Research study designs

1. Research Study Designs
Presenter – Dr. Sneha Dange, JR3
Dept. Of Pharmacology,
GMC, Nagpur

2. Overview
Key areas
Types of Research Study Designs
Randomized controlled clinical trials
Conclusion
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3. Research
• Research is defined as the creation of new knowledge
and/or the use of existing knowledge in a new and creative
way so as to generate new concepts, methodologies and
understandings.
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4. Dimension of health research
• Theoretical research and applied research
• Preventive and therapeutic research
• Bench based research and bedside research
• Exploratory research and confirmatory research
• Implementation research and translational research
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• Planning stage
• Team work
• Review
Scientific review: novelty, rationality, justification
Ethics review: human subjects protection
Regulatory review: foreign funding, intellectual property

5. Objectives of health research
• Getting additional or new information
• Verifying and confirming available information
• Explaining cause and effect relationship
• Testing new drugs, vaccines, tools or interventions for prevention,
treatment and control of a disease
• Evaluating ongoing programs and assessing feasibility of new programs
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6. The life cycle of research
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7. Key areas in Research
 Spell out research question
 State research hypothesis
 Formulate objectives
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8. Research question
• Uncertainty about something in the population that the investigator
wants to resolve by making measurements in the study population
• Uncertainty = ‘data needs’
• What the investigator wants to know
• Clear question facilitates to
Choose the most optimal design
Identify who should be included, what the outcomes should be, and when the
outcomes need to be measured
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9. Categories of research question
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• Involve observations to measure quantity
• No comparison groups / interventions
Descriptive questions
• Involve comparisons / interventions to test a
hypothesis
Analytical questions
 What is extent of walking practiced by diabetics (type 2 diabetes)
regularly? [Descriptive question]
 In order to improve management of type 2 diabetes, we wish to know
whether brisk walking by diabetics for atleast one hour daily reduce
fasting blood sugar level as compared to those who do not?
[Analytical question]

10. Research hypothesis
• A specific version of research question
Summarizes main elements of study
Establishes basis for test(s) of statistical significance
• Stated for analytical questions with comparison groups
• Descriptive questions DO NOT require hypothesis
• Focused around the primary objective
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 What is extent of walking practiced by diabetics (type 2 diabetes)
regularly? [Descriptive question]
 In order to improve management of type 2 diabetes, we wish to know
whether brisk walking by diabetics for atleast one hour daily reduce
fasting blood sugar level as compared to those who do not?
[Analytical question]
 Among diabetics (type 2 diabetes) from the study area, who do brisk
walking for atleast one hour daily results in average reduction of 10
mg% of fasting blood sugar level as compared to those who do not
Research hypothesis

12. Research objectives
• Framing/writing a research question in scientific/epidemiological
language
• Be clear about the type of question:
Descriptive questions {measuring a quantity}
Analytical/experimental questions {testing a hypothesis}
• Make use of no more than one verb for each
• Sort as primary and secondary
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13. Research objectives
• Descriptive: Estimating a quantity
Use the verb “Estimate”
E.g., Estimate prevalence of physical activity
• Analytical: Testing a hypothesis
Use the verb “Determine”
E.g., Determine whether exercise reduces blood sugar level
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14. Challenges/Errors in designing and implementation of
research studies
• Random error representing wrong result due to chance
 Minimized by increasing sample size and increasing precision
• Systematic error results due to bias
 Minimized by improving study design
• Confounders (affect both study variable & outcome)
 Minimized by proper study design and through stratified analysis
• Effect modifiers (alter negatively the relationship between study variable
and outcome)
 Good to be aware & not to include them in the study
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15. Types of study design
 Qualitative studies or Quantitative studies
 Observational studies or Experimental studies
 Retrospective studies or Prospective studies
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16. Quantitative versus Qualitative research methods
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Quantitative Qualitative
Data Numbers Text
View of the world Social reality - measuring
investigators point of view
Social reality interpreted
and experienced from
participant point of view
Logic of enquiry Deductive – testing formal
hypotheses
Inductive – understanding
of processes derived from
data
Research design Ensures repeatability Interpretation of
responses by participants
Validity Objective (reliability) Subjective (credibility)

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Focus Group
Discussions
• Open-ended group
interviews
• Usually 6-8 ‘similar’
participants
• Similar age, gender,
socio-economic status,
education, cognitive
structures, perceptions
of their social
environment, normative
beliefs
• Moderator and note-
taker
• Flexible interview guide
In-depth (Individual)
Interviews
• Open-ended
interviews
• Most in-depth - Why
behaviors are
practiced?
• Data on how people
think and talk
Participant
Observation
• The researcher
becomes participant
in social event or
group under study and
records observations
Qualitative research : (methods)

