpoints” categorical analysis•Meta-analysis of multiple studies
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: CLOSEOUT
The closeout of a clinical trial is usually a fairly complex process that requires careful planning, if it is to be accomplished in an orderly fashion.
CLINICAL TRIALS OVERVIEW
Termination ProceduresPost Study Follow-upData Clean-up and VerificationStorage of Study MaterialDissemination of Results
CLOSEOUT
“You must account for every participant’s primary outcome status”
SYST - EURSYST - EURA WORST CASE ANALYSIS?A WORST CASE ANALYSIS?
LOST TO N STROKE CHD TOTAL FOLLOW-UP SYST-EUR 4695 124 (250) 131 255 237 Placebo 2297 77 73 150 116 Active 2398 47 58 105 121 SHEP 4736 262 (270) 245 507 10 Placebo 2371 159 141 300 5 Active 2365 103 104 207 5
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: REPORTING AND INTERPRETING OF RESULTS
The investigators have an obligation to review their study and its findings critically and to present sufficient information so that readers can properly evaluate the trial.
Potential Annual Global Impact Ramipril: Assume HOPE Results
• approximately 1 to 1.5 million deaths, myocardial infarction, stroke or revascularization procedures will be prevented globally every year
• Plus impact on CHF, diabetic complications and prevention of diabetes, which will prevent an additional 0.5 to 0.6 million such events/year
If 1/4 of eligible patients with vascular disease in developing countries and 1/2 in developed countries are given Ramipril:
Total benefit of about 2 million events prevented