Pediatr Invest 2019 Dec; 3(4): 245-252 245

LeCTure

Clinical research study designs: The essentials

Ambika G. Chidambaram　Maureen Josephson

Children’s Hospital of Philadelphia,

Philadelphia, Pennsylvania, USA AbSTrACT
In clinical research, our aim is to design a study which would be able to
Correspondence derive a valid and meaningful scientific conclusion using appropriate
Maureen Josephson, Children’s statistical methods. The conclusions derived from a research study can
Hospital of Philadelphia, PA either improve health care or result in inadvertent harm to patients.
19104, USA. Hence, this requires a well-designed clinical research study that rests on
Email: [email protected]. a strong foundation of a detailed methodology and governed by ethical
edu clinical principles. The purpose of this review is to provide the readers
an overview of the basic study designs and its applicability in clinical
Received: 16 November, 2019 research.
Accepted: 3 December, 2019
KeywOrDS
Clinical trials, Clinical research study design, Experimental study designs,
Observational study designs, Randomization

introduction
of the association between the exposure and the outcome.
In clinical research, our aim is to design a study, which
Experimental studies, on the other hand, are hypothesis
would be able to derive a valid and meaningful scientific
testing studies. It involves an intervention that tests the
conclusion using appropriate statistical methods that can
association between the exposure and outcome. Each
be translated to the “real world” setting.1 Before choosing
study design is different, and so it would be important to
a study design, one must establish aims and objectives
choose a design that would most appropriately answer
of the study, and choose an appropriate target population
the question in mind and provide the most valuable
that is most representative of the population being
information. We will be reviewing each study design in
studied. The conclusions derived from a research study
detail (Figure 1).
can either improve health care or result in inadvertent
harm to patients. Hence, this requires a well-designed
Study designs
clinical research study that rests on a strong foundation
of a detailed methodology and is governed by ethical
principles.2

From an epidemiological standpoint, there are two Observational Experimental

major types of clinical study designs, observational and
experimental. 3 Observational studies are hypothesis- Figure 1 Overview of clinical research study designs
generating studies, and they can be further divided into
descriptive and analytic. Descriptive observational studies Observational study designs
provide a description of the exposure and/or the outcome,
and analytic observational studies provide a measurement Observational studies ask the following questions: what,

DOI: 10.1002/ped4.12166

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
2019 Chinese Medical Association. Pediatric Investigation published by John Wiley & Sons Australia, Ltd on behalf of Futang Research Center of Pediatric
Development.
246 wileyonlinelibrary.com/journal/ped4

Observational study designs

Case report Ecologic Cross-sectional Case-control Cohort study Case-control

Case series study study studies based study
within a
defined cohort

Nested case- Case-cohort

control study study

Figure 2 Classification of observational study designs

who, where and when. There are many study designs that the whole group and so the individual characteristics are
fall under the umbrella of descriptive study designs, and unknown.
they include, case reports, case series, ecologic study,
cross-sectional study, cohort study and case-control study Cross-sectional study
(Figure 2). Cross-sectional studies are study designs used to evaluate
Case reports and case series an association between an exposure and outcome at the
same time. It can be classified under either descriptive
Every now and then during clinical practice, we come or analytic, and therefore depends on the question being
across a case that is atypical or ‘out of the norm’ type of answered by the investigator. Since, cross-sectional
clinical presentation. This atypical presentation is usually studies are designed to collect information at the same
described as case reports which provides a detailed and point of time, this provides an opportunity to measure
comprehensive description of the case.4 It is one of the prevalence of the exposure or the outcome. For example,
earliest forms of research and provides an opportunity a cross-sectional study design was adopted to estimate
for the investigator to describe the observations that the global need for palliative care for children based on
make a case unique. There are no inferences obtained and representative sample of countries from all regions of the
therefore cannot be generalized to the population which is world and all World Bank income groups.6 The limitation
a limitation. Most often than not, a series of case reports of cross-sectional study design is that temporal association
make a case series which is an atypical presentation found cannot be established as the information is collected at the
in a group of patients. This in turn poses the question for same point of time. If a study involves a questionnaire,
a new disease entity and further queries the investigator then the investigator can ask questions to onset of
to look into mechanistic investigative opportunities to symptoms or risk factors in relation to onset of disease.
further explore. However, in a case series, the cases are This would help in obtaining a temporal sequence between
not compared to subjects without the manifestations the exposure and outcome.7
and therefore it cannot determine which factors in the
description are unique to the new disease entity. Case-control study

