Transcript Dia 1 - IFFS-UIT

How to design a study
Nikolaos P. Polyzos M.D. PhD
What kind of study should I perform?
It depends on what you
are seeking for..
General types of studies

Observational studies
Checking association or relationship

Interventional studies (Clinical trials)
Checking a specific treatment protocol
Type of studies and level of evidence
RCTs
Metaanalyses
of RCTs
Cohorts, case control
studies, crosssectional surveys
Case series, case reports,
guidelines, expert opinions
LEVEL I
evidence
LEVEL II
evidence
LEVEL III
evidence
Clinical trials

Randomized and non randomized

Treatment arm --with or without a control arm

Testing the safety and effectiveness of a
drug or intervention
Clinical Trials-Phases

Phase I
Safety testing- small groups of patients 10-15 patients

Phase II
Pilot studies to confirm the effectiveness of the drug less than 100
patients

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(1)
Description:
After assessment of eligibility and recruitment, but before the
intervention to be studied begins, are randomly allocated to receive
one or other of the alternative treatments under study
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
Disadvantage:



Costs
Time
Rare events
Designing a clinical and especially a
randomized trial …….
Is it that easy?
THE STUDY PROTOCOL
…..possibly the most important part of your trial
The proper study protocol
1.
Research question-rationale
2.
Exact study design
3.
Inclusion-exclusion criteria
4.
Randomization procedure, allocation concealment, blinding
5.
Timing of blood sampling and monitoring
6.
Clearly defined interventions
7.
The primary outcomes
8.
Appropriate statistical analysis
9.
Feasibility of the study
10.
Data management
11.
Ethical considerations
1. The research question & hypothesis

Simple –one question and one answer

In accordance with the available evidence

Ask yourself
1. Why is such a study valuable?
2. Can it change clinical practice?
2. Study design

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).
3. The population to include..

Clearly defined

Easy to recruit

Easy to follow
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
different definition
Who are the poor ovarian
responders
4.Randomization procedure



Simple randomization
Block randomization
Computer generated list
4. Concealment of patients allocation

The procedure for protecting the randomisation process
so that the treatment to be allocated is not known before
the patient is entered into the study

Methods to ensure
1.
2.
3.
4.
sequentially numbered, opaque, sealed envelopes
(SNOSE);
sequentially numbered containers;
pharmacy controlled randomization;
central randomization
4. Blinding

Procedures that prevent study participants,
caregivers, or outcome assessors from
knowing which intervention was received

Types
1.
2.
3.
Single-blind
Double-blind
Open Label
5. Patients’ monitoring
6. Clearly defined interventions
7. The primary outcomes

Do not select surrogate outcomes
e.g. pregnancy ---not oocytes, nor embryos

Exact timing when the primary outcome is
measured
8. 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 jeopardise the work
of years
8. Sample size calculation


Power-sample calculation
1.
80% power, level of significance 0.05
2.
Estimate your sample based on previous evidence
3.
Do not make your sample size based on unrealistic
assumptions
During the protocol formulation describe the
statistics you will use
9. The feasibility of conducting the study

Resources available ( funding, personnel)

Available number of patients

Easy to follow your patients
10. Data management

Uniform templates for extracting data
11. Ethical considerations




IRB approval
Inform consents
Trial registration
Sponsorship
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 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 !

After approval of IRB register your trial in a
trial registry (e.g. clinicaltrials.gov)

Most journals require trial registration prior
the conduction of the study
Declare any indirect or direct funding
from the industry

ICJME suggests reporting of any potential
conflict of interest related or not to the study

Industry funding should be reported
Why is so crucial to design and perform a
clinical trial correct?
A research finding is less likely to be true when
1. the studies conducted in a field are smaller
2. effect sizes are smaller;
3. where there is greater flexibility in designs, definitions, outcomes,
and analytical modes;
4. when there is greater financial and other interest and prejudice;
Top cited articles are they always telling the
truth
Initial findings…might prove wrong in the
future

Highly cited studies (>1000 citations) with
efficacy claims

16% were contradicted by subsequent research

16% were found to have initially stronger effects.

44% were replicated also with a larger sample
size in subsequent research compared with the
original highly cited study)

24% had remained largely unchallenged.
Ioannidis JP, JAMA 2005
ALL RANDOMIZED TRIALS REPRESENT
TOP LEVEL OF EVIDENCE
Poor study design….wrong conclusions
RANDOMIZED TRIALS ARE EASILY
PUBLISHED
NO
Show a benefit and get published!!
Negative RCTs may left unpublished….
INDUSTRY SPONSORHIP DOES NOT
AFFECT THE OUTCOMES OF RCTS
Get the money …..and the
results can benefit the drug
that sponsors you!
Industry and positive results…
BMJ. 2003 May 31;326(7400):1167-70.
SPONSORSHIP ---- 4 times more like to
have a positive result in your trial
41
titel
20-7-2015
New drugs are cost-effective even if they cost
thousands of Euros
…..only If you get some sponsorship of course
Industry and positive results in cost-effectiveness
analysis (CEAs) of novel drugs
82% of Sponsored cost-effectiveness analyses show that
drugs are cost effective
Do not follow ethical guidelines and you can
publish everything
Not always….
Data fabrication….even in the top journals

Sudbø case (Lancet)

Among 908 in the study
250 had the same birth
date
Copy-paste…..
Conclusions

Build your protocol

Select carefully your population
No trial is without a limitation and always results can
be due to chance…

Decide which study design you will choose
The higher
level
of evidence …the most likely to
based
on the
your
resources
be true

Always consider your study design when you
interpret your results
Conclusions

Select your people for conducting your trial
1. Investigators
2. Study nurses
3. Co-ordinator
4. Statisticians

Follow rigorously the ethical guidelines
Do not attempt to publish at any cost!

Otherwise………….. You will simply get into…
Thank you