Experimental/Interventional studies

Introduction

Dear students, as you may know from literatures, there are different epidemiological study
designs that we use during conducting research. Those designs are mainly classified as
observational and interventional study designs. Intervention studies differ from observational
studies in that the investigator assigns the exposure. They are used to determine the effectiveness
of an intervention or the effectiveness of a health service delivery. They can also be used to
establish the safety, cost-effectiveness and acceptability of an intervention. In contrast, analytical
observational studies (i.e. cohort and case control studies) look at the relationships between risk
factors or characteristics of patients and their likelihood of getting a particular disease. There are
two types of intervention studies: randomised controlled trials and non-randomised or quasi-
experimental trials. The randomised controlled trial is considered to be the gold standard of
clinical research because it is the only known way to avoid selection and confounding biases. It
approximates the controlled experiment of basic science. Therefore, this chapter aims to
introduce to you how we can design and conduct randomised controlled trials, types of
randomisation, phases of interventional studies and strength, weakness of interventional studies
and ethical issues during randomised controlled trials.

Learning objectives: After the end of this chapter, you will be able to:

 Define interventional study design

 Discuss characteristics of interventional studies
 Know basic outline of the design of a randomised controlled trial
 Discuss the different types of randomization
 Discuss phases of interventional studies
 Discuss strength and weakness of interventional studies
Contents

Section 1: Definition of interventional study and types of trials

Section 2: Characteristics of intervention studies

Section 3: Randomised controlled trials

3.1. Basic outline of the design of a randomized controlled trial

Section 4: Randomisation

4.1 Simple randomisation

4.2 Block randomisation

4.3 Stratified randomisation

4.4 Minimized randomisation

4.5 Advantage of randomisation

4.6 Disadvantage of randomisation

Section 5: Blinding

Section 6: Phases of intervention studies

Section 7: Strength and weakness

Section 8: Ethics of randomised controlled trials

Pretest questions

1. Define interventional study.

2. What is the benefit of interventional studies over other epidemiological studies?
3. Discuss randomizations in interventional studies and the different methods of
randomization.
4. What are the basic outlines to design randomized controlled trials?
5. What are the strength and weakness of randomized controlled trials?
 1. Definition:

As the name implies, these are studies in which the participants undergo some kind of
intervention in order to evaluate its impact. An intervention could include a medical or surgical
intervention, a new drug, or an intervention to change lifestyle. Because they are the most
methodologically rigorous design, experiments are the default choice for providing evidence for
best practice in patient management, so this discussion will begin with them. The experimental
researcher has control over the intervention, its timing, and dose or intensity. Interventional
studies are often performed in laboratories and clinical studies to establish beneficial effects of
drugs or procedures.

Intervention studies are considered to provide the most reliable evidence in epidemiological
research. Intervention studies can generally be considered as either preventative or therapeutic

Therapeutic trials are conducted among individuals with a particular disease to assess the
effectiveness of an agent or procedure to diminish symptoms, prevent recurrence, or reduce
mortality from the disease.

Preventative trials are conducted to evaluate whether an agent or procedure reduces the risk of
developing a particular disease among individuals free from that disease at the beginning of the
trial, for example, vaccine trials. Preventative trials may be conducted among individuals or
among entire communities

Types of experimental interventions may include:

- Therapeutic agents
- Prophylactic agents
- Diagnostic agents
- Surgical procedures
- Health service strategies
 2. Characteristics of an intervention study

 A distinguishing characteristic of an intervention study is that the intervention (the

preventative or therapeutic measure) being tested is allocated by the investigator to
a group of two or more study subjects (individuals, households, communities).
 Subjects are followed prospectively to compare the intervention vs. the control
(standard treatment, no treatment or placebo).

The main intervention study design is the randomised controlled trial (RCT).

Cross-over trials

A pre-post clinical trial/cross-over trial is one in which the subjects are first assigned to the
treatment group and, after a brief interval for cessation of residual effect of the drug, are shifted
into the placebo /alternative group. Thus, the subjects act as their own control at the end of the
study. However, such studies are not feasible if there is mortality, or if the disease is easily cured
by one of the interventions.

3. Randomised controlled trials

The randomized controlled trial is considered as the most rigorous method of determining
whether a cause-effect relationship exists between an intervention and outcome. The strength of
the RCT lies in the process of randomization that is unique to this type of epidemiological study
design.

Generally, in a randomized controlled trial, study participants are randomly assigned to one of
two groups: the experimental group receiving the intervention that is being tested and a
comparison group (controls) which receives a conventional treatment or placebo. These groups
are then followed prospectively to assess the effectiveness of the intervention compared with the
standard or placebo treatment.

