GOOD MORNING

RANDOMIZED CONTROLLED TRIALS

PRESENTED BY:DR. NABEELA BASHA

CONTENTS

INTRODUCTION

STEPS IN CONDUCTING RCT

TYPES OF RCT

ETHICAL CONSIDERATIONS

CONCLUSIONS

REFERENCES

PREVIOUS YEAR QUESTIONS

Upon People Science

INTRODUCTION

Epidemiology is derived from the word “epidemic”

• Epidemiology is the study of the distribution and

determinants of health-related states and events in

specified populations, and the application of this study to

the control of health problems. ( John M. Last in 1988 )

CLASSIFICATION1. Observational studies a. Descriptive studies b. Analytical studies (i) Ecological (ii) Cross-sectional (iii) Case-control (iv) Cohort2. Experimental/Intervention studies a. Randomized controlled trials b. Field trials c. Community trials

EXPERIMENTAL STUDIES

• In the 1920s, “Experimental epidemiology” meant 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”.

• Experimental or intervention studies are similar in approach to cohort studies expecting that the conditions in which study is carried out are under the direct control of the investigator.

• Thus experimental studies involve some action, intervention or manipulation such as deliberate application or withdrawal of the suspected cause or changing one variable in the causative chain in the experimental group while making no change in the control group, and observing and comparing the outcome of the experiment in both the groups.

• This contrasts sharply with observational studies (descriptive, case control, cohort studies), where the epidemiologist takes no action but only observes the natural course of events or outcome.

AIMS

• To provide “scientific proof” of etiological or risk factors which may permit the modification or control of those diseases.

• To provide a method of measuring the effectiveness and efficiency of health services for the prevention, control and treatment of diseases and improve the health of the community.

ADVANTAGES OF EXPERIMENTAL RESEARCH DESIGNS

• Researcher ‘control’ over the intervention and over which

subjects receive any intervention.

• Results are ensured.

• Reliable and well-respected research design

• Individual factors can be identified.

DISADVANTAGES OF EXPERIMENTAL RESEARCH DESIGNS

• Problems in dealing with multiple causation; isolating

individual factors may over-simplify complex issues.

• Ethical issues.

• Researcher bias and subjectivity in research design, methods

and analysis.

• Hawthorne effect upon groups being researched.

RANDOMIZED CONTROLLED TRIALS

• It is mainly in the last 35 to 40 years, determined efforts have been made to use scientific techniques to evaluate methods of treatment and prevention.

• An important advance in this field has been the development of an assessment method, known as Randomized Controlled Trial(RCT).

• It is really an epidemiologic experiment.

What is a Randomized Controlled Trial?

• RCT is widely regarded as gold standard for evaluating health care

technologies as it allows us to be confident that a difference in

outcome can be directly attributed to a difference in the treatments &

not due to some other factor.

• RCTs: Gold Standard

Definition: (Stedman’s medical dictionary)

RCTs are quantitative, comparative, controlled experiments in which investigators study two or more interventions in a series of

individuals who receive them in random order.

The RCT is one of the simplest and most powerful tools in clinical research.

What is this method of carrying out scientific research, and why is it so highly valued?

• A Randomized Controlled Trial is an experiment or study

conducted in such a way that as many sources of bias as

possible are removed from the process.

• Basically, scientific errors of the past have taught us where we

can go wrong, drawing false conclusions from our research.

RCTs are designed to eliminate these major errors.

• For new programmes or new therapies, the RCT is the No.1

method for evaluation.

Progression of Study Design: Clinical Research

The role of oxygen in retrolental fibroplasia RLF

among premature infants.

First Case - Feb. 14, 1941, Dr. Clifford, Boston

Case Series - 1941 (Silverman 1980)

Ca-Co Study (53 RLF Children, 298 Normal Children)

Association was observed. Still, it was postulated that poor

health of infants necessitated longer hours of oxygen. Poor

health and no oxygen use caused RLF.

I RCT: Gallinger Muncipal Hospital, Washington, DC

II Collaborative Multi-centred Trial

Confirmed the role of oxygen in the etiology of Retrolental

Fibroplasia

DESIGN OF RANDOMIZED CONTROLLED TRIAL

Select suitable population(reference or target)

Select suitable sample(experimental or study)

Make necessary exclusionsThose not eligible

Those who do not wish to give consent

Randomize

Experimental Control

Manipulation & Follow-up

Assessment

1. DRAWING UP A PROTOCOL

• Strict protocol• Aims & objectives• Questions to be answered• Criteria of selection: Study & control groups• Intervention to be applied• Standardization of working procedures• Schedules

Strictly followed through the study

Preliminary test runs:

• Sometimes, before a protocol is completed, preliminary(pilot)

studies have to be made to find out the feasibility or

operational efficiency of certain procedures or unknown

effects or the acceptability of certain policies.

