1. What is a Clinical Trial (alpha version) John M. Harris Jr., MD President Medical Directions, Inc.

2. Learning Objectives  The US Government’s definition of a clinical trial  Important terms that describe clinical trials  The four phases of clinical trials  Controls in clinical trials  Randomization in clinical trials  Blinding in clinical trials

3. The US Government’s Definition of a Clinical Trial

4. US Government’s Definition  Practical definition of the term, “clinical trial” that clarifies the difference between clinical trials and other types of human research  If a research project is funded or regulated by the US government, then it must also meet a number of legal and regulatory requirements that do not apply to other types of research

5. US Government’s Definition  It is a prospective study  It is in humans  It is designed to answer questions about an intervention –a biomedical intervention –a behavioral intervention  A prospective biomedical or behavioral research study of human subjects, that is designed to answer specific questions about biomedical or behavioral interventions.

6. What is NOT a Clinical Trial?  A study that seeks to understand how a disease affects people is not a clinical trial unless participants are deliberately given either the disease or a treatment for it.

7. Drug abuse research projects that are not clinical trials  Primate (monkey) testing of a new HIV therapy intended for humans  Ethnographic research to understand information gathering patterns of injecting drug users  A program evaluation of a government initiative to reduce cocaine use by unwed mothers  A descriptive (epidemiologic) study of drug abuse patterns among persons receiving naltrexone for alcohol dependency

8. Examples of activities that are clinical trials  Suppose you supervise four drug abuse clinics –female patients may not be attending drug abuse program due to child care problems –provide supervised child care and a hot meal in two clinics for 6 months –Is this a clinical trial?  Yes - prospectively testing an intervention (food and child care) in humans.

9. What do you have to worry about?  Ethical issues  Scientific issues  Successful management of ethical and scientific issues, in addition to any local regulatory requirements

10. Important Terms That Describe Clinical Trials

11. Four Major Features to Clinical Trials  The stage of the study intervention (study phase)  Whether the trial is a controlled study  Whether participants are randomized  Whether participants are unaware of (or “blinded” to) treatments and results

12. Key terms to describe the four basic features of a clinical trial FEATURETERMS USED Study Stage Phase I (New intervention) Phase II (Intervention is promising) Phase III (Real world evaluation ) Phase IV (Intervention is in use) ControlsUncontrolledPlaceboActive Control(s) RandomizationNon-randomizedRandomized BlindingUnblinded Single- blind Double-blindTriple(+)-blind

13. The Four Phases of Clinical Trials

14.  Phase I – The intervention is new and is being tested in a small group of people for safety  Phase II – The intervention looks promising and is being evaluated in a larger group of people for safety and efficacy  Phase III – The intervention appears safe and effective and is being evaluated in a real-world study  Phase IV – The intervention is now in use and is being monitored for safety

15. How clinical trials can be interpreted  The US NIH definitions of a clinical trial used for human subjects research give estimates of the number of people involved and specifically state that all phase III trials require comparison studies definitions of a clinical trial used for human subjects researchdefinitions of a clinical trial used for human subjects research  The US NIH definitions of a clinical trial used to register clinical trials do not mention the number of persons involved in the different phases but note that phase II studies involve comparisons (controls), while phase III studies may not definitions of a clinical trial used to register clinical trialsdefinitions of a clinical trial used to register clinical trials

16. Controls in Clinical Trials

17. What is a clinical control?  What has been done in the past?  Current treatments (standard treatment)?  A similar-looking but ineffective treatment (placebo)?  Whenever an intervention is compared to something else, the alternative is called a “control”.

18. Placebo Controls  Designed to duplicate the experience of the intervention without providing the active component  Recognizes that many health outcomes are dependent on the patient’s willingness to participate and the patient’s and physician’s perception of benefit  Can provide clear improvement in symptoms (the “placebo effect”)  Can more accurately determine the extent to which the intervention alone affects treatment

19. Interventions  The control contains an active component and is, therefore, an active control  Active controls are frequently done in phase III trials where the intent is to understand the benefits of a new treatment in a real-world setting

20. Randomization in Clinical Trials

21. Why is randomization necessary  How does the researcher decide who gets which treatment? –every person will get the new treatment –some persons may be willing to accept the new treatment while others are not.  Whenever there is a good possibility that the control group and the intervention group are not identical, there is also a good possibility that the results will differ because of some factor totally unrelated to the treatment.

22. What is Randomization?  Randomization -the assigning of persons to the control group or the intervention groups based on chance.  An essential feature of good clinical trial design whenever there are one or more control groups.  The process of randomization must be totally unrelated to the variables of interest.

23. Common randomization schemes  Complete randomization  Block randomization  Urn randomization  Stratified randomization  Cluster randomization

24. Complete randomization  Individuals are assigned to control and intervention groups based on a random event that is proportional to the size of the groups  The event could be a coin toss for two groups of equal size or a more complex computer generated algorithm  Resulting group sizes may not be equal (or in the desired ratio) because the process is truly random

25. Block randomization  Also known as permuted block randomization  Ensures that the number of subjects assigned to treatment and control groups is balanced  Individuals are placed into small groups (blocks) and then randomly assigned to control and intervention groups. –Example:  Two groups (A & B) and block size is four  Two persons are randomly assigned to group A  Remaining two in that block are assigned to group B  Creates the potential for bias because the assignment of certain block members is determined by the assignment of others.

26. Urn randomization  Form of “adaptive randomization” whose intent is to balance the number of individuals in each group without specifying that an individual must be assigned to a specific group  The chances that an individual will be assigned to a treatment or control group are allowed to vary based on prior assignments

27. Stratified randomization  Used to guarantee that there is a balance of certain characteristics in treatment and control groups  Individuals are separated into subgroups (strata) based on a predetermined feature  Randomly assigned to control and intervention groups using one of the methods mention in previous slides

28. Cluster randomization  Created in an attempt to deal with issues of contamination within subgroups  Individuals are placed in subgroups  The entire subgroup (cluster) is randomly assigned to be part of a control or intervention group  Increasingly popular but requires an adequate number of clusters and careful design

29. Blinding in Clinical Trials

30. The purpose of blinding  Many clinical trials lack well-defined, objective endpoints  Such measures are subject to intentional manipulation and unintentional bias  Researchers may seek to disguise whether the subjects are receiving the intervention or the control treatment

31. What is Blinding?  The term “blinding” is used to describe the techniques used to disguise treatments, and sometimes outcomes  Different types of blinding –Unblinded or Open Label –Single blind –Double blind –Triple blind

32. Summary  US Government’s Definition of a Clinical Trial as a prospective study, that deals with human subjects and designed to answer questions about an intervention  There are important features and terms that help describe clinical trials  The four phases of clinical trials help define the intent of the research project than its scientific details  Controls, randomization, and blinding are tools used in in clinical trials to reduce data manipulation and bias