Julio A. Ramirez, MD, FACP Professor of Medicine Chief, Infectious Diseases Division, University of Louisville Chief, Infectious Diseases Section, Veterans Affairs Medical Center Louisville, Kentucky, USA Principles of Clinical & Translational Research “Interventional Studies”

Interventional Studies 4. Disadvantages of Interventional Studies 4. Disadvantages of Interventional Studies 1. Classifications of Interventional Studies 1. Classifications of Interventional Studies 3. Advantages of Interventional Studies 3. Advantages of Interventional Studies Clinical & Translational Research 2. Analyzing Results of Interventional Studies 2. Analyzing Results of Interventional Studies

Investigator takes a passive role Study Designs Study Designs Study Subjects Planning The Study Investigator takes an active role

Investigator takes a passive role Study Designs Study Designs Study Subjects Planning The Study Investigator takes an active role Observational Designs Interventional Designs

Experimental Group Planning The Study The investigator applies a treatment (intervention) and observes the effect on an outcome O Control Group O A B Interventional Study Interventional Study Intervention YES Intervention NO

Planning The Study The investigator applies a treatment (intervention) and observes the effect on an outcome Interventional Study Interventional Study The principle of “clinical equipoise”: genuine uncertainty within the expert medical community about the preferred treatment Experimental Group O Control Group O A B Intervention YES Intervention NO

Planning The Study Interventional Study Interventional Study Randomized StudyNon-Randomized Study Experimental Group O Control Group O A B Intervention YES Intervention NO

Planning The Study Interventional Study Interventional Study Randomized StudyNon-Randomized Study Experimental Group O Control Group O A B Intervention YES Intervention NO True ExperimentQuasi Experiment

Planning The Study Subjects Time R Interventional Study Interventional Study Experimental Group O Control Group O A B 1. Patient randomization 2. Application of interventions 3. Measurement of outcomes Randomized StudyNon-Randomized Study IC

Planning The Study Interventional Study Interventional Study Experimental Group O Control Group O A B Intervention YES Intervention NO Non Randomized Controlled Trials rely on participants who: 1)volunteer to join the study 3) conveniently turn up (at a clinic) while the study is being conducted

Planning The Study Interventional Study Interventional Study Non-Randomized Study: The study groups are opportunistically rather than randomly composed Experimental Group O Control Group O A B Intervention YES Intervention NO Non Randomized Controlled Trials rely on participants who: 1)volunteer to join the study 3) conveniently turn up (at a clinic) while the study is being conducted

Planning The Study Subjects Time R Interventional Study Interventional Study Experimental Group O Control Group O A B 1. Patient randomization 2. Application of interventions 3. Measurement of outcomes Blinded StudyUnblinded Study/Open Label Study IC

Planning The Study Subjects Time R Interventional Study Interventional Study Experimental Group O Control Group O A B 1. Patient randomization 2. Application of interventions 3. Measurement of outcomes B IC Blinded StudyUnblinded Study/Open Label Study

Planning The Study Subjects Time R Interventional Study Interventional Study Experimental Group O Control Group O A B 1. Patient randomization Parallel GroupCrossover 2. Application of interventions 3. Measurement of outcomes B ClusterHistorical IC

Planning The Study Subjects Time R Interventional Study Interventional Study Experimental Group O Control Group O A B 1. Patient randomization Efficacy Study (Explanatory)Effectiveness Study (Pragmatic) 2. Application of interventions 3. Measurement of outcomes B IC

Planning The Study Subjects Time R Interventional Study Interventional Study Experimental Group O Control Group O A B 1. Patient randomization Placebo-Controlled 2. Application of interventions 3. Measurement of outcomes B Non-Placebo-Controlled IC

Planning The Study Subjects Time R Interventional Study Interventional Study Experimental Group O Control Group O A B 1. Patient randomization SuperiorityNoninferiority 2. Application of interventions 3. Measurement of outcomes B Equivalence IC

Interventional Studies 4. Disadvantages of Interventional Studies 4. Disadvantages of Interventional Studies 1. Classifications of Interventional Studies 1. Classifications of Interventional Studies 3. Advantages of Interventional Studies 3. Advantages of Interventional Studies Clinical & Translational Research 2. Analyzing Results of Interventional Studies 2. Analyzing Results of Interventional Studies

Planning The Study Subjects Time R Interventional Study Interventional Study Experimental Group Outcome Control Group Outcome A B IC Analyzing the Results

Planning The Study Subjects Time R Interventional Study Interventional Study Experimental Group Outcome Control Group Outcome A B IC Analyzing the Results 1. Intention-to-treat2. Per Protocol3. Subgroup Analysis

Interventional Studies 4. Disadvantages of Interventional Studies 4. Disadvantages of Interventional Studies 1. Classifications of Interventional Studies 1. Classifications of Interventional Studies 3. Advantages of Interventional Studies 3. Advantages of Interventional Studies Clinical & Translational Research 2. Analyzing Results of Interventional Studies 2. Analyzing Results of Interventional Studies

Planning The Study Interventional Study Interventional Study A. Randomized Study B. Blinded Study C. Parallel Group D. Efficacy Study F. Superiority E. Placebo-Controlled

Planning The Study What is the best way to prevent the influence of confounding variables? Interventional Study Interventional Study A. Randomized Study B. Blinded Study C. Parallel Group D. Efficacy Study F. Superiority E. Placebo-Controlled

