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Clinical Trials Hanyan Yang [email protected] 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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  • 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.

Studies of treatment effects
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.

Experimental versus observational study designs
Experimental versus Observational Study Designs

  • Experimental

    • Clinical Trials

    • Community Trials

  • Observational

    • Cohort Studies

    • Case-Control Studies

    • Cross-sectional Studies

    • Ecologic Studies

Clinical trial definition
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.

Clinical trials objective
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.

General design of clinical trial











General Design of Clinical Trial



PAR = Population at Risk

S = Sampling design

R = Randomize intervention

T = Elapsed time

Key principles of a clinical trial
Key Principles of a Clinical Trial

  • Randomization

  • Controls

  • Blinding

Key elements of a clinical trial
Key Elements of a Clinical Trial

  • Selection of subjects

  • Allocation of exposure

  • Blinding

  • Data collection

  • Statistical issues

Clinical trials selection of subjects
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

Clinical trials allocation of treatment
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

Historical controls
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

Clinical trials simultaneous non randomized controls
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

Clinical trials randomization
Clinical Trials: Randomization

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

Clinical trials randomization1
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

Clinical trials data collection
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

Clinical trials blinding
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.

Clinical trials blinding1
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

Clinical trials placebo
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

Clinical trials statistical issues
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

Clinical trials analysis

Fundamental measure of association

Relative Risk





Efficacy =



Efficacy = 1 -

= 1 - Relative Risk


Clinical Trials: Analysis


  • 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.

  • 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.