Presentation on theme: "Inclusion and Exclusion Criteria (Defining the Study Population)"— Presentation transcript:
1 Inclusion and Exclusion Criteria (Defining the Study Population) General considerationsRun-in periods (enrichment)Regression toward the mean
2 Some Issues in Selecting Patients for Clinical Trials Broad or narrow criteriaRecruitment and patient logsNature of clinical sites (patient to research or research to patients)
3 Relationship of Study Sample to Study Population and Population at Large Population without ConditionDefinition of ConditionPopulation with ConditionWith Condition but IneligibleEntry CriteriaStudy PopulationEligible but not EnrolledEnrollmentStudy SampleSource: Friedman, Furberg and DeMets.
4 Internal and External Validity Internal validity – can you attribute the differences among treatment groups to the treatments studiedRandomizationBlindingSample sizeRandom and systematic errors minimizedExternal validity – can you generalize the results to patients outside the trial (the same or larger target population); to whom to the results apply?Inclusion criteriaCharacteristics of those randomizedSetting of trialOutcomes assessed and duration of follow-up
5 The Study Population is Defined by Inclusion and Exclusion Criteria Eligibility Criteria:Should be defined in advanceNo exceptions should be made unless a priori statedCharacterize population (e.g., labeling indication for a new drug/device)Impact of results (assessment by others)Replication of study
6 Considerations in Developing Eligibility Criteria 1. Enroll patients who have potential to benefit from intervention2. Enroll patients for whom there is a high probability of detecting results of intervention3. Do not enroll patients to whom intervention is potentially harmful4. Do not enroll patients at high risk of conditions which preclude ascertainment of endpoints5. Do not enroll patients who cannot comply with protocolFriedman, Furberg, DeMets: Fundamentals of Clinical Trials, Chapter 4
7 Selection of Patients for a Trial Yusuf et al., Stat Med, 9:73-86, 1990.Drug clearly indicated based on current knowledge ExcludeDrug effect unknown:But likely to be beneficial to certain patients Include*And outcome uncertain in certain patients ? IncludeBut theoretical possibility of harm or little hope ?? Include* of benefitSpecial exclusions (competing risk, poor Exclude compliance, inability to ascertain endpoint)Drug contraindicated based on current knowledge Exclude* Include such patients with explicit prior statement of a subgroup hypothesis
8 Advantages and Disadvantages of Opposing Selection Strategies Highly restrictive selection criteriaAdvantagesProvides more precise comparison of the test and control treatmentsResults of the trial less likely to be affected by population variabilityDisadvantagesIncreases the cost and time required for patient recruitmentLimits the generalizability of the study findingsMinimally restrictive selection criteriaMakes patient recruitment easierProvides base for wider generalization of findingsMay obscure treatment effects because of variability in composition of study populationResults of the trial may be confusing, especially if an observed effect appears to be associated with a subgroup of patients in the study and the subgroup is too small to yield a reliable treatment comparisonMeinert C., Clinical Trials. Design, Conduct and Analysis.
9 Usually Favor Minimal Restrictions for Large Outcome Trials A priori, often not clear who will do bestRare that there are large subgroup differences of a qualitative natureFaster answer to questionWith few restrictions, risk stratification after the trial is completed can be performed (more information to formulate treatment guidelines; cannot assess consistency of results in a subgroup if they were excluded)
10 Does it Work? “Practical Clinical Trials: Increasing the Value of Clinical Research for Decision Making in Clinical and Health Policy”Treatments that mimic use in practiceDiverse patient population; minimal exclusionsMany clinical sites; heterogeneous practice settingsMultiple, easily ascertained, clinically relevant endpointsTunis SR et al, JAMA Center for Medicare and Medicaid Services and Agency for Healthcare Research and Quality
11 Explanatory and Pragmatic Trials Explanatory (“laboratory” conditions)Strict selection criteria aimed at creating a homogenous patient populationPragmatic (“normal” conditions)Heterogeneous patient population, one where might expect more non-adherenceSchwartz & Lellouch J Chronic Dis 1967)
12 Recruitment Considerations Always more difficult than anticipated (need a backup plan to the backup plan)Easier with broad eligibility criteria (e.g., large simple trials)Yield not 100%Eligibility criteria (age, prior history, prior treatment, etc.)Exclusion criteriaPhysician refusalPatient refusalMRFIT screened 361,662 men to identify 12,866Must closely monitor to ensure target is met
13 Patient Logs Should You Count Those Not Included? Possible AdvantagesMay provide insights on how to improve slow enrollmentMay allow more reasonable recommendations concerning findings – generalizabilityAllows an assessment of how many eligible patients are being enrolledDisadvantagesTime-consumingOften uncertain where the counting startsIssue of generalizability usually cannot be addressed with logs alone
15 Randomized Trial of Extracranial-Intracranial Arterial Bypass Patients Undergoing Randomization versus Patients Operated on Outside of the Trial in 57 of 71 Participating CentersNo. ofCentersSurveyed/TotalRandomizedto MedicalTreatmentOperatedon Outsidethe TrialRandomizedto SurgeryLocationno. of patientsUnited States 30/Europe 15/Japan 12/Canada 5 * ?TOTAL* These centers were not surveyed; randomization was assumed to have been complete.Sundt, TM. N Eng J Med 316:814-16, 1987.
