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Principles of Clinical Trials Introduction and Learning Objectives Learning Objectives Understand the purposes for conducting clinical trials. Discuss the types of study designs typically used in clinical trials. Discuss critical features of research methodology used in clinical trials, including randomization and blinding. Explain important elements of planning and execution involved in a successful clinical trial. This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 1 History and Ethical Issues Important Events in the History of Clinical Trials First randomized trial1 First use of placebo1 First use of randomization2 1830 1920 1930 Kefauver-Harris Amendments3 1940 1950 1970 1960 1980 1. Peppercorn J et al. In: Gad SC. Clinical Trials Handbook. John Wiley & Sons, Inc.; 2009:115–134. 2. Chalmers I. Int J Epidemiol. 2001;30:1156–1164. 3. Dagher R et al. In: Gad SC. Clinical Trials Handbook. John Wiley & Sons, Inc.; 2009:1153–1171. 5 Important Events in the History of Clinical Trials First randomized trial1 Nuremberg Code4 First use of placebo1 First use of randomization2 1830 1920 1930 Declaration of Helsinki4 Belmont Report4 Kefauver-Harris Amendments3 Tuskegee Syphilis Study ends1 1950 1970 1940 1960 1980 1. Peppercorn J et al. In: Gad SC. Clinical Trials Handbook. John Wiley & Sons, Inc.; 2009:115–134. 2. Chalmers I. Int J Epidemiol. 2001;30:1156–1164. 3. Dagher R et al. In: Gad SC. Clinical Trials Handbook. John Wiley & Sons, Inc.; 2009:1153–1171. 4. Tremellen K et al. In: Gad SC. Clinical Trials Handbook. John Wiley & Sons, Inc.; 2009:1111–1152. This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 6 2 Types of Clinical Research Studies Types of Studies in Clinical Research Observational studies Interventional studies Hybrid designs Observational Studies Case series Patients with complication This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 3 Observational Studies Case series Cross-sectional design Surgical complication No surgical complication Observational Studies Case series Cross-sectional design Case-control design Compare exercise, social isolation, diet, etc. Cases (with dementia) Cases Matched Matched controls controls (no dementia) Retrospectively evaluated over 5 years Observational Studies Case series Cross-sectional design Case-control design Cohort design Cases (regular exercise) Compare percentage with dementia Controls (minimal exercise) Prospectively evaluated over 5 years This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 4 Interventional Studies Pilot Hypothesis-testing – Crossover Washout period Patient Group 1 Placebo Patient Group 2 Drug A Placebo Drug A Evaluate treatment effect Evaluate treatment effect Interventional Studies Pilot Hypothesis-testing – Crossover – Parallel groups Patient Group 1 Placebo Patient Group 2 Drug A Evaluate treatment effect Comparators and Types of Efficacy Trials Comparators used in clinical trials – Placebo – Active comparator (or active control) Andrew S/Veer.com Types of efficacy trials – Superiority: Is drug A more effective than placebo? – Noninferiority: Is drug A no worse than drug B? Photodisc/Photodisc/Getty Ryanking999/Veer.com This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 5 Hybrid Designs Hybrid designs have components of both observational and interventional designs – Large, simple trials Observe groups with little intervention Patient Group 1 Drug A Patient Group 2 Drug B Evaluate treatment effect Rationale for Randomized, Controlled Trials in Drug Development Observational Studies Interventional Studies Rationale for Randomized, Controlled Trials in Drug Development Observational Studies Interventional Studies This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 6 Rationale for Randomized, Controlled Trials in Drug Development Observational Studies Interventional Studies Rationale for Randomized, Controlled Trials in Drug Development Observational Studies Interventional Studies Randomization and Blinding This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 7 Random Assignment to Treatment Groups Placebo Treatment Principle of equipoise Active Treatment Randomization procedures Types of randomization – Simple Random Assignment to Treatment Groups Placebo Treatment Principle of equipoise