2015-9-31 experimental epidemiology (clinical trial) lecturer: hui jin
TRANSCRIPT
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Experimental Epidemiology (Clinical Trial)
Lecturer: Hui Jin
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Overview of research studies
Introduction of Clinical Trials
Randomized Controlled Trials
Alternatives to Randomized trials
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Overview to Research StudiesWhy Do Research Studies? • To collect data on usual and unusual
events, conditions, & population groups
• To test hypotheses formulated from observations and/or intuition
• Ultimately, to understand better one’s world and make “sense of it”
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Overview to Research Studies Various types of research studies Many classified as “Epidemiological
Studies”
Epidemiology is defined as:
The study of the distribution of a disease or The study of the distribution of a disease or condition in a population and the factors that condition in a population and the factors that influence that distribution.influence that distribution.
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Classifications of Research Studies: Two Main Types
Observational studies:Observational studies:• Groups are studied & contrasts made between
groups• The observed data collected are analyzed
Experimental Studies:Experimental Studies:• Study the impact of a certain therapy• Ultimately the investigator controls factor being
studied• Clinical Trial---RCT( Clinical Trial---RCT( Randomized Controlled TrialsRandomized Controlled Trials))
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Started in the 1920’s by:
The study of epidemics among colonies of experimental animals such as rats and mice.
In modern usage, experimental epidemiology is often equated with :
RANDOMIZED CONTROLLED TRIALS
Clinical Trials
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Animal Studies•Herd immunity
•Reproduction of human disease to confirm aetiological cause
•Study pathogenetic mechanism
•Testing the efficacy of preventive and therapeutic measures (vaccines and drug)
•Completing the natural history of disease
Clinical Trials
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Advantages
• Easy manipulation; Rapid multiplication to provide outcome
Disadvantages
• Not all diseases reproduced in animals; Conclusion may not be applicable in human (e.g.Typhoid vaccine)
Clinical Trials
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What is a clinical trial?
A clinical trial is a controlled experiment in human subjects which involves an intervention and observation of the subsequent effect of that intervention.
Disease …
Desire to impact on patient condition (i.e., improve outcome)
CT tests whether new treatment is effective or better than another treatment
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Meinert: "… a planned experiment designed to assess the efficacy of a treatment in man by comparing the outcomes in a group of patients treated with the test treatment with those observed in a comparable group of patients receiving a control treatment, where patients in both groups are enrolled, treated, and followed over the same time period."
FFD: "… a prospective study that compares the effect and value of an intervention against a control in human beings."
Pocock: "… a planned experiment involving patients, designed to identify a more appropriate treatment for future patients."
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The term “clinical trial” is preferred over “clinical experiment” since
the latter may connote disrespect for the value of human life.
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What is a clinical trial?
A prospective study comparing the effect and value of intervention(s) against a
control in human beings
Clinical Trials
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Figure 7.1. The structure of a clinical trial
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Aims
• to provide scientific proof of an etiological or a risk factor which may permit modification or control of diseases
• to measure the effectiveness and the efficiency of a preventive, control or a treating measure
Clinical Trials
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Why Are Clinical Trials Important? Clinical trials translate results of
basic scientific research into better ways to prevent, diagnose, or treat disease
The more people take part, the faster we can:
- Answer critical research questions
- Find better treatments and ways to prevent disease
Clinical Trials
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Types of Clinical Trials
PHASE I TRIAL
Phase II TRIAL
Phase III TRIAL
Phase IV TRIAL
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Phase I Trial
Objective : To determine an acceptable range of doses and schedules for a new drug
Usually seeking maximum tolerated dose Participants often those that have failed other
treatments Important, however, that they still have
“normal” organ functions
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Phase II Trial
Objective: To determine if new drug has any beneficial activity and thus worthy of further testing / investment of resources.
Doses and schedules may not be optimum Begin to focus on population for whom this
drug will likely show favorable effect
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Phase III Trial
Objective : To compare experimental or new therapies with standard therapy or competitive therapies.
Very large, expensive studies Required by FDA for drug approval If drug approved, usually followed by Phase
IV trials to follow-up on long-range adverse events – concern is safety
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Characterization of Trials
Phase Single Center Multi Center
Randomized Non-Rand. Randomized Non-Rand.
I Never Yes Never Sometimes
II Rare Yes Yes Sometimes
III Yes Use of Historical Controls
Yes Use of Historical Controls
Carrying out a multi-center randomized clinical trial is the most difficult way to generate scientific information.
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What Are the Different Types of Clinical Trials?
Treatment Prevention Early detection/screening Diagnostic Quality of life/supportive care
Clinical Trials
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Treatment Trials
What new treatments can help people with a particular disease?