• Sometimes it is useful to have a short test run of the protocol

to see whether it contains flaws.

• It is important that the final version of the protocol should be

agreed upon by all concerned before the trial begins.

2. SELECTING REFERENCE AND EXPERIMENTAL POPULATION

a) Reference or target population: It is the population to which the findings of the trial if found

successful, are expected to be applicable.

It may be as broad as mankind or it may be geographically limited or limited to persons in specific age, gender, occupational or social groups.

E.g.: population of the whole city, school children, industrial workers etc

b) Experimental /Study Population:

• It is derived from the reference population.

• Ideally should be randomly chosen from the reference

population.

• It should have the same characteristics as target population.

• It is also important to choose a stable population whose co-

operation is assured to avoid loses to follow-up.

The participants should fulfill the following criteria:

• They must give informed consent.

• Should be representative of the population.

• Should be qualified or eligible for the trial.

E.g.: new drug : treatment of anemia.

3. RANDOMIZATION

• “Heart" of a control trial.

• It is the statistical procedure by which the participants are

randomly allocated into groups usually called the "study" and

"control" groups.

• It is an attempt to eliminate "bias" and allow for

comparability.

• Randomization eliminates “selection bias”

• Randomization is done only after the participant has entered

the study and it can be done by using table of random

numbers.

• In other words, by random allocation, every individual gets an

equal chance of being allocated into either group.

• Finally, randomization guarantees that statistical tests of

significance will be valid.

TYPES OF RANDOMIZATION

1. RANDOM ASSIGNMENT:

Flip a coin

o “Heads”—Tx A

o “Tails”—Tx B

Roll a six-sided dice

o Even number—Tx A

o Odd number—Tx B

2. BLOCK RANDOMIZATION:

• Subjects are divided into ‘blocks’ and randomization is carried

out in each blocks.

• Ex; for two treatments and a block size of four, two of every

four consecutive patients would receive the experimental

therapy and the other two would receive control therapy.

EECC,ECEC, ECCE, CCEE, CECE,……..

3. STRATIFIED RANDOMIZATION:

• It may be important to ensure that the treatment and control

groups are balanced on important prognostic factors that can

influence the study outcome (e.g., gender, ethnicity, age,

socioeconomic status).

• Before doing the trial, the investigator decides which strata are

important and how many stratification variables can be

considered given the proposed sample size.

• A separate simple or blocked randomization schedule is

developed for each stratum.

4. MANIPULATION

• This refers to the deliberate application or withdrawal of the

suspected causal factor as laid down in the protocol.

Eg : drug, vaccine, dietary component, habit

• Manipulation creates an independent variable (drug, vaccine,

new procedure) whose effect is then determined by the

measurement of the final outcome, which constitutes the

dependant variable (incidence of disease, survival time,

recovery period).

5. FOLLOW-UP

• Examination of groups at defined intervals of time under the same

conditions, in a standard manner, with equal intensity, same

circumstances, same time frame.

• Follow-up can vary from a short period to many years.

• Over the years, there may be loss of subjects from either group due

to a number of reasons. This is called as “attrition”.

Death

Migration

Loss of interest

6. ASSESSMENT

The final step in the outcome of the trial is in terms of:

a) Positive results: that is, benefits of the experimental measure

such as reduced incidence or severity of the disease, cost to the

health service or other appropriate outcome in the study and

control groups.

b) Negative results: that is, adverse effects, severity and

frequency of side effects and complications, if any including

death.

• Errors in assessment can lead to “Bias”.

• Bias can arise from three sources:

Subject variation

Observer bias

Evaluation Bias

• Randomization cannot guard against these sort of bias.

• To avoid the above situations, “Blinding” is done.

Blinding :

• Blinding can be done in three ways –

(a) SINGLE BLIND TRIAL : The trial is so planned that the

participant is not aware whether he belongs to the study group or

control group

(B) DOUBLE BLIND TRIAL : The trial is so planned that

neither the doctor nor the participant is aware of the group

allocation and the treatment received

(C) TRIPLE BLIND TRIAL : This goes one step further. The

participant, the investigator and the person analyzing the data are

all "blind". Ideally, of course, triple blinding should be used; but

double blinding is the most frequently used method when a blind

trial is conducted.

