Download Principles of Clinical Trials Introduction and Learning Objectives

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
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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