What is the most effective treatment for people with that disease?
Clinical Trials
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What is the question? Who is the population of interest? What is the intervention? How will the efficacy of the intervention
be assessed?
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What is the Question? Primary
most important (i.e., central question) ideally, only one stated in advance basis for design and sample size
Secondary related to primary also stated in advance limited in number but usually more than 1
Clinical Trials
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Basic Steps in Conducting a RCT
1- Drawing up a protocol
2- Selecting reference and experimental populations
3- Randomization
4- Manipulation or intervention
5- Follow up
6- Assessment of outcome
Clinical Trials
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23/4/19 27Assessment
Reference or Target Population
Select suitable sample
Make necessary exclusions
RANDOMIZE
Experimental group Control group
Manipulation and Follow up
No Consent
Not Eligible
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1- Drawing a protocolA. Background of the study
B. Objectives
1- Primary question and response variable
2- Secondary question and response variable
3- Subgroups hypotheses
4- Adverse effects
C. Design of the study
1- Study population
a) Inclusion criteria
b) Exclusion criteria
Clinical Trials
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1- Drawing a protocol (con’t)
2- Sample size assumptions and estimates
3- Enrollment of participants
a) Informed consent
b) Assessment of eligibility
c) Baseline examination
d) Intervention allocation (randomization)
4- Intervention
a) Description and schedule
b) Measures of compliance
5- Follow up visit description and schedule
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1- Drawing a protocol (con’t)
6- Ascertainment of response variables
a) Training
b) Data collection
c) Quality control
7- Data analysis
8- Termination policy
D. Organization
1- Participating investigators
a) Data coordinating center
b) Labs and other special units
c) Clinical centers
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1- Drawing a protocol (con’t)
2- Study administration
a) Steering committees
b) Data monitoring committee
c) Funding organization
Appendix
Definitions of eligibility criteria
Definitions of response variable
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2- Selecting Reference and Experimental Population
It is the subset of the population of the condition or characteristics of interest defined by eligibility criteria. Three account for the losses: ineligible, eligible but no entry or no cooperation with the conduct of the trial.---highly selected biased sample
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2- Selecting Reference and Experimental Population
Population at Large
Population with the condition
Study Population
Study sample
Definition of the condition
Population w/o condition
Entry criteriaIneligible
EnrollmentEligiblebut not enrolled
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2- Selecting Reference and Experimental Population
Study Populations should be
1- Chosen randomly
2- Stable population (to avoid losses)
3- Informed (Written consent)
4- Representative
5- Eligible
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2- Selecting Reference and Experimental Population
Comparison groups
No Intervention (receiving nothing)
Observation (Hawthorne effect)
Placebo Treatment (placebo effect)
Usual Treatment
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Hawthorne effect: People tend to change their behavior because they are the target and attention in a study, regardless of the specific nature of the intervention they might be receiving.
placebo effect: a placebo, an intervention that is indistinguishable from the active treatment—in physical appearance, color, taste, and smell—but does not have
a specific, known mechanism of action.
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Ethical Considerations
• A well designed trial can answer important public health questions w/o impairing the welfare of the individuals
• International Ethical Guidelines for Biomedical Researches Involving Human Subjects
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3- Randomization
Randomization tends to produce study groups
comparable with respect to known and unknown
risk factors, removes investigator bias in the
allocation of the participants, and guarantees that
statistical tests will have valid significance levels
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3- Randomization
An independent central unit should be
responsible of the process of randomization
and assigning people to intervention groups
Those recruiting or entering patients into a
trial should not be aware of the next
intervention assignment
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Randomization
Clinical Trials
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Why is Randomization Important? So all groups are as alike as possible Provides the best way to prove the
effectiveness of a new agent or intervention
Clinical Trials
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Baseline Assessment
• Done immediately after randomization
• Analysis of baseline comparability
• Stratification and subgrouping according to prognostic variables
• Evaluation of change
• Natural history analysis
* Imbalance can yield misleading results
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4- Manipulation
Intervention application
1) Concurrent parallel study design
2) Cross over study design
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Concurrent Parallel
Study Population
Therapy A
Therapy B
OutcomeOutcome
Randomize
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Cross-over Study Design
Study Population
Group I Group II
Drug A Drug B
1
2
1
2
Randomize
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Data Collection and Quality Control Problems in data collection
Missing data Incorrect data Excess variability
Minimizing poor quality data Available protocol and manual Development of forms Training Pretesting Techniques to reduce variability (Repeat and
Blind assessment)
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Concealment (Blinding)
• Masking of treatment from patient, clinician, designer, analyst
• Of greatest importance if outcome is subjective
• Protect against bias in outcome assessment
• Sometimes may not be feasible
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Quality Monitoring
Monitoring of forms Completeness and consistency even over time
Monitoring of procedures Extreme lab values Internal QC system
Monitoring of drug handling Quality of drug preparation and misslabelling Discoloration or breaking of the capsules or
tablets and changes over time Proper coding of the medications
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Assessing and Reporting Adverse Effects
Should be well defined as the response variable especially the important ones
Comparing the rate of different adverse effects in both groups
Adverse effects are not considered in sample size calculation
Length of follow up give more opportunity for adverse effect to arise
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Participant Adherence (Lost to Follow)
• The shorter a study the more likely is the adherence to the intervention regimen
• Single daily dose drug is preferable than a multiple daily dose drug
• Patient’s belief in his susceptibility to consequences of the disease
• Serious consequences make participants more likely to adhere
• Higher level of education
• Multicenter trial
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Specific groups
Compliance (non-compliance) is the extent to which patients follow (neglect) medical advice.
