Design in Clinical Research

Clinical study design is the formulation of trials and experiments, as well as observational studies in
medical, clinical and other types of research (e.g., epidemiological) involving human beings. The goal of
a clinical study is to assess the safety, efficacy, and / or the mechanism of action of an investigational
medicinal product or procedure, or new drug or device that is in development, but potentially not yet
approved by a health authority (e.g. Food and Drug Administration). It can also be to investigate a drug,
device or procedure that has already been approved but is still in need of further investigation, typically
with respect to long-term effects or cost-effectiveness.

Two types: Treatment & Observational studies

Treatment Studies

Randomized Non- Randomized Adaptive Clinical

controlled Trails controlled Trails Trail

Blinded Non Blinded Sequential Design Rolling Design

Single Double Blinded Triple

Treatment Studies

1. Randomized controlled trail:

A randomized controlled trial (or randomized control trial: RCT) is a type of scientific experiment which
aims to reduce bias when testing a new treatment.

The people participating in the trial are randomly allocated to either the group receiving the treatment
under investigation or to a group receiving standard treatment (or placebo treatment) as the control.
Randomization minimizes selection bias and the different comparison groups allow the researchers to
determine any effects of the treatment when compared with the no treatment (control) group, while
other variables are kept constant.

The RCT is often considered the gold standard for a clinical trial. RCTs are often used to test the efficacy
or effectiveness of various types of medical intervention and may provide information about adverse
 Design in Clinical Research
effects, such as drug reactions. Random assignment of intervention is done after subjects have been
assessed for eligibility and recruited, but before the intervention to be studied begins.

Random allocation in real trials is complex, but conceptually the process is like tossing a coin. After
randomization, the two (or more) groups of subjects are followed in exactly the same way and the only
differences between them are the care they receive. For example, in terms of procedures, tests,
outpatient visits, and follow-up calls, should be those intrinsic to the treatments being compared.

The most important advantage of proper randomization is that it minimizes allocation bias, balancing
both known and unknown prognostic factors, in the assignment of treatments.

Classification of RCT: One way to classify RCTs is by study design. From most to least common in the
healthcare literature, the major categories of RCT study designs are

• Parallel-group – each participant is randomly assigned to a group, and all the participants in the
group receive (or do not receive) an intervention.
• Crossover – over time, each participant receives (or does not receive) an intervention in a
random sequence.
• Cluster – pre-existing groups of participants (e.g., villages, schools) are randomly selected to
receive (or not receive) an intervention.
• Factorial – each participant is randomly assigned to a group that receives a particular
combination of interventions or non-interventions (e.g., group 1 receives vitamin X and vitamin
Y, group 2 receives vitamin X and placebo Y, group 3 receives placebo X and vitamin Y, and
group 4 receives placebo X and placebo Y).

PLACEBO:

 A placebo is a substance or treatment with no active therapeutic effect.

 A placebo may be given to a person in order to deceive the recipient into thinking that it is an
active treatment.
 In drug testing and medical research, a placebo can be made to resemble an active medication
or therapy so that it functions as a control; this is to prevent the recipient(s) and/or others from
knowing (with their consent) whether a treatment is active or inactive, as expectations about
efficacy can influence results.
 This psychological phenomenon, in which the recipient perceives an improvement in condition
due to personal expectations, rather than the treatment itself, is known as the placebo effect or
placebo response.

Role of Placebo in Clinical Trail:

 No standard treatment exists.

 Standard treatment is ineffective.
 Standard treatment is inappropriate for the particular clinical trials.
 The placebo is reportedly effective in treating the disease.
 The disease is mild and lack of treatment is not considered to be medically important
 Design in Clinical Research
 The placebo is given as an add-on treatment to an already existing regimen that is not sufficient
to treat patients.
 The disease process is characterized by frequent spontaneous exacerbations and remission (e.g.,
peptic ulcer).
 “Escape clauses” or points are designed into the protocol

RUN IN PERIOD:

Before randomization of patients a run-in (or lead-in) period of placebo, no active treatment, dietary
control, or active maintenance therapy is usually employed.

Advantages:

 It acts as a washout period to remove effects of previous therapy.