18. Qualitative research :
How to use qualitative research methods?
• A preliminary step in developing a quantitative study
• To help understand the results of a quantitative study
• The primary data collection method
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19. Qualitative research :
How are qualitative research methods useful?
• Identify health determinants Underlying behaviours Attitudes
Perceptions
• Shed light on the success of intervention
• Understanding of policy, social and legal context in which decisions
are made
• Explain social and programmatic obstructions in use of services
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20. Algorithm for classification of types of clinical research
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Did investigator assign
exposure?
Experimental study Observational study
Analytical
study
Random allocation Comparison group?
YES NO
Descriptive
study
NO
YES
RCT
Non-
random
ized
YES NO
Cohort
Study
Case-
control

22. Case reports
• Detailed presentation of a single case
• New or unfamiliar diseases
• Rare manifestations
• Generate hypothesis regarding pathophysiological mechanism
• Published in journals in separate section under case series
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Descriptive study

23. Case series
• Study of larger group of patients (> 10) with a particular disease
• Findings due to disease or due to chance
• Gives clinical pictures of a disease
• Absence of comparison group
• Eg., A case series on uncommon disease pneumocystis pneumonia
observed in 5 gay men which leads to discovery of AIDS
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Descriptive study

24. Ecological studies
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• Group as the unit of analysis and see possible reasons why problem is
occurring
• No individual-level information on the distribution of exposure and
disease
Eg., average intake of fat in particular state & then get prevalence of CVD in
that state
• Useful to generate hypothesis (establish correlation)
Eg., state with high per capita consumption of fat also has high incidence of CVD
Descriptive study

25. Cross sectional study
• Observation of a cross-section of a population at a single point in
time
Unit of observation and analysis: The individual
• Collect information about disease burden or magnitude of disease
Also known as “prevalence studies”
• Recruitment of study participants
Population
Population sample
• Observation for the presence of:
One or more outcomes
One or more exposures
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Descriptive study

26. Uses of Cross sectional study
• Estimate prevalence of disease or their risk factors
• Distribution of health problem by time, place and person
Plan health care services delivery
• Set priorities for disease control
• Generate hypotheses
• Examine evolving trends
Before / after surveys
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Descriptive study

27. Cross sectional study
• Advantages
Fairly quick and easy to perform
Less expensive
• Limitations
Not useful to study disease etiology
Not suitable for the study of rare diseases
Exposure and outcome can not be linked very well
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Descriptive study

28. Cohort study
• Cohort - group of people sharing some common characteristics
• No randomization
• Prospective: follow groups forward in time from exposure to defined
outcome of interest (disease)
• Provide a direct estimate of relative risk: the probability of
developing disease during a given time period
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Analytical study

29. Cohort study
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Analytical study
Exposure Outcome

30. Cohort study
• Relative risk =
Incidence of disease in exposed = a/a+b
Incidence of disease in unexposed = c/c+d
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Analytical study
Diseased Non-
Diseased
Total
Exposed a b a+b
Unexposed c d c+d
a+c b+d a+b+c+d
This part is known at start of study
Interpreting Relative risk
•RR=1
•Incidence in exposed and unexposed is same
•Exposure is not associated with disease
•RR > 1
•Incidence in exposed is higher than unexposed
•Exposure is positively associated with disease
•RR < 1
•Incidence in exposed is lower than unexposed
•Exposure is negatively associated with disease

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Cohort study
Analytical study

32. Cohort study
Strengths
• Allows calculation of incidence
• Examine multiple outcomes for a
given exposure
• Good for investigating rare
exposures
Weakness
• May have to follow large numbers
of subjects for a long time
• Expensive and time consuming
• Not good for rare diseases
• Not good for diseases with a long
latency
• Loss to follow up can introduce bias
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Analytical study

33. Case control study
• Focus on the etiology of a disease or health issue
• Patients with a particular health concern / characteristic /
disease are taken and then followed retrospectively for exposure
• Matched with “controls”
• Data often is collected by searching through patient histories or
through patient recall surveys
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Analytical study