TYPES OF RANDOMIZED CONTROLLED TRIALS

BASED ON RANDOMIZATION:

1. Randomized controlled trials: where randomization is used for allocation of products and / or subjects.

2. Non-randomized or “non-experiment” or quasi-experiment: those departing from strict randomization for practical purposes in such a manner that non-randomization does not seriously affect the theoretical basis of conclusions

e.g. natural experiments, water fluoridation studies

BASED ON STUDY DESIGNS:

1. Concurrent parallel study design:

• In this design, comparisons are made between two randomly

assigned groups, one group exposed to specific treatment, and

the other group not exposed.

• Patients remain in the study group or the control group for the

duration of the investigation.

2. Factorial Design:

• Factorial design study may be more efficient than a parallel

design if there is an interest in studying more than one

intervention at a time.

• In addition to efficiency, an advantage to this design is that

one might derive suggestions of differential effect of treatment

in the presence or absence of the other treatment.

3. Cross-over type of study designs:

• With this type of study design, each patient serves as his own

control.

• As before, the patients are randomly assigned to a study group

and control group. The study group receives the treatment

under consideration. The control group receives some alternate

form of active treatment or placebo.

• The two groups are observed over time. Then the patients in

each group are taken off their medication or placebo to allow

for the elimination of the medication from the body and for the

possibility of any "carry over" effect.

• After this period of medication (the length of this interval is

determined by the pharmacologic properties of the drug being

tested), the two groups are switched. Those who received the

treatment under study are changed to the control group therapy

or placebo, and vice versa.

Split mouth design:

• Dental arches, quadrants, sextants, or individual teeth within

patients are randomized for treatment.

• Not applicable for systemic therapies, only to evaluate site-

specific therapies.

• It is often seen in trials that evaluate dental filling materials;

subjects would require two similar cavities on the opposite

side before entering the trial.

• The test material can then be compared in the same

environment as the control material.

BASED ON USES:

1. Clinical trials

2. Preventive trials

3. Risk factor trials

4. Cessation experiment

5. Trial of etiological agents

6. Evaluation of health services

7. Community intervention trials

1. CLINICAL TRIALS

WHO definition of a Clinical Trial:

Any research study that prospectively assigns human participants or

groups of humans to one or more health-related interventions to

evaluate the effects on health outcomes.

Health outcomes include any biomedical or health-related measures

obtained in patients or participants, including pharmacokinetic

measures and adverse events.

EARLY TRIALS

• 1747 - James Lind study on scurvy patients

• 1796 – Edward Jenner experiment with cow pox

• 1881-1900 – Finlay and Reeds experiment to elucidate the mosquito-borne nature of yellow fever

• 1915 – Goldberger’s classical study inducing pellagra by diet deficient in nicotinic acid

• 1945 – Water fluoridation study

• 1953 – first Randomized Controlled Trial on tuberculosis patients

PHASES OF CLINICAL TRIAL

Traditionally, clinical trials of new therapies or devices passthrough the following phases:

1. Phase I clinical trial 2. Phase II clinical trial 3. Phase III clinical trial 4. Phase IV clinical trial

PHASE 0 ( Human microdosing studies):

• Phase 0 is a recent designation for exploratory, first-in-human

trials, also known as human microdosing studies.

• Phase 0 trials gives no data on safety or efficacy.

• Distinctive features include administration of single

subtherapeutic doses of the study drug to a small number of

subjects (10 to 15) to gather data on agent’s

Pharmacodynamics and Pharmacokinetics.

PHASE I (dose ranging / dose escalating/ safety trial)

• Phase I trials are the first-stage of testing in human subjects.

• Normally a small group of 20-100 healthy volunteers will be

recruited.

• These trials are conducted in an inpatient clinic, where the

subject can be observed by full-time medical staff until several

half-lives of the drug have passed.

PHASE II (Safety and intervention tolerance trial):

• Phase II trials are performed on larger groups (100-300) and

are designed to assess the activity of the therapy, as well as to

continue Phase I safety assessments in a larger group of

volunteers and patients.

• Phase II studies are sometimes divided into Phase IIA and

Phase IIB. Phase IIA is specifically designed to assess dosing

requirements, whereas Phase IIB is specifically designed to

study efficacy.

