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Clinical Trials Hanyan Yang yhy@zzu 2008.12

Clinical Trials Hanyan Yang yhy@zzu.edu.cn 2008.12. Treatment. Once the nature of a patient’s illness has been established and its expected, the next question is: what can be done about it? Is there a treatment that improves the outcome of disease?

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Clinical Trials Hanyan Yang yhy@zzu 2008.12

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  1. Clinical TrialsHanyan Yangyhy@zzu.edu.cn 2008.12

  2. Treatment • Once the nature of a patient’s illness has been established and its expected, the next question is: what can be done about it? Is there a treatment that improves the outcome of disease? • This chapter describes ways of deciding whether a well-intentioned treatment dose in fact do more good than harms.

  3. Studies of treatment effects • ideas about what might be useful treatment arise from virtually any activity within medicine. • Usually, the effects of treatments are considerably less dramatic. It is then nece- ssary to put ideas about treatment to a formal test, because a variety of conditions----coin- cidence, faulty comparisons, spontaneous changes in the course of disease, wishful thinking, etc----can obscure the true relation- ship between treatment and effect.

  4. Clinical Trials

  5. Experimental versus Observational Study Designs • Experimental • Clinical Trials • Community Trials • Observational • Cohort Studies • Case-Control Studies • Cross-sectional Studies • Ecologic Studies

  6. Clinical Trial: Definition A clinical trial is a prospective study comparing the effect and value of intervention(s) against a control in human beings. A special kind of cohort study in which the conditions of study ---selection of treatment groups, nature of intervention, management during follow-up,etc.---are specified by the investigator for the purpose of making unbiased comparison.

  7. Clinical Trials: Objective • To asses the efficacy and effectiveness of a new intervention or drug • To help establish the role of the new drug or intervention in clinical practice.

  8. R Outcome Intervention Study Group PAR No Intervention No Outcome General Design of Clinical Trial T S PAR = Population at Risk S = Sampling design R = Randomize intervention T = Elapsed time

  9. Key Principles of a Clinical Trial • Randomization • Controls • Blinding

  10. Key Elements of a Clinical Trial • Selection of subjects • Allocation of exposure • Blinding • Data collection • Statistical issues

  11. Clinical Trials: Selection of Subjects • Population at risk, or target population, must be defined • The intervention is intended to benefit this population • Criteria must be explicitly stated that capture the population at risk • Inclusion criteria – identifies the target population • Exclusion criteria – excludes people from target population for safety reasons

  12. Clinical Trials:Allocation of Treatment • Studies without controls - not a clinical trial • Comparison groups • Historical controls • Often advocated, but usually flawed • Cannot exclude cohort effects • Usually concludes that new treatment is better than old • Simultaneous non-randomized controls • Does not address bias • Reduces chances of cohort effects • Randomization - true controls

  13. Historical Controls • Comparison of current experience with the past • Problems • Data collection differences introduce potential bias • Temporal effects not related to the intervention or therapy

  14. Clinical Trials:Simultaneous Non-Randomized Controls • A concurrent group of subjects is selected to act as a comparison group but are not offered the intervention or therapy • Problems • The concurrent groups may be fundamentally different for unrecognized reasons • Systematic allocation may be abused

  15. Clinical Trials: Randomization Randomization will, on average, balance the known and unknown risk factors for the outcome under study.

  16. Clinical Trials: Randomization • Allocation of treatment is randomized • Every participant has an equal chance to receive either the intervention or the control • Stratified randomization may be used to assign treatment within pre-defined strata • Methods for randomization • Random number table • Computer-generated list of assignments • Randomization often done at a coordinating center

  17. Clinical Trials: Data Collection • Treatment • What treatment did the subject actually take? • Assigned versus received • Links directly with intent-to-treat analysis • Outcome • Assessment of outcome must be comparable between groups • Avoid detection bias • Prognostic Profile at Entry • Groups must have similar risk for outcome at the start of the study

  18. Clinical Trials: Blinding • Blinding refers to any attempt to make the various participants in a study unware of which treatment patients have been offered, so that the knowledge cannot cause them to act differently and thereby damage the internal validity of the study.

  19. Clinical Trials: Blinding • Masking individuals participating in the trial from the treatment assignment • Levels of blinding • Individual • Data Collectors • Investigators • Analyst • Data Safety Monitoring Board

  20. Clinical Trials: Placebo • Placebo is an inert compound randomly allocated to subjects in a clinical trial. • Placebo arm is a true control for an intervention. • Assess relative effect of intervention - relative risk • Assess risk for adverse events • Placebo arms are not ethical if there is an established intervention

  21. Clinical Trials: Statistical Issues • Sample Size • Determine for primary study outcome • Must account for multiple comparisons • Often requires statistical consultation • Monitoring of events • Interim analyses are performed to determine whether to stop the study early • Sample size must be adjusted for the number of interim analyses • Data Safety Monitoring Board review • Analysis

  22. Fundamental measure of association Relative Risk Efficacy - Incidencetreatment Incidenceplacebo Efficacy = Incidenceplacebo Incidencetreatment Efficacy = 1 - = 1 - Relative Risk Incidenceplacebo Clinical Trials: Analysis

  23. Summary • Promising ideas about what might be good treatment should be put to a rigorous test before being accepted. • The best test is a randomized controlled trial, a special case of a cohort study in which the intervention is allocated without bias.

  24. Patients in clinical trials are usually highly selected, reducing generalizability. They are randomly allocated to receive either an experimental intervention or some comparison management: usual treatment, a placebo, or simple observation.

  25. On the average, the compared groups have a similar prognosis just after randomization (and before the interventions), but differences not attributable to treatment can arise later, including dropouts and crossovers, co-interventions, and non-compliance. • Blinding all participants in the trial can help to minimize bias.

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