Randomization procedures Types of randomization – Simple – Blocked Active Treatment Block 1 Block 2 Block 3 Block 4 Block 5 Random Assignment to Treatment Groups Placebo Treatment Principle of equipoise Active Treatment Randomization procedures Types of randomization – Simple – Blocked – Stratified Ages 18–35 y Ages 36–55 y Ages 56–68 y This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 8 Importance of Randomization Random assignment to groups means that the groups are very likely to be similar at baseline Mean Baseline Characteristics by Treatment Group Active Treatment Placebo Treatment Age, y 43.2 44.1 Gender, % male 48.2 46.7 Disease duration, y 3.1 3.3 Disease severity 12.7 13.0 Functional disability index 28.4 26.8 Baseline Characteristic Blinding Blinded: Multiple people involved in the study may be blinded to treatment Nonblinded Andrew S/Veer.com Svetikd/the Agency Collection/Getty Images Patients and caregivers Image Source/Image Source/Getty Images Health care providers altrendo images/Stockbyte/ Getty Images Evaluators Open-label medication Study Planning and Execution This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 9 Types of Efficacy End Points Used in Clinical Trials Type of End Point Definition Examples Definitive (clinical endpoint)1 • Clinically meaningful or biologically definitive outcomes • Measures of how patients feel, function, or survive • May be difficult or costly to measure in a clinical study • Death • Heart attack • Bone fractures Surrogate1 • Measures that serve as substitutes for clinically meaningful end points • Usually biomarkers or physical signs • Should predict definitive outcomes • Cholesterol • Hemoglobin A1c • C-reactive protein Patientreported2 • Reports of health status that come directly from the patient, without interpretation by anyone else • Quality of life • Functional disability • Treatment satisfaction Health economic3 • Measures of the economic impact of disease, including work outcomes, health care costs, and utilization of health care resources • Work disability • Cost of emergency department visits 1. Biomarker Definitions Working Group. Clin Pharmacol Ther. 2001;69:89–95. 2. US Department of Health and Human Services (USDHHS). Guidance for Industry: Patient-Reported Outcome Measures. USDHHS; 2009. 3. Husereau D et al. Clin Ther. 2013;35:356–363. Protecting Study Participants Good clinical practices Institutional review board Data and safety monitoring board OJO Images Photography/Veer.com Participant Selection and Sampling Diverse Population A homogeneous sample is best for detecting clear efficacy signals. A diverse sample is best for generalizing results of the study to the population. Apply Inclusion Criteria Apply Exclusion Criteria Homogeneous Study Sample This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 10 Study Execution Study protocol – Defines procedures in the study – Completed before the study begins Fancy Photography/Veer.com – Followed closely during the study Study sites – Investigator/site experience is important Ryan McVay/Lifesize/ Getty Images – Appropriate patient population available at the site Clinical supplies – Transport, store, monitor, and secure study medication Getty Images Data Analysis Developing a statistical analysis plan – Specify methods for analysis of all data from the study – Provide sample size calculation – Must be in place before unblinding Assessing data quality Interpreting data and drawing conclusions Getty Images Study Timeline Screening Period Washout Period Treatment Period Follow-up Period Placebo Treatment Active Treatment Screening Assessments Randomization/ Baseline Assessments Interim Visit Assessments Adverse Event Reports End of Treatment Assessments This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 11 Schedule of Assessments Clinical Study Protocol CV 105-38x Study Visits Screening Baseline (Day 0) Vital signs X X Laboratory tests X Health status assessment X Electrocardiogram X Blood Chemistries X Assessment/Event Hematology Visit 1 (Week 1) Visit 2 (Week 2) Visit 3 (Week 3) Visit43 (Week 4) Visit 5 (Week 5) X X X X X X X Medical History General Physical Examination Current Medications X X X Screening X X X X Visit 1 (Week 1) X X X X X X X XX X X X X Visit 2 (Week 2) X X X X Health status assessment Electrocardiogram