34. Case control study
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Analytical study
Exposure Outcome

35. Case control study
Odds that case was exposed
• Odds ratio= Odds that control was exposed
= [a/c]/[b/d] = ad/bc
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Analytical study
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Diseased Non-
Diseased
Total
Exposed a b a+b
Unexposed c d c+d
a+c b+d a+b+c+d
This part is known at start of study
Interpreting Odds Ratio
•OR=1
•Odds of exposure among cases and controls are same
•Exposure is not associated with disease
•OR > 1
•Odds of exposure among cases are higher than controls
•Exposure is positively associated with disease
•OR < 1
•Odds of exposure among cases are lower than controls
•Exposure is negatively associated with disease

36. Case control study
Strengths
• Good for examining rare outcomes
or outcomes with long latency
• Relatively quick to conduct,
inexpensive
• Requires comparatively few
subjects
• Multiple exposures or risk factors
can be examined
Weakness
• Susceptible to recall bias
• Selection of an appropriate
comparison group is difficult
• Rates (incidence) of disease in
exposed and unexposed
individuals cannot be determined
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Analytical study

37. Clinical trial
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Clinical trials translate results of basic scientific research into better
ways to prevent, diagnose, or treat disease
Experimental study
To evaluate new forms of therapy or prevention methods such as
 New drugs/ treatment
 New medical / health care technology
 New organization/ delivery system of health care
 New methods of primary prevention
 New programs of screening or early detection

38. Randomized controlled trials
• A clinical trial is a planned experiment designed to assess the
efficacy of prophylactic / diagnostic / therapeutic agents, devices,
regimens, procedures etc. applied to human subjects by comparing
the outcomes in a group of patients treated with a test treatment
with those patients receiving a control treatment
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Experimental study

39. Clinical trial
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Experimental study

40. Clinical trial
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Experimental study

41. Bias
• Systematic error in an epidemiological study, occurring during data
collection, compilation, analysis and interpretation
• It can simply called as “deviation from the truth”
• Bias can occur during –
Before the trial starts
Actual course of the trial
Reporting of a trial
Dissemination of the trial
Uptake phase of trial
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42. Techniques to control bias
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Randomization Blinding

43. Randomization
Randomization is a statistical procedure by which the participants are
allocated into groups usually called "study“ and "control" groups, to receive
or not to receive an experimental, preventive or therapeutic procedure or
intervention
Gives each patient equal chance of being assigned to any of groups
Benefits of randomization
• Eliminates the selection bias,
• Balances the groups with respect to many known and unknown confounding or
variables
• Forms the basis for statistical tests
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44. Randomization
1. Simple randomization
• Randomization based on a single sequence of random assignments is
known as simple randomization eg., flipping a coin
2. Block randomization
• Blocking is the arranging of experimental units in groups (blocks) that
are similar to one another
• Blocks are small and balanced with predetermined group assignments,
which keeps the numbers of subjects in each group similar at all time
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45. Randomization
3. Stratified randomization
• Non-homogenous population is divided into homogenous groups called as
strata & then sample is drawn randomly from each stratum
• Can be used to achieve balance among groups in terms of subject’s
baseline characteristics (co-variates)
4. Cluster randomization
• Cluster is randomly selected group which is geographical group
• Used in vaccination programme
• Each cluster forms a unit of the trial and either active or comparator
intervention is administered for each cluster
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46. Blinding
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To minimize biases in the conduct of a clinical trial and in the interpretation
of its results
1.Open label
2.Single blind
3.Double blind
4.Triple blind
Subject/Participant
Investigator
(Clinicians/data collectors)
Monitoring committee
(Analysts/Sponsors)

47. Uncontrolled Trials
• There is no control group for comparison
• Not possible to use blinding and randomization to minimize bias
• Used to test new experimental interventions for diseases for which
no established, effective treatments are available and the prognosis
is universally poor without therapy
• Outcomes for research participants receiving the experimental
intervention are compared with the outcomes before the availability
of the intervention
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48. Selection of controls
• A control group in a clinical trial is a group of individuals used as a
comparison for a group of participants who receive the experimental
treatment.
• Main purpose - to permit investigators to determine whether an
observed effect is truly caused by the experimental intervention
being tested or by other factors
• Control group serve as a baseline
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49. Control Arm Options
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Placebo
No treatment
Active treatment
Dose response
External