Planning The Study What is the best way to prevent the influence of confounding variables? What is the best way to prevent biased assessment of outcome? Interventional Study Interventional Study A. Randomized Study B. Blinded Study C. Parallel Group D. Efficacy Study F. Superiority E. Placebo-Controlled

Planning The Study Interventional Study Interventional Study A. Randomized Study B. Blinded Study C. Parallel Group D. Efficacy Study F. Superiority E. Placebo-Controlled What is the best way to prevent the influence of confounding variables? Randomization What is the best way to prevent biased assessment of outcome? Blinding

Planning The Study Interventional Study Interventional Study What is the best way to prevent the influence of confounding variables? Randomization What is the best way to prevent biased assessment of outcome? Blinding Randomized Blinded Clinical Trial The best study design to demonstrate causality Randomized Blinded Clinical Trial The best study design to demonstrate causality

Planning The Study Interventional Study Interventional Study Advantages:  Confounding  Bias The best study design to demonstrate causality Randomized Clinical Trial RCTs or Systematic Reviews of RCTs are the highest- quality evidence available

Interventional Studies 4. Disadvantages of Interventional Studies 4. Disadvantages of Interventional Studies 1. Classifications of Interventional Studies 1. Classifications of Interventional Studies 3. Advantages of Interventional Studies 3. Advantages of Interventional Studies Clinical & Translational Research 2. Analyzing Results of Interventional Studies 2. Analyzing Results of Interventional Studies

Planning The Study Interventional Study Interventional Study Advantages:  Confounding  Bias The best study design to demonstrate causality Randomized Clinical Trial RCTs or Systematic Reviews of RCTs are the highest- quality evidence available Disadvantages:  Cost  Time

Planning The Study Interventional Study Interventional Study Advantages:  Confounding  Bias The best study design to demonstrate causality Randomized Clinical Trial RCTs or Systematic Reviews of RCTs are the highest- quality evidence available Disadvantages:  Cost  Time Results may be “false positive” or “false negative”

Planning The Study Interventional Study Interventional Study Statistical Error Randomized Clinical Trial False Positive or Type I Error A.1 in 10 B.1 in 20 C.1 in 50 D.1 in 100 False Positive or Type I Error A.1 in 10 B.1 in 20 C.1 in 50 D.1 in 100

Planning The Study Interventional Study Interventional Study Statistical Error Randomized Clinical Trial False Negative or Type II Error The sample sizes of many "negative" RCTs are too small to make definitive conclusions about the negative results False Negative or Type II Error The sample sizes of many "negative" RCTs are too small to make definitive conclusions about the negative results False Positive or Type I Error A typical RCT will use 0.05 (i.e., 1 in 20) as the probability that the RCT will falsely find two equally effective treatments significantly different False Positive or Type I Error A typical RCT will use 0.05 (i.e., 1 in 20) as the probability that the RCT will falsely find two equally effective treatments significantly different

Planning The Study Interventional Study Interventional Study Advantages:  Confounding  Bias The best study design to demonstrate causality Randomized Clinical Trial RCTs or Systematic Reviews of RCTs are the highest- quality evidence available Disadvantages:  Cost  Time External validity may be limited Results may be “false positive” or “false negative”

Patients in the Universe Truth in the Universe ResearchQuestion StudyResults ActualStudy Patients in the Protocol Truth in the Study StudyProtocol Plan Implement Infer Analysis Analyzing the Data: Drawing Conclusions Analyzing the Data: Drawing Conclusions Patients in the Database Clinical & Translational Research

Patients in the Universe Truth in the Universe ResearchQuestion StudyResults ActualStudy Patients in the Protocol Truth in the Study StudyProtocol Plan Implement Infer Errors Analysis Analyzing the Data: Drawing Conclusions Analyzing the Data: Drawing Conclusions Patients in the Database Clinical & Translational Research

Patients in the Universe Truth in the Universe ResearchQuestion StudyResults ActualStudy Patients in the Protocol Truth in the Study StudyProtocol Plan Implement Infer Analysis Analyzing the Data: Drawing Conclusions Analyzing the Data: Drawing Conclusions Patients in the Database Clinical & Translational Research Errors External Validity Errors Internal Validity

Patients in the Universe ResearchQuestion StudyResults ActualStudy Patients in the Protocol StudyProtocol Plan Implement Infer Analysis Analyzing the Data: Drawing Conclusions Analyzing the Data: Drawing Conclusions Patients in the Database Clinical & Translational Research Errors Internal Validity Truth in the Universe Truth in the Study Infer Errors External Validity Applicability / Generalizability

Patients in the Universe Truth in the Universe ResearchQuestion StudyResults ActualStudy Patients in the Protocol Truth in the Study StudyProtocol PlanPerform Patients in the Database Analyzing the Data: Study Results Analyzing the Data: Study Results Clinical & Translational Research Clinical & Translational Research Infer Infer

Planning The Study Interventional Study Interventional Study Advantages:  Confounding  Bias The best study design to demonstrate causality Randomized Clinical Trial RCTs or Systematic Reviews of RCTs are the highest- quality evidence available Disadvantages:  Cost  Time External validity may be limited Results may be “false positive” or “false negative” Difficulty in studying rare events

Interventional Studies 4. Disadvantages of Interventional Studies 4. Disadvantages of Interventional Studies 1. Classifications of Interventional Studies 1. Classifications of Interventional Studies 3. Advantages of Interventional Studies 3. Advantages of Interventional Studies Clinical & Translational Research 2. Analyzing Results of Interventional Studies 2. Analyzing Results of Interventional Studies