X Baseline (Day 0) X Laboratory tests X X X X X X Study Visits X X Vital signs Inclusion/Exclusion Criteria Final Visit X X X X X Assessment/Event Urine Analysis Visit 6 (Week 6) X X X X X X X X X X X X Clinical Trial Phases in Drug Development Clinical Trial Phases in Drug Development Phase I Phase II Phase III Phase IV The goals, study designs, and number of patients included in a trial will differ considerably across each phase. This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 12 Clinical Trial Phases in Drug Development1 (continued) Phase Patients Goals Phase I 20–100 • Assess toxicity • Determine maximum tolerated dose • Evaluate pharmacokinetics and pharmacodynamics Phase II 100–500 • Demonstrate efficacy (proof of concept) • Establish short-term safety • Refine dose range Phase III ~1,000– 5,000 • Demonstrate efficacy • Confirm safety and tolerability • Support regulatory approval of product information and labeling Phase IV (Postmarketing) Varies • • • • Provide evidence for regulatory authorities Support the marketing of the drug Evaluate subsets of patients Monitor safety over longer periods of time 1. Pharmaceutical Research and Manufacturers of America (PhRMA). Drug Discovery and Development. PhRMA; 2007. Registration of Clinical Trials Clinical trials are registered in a public registry before patient enrollment begins.1 After study completion, results must be posted.2 ClinicalTrials.gov is 1 of several existing registries.3 National Library of Medicine 1. ClinicalTrials.gov. Why Should I Register and Submit Results? US National Institutes of Health; 2012. 2. ClinicalTrials.gov. FDAAA 801 Requirements. US National Institutes of Health; 2012. 3. Tse T et al. Chest. 2009;136:295–303. Virtual Clinical Trials Existing data can be used to generate complex mathematical models of human physiology, aspects of disease, treatments, and health systems.1 Virtual patient populations are created and treatments are applied to them. 2 Models can predict effects of various factors on outcomes:1,3 – Patient characteristics, including comorbidities – Drug interactions – Dosing schedules – Types of treatment – Physician behaviors and practice patterns 1. Holford N et al. Clin Pharmacol Ther. 2010;88:166–182. 2. Nedelman J et al. In: Gad SC. Clinical Trials Handbook. John Wiley & Sons, Inc.; 2009:185–202. 3. Gray B et al. Health Aff. 2012;31:140–149. This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 13 Summary Clinical trials are important for determining the safety and efficacy of new treatments. The study designs and methodologies used in clinical trials have evolved over time and are increasingly more complex. Each type of study design is appropriate for different research questions. Performing a high-quality clinical study involves the expertise of many people and a great deal of careful planning before the study begins. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. NOND-1153276-0001 07/15 This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 14 References Biomarker Definitions Working Group. Clin Pharmacol Ther. 2001;69:89–95. Chalmers I. Int J Epidemiol. 2001;30:1156–1164. ClinicalTrials.gov. Why Should I Register and Submit Results? US National Institutes of Health; 2012. ClinicalTrials.gov. FDAAA 801 Requirements. US National Institutes of Health; 2012. Dagher R et al. In: Gad SC. Clinical Trials Handbook. John Wiley & Sons, Inc.; 2009:1153–1171. Gray B et al. Health Aff. 2012;31:140–149. Holford N et al. Clin Pharmacol Ther. 2010;88:166–182. Husereau D et al. Clin Ther. 2013;35:356–363. Nedelman J et al. In: Gad SC. Clinical Trials Handbook. John Wiley & Sons, Inc.; 2009:185–202. Peppercorn J et al. In: Gad SC. Clinical Trials Handbook. John Wiley & Sons, Inc.; 2009:115–134. Pharmaceutical Research and Manufacturers of America. Drug Discovery and Development. PhRMA; 2007. Tremellen K et al. In: Gad SC. Clinical Trials Handbook. John Wiley & Sons, Inc.; 2009:1111–1152. Tse T et al. Chest. 2009;136:295–303. United States Department of Health and Human Services (USDHHS). Guidance for Industry: Patientreported Outcome Measures. USDHHS; 2009. This is an abbreviated version of the slide presentation. For more information, visit merckacademy.com. Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. NOND-1153276-0002 07/15 15