EXPERIMENTAL STUDIES

Presented by: Samarpita Dutta

FRAMEWORK:

Introduction Types of experimental studies Randomized control trial

– Types of randomized controlled trial (RCT)– Phases of clinical trial– Design and conduct of an RCT– General plan and protocol of an RCT– Study population– Randomization– Blinding– Sample size– Trial designs– Expressing results of a randomized control trial– Problems in conduct of an RCT

– Reporting and interpretation  Field trials Community trials Quasi-experimental studies

INTRODUCTION

The idea of epidemiology has its origins almost 2000 years back- Hippocrates – environmental factors can influence the occurrence of disease

Formal beginnings of epidemiology- until 19th century- John Snow- risk of cholera in London was associated with source of drinking water supply

“The study of distribution and determinants of health-related states or events in specified populations, and the application of this study to the control of health problems.” (John Last, 1995)

Epidemiologic studies -observational or experimental

Observational studies allow nature to take its course: the

investigator measures but does not intervene

Experimental studies: investigator intervenes.

EPIDEMIOLOGIC STUDY DESIGNS

TYPE OF STUDY ALTERNATE NAME

UNIT OF STUDY

OBSERVATIONAL Descriptive

Analytical

EcologicalCross-sectionalCase controlCohort

•Co relational•Prevalence•Case reference•Follow-up

•Population•Individuals•Individuals• Individuals

EXPERIMENTAL Randomized controlled studies

Intervention studiesClinical trials

Patients

Field trials Healthy people

Community trials Community intervention studies

Communities

WHY THE NEED FOR EXPERIMENTAL STUDIES?

Because of variability We wouldn’t need a science of experimental design if

– If all units (patients; communities) were identical – If all units responded identically to treatments

We need experimental design to control variability so that treatment effects can be identified

The idea of controlling variability through design has a long history

In 1747 Sir James Lind’s studies of scurvy “Their cases were as similar as I could have them. They all in general had

putrid gums, spots and lassitude, with weakness of their knees. They lay together on one place … and had one diet common to all….

Lind then assigned six different treatments to groups of patients

In 1904, Karl Pearson suggested matching and alternation in typhoid trials

Randomization for experimental studies was established by R.A. Fisher in 1923

In 1937, Sir Bradford Hill advocated alternation of patients in trials rather than randomization

The first modern randomized clinical trial in medicine is usually considered to be the trial of streptomycin for treating tuberculosis

It was conducted by the British Medical Research Council in 1946 and reported in 1948

RANDOMIZED CONTROLLED TRIAL

A randomized controlled trial is an epidemiological experiment to study a new preventive or therapeutic regimen.

Subjects in a population are randomly allocated to groups, usually called treatment and control groups

Results are assessed by comparing the outcome in the two or more groups.

The outcome of interest will vary but may be the development of new disease or recovery from the established disease.

For example, a trial conducted in Bangladesh (Molla et al, 1985) compared the use of rice-based and glucose based oral rehydration solution in 342 patients with acute watery diarrhoea during an epidemic of cholera in Bangladesh.

The study showed that the glucose component of the solution could be replaced by rice powder with improved results, as indicated by decrease in mean stool output and intake of solution

TYPES OF RANDOMIZED CLINICAL TRIAL

THERAPEUTIC TRIAL: In this type therapeutic agent or procedure is given an attempt to cure the disease, relieve the symptom or prolong the survival of those with the disease.

INTERVENTION TRIAL: In this type investigator intervenes before a disease has developed in individuals with characteristics that increase their risk of developing the disease.

PREVENTIVE TRIAL: In this type, an attempt is made to determine the efficacy of a preventive agent or procedure among those without the disease. These trials are also referred to as prophylactic trials.

SR. NO.

TYPE EXAMPLES

1. THERAPEUTIC AZT treatment for AIDS

Simple mastectomy for breast cancer

Early photocoagulation for persons who have developed Diabetic Retinopathy(Early Treatment Diabetic Retinopathy Study Research Group,1991)

Beta Blocker Heart Attack Trial, 1982

2. INTERVENTION AZT treatment of HIV positive patients without AIDS

Mammography to detect asymptomatic breast cancer

Cholesterol lowering drugs to reduce risk of MIe.g. Coronary Primary Prevention Trial, Oslo Heart Study.

3. PREVENTIVE Hepatitis B vaccination to prevent hepatitis and HCC

Education on use of condoms to reduce risk of HIV transmission

PHASES OF A CLINICAL TRIAL

PHASE I– The researchers test an experimental drug or treatment in a

small group of people (20-80) – It is tested for the first time in humans to evaluate its safety– Determine a safe dosage range (Maximally Tolerated dose),

and– Identify any toxic or side effects

PHASE II– The experimental study drug or treatment is given to a larger

group of people (100 300) with the target disease– To look for the pharmacokinetic and pharmacodynamic

effects of the drug on these patients– To see if it is effective and to further evaluate its safety.

PHASE III: – The experimental study drug or treatment is given to large

groups of people (1,000 3,000)– To confirm its effectiveness– Monitor side effects– Compare it to commonly used treatments, and – Collect information that will allow the experimental drug or

treatment to be used safely.

