research design 3

8/6/2019 Research Design 3

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RANDOMIZED CONTROLLED TRIAL (RCT)

A controlled experiment to assess thesafety and efficacy of treatments for human

diseases and health problems in which,

treatments are assigned at random.

GENERAL FEATURES:

Direct control of the investigator in theassignment of subjects to the comparison

groups (manipulation of exposure)

-Treatment

- Control

1. Procedure and analysis follow the cohortstudy

-prospective -what will happen

after certain time?

- analysis -comparison of incidence

of outcome in the treatment and

control groups

2. Random allocation to the comparisongroups is the hallmark of an experiment

- Quasi experiment: no randomization/ no

control/ all will have intervention/ all with

medication

- True experiment

o with RCTo EXPERIMENTAL STUDY

3. Strongest evidence for testing hypothesesof causation

Why are RCTs important?

Results of RCTs provide the most securebasis for valid causal inferences

Control for confounders

Prevent selection bias

Hierarchy of evidence for cause-effect relationships

The best study that will give best evidence will be

RCT

Diseases that cant use RCT:

-fatal diseases

-rare diseases

TYPES OF EXPERIMENT

1. According to unit of randomization

o Clinical trial often used with drugs/ newtreatments

o Community trial2. According to purpose

o Preventive/prophylactic trial*Reduction of risk of disease

i.e. reduce recurrence of stroke

o Therapeutic trial*Reduction of symptoms

*Prevention of recurrence

*Reduction of risk of death

I.e. new drugs for prevention of skin

cancer; new drugs for treatment of MI

Subject: Family and CommunityMedicineTopic: Research Design 3Lecturer: Dr. SosaDate of Lecture: August 3, 2011Transcriptionist: Mating Cats =^.^=

Pages: 5SY

2011-2012


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trials must be used where the px

know what they are taking

o I.e. Immunoglobulin for dengue-- Not only placebo is given but with other treatment

( plasma effusions, blood transfusions,

control of shock,

In this particular example standardtreatment was given to both groups

however, the immunoglobin is given

only to one group. This is okay

because the std treatment is given

to both

Issuesintheallocationtotreatmentorcontrol

group

y Randomy Compliance to treatment of the

treatment group

yRandomization:

o The process of assigning individualpatients to different treatment groups

in such a way that each patient has the

same chance, equal to and independent

of every other patient, of being selected

for any particular study or treatmentgroup.

o The idea is to make all study groups asequal as possible at the beginning of

the experiment this allows you to give

the subjects equal chances to be in a

part group; Investigators shouldnt

know between treatment A and B to

prevent selection bias

y Use the same methods ofascertainment for treatment and control

groups

Singleblinded- subject doesnt know, observer and

analyst know

Double blinded- subject and observer doesnt

know; only the analyst knows

Triple blinded- subject, observer, analyst dont

know

***This is where bias of subjects develops. Ie the px

know that the pill is only sugar result to negative

effect on subject even at treatment group; if the

subject knows about the treatment- even at the

placebo group, he/she experiences the effect

Procedures whichcantbeblinded:

-Surgical procedures

-Orthopaedic procedures

(Blinding subjects for these procedures are

considered unethical because the risk is high!!)

Blinding:

o The process of ensuring that almosteveryone involved in the drug trial is

unaware of who is receiving theexperimental drug and who is receiving a

traditional drug treatment, or a placebo,

throughout the duration of the study.

o But there are times when you need tounblind like when severe adverse effects or

fatalities are happening

I f at placebo group you have to

treat

I f at treatment group you have to

unblind and give treatment

Then, you may then include these

subjects in withdrawal group

(failure of treatment)


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Compliance withtreatment:

o The failure of patients to take drugs asprescribed is called noncompliance.

o Investigators cannot be certain that atreatment is or is not effective unless they

can be assured that the treatment group is

actually receiving the treatment.

o How will you if your subject is compliant?--The patient can tell you directly (Hindi ko

po iniinom, sumasakit po kasi tiyan ko eh )

o How to ensure compliance?-- Give them allowance; this is ethical as

long it is not too much and just enough to

comply! (Minimum is P500.00/ patient)

-- Ask for the drug blister to make sure that

he/she drank it

-- Ask for the vial before you give another

set

-- The subject has the right to withdraw

anytime during the treatment, just state in

the report the reason why s/he cannot be

included in the AE of the drug. Do not

forget to treat the patient if his/her reason

for withdrawal is the occurrence of side

effects.

Possiblereasonsfornoncompliancein RCTs

o Misunderstanding of instructions.o Inconvenience of participation.o Side effects of treatment.o Cost of participation.o Forgetfulness.o Disappointment with results.o

Preference for another treatment.