Ecologic study Case-control studies are study designs that compare

two groups, such as the subjects with disease (cases) to
Ecological studies are observational studies that provide the subjects without disease (controls), and to look for
a description of population group characteristics. That differences in risk factors.8 This study is used to study risk
is, it describes characteristics to all individuals within a factors or etiologies for a disease, especially if the disease
group. For example, Prentice et al5 measured incidence is rare. Thus, case-control studies can also be hypothesis
of breast cancer and per capita intake of dietary fat, and testing studies and therefore can suggest a causal
found a correlation that higher per capita intake of dietary relationship but cannot prove. It is less expensive and less
fat was associated with an increased incidence of breast time-consuming than cohort studies (described in section
cancer. But the study does not conclude specifically “Cohort study”). An example of a case-control study
which subjects with breast cancer had a higher dietary was performed in Pakistan evaluating the risk factors for
intake of fat. Thus, one of the limitations with ecologic neonatal tetanus. They retrospectively reviewed a defined
study designs is that the characteristics are attributed to cohort for cases with and without neonatal tetanus.9 They
Pediatr Invest 2019 Dec; 3(4): 245-252 247

found a strong association of the application of ghee Disease

(clarified butter) as a risk factor for neonatal tetanus.
Exposed/Risk
Although this suggests a causal relationship, cause cannot factor
be proven by this methodology (Figure 3). No disease

Exposed
Cases Disease
(with disease) Non-exposed/
Non-exposed No risk factor

No disease

Exposed
Controls Figure 4 Cohort study design
(without disease)
then assess if they had developed the disease/outcome at
Non-exposed
the time of study. Thus, the study design for prospective
Figure 3 Case-control study design and retrospective cohort studies are similar as we are
comparing populations with and without exposure/risk
factor to development of outcome/disease.
One of the limitations of case-control studies is that they
cannot estimate prevalence of a disease accurately as a Cohort studies are typically chosen as a study design
proportion of cases and controls are studied at a time. when the suspected exposure is known and rare, and the
Case-control studies are also prone to biases such as recall incidence of disease/outcome in the exposure group is
bias, as the subjects are providing information based on suspected to be high. The choice between prospective and
their memory. Hence, the subjects with disease are likely retrospective cohort study design would depend on the
to remember the presence of risk factors compared to the accuracy and reliability of the past records regarding the
subjects without disease. exposure/risk factor.
One of the aspects that is often overlooked is the selection Some of the biases observed with cohort studies include
of cases and controls. It is important to select the cases selection bias and information bias. Some individuals who
and controls appropriately to obtain a meaningful and have the exposure may refuse to participate in the study
scientifically sound conclusion and this can be achieved by or would be lost to follow-up, and in those instances, it
implementing matching. Matching is defined by Gordis et becomes difficult to interpret the association between
al as ‘the process of selecting the controls so that they are an exposure and outcome. Also, if the information is
similar to the cases in certain characteristics such as age, inaccurate when past records are used to evaluate for
race, sex, socioeconomic status and occupation’.7 This exposure status, then again, the association between the
would help identify risk factors or probable etiologies that exposure and outcome becomes difficult to interpret.
are not due to differences between the cases and controls.
Case-control studies based within a defined cohort
Cohort study
Case-control studies based within a defined cohort is a
Cohort studies are study designs that compare two form of study design that combines some of the features
groups, such as the subjects with exposure/risk factor to of a cohort study design and a case-control study design.
the subjects without exposure/risk factor, for differences When a defined cohort is embedded in a case-control
in incidence of outcome/disease. Most often, cohort study design, all the baseline information collected before
study designs are used to study outcome(s) from a single the onset of disease like interviews, surveys, blood or
exposure/risk factor. Thus, cohort studies can also be urine specimens, then the cohort is followed onset of
hypothesis testing studies and can infer and interpret a disease. One of the advantages of following the above
causal relationship between an exposure and a proposed design is that it eliminates recall bias as the information
outcome, but cannot establish it (Figure 4). regarding risk factors is collected before onset of disease.
Case-control studies based within a defined cohort can be
Cohort studies can be classified as prospective and further classified into two types: Nested case-control study
retrospective.7 Prospective cohort studies follow subjects and Case-cohort study.
from presence of risk factors/exposure to development
of disease/outcome. This could take up to years before Nested case-control study
development of disease/outcome, and therefore is
time consuming and expensive. On the other hand, A nested case-control study consists of defining a cohort
retrospective cohort studies identify a population with and with suspected risk factors and assigning a control within
without the risk factor/exposure based on past records and a cohort to the subject who develops the disease.10 Over a
248 wileyonlinelibrary.com/journal/ped4

