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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

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

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."

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

Types of Clinical Trials

PHASE I TRIAL

Phase II TRIAL

Phase III TRIAL

Phase IV TRIAL

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

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

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

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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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.

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 jinhuimc@163.com before December 10th Notice: the score of the review as a part of total score

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.