HOW TO DESIGN
A STUDY
Nikolaos P. Polyzos M.D. PhD
The material was supported by an educational grant from Ferring
Type of Study and Level of Evidence
RCTs
Meta-analyses
of RCTs
LEVEL I
Cohorts, case
control studies, crosssectional surveys
Case series, case reports, guidelines, expert
opinions
LEVEL II
LEVEL III
What type of study should I perform?
It depends on what you are seeking
General Types of Studies
• Observational:
– Searching for association or relationship
• Interventional: (clinical trials)
– Validating a specific treatment protocol
Observational Studies
• Cross-sectional studies
• Case-control studies
• Cohort studies
Cross-sectional study
Cross-sectional surveys
A “photograph” of the population at a specific
moment
Aim
• Assess the prevalence of acute or chronic
conditions
• Check association between characteristics of the
population
Example of cross-sectional study
Association of blood type and patient characteristics
with ovarian reserve.
• Determination of blood type
• Determination of FSH levels
Timberlake KS et al., Fertil Steril. 2013
Case-control study
Case-control studies (1)
Cases (patients with a disease)
Controls (patients without the disease)
Advantages:
• Case-control studies are simple to organise
• Retrospectively compare two groups
• Aim to identify predictors of an outcome
Case control studies (2)
Exposure
CASES
(present)
(?)
CONTROLS
(absent)
e.g.
BMI
e.g.
Endometriosis
Investigator
(?)
Disease
Deep infiltrating endometriosis is associated with
markedly lower body mass index: a 476 casecontrol study.
• Cases- endometriosis
• Controls- no endometriosis
• Check for difference in BMI
Cohort study
Cohort studies
• Follow a specific cohort
• A cohort is a group of people who share a
common characteristic or experience within a
defined period
Advantage:
Can examine causal relationship and predictive
ability of a marker
Cohort studies- retrospective
Exposure
(?)
NO
(?)
e.g.
AMH values
e.g.
Pregnancy outcome
Investigator
YES
Disease-outcome
Examples of a retrospective cohort
Predictors of ovarian response in women treated
with corifollitropin alfa for IVF/ICSI. Polyzos et al.,
Fertil Steril 2013
Anti-Müllerian hormone for the assessment of
ovarian response in GnRH-antagonist-treated
oocyte donors. Polyzos et al., RBMonline 2013
• Retrospectively examined patients files
• Recorded AMH values
• Checked who were the patients pregnant and not
pregnant
Cohort studies- prospective
Disease-outcome
Exposure
NO
e.g.
AMH values
Investigator
YES
(?)
(?)
e.g.
Pregnancy outcome
Example of a prospective cohort
The predictive value of circulating anti-Müllerian
hormone in women with polycystic ovarian
syndrome receiving clomiphene citrate:
a prospective observational study. Mahran et al.,
JCEM 2013
•
•
•
Prospectively enrolled patients before treatment begins
Recorded AMH values
Waited till the cycles finished to evaluate how many
responded
Clinical trials
Types of Clinical Trials
• Randomized versus non-randomized
• Treatment arm -- with or without a control arm
• Testing the safety and effectiveness of a drug or
intervention
Clinical Trials: Phases I - IV
• Phase I
– Safety-testing small groups of 10 to 15 patients
• Phase II
– Pilot studies to confirm effectiveness
of the drug - less than 100 patients
Clinical Trials: Phases I - IV
• Phase III
– Large groups of patients for statistical confirmation of
effect and incidence of side-effects > 100 patients
• Phase IV
– Post marketing studies - fine tuning, and new rare
findings from a very large population
Randomized Clinical Trials
LEVEL I Evidence
Randomized Controlled Studies
Description:
• After assessment of eligibility and recruitment, but
before the intervention to be studied begins,
randomly allocated to receive one or other of the
alternative treatments under study
Randomized Controlled Studies
Advantage:
• RCTs are considered by most to be the most
reliable form of scientific evidence in the hierarchy
of evidence that influences healthcare policy and
practice
Randomized Controlled Studies
Disadvantages:
• Costs
• Time
• Rare events
Designing a clinical and especially a randomized
trial …
… Is it that easy?
It can be...
The Study Protocol
...possibly the most important part
of your trial
Proper Study Protocol
•
•
•
•
Research question--rationale
Exact study design
Inclusion-exclusion criteria
Randomization procedure, allocation
concealment, blinding
• Timing of blood sampling and monitoring
• Clearly defined interventions
Proper Study Protocol
•
•
•
•
•
Primary outcomes
Appropriate statistical analysis
Feasibility of the study
Data management
Ethical considerations
Research Question and Hypothesis
• Simple – one question and one answer
• In accordance with the available evidence
• Ask yourself:
– Why is such a study valuable?