period, cases and controls are identified and followed as specifics of each study design are explained below (Figure 5).
per the investigator’s protocol. Hence, the case and control
are matched on calendar time and length of follow-up. Clinical trial
When this study design is implemented, it is possible for Clinical trials are also known as therapeutic trials, which
the control that was selected early in the study to develop involve subjects with disease and are placed in different
the disease and become a case in the latter part of the treatment groups. It is considered a gold standard approach
study. for epidemiological research. One of the earliest clinical
Case-cohort Study trial studies was performed by James Lind et al in 1747 on
sailors with scurvy.12 Lind divided twelve scorbutic sailors
A case-cohort study is similar to a nested case-control into six groups of two. Each group received the same
study except that there is a defined sub-cohort which forms diet, in addition to a quart of cider (group 1), twenty-five
the groups of individuals without the disease (control), and drops of elixir of vitriol which is sulfuric acid (group 2),
the cases are not matched on calendar time or length of two spoonfuls of vinegar (group 3), half a pint of seawater
follow-up with the control.11 With these modifications, it is (group 4), two oranges and one lemon (group 5), and a
possible to compare different disease groups with the same spicy paste plus a drink of barley water (group 6). The
sub-cohort group of controls and eliminates matching group who ate two oranges and one lemon had shown the
between the case and control. However, these differences most sudden and visible clinical effects and were taken
will need to be accounted during analysis of results. back at the end of 6 days as being fit for duty. During
Lind’s time, this was not accepted but was shown to have
experimental study design similar results when repeated 47 years later in an entire
fleet of ships. Based on the above results, in 1795 lemon
The basic concept of experimental study design is to study
juice was made a required part of the diet of sailors. Thus,
the effect of an intervention. In this study design, the risk
clinical trials can be used to evaluate new therapies, such
factor/exposure of interest/treatment is controlled by the
as new drug or new indication, new drug combination,
investigator. Therefore, these are hypothesis testing studies
new surgical procedure or device, new dosing schedule or
and can provide the most convincing demonstration of
mode of administration, or a new prevention therapy.
evidence for causality. As a result, the design of the study
requires meticulous planning and resources to provide an While designing a clinical trial, it is important to select
accurate result. the population that is best representative of the general
population. Therefore, the results obtained from the study
The experimental study design can be classified into
can be generalized to the population from which the
2 groups, that is, controlled (with comparison) and
sample population was selected. It is also as important
uncontrolled (without comparison).1 In the group without
to select appropriate endpoints while designing a trial.
controls, the outcome is directly attributed to the treatment
Endpoints need to be well-defined, reproducible, clinically
received in one group. This fails to prove if the outcome
relevant and achievable. The types of endpoints include
was truly due to the intervention implemented or due to
continuous, ordinal, rates and time-to-event, and it is
chance. This can be avoided if a controlled study design
typically classified as primary, secondary or tertiary.2 An
is chosen which includes a group that does not receive
ideal endpoint is a purely clinical outcome, for example,
the intervention (control group) and a group that receives
cure/survival, and thus, the clinical trials will become very
the intervention (intervention/experiment group), and
long and expensive trials. Therefore, surrogate endpoints
therefore provide a more accurate and valid conclusion.
are used that are biologically related to the ideal endpoint.
Experimental study designs can be divided into 3 broad Surrogate endpoints need to be reproducible, easily
categories: clinical trial, community trial, field trial. The measured, related to the clinical outcome, affected by