The random allocation of subjects is used to ensure that the intervention and control groups are
similar in all respects (distribution of potential confounding factors) with the exception of the
therapeutic or preventative measure being tested. The choice of comparison treatments may
include an existing standard treatment or a placebo (a treatment which resembles the intervention
treatment in all respects except that it contains no active ingredients).

Note that ethical constraints limit the choice of comparison treatments.

Figure 1. General outline of a two armed randomized controlled trial.
3.1. Basic outline of the design of a randomized controlled trial

1. Development of a comprehensive study protocol. The study protocol will include:

 Aim and rationale of the trial

 Proposed methodology/data collection
 Definition of the hypothesis
 Ethical considerations
 Background/review of published literature
 Quality assurance and safety
 Treatment schedules, dosage, toxicity data etc.

2. Formulation of hypothesis.

3. Objectives of the trial.

4. Sample size calculations.

5. Define reference population.

6. Choice of a comparison treatment - placebo or current available best treatment.

7. Selection of intervention and control groups, including source, inclusion and exclusion
criteria, and methods of recruitment.

8. Informed consent procedures.

9. Collection of baseline measurements, including all variables considered or known to affect the
outcome(s) of interest.

10. Random allocation of study participants to treatment groups (standard or placebo vs. new).

11. Follow-up of all treatment groups, with assessment of outcomes continuously or

intermittently.
12. Monitor compliance and losses to follow-up.

13. Interim analysis.

14. Analysis - comparison of treatment groups.

15. Interpretation (assess the strength of effect, alternative explanations such as sampling
variation, bias).

16. Publication.

4. Randomisation

The aim of randomization is to ensure that any observed differences between the treatment
groups are due to differences in the treatment alone and not due to the effects of confounding
(known or unknown) or bias. That is, that the groups are similar in all respects with the exception
of the intervention under investigation.

Methods of random allocation are used to ensure that all study participants have the same chance
of allocation to the treatment or control group, and that the likelihood of receiving an
intervention is equal regardless of when the participant entered the study. Therefore, the
probability of any participant receiving the intervention or the standard treatment/placebo is
independent of any other participant being assigned that treatment.

The assignment of study subjects to each intervention is determined by formal chance process
and cannot be predicted or influenced by the investigator or participant. In a well designed RCT,
random allocation is determined in advance.

Methods of randomisation - allocation of subjects to intervention and control groups

4.1. Simple randomisation

For example, computer generated random number tables. Simple randomisation is rarely used.

4.2. Block randomisation

Block randomisation is a method used to ensure that the numbers of participants assigned to each
group is equally distributed and is commonly used in smaller trials.

4.3. Stratified randomisation

Stratified randomization is used to ensure that important baseline variables (potential

confounding factors) are more evenly distributed between groups than chance alone may assure.
However, there are a limited number of baseline variables that can be balanced by stratification
because of the potential for small numbers of subjects within each stratum.

4.4. Minimized randomization

This method may be used when the study is sufficiently small and simple randomization will not
result in balanced groups.
Note that deterministic methods of allocation such as by date of birth or alternate assignment to
each group are not considered as random.

4.5. Advantages of randomization

 Eliminates confounding - tends to create groups that are comparable for all factors that
influence outcome, known, unknown or difficult to measure. Therefore, the only
difference between the groups should be the intervention.
 Eliminates selection bias.
 Gives validity in statistical tests based on probability theory.
 Any baseline differences that exist between study groups are attributable to chance rather
than bias. Though this should still be considered as a potential concern.

4.6. Disadvantages of randomization

Does not guarantee comparable groups as differences in confounding variables may arise by
chance.
 5 Blinding in randomized controlled trials

Blinding is a process where the critical information on allocation of treatment is hidden either
from the patients, or from observer or the evaluator in the study. The method of blinding in RCT
is used to ensure that there are no differences in the way in which each group is assessed or
managed, and therefore minimize bias. Bias may be introduced, for example, if the investigator
is aware of which treatment a subject is receiving, as this may influence (intentionally or
unintentionally) the way in which outcome data is measured or interpreted. Similarly, a subject's
knowledge of treatment assignment may influence their response to a specific treatment.

Blinding also involves ensuring that the intervention and standard or placebo treatment appears
the same.

Double blinding is when neither the investigator nor the study participant is aware of treatment
assignments. However, this design is not always possible.

A single blind RCT is when the investigator but not the study participants know which treatment
has been allocated.

