how to design a study
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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) - PowerPoint PPT PresentationTRANSCRIPT
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How to design a study
Nikolaos P. Polyzos M.D. PhD
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What kind of study should I perform?
It depends on what you are seeking for..
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General types of studies
Observational studies Checking association or relationship
Interventional studies (Clinical trials)
Checking a specific treatment protocol
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Type of studies and level of evidence
RCTs
Metaanalyses
of RCTs
Cohorts, case control studies, cross-
sectional surveys
Case series, case reports, guidelines, expert opinions
LEVEL I evidence
LEVEL II evidence
LEVEL III evidence
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Clinical trials
Randomized and non randomized
Treatment arm --with or without a control arm
Testing the safety and effectiveness of a drug or intervention
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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 IIILarge groups of patients for statistical confirmation of effect and
incidence of side-effects >100 patients
Phase IVPost marketing studies. Fine tuning and new rare findings from a very
large population
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Randomized clinical trials
LEVEL I evidence
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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
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Designing a clinical and especially a randomized trial …….
Is it that easy?It c
an be..
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THE STUDY PROTOCOL
…..possibly the most important part of your trial
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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
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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?
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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).
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3. The population to include..
Clearly defined
Easy to recruit
Easy to follow
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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
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4.Randomization procedure
Simple randomization Block randomization Computer generated list
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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 ensure1. sequentially numbered, opaque, sealed envelopes
(SNOSE);
2. sequentially numbered containers;
3. pharmacy controlled randomization;
4. central randomization
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4. Blinding
Procedures that prevent study participants, caregivers, or outcome assessors from knowing which intervention was received
Types
1. Single-blind
2. Double-blind
3. Open Label
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5. Patients’ monitoring
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6. Clearly defined interventions
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7. The primary outcomes
Do not select surrogate outcomes
e.g. pregnancy ---not oocytes, nor embryos
Exact timing when the primary outcome is measured
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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
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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
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9. The feasibility of conducting the study
Resources available ( funding, personnel)
Available number of patients
Easy to follow your patients
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10. Data management
Uniform templates for extracting data
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11. Ethical considerations
IRB approval Inform consents Trial registration Sponsorship
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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
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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
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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
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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
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Why is so crucial to design and perform a clinical trial correct?
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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;
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Top cited articles are they always telling the truth NO
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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
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ALL RANDOMIZED TRIALS REPRESENT TOP LEVEL OF EVIDENCENO
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Poor study design….wrong conclusions
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RANDOMIZED TRIALS ARE EASILY PUBLISHED
NOShow a benefit and get published!!
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Negative RCTs may left unpublished….
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INDUSTRY SPONSORHIP DOES NOT AFFECT THE OUTCOMES OF RCTS
Get the money …..and the results can benefit the drug
that sponsors you!
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Industry and positive results…
titel41 19-04-2023
BMJ. 2003 May 31;326(7400):1167-70.
SPONSORSHIP ---- 4 times more like to have a positive result in your trial
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New drugs are cost-effective even if they cost thousands of Euros
…..only If you get some sponsorship of course
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Industry and positive results in cost-effectiveness analysis (CEAs) of novel drugs
82% of Sponsored cost-effectiveness analyses show that drugs are cost effective
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Do not follow ethical guidelines and you can publish everything
Not always….
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Data fabrication….even in the top journals
Sudbø case (Lancet)
Among 908 in the study 250 had the same birth date
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Copy-paste…..
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Conclusions
Build your protocol
Select carefully your population
Decide which study design you will choose based on your resources
Always consider your study design when you interpret your results
No trial is without a limitation and always results can be due to chance…
The higher the level of evidence …the most likely to be true
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Conclusions
Select your people for conducting your trial
1. Investigators
2. Study nurses
3. Co-ordinator
4. Statisticians
Follow rigorously the ethical guidelinesDo not attempt to publish at any cost!
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Otherwise………….. You will simply get into…
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Thank you