Experimental study designs

Clinical trial Field trial Community trial

Randomized Non-randomized Cross-over Factorial

Figure 5 Experimental study designs

Pediatr Invest 2019 Dec; 3(4): 245-252 249

treatment and occurring earlier than clinical outcome.2 would help eliminate residuals effects of the intervention/
experiment when the experiment group transitions to be
Clinical trials are further divided into randomized clinical the control group. Hence, the outcomes of the intervention/
trial, non-randomized clinical trial, cross-over clinical trial experiment will need to be reversible as this type of study
and factorial clinical trial. design would not be possible if the subject is undergoing a
surgical procedure.
Randomized clinical trial
Factorial trial
A randomized clinical trial is also known as parallel
group randomized trials or randomized controlled A factorial trial study design is adopted when the
trials. Randomized clinical trials involve randomizing researcher wishes to test two different drugs with
subjects with similar characteristics to two groups (or independent effects on the same population. Typically, the
multiple groups): the group that receives the intervention/ population is divided into 4 groups, the first with drug A,
experimental therapy and the other group that received the second with drug B, the third with drug A and B, and
the placebo (or standard of care). 13 This is typically the fourth with neither drug A nor drug B. The outcomes
performed by using a computer software, manually or by for drug A are compared to those on drug A, drug A and B
other methods. Hence, we can measure the outcomes and and to those who were on drug B and neither drug A nor
efficacy of the intervention/experimental therapy being drug B.15 The advantages of this study design that it saves
studied without bias as subjects have been randomized time and helps to study two different drugs on the same
to their respective groups with similar baseline study population at the same time. However, this study
characteristics. This type of study design is considered design would not be applicable if either of the drugs or
gold standard for epidemiological research. However, this interventions overlaps with each other on modes of action
study design is generally not applicable to rare and serious or effects, as the results obtained would not attribute to a
disease process as it would unethical to treat that group particular drug or intervention.
with a placebo. Please see section “Randomization” for
detailed explanation regarding randomization and placebo. Community trial

Non-randomized clinical trial Community trials are also known as cluster-randomized

