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How to design a study

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)

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How to design a study

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  1. How to design a study Nikolaos P. Polyzos M.D. PhD

  2. What kind of study should I perform? It depends on what you are seeking for..

  3. General types of studies • Observational studies Checking association or relationship • Interventional studies (Clinical trials) Checking a specific treatment protocol

  4. Type of studies and level of evidence LEVEL I evidence LEVEL II evidence LEVEL III evidence

  5. Clinical trials • Randomized and non randomized • Treatment arm --with or without a control arm • Testing the safety and effectiveness of a drug or intervention

  6. 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

  7. Randomized clinical trials LEVEL I evidence

  8. 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

  9. Designing a clinical and especially a randomized trial ……. Is it that easy? It can be..

  10. THE STUDY PROTOCOL …..possibly the most important part of your trial

  11. The 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 • The primary outcomes • Appropriate statistical analysis • Feasibility of the study • Data management • Ethical considerations

  12. 1. The research question & 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?

  13. 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).

  14. 3. The population to include.. • Clearly defined • Easy to recruit • Easy to follow

  15. 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

  16. 4.Randomization procedure • Simple randomization • Block randomization • Computer generated list

  17. 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 • sequentially numbered, opaque, sealed envelopes (SNOSE); • sequentially numbered containers; • pharmacy controlled randomization; • central randomization

  18. 4. Blinding • Procedures that prevent study participants, caregivers, or outcome assessors from knowing which intervention was received • Types • Single-blind • Double-blind • Open Label

  19. 5. Patients’ monitoring

  20. 6. Clearly defined interventions

  21. 7. The primary outcomes • Do not select surrogate outcomes e.g. pregnancy ---not oocytes, nor embryos • Exact timing when the primary outcome is measured

  22. 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

  23. 8. Sample size calculation • Power-sample calculation • 80% power, level of significance 0.05 • Estimate your sample based on previous evidence • Do not make your sample size based on unrealistic assumptions • During the protocol formulation describe the statistics you will use

  24. 9. The feasibility of conducting the study • Resources available ( funding, personnel) • Available number of patients • Easy to follow your patients

  25. 10. Data management • Uniform templates for extracting data

  26. 11. Ethical considerations • IRB approval • Inform consents • Trial registration • Sponsorship

  27. 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

  28. 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

  29. 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

  30. 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

  31. Why is so crucial to design and perform a clinical trial correct?

  32. A research finding is less likely to be true when the studies conducted in a field are smaller effect sizes are smaller; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice;

  33. Top cited articles are they always telling the truth NO

  34. 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

  35. ALL RANDOMIZED TRIALS REPRESENT TOP LEVEL OF EVIDENCE NO

  36. Poor study design….wrong conclusions

  37. RANDOMIZED TRIALS ARE EASILY PUBLISHED NO Show a benefit and get published!!

  38. Negative RCTs may left unpublished….

  39. INDUSTRY SPONSORHIP DOES NOT AFFECT THE OUTCOMES OF RCTS Get the money …..and the results can benefit the drug that sponsors you!

  40. 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 titel

  41. New drugs are cost-effective even if they cost thousands of Euros …..only If you get some sponsorship of course

  42. Industry and positive results in cost-effectiveness analysis (CEAs) of novel drugs 82% of Sponsored cost-effectiveness analyses show that drugs are cost effective

  43. Do not follow ethical guidelines and you can publish everything Not always….

  44. Data fabrication….even in the top journals • Sudbø  case (Lancet) • Among 908 in the study 250 had the same birth date

  45. Copy-paste…..

  46. 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

  47. Conclusions • Select your people for conducting your trial • Investigators • Study nurses • Co-ordinator • Statisticians • Follow rigorously the ethical guidelines • Do not attempt to publish at any cost!

  48. Otherwise………….. You will simply get into…

  49. Thank you

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