 It can be used to obtain baseline data and to evaluate if patient fulfils study entry criteria.
 It can be used as a training period for patients, investigators, and their staff.
 It helps in identifying placebo responders.
 It provides useful information regarding patient compliance.
 It can be used to estimate and compare the magnitude of possible placebo effects between
groups.
 Design in Clinical Research

2. Non-randomized controlled trial :

An experimental study in which people are allocated to different interventions using methods
that are not random

3. Adaptive Clinical Trail:

These designs are used when an RCT clearly begin to favour one intervention over another.

Advantage: Over time more patients will be assigned to the more successful treatment.

Disadvantages: In most trials, patients are heterogeneous with respect to important prognostic factors.
It does not protect against bias introduced by changes in the types of patients entering into trial
overtime.

Adaptive designs can be of two types: Sequential designs & Rolling designs

Sequential design:

Here the participants are sequentially enrolled in the study and are assigned a treatment (usually at
random).

The efficiency, safety and efficacy of the experiment is improved by changing the rules as the study
progresses.

Various sequential designs are:

 Up & down methods (Most Common)

 Stochastic approximation methods
 Maximum likelihood methods
 Bayesian methods

Problems with sequential designs:

 Uncertainty of sample size.

 Duration of trial cannot be stipulated in advance.
 Resources (funding).

Rolling Design:

 Design that can roll on continually by introducing new treatment options from the evidence
accumulated, dropping those of either proven efficacy or if found not to be effective.
 Make use of intermediate endpoints (in contrast to the traditionally used endpoints that require
longer patient follow-up).
 Design in Clinical Research
Observational Studies:

Observational studies

Cohort Study Case Control study Cross Sectional study Ecological Study

Prospective Retrospective Time series study

Nested Case control

Community Survey

Cohort study:

 A cohort study tracks two or more groups forward from exposure to outcome.
 Compares the experience of a group exposed to some factor with another group not exposed to
the factor. If the former group has a higher or lower frequency of an outcome than the
unexposed, then an association between exposure and outcome is evident
 A Cohort study, used in the medical fields and social sciences, is an observational study used to
estimate how often disease or life events happen in a certain population. “Life events” might
include: incidence rate, relative risk or absolute risk.
 A cohort is a defined group, like “nurses,” “10-19 year-olds,” or “college students.” Participants
are chosen for a reason, rather than randomly
 Design in Clinical Research

The study usually has two groups: exposed and not exposed. If the exposure is rare (for example,
exposure to an industrial solvent), then the cohort is called a “special exposure cohort.” Both groups are
followed to see who develops a disease and who does not. For example, you could look at cigarette
smokers to see who gets breast cancer and who does not. The study would include a group of smokers,
and a group of non-smokers.

Prospective cohort study: Prospective studies are carried out from the present time into the future.
Because prospective studies are designed with specific data collection methods, it has the advantage of
being tailored to collect specific exposure data and may be more complete. The disadvantage of a
prospective cohort study may be the long follow-up period while waiting for events or diseases to occur

Retrospective cohort study: Retrospective cohort studies, also known as historical cohort studies, are
carried out at the present time and look to the past to examine medical events or outcomes. In other
words, a cohort of subjects selected based on exposure status is chosen at the present time, and
outcome data (i.e. disease status, event status), which was measured in the past, are reconstructed for
analysis. The primary disadvantage of this study design is the limited control the investigator has over
data collection

Case control Study:

 Design in Clinical Research

Cross Sectional study: In a cross-sectional study, data are collected on the whole study population at a
single point in time to examine the relationship between disease (or other health related state) and
other variables of interest.

Cross-sectional studies therefore provide a snapshot of the frequency of a disease or other health
related characteristics in a population at a given point in time. This methodology can be used to assess
the burden of disease or health needs of a population, for example, and is therefore particularly useful
in informing the planning and allocation of health resources

Ecological study: are studies of risk-modifying factors on health or other outcomes based on
populations defined either geographically or temporally. Both risk-modifying factors and outcomes are
averaged for the populations in each geographical or temporal unit and then compared using standard
statistical methods