trials, involve groups of individuals with and without
A non-randomized clinical trial involves an approach to disease who are assigned to different intervention/
selecting controls without randomization. With this type experiment groups. Hence, groups of individuals from a
of study design a pattern is usually adopted, such as, certain area, such as a town or city, or a certain group such
selection of subjects and controls on certain days of the as school or college, will undergo the same intervention/
week. Depending on the approach adopted, the selection experiment. 16 Hence, the results will be obtained at a
of subjects becomes predictable and therefore, there is larger scale; however, will not be able to account for inter-
bias with regards to selection of subjects and controls that individual and intra-individual variability.
would question the validity of the results obtained.
Field trial
Historically controlled studies can be considered as a
subtype of non-randomized clinical trial. In this study Field trials are also known as preventive or prophylactic
design subtype, the source of controls is usually adopted trials, and the subjects without the disease are placed
from the past, such as from medical records and published in different preventive intervention groups. 16 One of
literature.1 The advantages of this study design include the hypothetical examples for a field trial would be to
being cost-effective, time saving and easily accessible. randomly assign to groups of a healthy population and to
However, since this design depends on already collected provide an intervention to a group such as a vitamin and
data from different sources, the information obtained following through to measure certain outcomes. Hence,
may not be accurate, reliable, lack uniformity and/or the subjects are monitored over a period of time for
completeness as well. Though historically controlled occurrence of a particular disease process.
studies maybe easier to conduct, the disadvantages will
need to be taken into account while designing a study. Overview of methodologies used within a
study design
Cross-over clinical trial
Randomization
In cross-over clinical trial study design, there are two
groups who undergoes the same intervention/experiment Randomization is a well-established methodology adopted
at different time periods of the study. That is, each group in research to prevent bias due to subject selection, which
serves as a control while the other group is undergoing the may impact the result of the intervention/experiment
intervention/experiment.14 Depending on the intervention/ being studied. It is one of the fundamental principles
experiment, a ‘washout’ period is recommended. This of an experimental study designs and ensures scientific
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validity. It provides a way to avoid predicting which help determine the number of strata that would need to be
subjects are assigned to a certain group and therefore, chosen for a study.
prevent bias on the final results due to subject selection.
This also ensures comparability between groups as most Blinding
baseline characteristics are similar prior to randomization
Blinding is a methodology adopted in a study design
and therefore helps to interpret the results regarding the
to intentionally not provide information related to the
intervention/experiment group without bias.
allocation of the groups to the subject participants,
There are various ways to randomize and it can be as investigators and/or data analysts. 19 The purpose of
simple as a ‘flip of a coin’ to use computer software and blinding is to decrease influence associated with the
statistical methods. To better describe randomization, there knowledge of being in a particular group on the study
are three types of randomization: simple randomization, result. There are 3 forms of blinding: single-blinded,
block randomization and stratified randomization. double-blinded and triple-blinded. 1 In single-blinded
studies, otherwise called as open-label studies, the subject
Simple randomization participants are not revealed which group that they have
been allocated to. However, the investigator and data
In simple randomization, the subjects are randomly analyst will be aware of the allocation of the groups. In
allocated to experiment/intervention groups based on a double-blinded studies, both the study participants and the
constant probability. That is, if there are two groups A investigator will be unaware of the group to which they
and B, the subject has a 0.5 probability of being allocated were allocated to. Double-blinded studies are typically
to either group. This can be performed in multiple ways, used in clinical trials to test the safety and efficacy of the
and one of which being as simple as a ‘flip of a coin’ drugs. In triple-blinded studies, the subject participants,
to using random tables or numbers.17 The advantage of investigators and data analysts will not be aware of the
using this methodology is that it eliminates selection bias. group allocation. Thus, triple-blinded studies are more
However, the disadvantage with this methodology is that difficult and expensive to design but the results obtained
an imbalance in the number allocated to each group as will exclude confounding effects from knowledge of group
well as the prognostic factors between groups. Hence, it is allocation.
more challenging in studies with a small sample size.
Blinding is especially important in studies where
Block randomization subjective response are considered as outcomes. This is
because certain responses can be modified based on the
In block randomization, the subjects of similar knowledge of the experiment group that they are in. For
characteristics are classified into blocks. The aim of example, a group allocated in the non-intervention group
block randomization is to balance the number of subjects may not feel better as they are not getting the treatment,
allocated to each experiment/intervention group. For or an investigator may pay more attention to the group
example, let’s assume that there are four subjects in each receiving treatment, and thereby potentially affecting
block, and two of the four subjects in each block will be the final results. However, certain treatments cannot be
randomly allotted to each group. Therefore, there will be blinded such as surgeries or if the treatment group requires
two subjects in one group and two subjects in the other an assessment of the effect of intervention such as quitting
group.17 The disadvantage with this methodology is that smoking.
there is still a component of predictability in the selection
of subjects and the randomization of prognostic factors is Placebo
not performed. However, it helps to control the balance
between the experiment/intervention groups. Placebo is defined in the Merriam-Webster dictionary
as ‘an inert or innocuous substance used especially in
Stratified randomization controlled experiments testing the efficacy of another
substance (such as drug)’.20 A placebo is typically used
In stratified randomization, the subjects are defined in a clinical research study to evaluate the safety and
based on certain strata, which are covariates. 18 For efficacy of a drug/intervention. This is especially useful
example, prognostic factors like age can be considered if the outcome measured is subjective. In clinical drug
as a covariate, and then the specified population can trials, a placebo is typically a drug that resembles the
be randomized within each age group related to an drug to be tested in certain characteristics such as color,
experiment/intervention group. The advantage with this size, shape and taste, but without the active substance.
methodology is that it enables comparability between This helps to measure effects of just taking the drug,
experiment/intervention groups and thus makes result such as pain relief, compared to the drug with the
analysis more efficient. But, with this methodology the active substance. If the effect is positive, for example,
covariates will need to be measured and determined improvement in mood/pain, then it is called placebo
before the randomization process. The sample size will effect. If the effect is negative, for example, worsening
Pediatr Invest 2019 Dec; 3(4): 245-252 251