– Can it change clinical practice?
Study Design
• Parallel group
– Each participant is randomly assigned to a group,
and all participants receive (or not), an intervention.
• Crossover
– Over time, each participant receives
(or not), an intervention in a random sequence.
Study Design
• Cluster
– Pre-existing groups of participants, (e.g. villages,
schools) are randomly selected to receive, or not to
receive, an intervention
Study Design (3)
• 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)
Population to Include..
•
•
•
•
Clearly defined
Easy to recruit
Easy to follow
Sample presumed to represent population
Unclear Population…
Not Replicable Results
• 47 randomized trials using 41 definitions for poor
ovarian responders
• No more than 3 trials used the same definition
• Even trials from the same research group used a
different definition
Who are the poor ovarian responders?
Randomization Procedure (1)
• Simple randomization
• Block randomization
• Computer generated list
Randomization Procedure (2)
Generation of allocation sequences
• Adequate if sequences are suitable to prevent
selection bias: random numbers generated by
computer, table of random numbers, drawing of
lots or envelopes, tossing a coin, shuffling cards,
throwing dice, etc.
• Inadequate if sequences could be related to
prognosis and thus introduce selection bias: case
of record number; date of birth; day, month, or
year of admission; etc.
Juni P et al., BMJ 2001
Randomization and Concealment of
Patient Allocation
• The procedure for protecting the randomization
process so that the treatment to be allocated is
not known before patient is entered into the study
• Methods to ensure
– sequentially numbered, opaque, sealed envelopes
(SNOSE)
– sequentially numbered containers
– pharmacy controlled randomization
– central randomization
Juni P et al., BMJ 2001
Randomization and Concealment of
Patient Allocation (continued)
Generation of allocation sequences
• Adequate if sequences are suitable to prevent
selection bias: random numbers generated by
computer, table of random numbers, drawing of
lots or envelopes, tossing a coin, shuffling cards,
throwing dice, etc.
• Inadequate if sequences could be related to
prognosis and thus introduce selection bias: case
of record number; date of birth; day, month, or
year of admission; etc.
Juni P et al., BMJ 2001
Randomization and Concealment of
Patient Allocation (continued)
Generation of allocation sequences (cont):
• Inadequate if patients and investigators enrolling
patients can foresee assignments and thus
introduce selection bias: procedures based on
inadequate generation of allocation sequences,
open allocation schedule, alternation and other
unsealed or non-opaque envelopes, etc.
Juni P et al., BMJ 2001
Randomization and “Blinding” Status of
Subjects
• Procedures that prevent study participants,
caregivers, or outcome assessors from knowing
(by randomization) which intervention was
received
• Types
– Single-blind
– Double-blind
– Open Label
Strength of Randomization
• Inadequate if patients and investigators enrolling
patients can foresee assignments and thus
introduce selection bias: procedures based on
inadequate generation of allocation sequences,
open allocation schedule, alternation and other
unsealed or non-opaque envelopes, etc.
Juni P et al., BMJ 2001
Monitoring Patients
First
Consultation
Assessment
Clinical examination:
Vital signs and Weight
Pregnancy Test
Laboratory exams
(local lab):
- Chemistry/
Hematology
- FSH, LH, E2, P
- AMH
USS
ART Procedures
Previous and
Concomitant
Medication
(S)AEs
Cycle Summary
Subject Status
Stimulation Day
1
2
3
4
6
7
8
10 Day
of
hCG
OPU ET OPU +
 14
Days
ET +
35-42
Days
ET +
 4956
Days
Cycle
Disco
n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Whenever previous or concomitant mediation is used
Whenever an (S)AE occurs
At cycle discontinuation or completion
At trial discontinuation or completion
X
Clearly defining interventions
ADMINISTRATION DAY
MEDICATION
1
2
3
4
5
6
7
8
10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigational Group
Drug A
Drug B
X
X
X
X
Reference Group
Drug C
Drug D
X
X
X
X
X
Both Groups
Drug E
X
Choosing Primary Outcomes
• Select a primary
• Exact timing when the primary outcome is
measured
• Secondary outcomes may also be selected
• Do not select surrogate outcomes,
e.g., pregnancy – not oocytes, nor embryos
Juni P et al., BMJ 2001
Calculating Sample Sizes
• Power: What sample size needed? Calculation
will be based on:
– Expected 80% power, level of significance P< 0.05
– Estimated sample recruitment based on previous
evidence.