Issuesintheassessmentofoutcomestatus

o Use the same method of ascertainment fortreatment and control groups

o Minimize the follow-up bias (The intentionto treat and evaluation must be equal for

both groups. eg. The control group must be

treated the same way as the exposed

group)

Ethicalissuesin RCTs

o Safety of the proposed treatment orintervention

o Use of placebo in the control groupo It is unethical to not treat and keep

giving placebo on patients having

side effects/ disease during the

study.

o Give standard treatment if it isavailable.

o The safety of the patients is mostimportant.

o Informed consento Patients supply on the whole duration of

the study

o eg. It is unethical to give the patient1 month worth of supply when the

duration of the study is 2 months.

o The patient should get allnecessarysupport.

Ethicalconsiderationsoccurinbothdirections:

o Ethics of introducing new procedures toindividuals where these procedures might

harm them.

o Ethics in withdrawal of interventions fromindividuals when these interventions might

be of benefit to them.

SOME ETHICAL QUESTIONS

o Is it proper to withhold from any patient atreatment that might give him benefit?

o Is the proposed treatment safe for thepatient?

o Is it ethical to use a placebo?o Is it proper for the trial to be in any way

masked?

TO SOLVE SOME ETHICAL ISSUES


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o The trial should have a protocol which issubmitted to an independent committee for

approval.

o Before a trial can be carried out, theconsent of the subjects to participate must

be obtained (informed written consent).

o It is important that each participant shouldreceive an explanation of the trial; subjectsmust be informed that they may be

assigned to either the treatment or control

groups. The risks of having the treatment

must be explained; the possible benefits of

the treatment must also be explained.

o None of the treatment options includedshould be known to be inferior to another

based on previous randomization studies, &

if a standard treatment regimen exists, it

should be used as the control.

MeasureofAssociation:

Relative Risk

Measure ofAssociation

OutcomeTotal

+ -

Inter-

vention

+ A B A + B

- C D C + D

Total A + C B + D

A + B +

C + D

Interpretation:

RR=1 () association

RR1 (+) association

R>1 (+)causative association

RR0%: Treatment is beneficial

=0%:Treatment has no effect

0%: Treatment is beneficial

=0%: Treatment has no effect


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o Assessment of variableso SELECTION BIASo INFORMATION/ MISCLASSIFICATION BIASo CONFOUNDING BIAS

SELECTION BIAS

During the selection of the study population The study population is not representative

of the target population Due to:

Inappropriate sampling method

Non-responders or drop-outs

Comparison groups are different in

ways other than the variable of interest

INFORMATION/MISCLASSIFICATION BIAS

During the data collection: Assessment ofexposure status or outcome status

Subjects are misclassified as to exposure ordisease status

Subjects : Recall Bias, Follow-up Bias (If thepatient can/ cannot recall the effects of the

medication to him/herself)

Observers : Interviewer Bias (Variability intype of questioning makes the answers

variable)

Instruments/Methods: MeasurementBias

CONFOUNDING BIAS

o Occurs when a third variable confuses therelationship between the dependent and

independent variables

Confounder:

o May also produce changes in thedependent variable

o Associated with the independent variableo A variable independently associated with

the intervention or exposure

o Random allocation enableso controlling for known confounderso random distribution of unknown

confounders in treatment groups

Attritionbias

o Bias due to differences between groups inlosses of participants from the study

o Withdrawals, dropouts and protocoldeviation

DETECTION BIAS

o Were persons responsible for outcomeassessments unaware of the assigned

therapy?

ControllingforBiasand Confoundingatthe DesignStage

y Preventing SelectionBiaso Well-defined choice of populationo Use of appropriate sampling

scheme

o Use of hospitalized controls (incase-control studies)

y Preventing Information/ MisclassificationBias

o Clearly written protocols: definitionof terms

o Use of multiple sources of data toverify disease/exposure status

o Blindingo Training of observerso Use valid instruments, procedures

and questionnaires

y Preventing ConfoundingBiaso Randomizationo Matching

Allocation Concealment

y Centralisedo Coded, identical containerso On-site computer systemo Sequentially numbered, sealed,

opaque envelop

AdvantagesofRCTs

o Most efficient for investigating causality,because we can ensure that the cause

precedes the effect (causal relationship

between risk factors & disease).

o Possible confounding factors do not confusethe results.


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o Blinding of participants can reducedistortion in assessment of ourcomes

DisadvantagesofRCTs

o Decreased ability to generalize findings toother groups in the population(external

validity). Problem subjects as the very

young, the elderly & pregnant women who

may have an adverse reaction to treatment

are usually excluded from the trial.

o A long period of time often is required toreach a conclusion.

o A large number of participants may berequired.

o Financial costs are typically high.o Ethical concerns may arise.o Problem of attrition (dropouts).

Question 1

Is quadruple therapy better than triple therapy in

microbiological cure ofTB among adult TB patients

ofUMC in 2011?

Components of Good Research Question

P - population (TB patients)

E/I -exposure/ intervention (quadruple

therapy)

C -comparison (where to compare: triple )

O - outcome (microbiological cure)

M - methodology (what design? RCT)

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Come to me all who labor and are heavy laden,

and I will give you rest. Matthew 11:28

research design 3

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