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Alec Walker September 2013

Core Characteristics of Randomized Clinical Trials. Alec Walker September 2013. Preplanned Analysis. Goals Primary Secondary Strategy for unanticipated results Study size Statistical power Stopping rules. Preplanned Data Collection. Baseline

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Alec Walker September 2013

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  1. Core Characteristics of Randomized Clinical Trials Alec Walker September 2013

  2. Preplanned Analysis Goals • Primary • Secondary • Strategy for unanticipated results Study size • Statistical power • Stopping rules

  3. Preplanned Data Collection Baseline • Characteristics of each participant’s history • Concomitant illnesses • Diagnostic tests and procedures • Medical examination Treatment • Dose, route, frequency, duration, timing Endpoints • Symptoms and tests required for diagnosis Safety • Adverse outcomes • Contemporaneous assessment of causality

  4. Entry Criteria Treated disease • Definition • Severity, Prognosis Other health conditions • Concomitant diseases Others • Demographics – age, sex, race Implicit Criteria • Populations served by participating clinical sites • See also Informed Consent later Goals • 1o Clarify the comparison • 2oGeneralizabilty to target population

  5. Comparison of Results in Groups Groups • Anecdotes, however persuasive, are set aside • Frequency of outcome is the measure of effect • We are examining net effects • Improved as a result of treatment • No effect of treatment • Deleterious effect of treatment Comparisons • Substitution of another person’s experience for the impossible “What if?” question. (Counterfactual: What would have been the treated person’s experience if there had been no treatment?)

  6. Informed Consent • Introduced for ethical reasons • Patients should be aware that they are participating in an experiment • Actively agree to enter • A subtle selection criterion • Language skills • Education • Trust in the medical care system • Inclination to follow directions

  7. Random Assignment of Treatments • “Coin flip” metaphor • Mechanical process • Assignment not systematically associated with any patient characteristics • At the discretion of the investigator: • Number of compared treatments • Allocation ratio • Blocking • Effects • Expectation of similar outcomes between groups under the Null Hypothesis • Justification for the calculation of p-values

  8. Randomization • Treatment allocation is determined by a process • That generates An expectation of zero correlation between treatment and predictors of outcome. • The Predictors may be • Known or unknown to the experimenter • Measured or unmeasured • Measured poorly or well

  9. Balance • All characteristics other than treatment are balanced in expectation • Measured and unmeasured • Predictors and correlates of predictors • The intermediate states that later arise from these

  10. Balance • All characteristics other than treatment are balanced in expectation • Measured and unmeasured • Predictors and correlates of predictors • The intermediate states that later arise from these • Unadjusted estimates are unbiased estimates of treatment effect • Differences, ratios, more complex functions of • Risk, rates, hazards, survival, … • Costs, QoL, … • Even of dependent happenings, like epidemics (provided that exposure groups are not intermixed)

  11. Treatment Adherence • Commitment from patients • Encouragement from staff • Monitoring • Pill counts • Blood level

  12. Dedicated Outcome Data Collection • Disease prespecified • Expert consensus on diagnosis • Symptoms • Signs • Diagnostic testing • Recurrent monitoring

  13. Limited Follow-up • Need to get drug to market • For chronic conditions, no amount of follow-up will reproduce ultimate conditions of use • Surrogate outcomes • Examples • Control of blood pressure or HbA1c • Patient-reported outcomes • Desiderata • Well established correlates of clinically important • Generally not important clinically in themselves • Manifest earlier • Real clinical outcomes can be addressed later

  14. N Engl J Med. 2010 Apr 1;362(13):1192-202

  15. Balance

  16. Delta = Treatment Effect

  17. Delta = Treatment Effect

  18. Problems Solved, Problems Remaining • Randomization in RCTs provides the gold standard for inference • No hypothesis of confounding • Frequentist interpretation of measures is supported by the structure of the trial • RCT populations may be atypical • In baseline characteristics • In adherence to therapy • In care of follow-up • RCT follow-up may be short

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