1. Lecture 5 Objective 14. Describe the elements of design of experimental studies: clinical trials and community intervention trials. Discuss the advantages and disadvantages of each.

2. Definition of a clinical trial prospective studies in human subjects compare the outcomes between intervention groups one intervention may be a control group –could be the standard treatment or no treatment –placebo or sham indicates a treatment identical to the treatment to be tested in all aspects except with an inert substance.

3. Phases of Clinical Trials Preclinical Preclinical Trials I. Determine Maximum Tolerated Dose II. Evidence of a Response III. Safety, Efficacy (humans) IV.Safety, Acceptability, Efficacy

4. Issues in Clinical Trials Posing the right question Defining the right end points (outcomes) –Multiple end points Defining the population who might benefit –Inclusion criteria –Exclusion criteria

5. Design of Clinical Trials Parallel design –Randomized controls –Concurrent controls –Historical controls Crossover design Factorial design Equivalence design

6. May 1747, Aboard the Salisbury

7. 1954 Field Trial of Poliomyelitis Vaccine (Salk)

8. Breast Cancer Therapy

9. PHS Study: Aspirin Arm

10. AZT in AIDS

11. Lecture 5 Objective 15. Discuss the terms subject selection, exposure allocation, randomization, stratification, self ‑ selection, systematic assignment, outcome assessment, threats to validity: internal, external

12. Selection of Subjects from population at risk determined by inclusion and exclusion criteria (who will benefit or may be harmed how are patients ascertained and recruited for study referral bias

13. Assignment of Exposure self-selection (doctor selects or patient selects) can lead to bias/confounding exposure (treatment) assigned randomly is preferred (data coordinating center or other independent of investigators)

14. Why Randomize Treatment groups comparable wr to risk factors (known and unknown) Removes investigator bias in allocation of subjects Removes self-selection bias in allocation of subjects Guarantees that statistical tests have valid significance levels

15. Assignment of Exposure Simple Randomization Blocked Randomization Stratified Randomization Systematic assignment is not randomization

16. Temporal Relationship Investigator (I) to Exposure (E) and Outcome (O) I E O | | | ________________________ t

17. Measurement of Risk and Association Risk: Incidence rates (IR) can be cumulative incidence (CI) or incidence density (ID) Association: Risk Ratio (RR) or Risk Difference (RD)

18. Validity Confounding Bias: possibility reduced through random assignment of exposure; all minimized by matching, restriction Information Bias: prevent by "blinding"; reduce possibility with objective diagnostic criteria Selection Bias: very unlikely to occur (prospective study)

19. Control of Bias in Clinical Trials Selection Bias (randomize) Observation bias (blind/mask) Attrition bias (simple to participate/incentives) Compliance bias (simple regimen) Drop-in/Drop-out (timing)

20. Advantages can reduce potential of confounding through random assignment of exposure can estimate risk using incidence rates best design for interpreting causality

21. Limitations not suited for studying harmful exposures, only preventive or therapeutic agents difficult to study rare outcomes not well suited for studying outcomes with long latent periods

22. Limitations not well suited for studying a particular outcome; best suited for studying exposures cannot study traits of subjects that are present at the time of selection (such as age sex, genetic factors)

23. Ethics in Clinical Trials Informed Consent Interim Monitoring and Early Termination Proper Timing of Trials

24. Analysis of Data from Clinical Trials Intent to Treat Control of Confounding Subgroup analyses Meta-Analysis

25. Community trials assignment of school rooms, towns and cities to the intervention arms rather than individuals. COMMIT - Smoking trial CATCH - Child and Adolescent Trial for Cardiovascular Health Fluoridation studies

26. Evaluating a therapeutic effectiveness study Was the study properly conducted? –Were the entry criteria clearly specified? (evidence entry criteria fulfilled) –Were the study groups comparable? (potential confounders accounted for? attempts to control confounding?) –How was compliance assessed? –Did the loss to follow ‑ up exceed 20%?

27. Evaluating…. –Was the study blinded? –Were the outcomes clearly specified? (outcomes clearly specified and accurately measured?) –Was the study size sufficient to justify the author's conclusions? (if the results were not significant, was the power reported?)

28. Evaluating... What is the "value" of the study? –How were the subjects recruited? –Were the results clinically significant? –Do the subjects in the study resemble your patients? (Did the study contain men and women, minorities, elderly?)

29. Evaluating... –Could your patients avail themselves of the treatment? (Did the treatment used in the study involve medicines or treatments unavailable to the average patients? Cost? Distance? Side effects?)

30. Internal Mammary Artery Ligation (IMAL) in Angina

31. Supplemental Ascorbate in Treatment of Cancer 100 Treated (began ascorbate treatment) 1000 Controls 10 to 1 match (same sex, age, site, histology) Average Survival Time –Treated: 210 days –Controls: 50 days Cameron and Pauling, Proc. Natl Acad. 1976