16 MRFIT Recruitment 22 centers (specially funded to carry out the study) Sources of 12,866 participants (no. centers using source)Census tract listings (door-to-door) (3)Industry/government (15)HMOs (2)Union lists (10)Churches (7)Shopping centers (10)Civic clubs (8)Other (14)
17 ESPRIT HIV – IL-2 ELITE II CHF – Losartan 243 clinical sites25 countries4,150 patients288 sites45 countries3,152 patientsSome trials require many sites and different types of sites
18 Advantages of Multi-Center Trials SAMPLE SIZE!Faster enrollment and therefore faster answer to the research questionExternal validity (generalizability)diversity of patientsconvenience to patientsdiversity of clinical sitesCredibility (each site is a replicate)More clinicians involved in research3rd, as a consequence of exciting advances in the basic sciences, there is a growing pool of clinical research questions. This is one of the reasons why the Director of NIH wants to reengineer the clinical research enterprise. With our current system we have not been keeping pace; it is only going to get worse.4th, unfortunately public confidence in biomedical research is not high. With the exception of a few diseases, like breast cancer and HIV, we have not done a good job of engaging the community in the research process. Instead, the community reads about fraud, about commercial interests, and unsafe treatments.5th, we have tp figure out a way to do trials cheaper. We need to minimize what I call unnecessary defensive documentation and ancillary data. The “what if” game. You must have witnessed that. We need to collect this because what if this happened?.
20 Run-in Periods Def. A period before randomization in which patients are given a treatment (active or placebo) to establish eligibility.Run-ins involve compromises between internal and external validity and are often considered for reasons of efficiency.Pablo-Mendez A, JAMA 1998
21 Rationale for Run-In Periods May be active or placebo; generally considered when:1. Expected compliance is low;2. Substantial behavior change is required (SNaP);3. Contact with participants is infrequent (Physician’s Health Study);4. Possibility of side effects to experimental treatment;5. A large number of “placebo responders” are expected (e.g., pain study);6. It is necessary to assure disease status is stable (or washout);7. Efficacy of treatment on intermediate response variables is required, thereby enhancing clinical applicability (CAST).
22 ITT and Run-InsIf the primary interest (primary estimand) is the difference in outcome between treatment and control groups among patients who can tolerate the treatment, it is better to use a run-in period and ITT analysis than to try and estimate this estimand using only the patients who tolerated the treatment after randomization.
23 Run-In Periods in Trials - Examples To enhance clinical applicability (CAST)To screen for placebo response (pindolol + fluoxetine versus placebo + fluoxetine for depression)To assess tolerability of active treatment (carvedilol for the treatment of heart failure)To screen for non-adherence (Physician’s Health Study used carotene placebo and open-label aspirin during run-in)All have the potential to increase power or reduce sample size requirements
24 Potential Problems with Run-In Periods Carryover effectsBlinding jeopardizedInterpretation of results have to be qualifiedStrategy for enrichment wrongLeber PD and Davis CS, Cont Clin Trials 1998
25 Enrichment DesignsEnrichment designs refers to studies that aim to increase power by choosing patients that are more likely to show benefit than a broader population (personalized medicine).In heart failure and hypertension – initial studies were in more advance patientsActive run-in periods (e.g. CAST) or randomized withdrawal studiesBiomarkers and genetic traits that predict response (e.g., expression of HER-2 in tumors in women with metastatic breast cancer)Temple R, Commun Statist Theory Meth, 1994
26 An Example of Enrichment That Backfired Tacrine for the treatment of Alzheimer’s disease (N Engl J Med 1992;327: )Patients first randomized to 2 doses of tacrine (10 or 20 mg four times a day) or placebo (titration or enrichment phase) for 6 weeks (crossover).Following 2 week placebo washout period, responders in first phase randomized to their best dose or placebo for 6 weeks (parallel group).This was followed by an active treatment phase (uncontrolled).Concerns: Carryover effects, withdrawal effects, maintenance of blind, and generalizabilitySee also Leber and Davis, Cont Clin Trials, 1998 and Encyclopedia of Biopharmaceutical Statistics
27 Factors Influencing Efficiency of Targeted Therapy (Enrichment) Design Heterogeneity of effect across subgroups (e.g., test positive patients expected to do much better than test-negative patients)Prevalence of factor describing responder groupSensitivity and specificity of test to define the respondersThere is often uncertainty. Thus, may first have to determine efficacy oftreatment in both test-positive and test negative patients.Maitournam and Simon, Stat Med 2005
28 SummaryIn most trials eligibility requirements are too restrictive (an opinion)Arguments concerning logs versus no logs arise because of restrictionsTrial entry procedures are simplified with broad inclusion criteriaStudy design teams should carefully consider reasons for exclusionExemptions should not be grantedWe need to determine way of efficiently involving more clinicians in the community in researchThere are advantages and disadvantages to run-ins and enrichment designs. The latter are being actively pursued as part of a “personalized medicine” research agenda.