1. Designing and Managing Drug and Substance Abuse Clinical Trials Chapter I: What Is a Clinical Trial? (version 6)

2. Recognize when research projects are considered clinical trials under US laws and regulations Use appropriate research terminology to describe a clinical trial Learning Objectives

3. The First Recorded Clinical Trial In 1747 an English physician, James Lind thought that acidic foods might cure scurvy. He assigned 12 sailors with scurvy into one of six groups. All men then received the same daily diet plus: 1.Group one - A quart of cider daily 2.Group two – Twenty-five drops of elixir of vitriol (sulfuric acid) 3.Group three - Six spoonfuls of vinegar 4.Group four - Half a pint of seawater 5.Group five - Two oranges and one lemon 6.Group six - A spicy paste plus a drink of barley water At the end of 6 days, one sailor from group five was fit for duty and the second had almost recovered. Other than these two men, only the sailors from group one showed some effect of their treatment

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

5. US Government’s Definition Clarifies the difference between clinical trials and other types of human research, such as program evaluations If a research project is funded or regulated by the US government: –Legal requirements –Regulatory requirements

6. Clinical Trial Components It is a prospective study It is in humans It is designed to answer questions about a biomedical intervention or a behavioral intervention

7. US Government’s Definition of a Clinical Trial A clinical trial is a prospective biomedical or behavioral research study of human subjects, that is designed to answer specific questions about biomedical or behavioral interventions

8. Drug Abuse Research Projects That Are NOT Clinical Trials Primate testing of a new HIV therapy intended for humans Ethnographic research to understand patterns of IV drug users Program evaluation of a government initiative to reduce cocaine use by unwed mothers An epidemiologic study of drug abuse patterns among persons receiving naltrexone for alcohol dependency

10. Important Terms That Describe Clinical Trials

11. Four Major Features of Clinical Trials The stage of the study intervention (study phase) The trial is a controlled study The participants are randomized The 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 Phase II Phase III Phase IV Controls Uncontrolled Placebo Active Control(s) Randomization Non-randomized Randomized Blinding Unblinded Single-blind Double-blind Triple-blind

13. Study Stage: The Four Phases of Clinical Trials

14. The Four Phases of Clinical Trials 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. Controls in Clinical Trials

16. Controls In Clinical Trials Whenever an intervention is compared to something else, the alternative is called a “control” Compared to… –What has been done in the past –No treatment? –Current treatment(s) (standard treatment) –A similar-looking but ineffective treatment (placebo)?

17. Placebo Controls (“Placebo Effect”) Why? Recognizes that many health outcomes are dependent on the patient’s willingness to participate and the patient’s and physician’s perception of benefit Placebo controls can Duplicate the experience of the intervention without active component Provide clear improvement in symptoms (“placebo effect”) More accurately determine the extent to which the intervention alone affects treatment

18. Active Controls Contains an active component Frequently used in Phase III trials –Intent is to understand the benefits of a new treatment in a real-world setting

19. Randomization in Clinical Trials

20. What Is Randomization? The assigning of persons to the control group or the intervention groups based on chance Essential feature of a good clinical trial Randomization must be totally unrelated to the variables of interest

21. Why Is Randomization Necessary? How does the researcher decide who gets which treatment? Possibilities –every person will get the new treatment (historical controls?) –some persons may be willing to accept the new treatment while others are not Good possibility that control and intervention group are not identical –results will differ because of some factor totally unrelated to the treatment

22. Common Randomization Schemes Complete randomization Block randomization Urn randomization Stratified randomization Cluster randomization

28. Blinding in Clinical Trials

29. What Is Blinding? Techniques used to disguise treatments, and sometimes outcomes Types of blinding –Unblinded or Open Label –Single blind –Double blind –Triple blind

30. Purpose Of Blinding Many clinical trials lack well-defined, objective endpoints Such measures are subject to: –intentional manipulation –unintentional bias To reduce the possibility of manipulation and bias, researchers may seek to disguise whether the subjects are receiving the intervention or the control treatment

31. Summary A clinical trial is a prospective biomedical or behavioral research study of human subjects that is designed to answers specific questions about biomedical or behavioral interventions. 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

33. Credits Subject Matter Expert John M. Harris Jr., MD President Medical Directions, Inc. Tucson, Arizona E-Learning and Educational Technology Expert Jorge G. Ruiz, MD, FACP Associate Professor of Clinical Medicine Director, Geriatric Medicine Fellowship Program Division of Gerontology and Geriatric Medicine University of Miami Miller School of Medicine VAHCS GRECC Associate Director for Education/Evaluation Miami, FL Content Developers John M. Harris Jr., MD Jorge G. Ruiz, MD, FACP Medical Editor/Content Editor Jorge G. Ruiz, MD, FACP Reviewers/Consultants Jorge G. Ruiz, MD, FACP Bernard A. Roos, MD Marilyn C. Cheung Rudy W. Picardo Technical Development (Stein Gerontological Institute) Network Administrator David Freeman

34. Credits Instructional Designer Rudy W. Picardo Module Narrator Rudy W. Picardo Ownership GeriU – The Online Geriatrics University (www.geriu.org) National Institute on Drug Abuse Copyright 2008 Date of Release April 2008 Expiration Date April 2010 Contact Information John M. Harris Jr., MD Medical Directions, Inc. 6101 E. Grant Road Tucson, Arizona 85712 E-mail: sharris@md-inc.com Jorge G. Ruiz, MD, FACP VA Medical Center GRECC (11 GRC) 1201 NW 16th Street Miami, FL 33125 Telephone: 305-575-7000, ext. 6104 Fax: 305-575-3365

35. Credits Estimated Time to Complete This Activity 1 hour Key Words: clinical trials Citation: “Designing and Managing Drug and Substance Abuse Clinical Trials, Chapter I: What Is a Clinical Trial?.” E- Learning Program. GeriU, the Online Geriatrics University. Stein Gerontological Institute, 2008. Funding Provided by National Institute on Drug Abuse Acknowledgments/Special Thanks Stein Gerontological Institute 5200 NE 2nd Avenue Miami, FL 33137 GeriU – The Online Geriatrics University (www.geriu.org) University of Miami Miller School of Medicine