PHASE III

• Phase III studies are randomized controlled trials on large

patient groups (300–3,000 or more) and are aimed at being the

definitive assessment of the efficacy of the new therapy.

• They are the most expensive, time-consuming and difficult

trials to design and run.

• Phase III should be designed and conducted to a high

standard, with precise quantitative results on efficacy and

safety.

PHASE IV ( Post-marketing or surveillance studies):

• Phase IV trials involve the post-launch safety surveillance and ongoing technical support of a drug.

• This is designed to detect any rare or long-term adverse effects over a much larger patient population and timescale than was possible during the clinical trials.

• Such adverse effects detected by Phase IV trials may result in the withdrawal or restriction of a drug.

MULTICENTER TRIALS

• A Multicenter research trial is a clinical trial conducted at

more than one medical centre or clinic.

• Reasons for Multi-center Trials :

1. To recruit necessary number of subjects within a reasonable time.

2. May assure a more representative sample of the study or target population

3. Enables investigators with similar interest and skills to work together on a common problem

2. PREVENTIVE TRIALS

• To prevent or eliminate disease on an experimental basis.

• The most commonly occurring trials are that of vaccines and chemo prophylactic drugs.

Eg: Trial of whooping cough vaccines, Caries vaccine.

• Preventive trials involve larger number of subjects and long span of time to obtain results, hence are associated with greater number of practical problems in their organization and execution

3. RISK FACTOR TRIALS

• It is a preventive trial of risk factors in which the investigator

intervenes to interrupt the usual sequence in the development

of disease for those individuals who have “risk factor” for

developing the disease; often this involves risk factor

modification.

• Can be either “single factor” or “multi factor”.

• E.g.: The WHO promoted trial on primary prevention of

coronary heart disease was largest preventive trial.

4. CESSATION EXPERIMENTS

• An attempt is made to evaluate the termination of a habit,

which is considered to be causally related to a disease.

• If it results in significant reduction of the disease, the

hypothesis of cause is strengthened.

E.g. Smoking & lung cancer

5. TRIAL OF ETIOLOGICAL AGENTS

• To confirm or refute an etiological hypothesis.

• Since most diseases are fatal, disabling or unpleasant human

experiments to confirm etiological hypothesis are rarely

possible.

Ex: Development of retrolental fibroplasia (RLF) in premature

babies exposed to oxygen

6. EVALUATION OF HEALTH SERVICES

• To assess the effectiveness and efficiency.

• Since resources are limited and priorities must be set for the

implementation of a large number of activities.

• Eg: TB regimen in India – which demonstrated that

“domiciliary treatment” of pulmonary tuberculosis was as

effective as the more costlier “hospital treatment”.

7. COMMUNITY INTERVENTION TRIALS (CITs)

• CITs are usually carried out in hospitals or clinics, and are

usually directed at a patient group with specific health

conditions.

• However, randomized experiments are also sometimes done in

the community.

• In these types of studies, the major difference from the RCT is

that the randomization is done on communities rather than

individuals.

• Communities selected for entry to the study have to be similar

as much as is possible, especially since only a small number of

communities will be entered.

• Very often, blinding is not possible in these types of studies,

and contamination and co-interventions become serious

problems.

• Contamination occurs when individuals from one of the

receive the intervention from the other experimental group.

Typical examples of such trials include:

1. Evaluating the need for a service, i.e. Community diagnosis(assessment or evaluation of needs)

2. Evaluating the design of a health service (design evaluation)

3. Evaluating the performance or efficiency of the process of delivery of the services (efficiency or process evaluation)

4. Evaluating the effectiveness and impact of the programme or

procedure (effectiveness or impact evaluation)

5. Relating the outcome to the input and constraints of the

programme (system evaluation) including cost-benefit

analysis.

OTHER TRIAL DESIGNS:

Efficacy and Effectiveness trials:

• An efficacy trial answers the question: "Does this intervention

work under optimal conditions?" An effectiveness trial

answers the question: "Does this intervention work under

usual conditions?"

• Efficacy trials are sometimes called explanatory trials,

whereas effectiveness trials are also known as pragmatic trials.

Explanatory and Pragmatic trials:

• Explanatory trials: main purpose is to provide biological

information ( about the way the drug acts and the way body

reacts to them).

• Pragmatic trials: which aims to test procedures under the

condition in which they would be applied in practice.

