Experimental Studies Randomized Trials Clinical Trials

Research Design Epidemiology Descriptive Studies Case Reports Case Series Cross Sectional Survey Analytic Studies Observational Studies Case-Control or Case-Comparison Cohort Studies Intervention Studies Clinical Trials

History The Islamic-Persian scholar Avicenna (980– 1037) was an early proponent of the technique. James Lind (1716–1794) ran a clinical trial in 1747 to compare the effects of cider, oranges and lemons and four other treatments in 12 patients suffering from scurvy (two assigned to each treatment). The two given oranges and lemons recovered. The first modern randomized clinical trials were carried out by the Medical Research Council in the United Kingdom and their prime mover was the statistician Austin Bradford Hill (1897– 1991).

From Canon of Medicine "The drug must be tested with two contrary types of diseases, because sometimes a drug cures one disease by Its essential qualities and another by its accidental ones." "The time of action must be observed, so that essence and accident are not confused." "The effect of the drug must be seen to occur constantly or in many cases, for if this did not happen, it was an accidental effect." "The experimentation must be done with the human body, for testing a drug on a lion or a horse might not prove anything about its effect on man."

Randomized Clinical Trials Therapeutic AZT treatment for AIDS Mastectomy vs. lumpectomy Intervention Mammography for early detection Cholesterol lowering drugs Prevention Smoking cessation Clean needle program

Strength of Evidence WeakerStronger Case reports Randomized Case series Trials Observational studies Case/Control Cohort

Experimental Studies General features inherent to methodology prospective concurrent control group intervention with placebo or usual care investigator controls/ manipulates conditions studied (hence an experiment) investigator assigns exposure

Schematic diagram of a clinical trial Sample Nonparticipants Randomization Control Intervention Lost to follow-up Measure outcome

Randomization types Simple Systematic Balanced block Stratified

Simple randomization BBABABAABB BAAAAAAABA BABABBBBAB ABABABBBBB BAAABABBAA AABABBBABB ABBAABBBAB BAAABBABBB BAABABBBAB BBABBBBABA

Systematic randomization ABABABABAB ABABABABAB ABABABABAB ABABABABAB ABABABABAB ABABABABAB ABABABABAB ABABABABAB ABABABABAB ABABABABAB

Balanced block randomization 1.AABB 2.ABAB 3.ABBA 4.BBAA 5.BABA 6.BAAB

Balanced block randomization 1.AABB 2.ABAB 3.ABBA 4.BBAA 5.BABA 6.BAAB

Balanced block randomization 1.AABB 2.ABAB 3.ABBA 4.BBAA 5.BABA 6.BAAB AABB

Balanced block randomization 1.AABB 2.ABAB 3.ABBA 4.BBAA 5.BABA 6.BAAB AABB

Balanced block randomization 1.AABB 2.ABAB 3.ABBA 4.BBAA 5.BABA 6.BAAB AABBABBA

Balanced block randomization 1.AABB 2.ABAB 3.ABBA 4.BBAA 5.BABA 6.BAAB AABBABBA

Balanced block randomization 1.AABB 2.ABAB 3.ABBA 4.BBAA 5.BABA 6.BAAB AABBABBA ABAB

Balanced block randomization 1.AABB 2.ABAB 3.ABBA 4.BBAA 5.BABA 6.BAAB AABBABBA ABAB

Balanced block randomization 1.AABB 2.ABAB 3.ABBA 4.BBAA 5.BABA 6.BAAB AABBABBA ABABAABB

Balanced block randomization 1.AABB 2.ABAB 3.ABBA 4.BBAA 5.BABA 6.BAAB AABBABBA ABABAABB BAABBBAA ABBAABBA AABBABAB BABAABBA BBAAAABB ABBABBAA BABAABBA BAABAABB

Confounding and Bias By randomly assigning the exposure - reduce the risk of confounding because: “confounders - known and unknown” are randomly distributed among the treatment groups By blinding (masking) assessment of outcome reduce the risk of information bias

Masking (blinding) To avoid systematic differences between the treated and control groups during the course of the study in factors other than the one under study Double-blind Patient, care provider, and investigator (person collecting data) all unaware of treatment assignment Single-blind Patient unaware of treatment assignment

Blindness Open label (unblinding) Single blinding (patients only) Double blinding (patients and investigators) Triple blinding (patients and investigators and Monitoring investigators)

Concerns in RCT Loss to follow up Low compliance Publication bias