– Do not make your sample size based on unrealistic
assumptions.
•
During the protocol formulation describe the
statistics to be used.
Performing Statistical Analysis
Who is going to be the
“person behind your numbers”?
• Crucial part of any clinical trial
– Wrong analysis = wrong results
– Improper test = not valid study
– A statistical mistake can jeopardize
years of work
Determine Feasibility of Conducting the
Study
• Are resources available (funding,
personnel)?
• Can an adequate number of
patients be recruited?
• Will it be easy to follow your
patients (subjects)?
Data Management
Case report forms
(CRF)
Uniform templates for
extracting data
Ethical Considerations
• Institutional Review Board (IRB)
• ERB approval (Ethical Review Board)
• Inform consents
• Trial registration
• Sponsorship Acknowledgement
11. Ethical considerations
•
•
•
•
•
IRB approval
Inform consents
Acceptance from National competent authorities
Trial registration
Sponsorship
Institutional Review Board (IRB) Approval
• All institutions should have (by law or regulation)
an IRB to evaluate whether it’s ethical to conduct
a given study
• Submit your protocol and wait for acceptance
prior conducting a trial
• Follow institutional instructions and explain in
detail the rationale, population, interventions, and
goals of the study
Inform Your Patients Properly….
Obtain Their Written Consent…..
• Very detailed information for the treatment (drugs,
duration, procedures)
• Current gold standard
• Expectation that the new treatment may show
a difference
• Avoid scientific terms … let them understand
(6th - 8th grade level)
• List potential side effects and who takes
responsibility
• Obtain their signature, usually requiring a witness
Acceptance from National competent
authorities
• Regulatory authorities responsible for human
medicines
• Only for medicines or devices
• It is ILLEGAL to perform a trial with a medicinal
product without having acceptance from your
National competent authority
Register Your Trial !
• After approval of relevant IRB, register your trial in
a trial registry - (e.g. clinicaltrials.gov)
• For publication, most journals require trial
registration prior the conduction of the study
Declare Any Indirect or Direct Funding
From the Industry
• ICJME suggests reporting any potential conflict(s)
of interest related (or not related) to the study, err
on the conservative side
• Industry funding should be reported
Institutional Review Board (IRB) approval
• All institutions should have (by law) an IRB to
evaluate whether it is ethical to conduct the study
• Submit your protocol and wait for acceptance
prior to conducting a trial
• Explain in detail the rationale, the population, the
interventions and the goals of the study
Inform your patients properly….
Get their written consent…..
• Very detailed information for the treatment (drugs,
duration, procedures)
• What is the current gold standard
• Why do you expect the new treatment to show
difference
• Do not use scientific terms…let them understand
• Inform about potential side-effects and who is
taking any liability in such a case
• Obtain their signature
Register your trial in a public trial registry
(1)
• After approval of IRB register your trial in a trial
registry
• Most journals require trial registration prior to the
conduction of the study
Register your trial in a public trial registry (2)
AVAILABLE REGISTRIES FOR CLINICAL TRIALS
• Australia and New Zealand's (ANZCTR) (http://www.anzctr.org.au)
• Brazilian Clinical Trials Registry (ReBec)
(http://www.ensaiosclinicos.gov.br)
• Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org)
• Clinical Research Information Service (CRiS), Republic of Korea
(http://cris.cdc.go.kr)
• Clinical Trials Registry - India (CTRI) (http://ctri.nic.in)
• Cuban Public Registry of Clinical Trials(RPCEC)
(http://registroclinico.sld.cu)
• EU Clinical Trials Register (EU-CTR)
(https://www.clinicaltrialsregister.eu/)
Register your trial in a public trial registry (3)
AVAILABLE REGISTRIES FOR CLINICAL TRIALS
•
•
•
•
•
•
•
German Clinical Trials Register (DRKS) (http://www.drks.de)
Iranian Registry of Clinical Trials (IRCT) (http://www.irct.ir/)
Japan's UMIN-CTR (http://umin.ac.jp)
The Netherlands, Trialregister.nl
The United States, ClinicalTrials.gov
The International, ISRCTN.org
Pan African Clinical Trial Registry (PACTR) (http://www.pactr.org/)
Declare any indirect or direct funding
from industry
• ICJME suggests reporting of any potential conflict
of interest related or not to the study
• Industry funding should be reported
Randomized Clinical Trials
Thank you