Equivalency and Non – inferiority trials:

• Equivalence trial: A randomized clinical trial in which two

distinct agents are compared head-to-head against each other,

and sometimes, but not always, against an inert agent (a

placebo) as well. If two agents work equally well, the

treatment that is less expensive, better tolerated, or more easily

administered, may be preferable to use.

• Non – inferiority trial: A clinical trial that shows that a new

treatment is as good as the standard treatment.

QUALITY ASSESSMENT OF RCT

• Various approaches used:

Checklist approach

Quality scoring system approach

• Quality scores are complicated and tend to vary depending on

the instrument used –so, not encouraged

CHECKLIST APPROACH

QUALITY SCORE APPROACH

Jadad AR, et al. Assessing the quality of reports on randomized clinical trials: Is blinding necessary? Controlled Clin Trials1996;17:1-12. URL: http://www.bmjpg.com/rct/chapter4.html 59

INITIATIVE TO IMPROVE QUALITY OF REPORTING TRIALS

• The Consolidated Standards of Reporting Trials (CONSORT)

has become the gold standard for reporting the results of

RCTs.

• CONSORT encompasses various initiatives developed by the

CONSORT Group to alleviate the problems arising from

inadequate reporting of randomized controlled trials.

• The main product of CONSORT is the CONSORT Statement,

which is an evidence-based, minimum set of recommendations

for reporting randomized trials. It offers a standard way for

authors to prepare reports of trial findings, facilitating their

complete and transparent reporting, and aiding their critical

appraisal and interpretation.

• The CONSORT Statement comprises a 25-item checklist and a

flow diagram. The checklist items focus on reporting how the

trial was designed, analyzed, and interpreted; the flow diagram

displays the progress of all participants through the trial.

CONSORT: checklist and flow diagram

ETHICAL ISSUES IN CLINICAL TRIALS

Clinical trials should follow 3 principles:

• Beneficence: which require that good should result, harm

should be avoided, or that benefits should justify the expected

risk or harm

• Respect for rights: including the free choice of the subject and

protection for those diminished autonomy

• Justice: which require an equal distribution of burden and

benefits

CLINICAL EQUIPOISE (Freedman 1987):

There must be uncertainty as to the usefulness of the intervention

among those knowledgeable about the intervention.

Individual investigators or doctors may have personal beliefs about

the benefits of a new intervention. Those beliefs may prevent those

investigators from participating in or entering into a clinical trial.

INFORMED CONSENT:

• Informed consent of all study participants is essential.

The nature of informed consent may differ in different countries

and cultures, but the concept of individual choice to join or not

join a trial must be universal (Nuremberg Code 1949; World

Medical Association 2000 etc).

INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE

• Safeguards the rights, safety, and well-being of all trial

subjects.

• Composition:

• Should include: at least five members at least one member whose primary area of interest is in

non-scientific area at least one member who is independent of the

institution/trial site

• Documents which should be submitted to a IRB/IEC:

Trial protocol with amendments Written informed consent form Subject recruitment procedure Written information provided to the subjects Investigator’s brochure Available safety information Information about payments and compensation

CONCLUSIONS

• “Gold standard” of research designs

• Individual patients are randomly allocated to receive the

experimental treatment (intervention group) or the standard

treatment (control group)

• Maximizes the potential for attribution

• Good internal validity

• May lack generalisability due to highly selected participants

• Can be costly to set up and conduct, ethical issues.

REFERENCES• Park’s Textbook of Preventive And Social Medicine, K. PARK

. 23rd EDN

• Oxford Textbook of Public Health Vol 2. – The Methods of

Public Health. Fifth Edn. Detels, Beaglehole, Lansang,

Gulliford.

• Essentials of Public Health Dentistry (Community Dentistry),

Soben Peter. 5th EDN

• Essentials of Dental Public Health. Daly, Batchelor, Treasure,

Watt. 2nd EDN

• http://annals.org/article.aspx?articleid=745807

• http://www.consort-statement.org/consort-statement/flow-

diagram

• http://www.ebbp.org/course_outlines/

randomized_controlled_trials/

• http://medical-dictionary.thefreedictionary.com/

equivalence+trial

PREVIOUS YEAR QUESTIONS

• How will you assess the quality of a randomized controlled

trial. (20 marks) (RGUHS SEPTEMBER-2005)

• Clinical trials. (10 marks) (M.D.S Degree examination, 2000)

• Double blind trials. (10 marks) ( M.D.S.Degree examination,

1995)