  PHASE IV:

– Also called as the “Post Marketing Surveillance”, – Post marketing studies delineate additional information

including the drug's risks, benefits, and optimal use.

STEPS IN CONDUCT OF A RANDOMIZED CONTROLLED TRIAL

The protocol

Selecting reference and experimental populations

Randomization

Intervention

Follow up

Assessment

GENERAL PLAN AND PROTOCOL OF A CLINICAL TRIAL

The plan of a clinical trial is formally stated in a “protocol”

It contains the objectives and the specific procedures to be used in the trial.

It should be written before the start of the trial

Contain information as the methods for selecting and then allocating the study groups, details on performance of any laboratory tests or administration of drugs

Once the protocol has been written, the epidemiologist compiles the “manual of operations”.

GENERAL OUTLINE OF A PROTOCOL FOR CLINICAL TRIAL

Rationale and background of the study

Specific objectives for the study

Concise statement of the study design (masking, randomization schemes, types and duration of treatments, number of patients)

Criteria for including or excluding patients

Outline of treatment procedures

Definition of all clinical, laboratory and other methods

Methods of assuring integrity of the data

Major and minor outcomes

Provisions for observing and recording side-effects

Procedures for handling problem cases

Procedures for obtaining informed consent forms from the concerned subjects

Procedures for periodic review of the trial

Procedures for termination of the trial

Procedures for analysing results

Procedures for communicating results of trial to study subjects and other interested persons

Appendices: Forms

STUDY POPULATION AND RECRUITMENT OF PARTICIPANTS

POPULATION AT LARGE

POPULATION WITH CONDITION

STUDY POPULATION

STUDY SAMPLE

Populationwithout condition

With condition but ineligible

Eligible but not enrolled

Definition of condition

Entry criteria

Enrolment

RANDOMIZATION

Randomization is of central importance in clinical trials

Critical element of randomization- unpredictability of next assignment.

It prevents selection bias and ensures against accidental bias.

It produces comparable groups, and eliminates the source of bias in treatment assignments

Can be achieved through random number tables or computer generated.

DESIGN AND CONDUCT OF A RANDOMIZED CONTROLLED TRIAL

BLINDING

To remove the sources of bias in the observation 3 procedures have been developed- single masking, double masking or triple masking- also called as blinding.

TYPES OF BLINDING

SINGLE DOUBLE TRIPLE

SUBJECT X X X

OBSERVER - X X

DATA ANALYST - - X

SAMPLE SIZE

Clinical trials need to be designed with adequate power to answer the question being posed.

If N denotes the required sample size in each arm, then it is given by the formula:

2N= 2[ Zα√{2p(1-p)} + Zβ√{pc(1-pc)+ pi(1-pi)}]2

(pc-pi)2

Where, pc= prevalence or anticipated event rate in control arm, pi= prevalence or anticipated event rate in intervention arm, and p= (pc + pi)/2

TRIAL DESIGNS

PARALLEL DESIGN:– Participants are allocated to the intervention and control

groups and stay in that group until the end of the study

CROSS-OVER DESIGN:

– Each participant serves as his or her own control. – In the simplest case, half of the participants would receive

intervention followed by control, and the other half the reverse.

– Advantage -smaller sample size may be required.– Disadvantage-

Outcome in this design needs to be reversible Secondly there is assumption of no carry-over effect

from one period to the next.

FIGURE: DESIGN OF A PLANNED CROSS-OVER TRIAL

Planned cross-over Unplanned cross-over

UNPLANNED CROSS-OVER

FIGURE: UNPLANNED CROSS-OVER

FACTORIAL DESIGN

If there is an interest in studying more than one intervention at a time, a factorial design may be more effective than a parallel design

EXAMPLE OF FACTORIAL DESIGN (PHYSICIANS’ HEALTH STUDY)

BETACAROTENE

+ -

ASPIRIN+ Betacarotene

+AspirinAspirin only

- Betacarotene only Neither Aspirin, nor betacarotene

Randomized22,071

Aspirin11,037

Placebo,11,034

Beta carotene5,517

Placebo5,520

Beta carotene5,520

Placebo5,514

EXPRESSING RESULTS IN AN RCT

Relative risk (RR): – ID(exposed)/ID(unexposed)

Relative risk ratio(RRR):– (1-RR)

Absolute risk reduction(ARR):– ID(unexposed)-ID(exposed)

Efficacy= (Rate in those who receive placebo)- (Rate in those who receive vaccine)

Rate in those who received the placebo

NUMBER NEEDED TO TREAT (NNT): The number of patients who would need to be treated (NNT) to prevent one adverse outcome such as death. This can be calculated by:

NNT= __________________1__________________

(Rate in untreated group) - (Rate in treated group)

or,

1/ Absolute risk reduction(ARR)

NUMBER NEEDED TO HARM (NNH) - Risk of side-effects by calculating the number needed to harm to cause one additional person to be harmed.

INTENT TO TREAT ANALYSIS:

Also called as Randomized or Method Effectiveness Analysis. It compares the outcome according to the randomized group

(Gold Standard) and adherence to intervention is not necessary

Advantages: Randomization is maintained: Treatment assignment is based on chance alone. Randomization provides Theoretical foundation for Statistical

test of significance.