6. Phases of interventional studies

Once a new pharmaceutical treatment has been developed, it undergoes testing in a sequence of
phases before it can be approved by regulatory agencies for public use. Randomized trials form
one stage within this broader sequence, which begins with laboratory studies using animal
models, thence to human testing:

Phase I: The new drug or treatment is tested in a small group of people for the first time to
determine safe dosage and to identify possible side effects

Phase II: The drug or treatment is given to a larger group at the recommended dosage to
determine its efficacy under controlled circumstances and to evaluate safety. This is generally
not a randomized study
Phase III: The drug or treatment is tested on large groups to confirm effectiveness, monitor side
effects, compare it to commonly used treatments, and to collect information for the safe use of
the drug. Phase III testing normally involves a series of randomized trials. At the end of this
phase, the drug may be approved for public use. The approval may limit how the drug can be
used, for instance in specific diseases or in certain age groups

Phase IV: After the treatment enters the marketplace, information continues to be collected to
describe effectiveness on different populations and to detect possible side effects. This does not
involve an RCT and is called post-marketing surveillance; it is based on reports of side effects
from physicians (and patients) so it requires the active participation of treating physicians and is
necessary to detect rare or slowly developing side effects.

7. Strength and Weakness of randomised controlled trials

Strengths of a randomized controlled trial

 A well designed randomized control trial provides the strongest evidence of any
epidemiological study design that a given intervention has a postulated effectiveness and
is safe.
 A RCT provides the best type of epidemiological study from which to draw conclusions
on causality.
 Randomisation provides a powerful tool for controlling for confounding, even by factors
that may be unknown or difficult to measure. Therefore, if well designed and conducted,
a RCT minimizes the possibility that any observed association is due to confounding.
 Clear temporal sequence - exposure clearly precedes outcome.
 Provides a strong basis for statistical inference.
 Enables blinding and therefore minimizes bias.
 Can measure disease incidence and multiple outcomes.

Weaknesses of a randomized controlled trial

 Ethical constraints - for example, it is not always possible or ethical to manipulate

exposure at random.
  Expensive and time consuming.
 Requires complex design and analysis if unit of allocation is not the individual.
 Inefficient for rare diseases or diseases with a delayed outcome.
 Generalisability - subjects in a RCT may be more willing to comply with the treatment
regimen and therefore may not be representative of all individuals who might be given
the treatment.

8. Ethics of randomized controlled trials

Some special ethical issues arise in the conduct of all medical experiments. A tension may arise
between two basic principles: it is unethical to deny a patient access to an effective treatment, but
it is also unethical to adopt a new treatment without conducting rigorous testing to prove
efficacy. Therefore, if there is evidence that a treatment is superior, it may be unethical to prove
this in a randomized trial because this would entail denying it to patients in the control group.
Hence, the RCT can only ethically be applied when there is genuine uncertainty as to whether
the experimental treatment is superior; this is termed equipoise. It is also unethical to continue a
trial if the treatment is found to be obviously effective or obviously dangerous. Trials are
therefore planned with pre-set stopping rules that specify conditions under which they should be
prematurely concluded (see box ‘Early termination of trials’). It is also unethical to conduct trials
that offer only marginal benefits in terms of broader social value (e.g., studies that benefit the
publication record of the researcher more than the health of patients or studies which double as
marketing projects). These ethical principles mean that many established treatments will
probably never be evaluated by a controlled trial:

 Appendectomy for appendicitis

 Insulin for diabetes
 Anesthesia for surgical operations
 Vaccination for smallpox
 Immobilization for fractured bones
 Parachutes for jumping out of airplanes, as the British Medical Journal humorously
noted.
Post test questions

1. Define interventional study.

2. What is the benefit of interventional studies over other epidemiological studies?
3. Discuss randomizations in interventional studies and the different methods of
randomization.
4. What are the basic outlines to design randomized controlled trials?
5. What are the strength and weakness of randomized controlled trials?

References

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2. Kendall JM. Designing a research project: Randomised Controlled trials and their principles,
Emerg Med J. 2003, March;20(2)164-168.
3. Hollis S, Campbell F, What is meant by intention to treat analysis? Survey of published
randomised controlled trials. BMJ 1999; 319;670-74.

4. Pocock SJ. Clinical Trials: A practical approach, Chichester, Wiley, 1984.

5. Sibbald B, Roland M, Understanding controlled trials: Why are randomised controlled trials
important?, BMJ 1998, 316:201.
6. Altman DG, Randomisation. BMJ 1991;302;1481-2.