of mood/pain, then it is called nocebo effect.21 is, an investigator may pay closer attention to the group
receiving the treatment versus the group not receiving the
The ethics of placebo-controlled studies is complex and treatment. This may influence the results of the study. One
remains a debate in the medical research community. of the ways to decrease observer bias is to use blinding
According to the Declaration of Helsinki on the use of (discussed in section “Blinding”).
placebo released in October 2013, “The benefits, risks,
burdens and effectiveness of a new intervention must be Thus, while designing a study it is important to take
tested against those of the best proven intervention(s), measure to limit bias as much as possible so that the
except in the following circumstances: scientific validity of the study results is preserved to its
maximum.
Where no proven intervention exists, the use of placebo,
or no intervention, is acceptable; or
Overview of drug development in the united
Where for compelling and scientifically sound States of America
methodological reasons the use of any intervention less
Now that we have reviewed the various clinical designs,
effective than the best proven one, the use of placebo,
clinical trials form a major part in development of a drug.
or no intervention is necessary to determine the efficacy
In the United States, the Food and Drug Administration
or safety of an intervention and the patients who receive
(FDA) plays an important role in getting a drug approved
any intervention less effective than the best proven one,
for clinical use. It includes a robust process that involves
placebo, or no intervention will not be subject to additional
four different phases before a drug can be made available
risks of serious or irreversible harm as a result of not
to the public. Phase I is conducted to determine a safe
receiving the best proven intervention.
dose. The study subjects consist of normal volunteers
Extreme care must be taken to avoid abuse of this and/or subjects with disease of interest, and the sample
option”.22 size is typically small and not more than 30 subjects. The
primary endpoint consists of toxicity and adverse events.
Hence, while designing a research study, both the scientific Phase II is conducted to evaluate of safety of dose selected
validity and ethical aspects of the study will need to be in Phase I, to collect preliminary information on efficacy
thoroughly evaluated. and to determine factors to plan a randomized controlled
trial. The study subjects consist of subjects with disease
Bias
of interest and the sample size is also small but more that
Bias has been defined as “any systematic error in the Phase I (40–100 subjects). The primary endpoint is the
design, conduct or analysis of a study that results in a measure of response. Phase III is conducted as a definitive
mistaken estimate of an exposure’s effect on the risk trial to prove efficacy and establish safety of a drug. Phase
of disease”. 23 There are multiple types of biases and III studies are randomized controlled trials and depending
so, in this review we will focus on the following types: on the drug being studied, it can be placebo-controlled,
selection bias, information bias and observer bias. equivalence, superiority or non-inferiority trials. The study
Selection bias is when a systematic error is committed subjects consist of subjects with disease of interest, and
while selecting subjects for the study. Selection bias the sample size is typically large but no larger than 300 to
will affect the external validity of the study if the study 3000. Phase IV is performed after a drug is approved by
subjects are not representative of the population being the FDA and it is also called the post-marketing clinical
studied and therefore, the results of the study will not trial. This phase is conducted to evaluate new indications,
be generalizable. Selection bias will affect the internal to determine safety and efficacy in long-term follow-up
validity of the study if the selection of study subjects in and new dosing regimens. This phase helps to detect rare
each group is influenced by certain factors, such as, based adverse events that would not be picked up during phase
on the treatment of the group assigned. One of the ways III studies and decrease in the delay in the release of the
to decrease selection bias is to select the study population drug in the market. Hence, this phase depends heavily on
that would representative of the population being studied, voluntary reporting of side effects and/or adverse events
or to randomize (discussed in section “Randomization”). by physicians, non-physicians or drug companies.2

Information bias is when a systematic error is committed Conclusion

while obtaining data from the study subjects. This can
be in the form of recall bias when subject is required We have discussed various clinical research study designs
to remember certain events from the past. Typically, in this comprehensive review. Though there are various
subjects with the disease tend to remember certain events designs available, one must consider various ethical
compared to subjects without the disease. Observer aspects of the study. Hence, each study will require
bias is a systematic error when the study investigator is thorough review of the protocol by the institutional review
influenced by the certain characteristics of the group, that board before approval and implementation.
252 wileyonlinelibrary.com/journal/ped4

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