50. Control Arm Options
1. Placebo Control –
Placebo- inert substance – looks exactly like test drug but contains no drug
No standard treatment exists, standard treatment is ineffective/inappropriate
Given as an add-on treatment to an already existing regimen
2. No treatment control
Subjects are randomly assigned to test treatment or to no treatment
Subjects, investigators are not blind to treatment
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51. Control Arm Options
3. Active control –
Compare “new drug” to standard or standard to combination therapy that
involves the standard + “new drug”
4. Dose response control –
Subjects are randomized to one of several fixed dose groups
5. External control (including historical) –
Compares a group of subjects receiving test treatment with a group of patients
external to study
Can be historical, i.e, group of patients treated at an earlier time
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52. Advantages & Disadvantages of RCTs
Advantages
•The only effective method known to control selection bias
•Controls confounding bias without adjustment
•Facilitates effective blinding in trials
Disadvantages
•May be complex and expensive
•Ethical challenges are more
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53. Superiority trials :
Aim of this randomized controlled trial (RCT) is to show that one
treatment is superior to another
Non-inferiority trials :
Aim is to show that an experimental treatment is not (much) worse than
a standard treatment or at least have same benefits
Equivalence:
Aims at showing that two treatments are not too different in
characteristics in a clinical manner
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Traditional designs for
clinical trials
Parallel group trials
Cross over trials
Factorial design
Add on design
Randomized
withdrawal design
Early escape design
Special Design issues for
small clinical trials
N- of- 1 design
Decision analysis-
based design
Risk based
allocation design
Miscellaneous Designs
Cluster randomized
design
Placebo Challenging
design
Trial format

55. Parallel group trial Design
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Treatment Group/ Arm Control Group/ Arm
• Efficacy of treatment is compared using two groups (Treatment vs Control
group)
• Most common clinical design
• Complete randomized design in which each patient receives one and
only one treatment in a randomized fashion
Exp. Drug

56. Matched Pair Parallel Design
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Pair A Pair B Pair C Pair D
• In this method, subjects are grouped into pairs possessing same
characteristics who might be expected to respond similarly to
treatments
• Matching of patients is done before randomization

57. Cross over design
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Group A Group B
RANDOMIZATION
Drug A
Drug A
Drug B
Drug B
WASH OUT PERIOD
WASH OUT PERIOD

58. Factorial designs
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2×2 Factorial design
Used when it is desired to study effect of
two or more treatments as well as their
interaction with different treatments
+
Drug A Drug B Drug A+B Neither Drug

59. Add- on Design
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Group A Group B
Placebo-controlled trial of an experimental
intervention is tested with people already receiving
an established, effective treatment
Std. treatment
Novel drug
Std. treatment
+
+

60. Randomized withdrawal Design
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• Individuals who respond positively to an experimental
intervention are randomized to continue receiving that
intervention or to receive a placebo
• Return of symptoms in placebo group causes withdrawal of
subject from that group.
Exp. Intervention
Withdrawn
from study

61. Early escape design
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Intervention Arm Placebo Arm
• Participants are removed from study if symptoms
reached a defined level or they fail to respond to a
defined extent
• Patient could then be switched over to another
therapy, including test treatment if appropriate.
Exp. Intervention
Predefined negative
efficacy criterion

62. Risk based Allocation Design
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• This design allows individuals at higher risk or with
greater disease severity to benefit from a
potentially superior experimental treatment
•Advantages: Ethically more justifiable
•Disadvantage: It is a non-randomized design.
Individuals with lesser
risk or lesser disease
severity
Potentially superior
Experimental
treatment
Relatively inferior
Experimental
treatment
Individuals with
higher risk or greater
disease severity

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Phase Design
I Open label
Non-randomized
Dose escalation
Non-blind
Uncontrolled
II IIa - Placebo control, not- multi centered
IIb - Placebo/ active control, Multicentric
III Active controlled
Randomized
Double blinded
Parallel
Non-inferiority
Multicentric
IV Uncontrolled
Observational
Various designs in phases of clinical trial

64. Conclusion
• No research study design is perfect and no design provides optimum
answer to all research questions – optimum design should be chosen
• Success of clinical trial- appropriate clinical design, control group
• Blinding, randomization - minimize bias
• Randomized controlled trials – gold standard
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65. References
• Basic courses in biomedical research; Indian Council of Medical Research,
National Institute of Epidemiology
• Lawrence J. Appel. Primer on the Design, Conduct, and Interpretation of
Clinical Trials. Clin J Am Soc Nephrol 1: 1360–1367, 2006
• Kenneth F Schulz, David A Grimes. Blinding in randomised trials: hiding who
got what. THE LANCET 2002 ,359:2
• ICH E8 ,9,10 guidelines : general consideration for clinical trials, current
step 4 version, 1997
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