Disadvantages: Does not take into account - protocol violation. Groups do not remain comparable at the end Analysis may underestimate the adverse effect.

PER PROTOCOL ANALYSIS:

In this type analysis is done for only those who fully complied to the protocol

It does not include cross-over in final analysis

Provides a fair idea of efficacy for treatment

However, it may be biased, as randomization is compromised

AS TREATED ANALYSIS

Subject analyzed according to treatment taken or not.

(no relation with randomization).

Non compliant from treatment and vice versa analyzed accordingly.

AT is shown if ITT shows no effect ( why trial done).

REPORTING AND INTERPRETATION OF RCT

Background and rationale

Specification of the primary question and response variables used to assess it.

Pre-specified secondary questions

Nature of the study population including eligibility criteria and informed consent.

Sample size calculations and assumptions used for that calculation.

Basic study design and allocation procedures

Data collection procedures including efforts to minimize biases.

Presentation of key baseline characteristics, by group.

Process measures such as adherence, concomitant therapy use, participants lost to follow.

Results for the primary outcome, secondary outcomes and adverse events.

Adverse effects

Special analyses, such as subgroups, covariate adjustment, and data derived hypothesis.

Interpretation, implications and conclusion in context of the study and information external to the trial

A structured abstract that accurately reflects the body of the paper.

CONSORT STATEMENT

The CONSORT (Consolidated Standards for Reporting Trials) statement is used worldwide to improve the reporting of randomized controlled trials.

The CONSORT 2010 Statement is this paper including the 25 item checklist in the table and the flow diagram.

It provides guidance for reporting all randomised controlled trials, but focuses on the most common design type—individually randomised, two group, parallel trials.

Flow diagram of the progress through the phases of a parallel randomised trial of two groups (that is, enrolment, intervention allocation, follow-up, and data analysis)

PROBLEMS ENCOUNTERED WHILE CONDUCT OF AN RCT

Volunteers and non participants

Non-compliance and refusal to continue in the trial

Lost to follow up

Co-Interventions

FIELD TRIALS

Involve people who are disease free but presumed to be at risk; Data collection takes place in the field, usually among non-

institutionalized people in the general population. Field trials are often huge undertakings involving major logistic

and financial consideration.

COMMUNITY TRIALS

Experiments -involve communities

Unit of study – groups in community

For higher prevalence of risk factors for a certain disease in a population

In a community trial the epidemiologist selects two communities that are similar in many respects as possible.

Community assent for participation in the trial is obtained from various political and other community leaders following which the trial is started.

CONDUCT OF A COMMUNITY TRIAL

Community trials have six stages. Each stage depends upon successful completion of the previous stage:

Development of a protocol

Community selection and recruitment

Establishment of a baseline and community surveillance

Intervention selection and assignment

Oversight and data monitoring

Evaluation

GENERIC DESIGN OF COMMUNITY TRIAL

QUASI-EXPERIMENTAL STUDY

Ideally, an experimental design should have three essential elements of “randomization”; “controls” and “blinding”.

Sometimes one may not be able to randomly allocate subjects into two groups or at times the placebo part of the comparison group may not be possible.

Such circumstances, when an intervention has been given to one group of subjects and not given to another group but the procedure of random allocation or placebo control has not been enforced for various reasons of impracticability or ethics, are called as “Quasi-experimental” studies.

ETHICAL CONSIDERATIONS IN A RANDOMIZED CLINICAL TRIAL (Hill,1977)

REGISTRATION OF CLINICAL TRIALS IN INDIA

The Clinical Trials Registry–India is an online, primary register of the WHO’s International Clinical Trials Registry Platform.

It was launched on 20 July at the National Institute of Medical Statistics, New Delhi.

Registration is voluntary and free

The register is searchable free of charge.

Public disclosure of all 20 items in the WHO Trial Registration Data Set is mandatory for a valid registration number to be allocated.

REFERENCES:

Detels R, Beaglehole R, Lansang MA, Gulliford M. Oxford textbook of public health. Volume 2 . Methods of public health. 5th edition, Oxford University Press, 2009.

Beaglehole R, Bonita R, Kjellstorm T. Basic epidemiology. WHO, Geneva, 2002. Gordis L. Epidemiology. Third edition, Elsevier Saunders. 2004 Lillienfield DE, Stolley PD. Foundations of epidemiology. Third edition. Oxford

University Press, 1994. MacMohan B, Pugh TF. Epidemiology Principles and methods. Fifth edition,

Little, Brown and Company, Boston, 1970. Fletcher RH, Fletcher SW. Clinical epidemiology The essentials. 4th edition,

Lippincot Williams and Wilkins, 2005. Textbook of public health. AFMC, Pune in collaboration with WHO India Country

Office. Kenneth F Schulz, Douglas G Altman, David Moher, for the CONSORT Group.

CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials; BMJ; 2010; 340:698-702.

Donner Allan. Approaches to sample size estimation in the design of clinical trials-a review. Statistics in medicine, 1984; 3; 199-214.