Randomized (Clinical) Trials Questions and answers.

Case Study or Case Series -No randomization -No comparison is made w/an untreated group or a group getting some other treatment -Observations of clinical response Studies w/a Comparison -Historical controls -Simultaneous non-randomized controls -Randomization -Stratified randomization Historical Controls -The use of a comparison group from the past -Go back to records of patients w/the same disease w/the prior treatment used Problems w/Historical controls •Differences in: -base population -disease rates -disease definition -disease treatment -quality of data collection Simultaneous Non-randomized controls •Can be a problem if the assignment system can be predicted -for ex, if patients admitted on an even day got the new treatment and odd day admissions were the controls •Can lead to selection bias--increased admissions on even days Intervention Studies •Used to test efficacy of preventive or therapeutic measures •Two categories -controlled clinical trials -community interventions •Multicenter trials--results from several researchers are pooled Randomized Clinical Trials •Subjects are enrolled in the study and exposure, the intervention, is manipulated by the investigator •Subjects are randomized to the intervention or control (placebo) assignment •Subjects are followed up for disease outcome Design of a Randomized Trial -Study Population--randomly assigned into current treatment and new treatment -measure the people who improve and don't improve in each group Characteristics of Clinical Trials -assess the efficacy of a treatment -carefully designed and rigidly enforced protocol -random assignment of subjects to study groups (intervention and control) Examples of Clinical Trials •Medical Research Council Vitamin Study--studied role of folic acid in preventing neural tube defects •South Bronx, NY, STD program--evaluated effectiveness of education efforts to prevent spread of STDs Utility of Randomized Trials -Evaluate new drugs and other treatments (nutritional supplements) -Evaluate new medical technology -Assess new screening programs Randomized Clinical Trials Advantages -No selection bias -Certainty about exposure, although compliance should be monitored -Gold standard of study designs RCTs Limitations -Expensive -Can be lengthy -Lack of generalizability -Ethical issues Important Concepts in RCT Design •Concurrent controls •Randomization •Placebos •Double blind technique Selection of Subjects -Investigators must have clear criteria for who will be in the study -Criteria must be written in advance for both inclusion and exclusion -Remember, this will impact on the generalizability or external validity Why randomize? -To prevent investigator/patient bias -To establish balance at baseline in terms of potential confounders -To create the basis for statistical testing, that may rely on prior randomization Randomization Issues •If some subjects leave the study based on certain characteristics (old age) to a greater extent in the intervention or control groups--the benefits of randomization are lost •If one or both arms of the study are not compliant with the group assignment (intervention or control) it will lead to an underestimate of effectiveness •For ex, intervention=exercise--they refuse to do so and placebo start to exercise b/c of press stating benefits of exercise Randomization Randomization increases the probability that there is an even distribution of observable and unobservable potential confounders b/t the intervention and control groups -if age and sex strongly affect prognosis: use Stratified Randomization Blinding Blinding and placebo are used to ensure that neither study subjects or those assessing outcome are aware of group assignment--helps decrease bias Blinding (Masking) •To maintain the integrity of a study and reduce the potential for bias, the investigator may utilize one of two popular approaches: -Single-blind design: subject unaware of group assignment -Double-blind design: neither subject nor experimenter is aware of group assignment Why use a placebo in the control group? -The placebo effect exists and rates can vary (e.g. 0 to 35% in a study of soy and health) -May help control crossover -Even with a placebo, many guess treatment -The placebo group can also be important to study side effects Essential Data collection in Randomized Trials •Treatment--what was the assignment and what was the compliance •Outcome--measures of both drug efficacy and side effects. Need explicit criteria for evaluation and blinding is important •Compare the entry characteristics to determine if randomization was successful