1. Clinical Trials Hanyan Yang yhy@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
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. General Design of Clinical Trial
Intervention
Outcome No
Study
Group
PAR T S R No
Intervention
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. Clinical Trials: Analysis
Fundamental measure of association
Relative Risk
Efficacy
Efficacy =
Incidenceplacebo
Incidencetreatment -
Efficacy = 1 -
= 1 - Relative Risk

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.