1. 1 Experimental Study Designs Dr. Birgit Greiner Dep. of Epidemiology and Public Health

2. 2 Learning objectives At the end of this lecture you … Are familiar with areas of application of experimental studies Know different types of experimental studies Understand the essential components of the design Appreciate potential limitations Are familiar with ethical issues in trials

3. 3 Type of Study Alternative Name Unit of Study Randomised Controlled Trials Field Trials Community Trials Clinical Trials Community Intervention Studies Patients Healthy People Communities

4. 4 Trials are useful for evaluating: New drug or other treatment for disease New medical/health care technology Methods of prevention Methods of health promotion New health protection policies Programs for screening and diagnosis Methods of providing health care New health care policies

5. 5 Example of an RCT A randomised controlled trial investigated whether preoperative smoking intervention reduced postoperative complications in patients undergoing hip or knee replacement Moeller AM, Villebro N, Pedersen T. & Toennesen H. The Lancet, Vol 359 Jan 12, 2002

6. 6 InterventionRandomisation ControlBlinding

7. 7 population group 1 group 2 Outcome new treatment control treatment

8. 8 Randomised controlled trial Patients undergoing hip or knee replacement Preoperative Smoking intervention Standard care POC No POC POC No POC

9. 9 Chance - Sample Size Bias - Randomisation/Blinding/ Standardization Confounding - Randomisation Overview

10. 10 Chance: Sample size Large enough to have high probability (power) of detecting a clinically important difference of a given size Size of effect Error level (usually 5%) Statistical power (usually 80%) Variation of outcome Use StatCalc in the EpiInfo Software: http://www.cdc.gov/epiinfo/EI2000.htm

11. 11 Bias Systematic deviation of results from the truth Measurement bias Sytematic error arising from inaccurate measurement Selection bias Error due to systematic differences between those selected for the study and those who are not

12. 12 Confounding Effects of 2 exposures are not seperated EXPOSURE (coffee drinking) DISEASE (heart disease) CONFOUNDING VARIABLE (cigarette smoking)

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14. 14 Validity issues Internal validity Degree to which the investigator’s conclusions correctly describe what happened in the study External validity Degree to which the investigator’s conclusions are appropriate when applied to the universe outside the study

15. 15 Advantages of RCTs Strong ability to prove causal relationships Risk of confounding factors minimised by randomisation Efficient and powerful statistical manipulation possible

16. 16 Disadvantages of RCTs Loss-to-follow up of patients and non- compliance might constitute major biases Often based on volunteer samples, results may not be generalizable to the wider population Not feasible/ethical for major public health questions

17. 17 Basic Ethical Principles in Biomedical Research Involving Human Subjects Experimental procedure clearly formulated in protocol and reviewed by independent committee Importance of objective is in proportion to risk to the subject Assessment of predictable risks in comparison with forseeable benefits to subject Cease intervention if hazards outweigh benefits Informed consent from subject Subject can withdraw at any time Adapted from Helsinki Declaration: www.mrc.ac.uk/pdf-ctg.pdf

18. 18 Voluntary consent of human subject is absolutely essential….. free power of choice, without the intervention of …. ulterior form of constraint or coercion. Helsinki Declaration 2000

19. 19 Ethical Considerations in RCTs Is proposed treatment safe? For the sake of trial, can a treatment ethically be withheld? What patients may be brought into trial and allocated randomly to treatments? Is it ethical to use a placebo or dummy treatment? Is it proper for the trial to be in any way masked? Adapted from Hill (1977)

20. 20 Pooling of data from multiple studies addressing the same hypothesis. Provide a more “precise” estimate Watch out for publication bias !

21. 21 Database of Systematic Reviews Database of Abstracts of Reviews Cochrane Collaboration Trials Registry Cochrane Review Methodology Cochrane Collaboration www.cochrane.org