responders (nonresponders): the outcomes of patients who initially do (not) improve after treatment
No comparing responders with nonresponders to make a conclusion
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Lost to Follow
Treatment An=1,000
Treatment Bn=1,000
Ten years Follow up
600 alive200 dead
750 alive250 dead
200 lost 0 lost
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Monitoring Response Variables The investigator’s ethical responsibility to the
study participants demands that results in terms of safety and clinical benefit be monitored during the trial.
There are ethical, scientific and economic reasons for evaluation of a trial.
Data Monitoring Committee
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Close Out
Frequently used plan is to follow each participant to a common termination date or when this is not feasible.
Post - Study Follow up Data clean up and verification Storage of study material Dissemination of results
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Treatment Trials
Placebos are almost never used: Placebos are used only when no standard
treatment exists Patients are told of this possibility before
deciding to take part
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Prevention Trials Evaluate the effectiveness of ways to reduce the risk of a particular disease Enroll healthy people at high risk for developing that disease
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Prevention Trials
Action studies (“doing something”)
Agent studies (“taking something”)—also called “chemoprevention studies”
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Chemoprevention Trials
Phase 3 chemoprevention trials compare a promising new agent with either a:
--Standard agent
--Placebo
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Alternatives to Randomized Trials Randomized, controlled, blinded trials are the
standard of excellence for comparisons of treatment effects over time.
However, its limitation: lack of adequate patient Costly Time-consuming absence of conclusive evidence
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Alternatives to randomized trials usually make use of large databases such as those collected for patient care, billing, or administration.
secondary data analysis, answering the research question was not the primary reason for collecting the data.
Alternatives to Randomized Trials
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secondary data’s advantages: Higher degree of confidence, even
subgroups analysis more generalizable relatively inexpensive relatively short time
Alternatives to Randomized Trials
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secondary data’s disadvantages: Carelessly collected and classified Missing some important variables making biased comparisons
The trade-off between speed and ease, or between validity
Alternatives to Randomized Trials
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Comparisons across time and place non-concurrent controls (historical) or concurrent
controls: similar patients in the past, but methods of diagnosis, treatments and prognosis change with time. So RCT is taken as a standard of validity to avoid bias.
Different settings or same settings: it is preferable to
choose both treated and control patients from the same setting, because a variety of factors often result in very different prognoses in different settings, independently of the treatment under study.
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Uncontrolled trials
Assumption: whatever improvement is observed after treatment is because of treatment. This assumption may be unwarranted for several reasons.
Unpredictable Outcome Nonspecific Effects Regression to the Mean Predictable Improvement
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Nonrandom allocation of treatment If caring for the patients decide
Have all the advantages and disadvantages of cohort studies.
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Summary
RCT, a special case of a cohort study with randomly allocated intervention
highly selected Patients, reducing generalizability.
Blinding all participants minimize bias but is not always possible or successful
Alternative methods weaken internal validity of the study
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Compromises with the ideal include making comparisons to experience with past patients, to past
experience with the same patients, or to a concurrent
group of patients who are not randomly allocated. When these compromises are done, the internal validity of the study is weakened.
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Homework To search an article about clinical medicine study using
epidemiological methods, such as case-control study, cohort study, clinical trial study, published in Pubmed
To write a review about it more than 500 words, to explain its advantage and disadvantage.
the file title is your name + student number To send it to [email protected] before December 10th Notice: the score of the review as a part of total score
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Question?
Assigned readings, session 6 and 7 Topic: Clinical trials; randomization; intention-to-
treat analysis; per-protocol analysis; blinding Schulz KF, Altman DG, Moher D. CONSORT
2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010;152:726-32.