Module 3 Introduction Content Area: Analytical Epidemiology

1. Module 3 Introduction Content Area: Analytical Epidemiology Essential Question (Generic): Is there an association between the hypothesized cause and the disease? Essential Question (Drug Abuse Specific): Is there an association between the hypothesized cause and drug use? Enduring Epidemiological Understanding: Causal hypotheses can be tested by observing exposures and diseases of people as they go about their daily lives. Information from these observational studies can be used to make and compare rates and identify associations. Synopsis In Module 3, students explore how hypotheses are tested epidemiologically. Students begin to uncover and develop the following epidemiological concepts and skills: the meaning of the term “association;” the need for a control group; uses of the 2x2 table in calculating risks and relative risks; experimental study design; the importance of ethics in human research; observational study designs used in epidemiology; and the strengths and limitations of each design. Lesson 3-1: Associations and the 2x2 Table Lesson 3-2: Experimental Study - Buprenorphine Example Lesson 3-3: An Actual Randomized Controlled Trial Lesson 3-4: Observational Studies of Natural Experiments - Sensation-Seeking Example Lesson 3-5: Fundamentals of Study Design Lesson 3-6: Study Design Exercises

2. Module 3 - Analytical Epidemiology • Lesson 3-3 An Actual Randomized Controlled Trial • Content • Reviews concepts from Lessons 3-1 and 3-2 including definition of an association, need for a control group, and use of a 2x2 table to calculate risks and relative risks. • Describes experimental study design in terms of the key concepts of subject selection and random assignment, measurement of exposure and outcome, use of a placebo, study procedures, and protection of human subjects • Presents a real experimental study to reinforce these key concepts, and to help students understand the real-life issues in conducting such a trial. • Big Ideas • A real trial has to closely manage free-living people, which presents challenges and requires protection of the health and welfare of all subjects. • Successful randomization results in study groups that are the same with regard to all factors except the exposure under study. • A trial will not be scientifically valid unless the conditions of the trial are carried out successfully in terms of randomization, the administration of the “exposures.” and the accurate assessment of health outcomes. This project is supported by a Science Education Drug Abuse Partnership Award, Grant Number 1R24DA016357-01, from the National Institute on Drug Abuse, National Institutes of Health.

3. Where are we? Essential Questions Enduring Understandings

4. Review - What Is An Association? Tied Related Associated Linked What do we mean when we say that there is anassociationbetween two things? Things that are associatedare linked in some way that makes themturn up together.

5. Generate Test Descriptive Epidemiology Analytical Epidemiology Review - Generating and Testing Hypothesis Hypothesis An unproven idea, based on observation or reasoning, that can be supported or refuted through investigation An educated guess

6. Review of Lesson 3-2 Buprenorphine Buprenorphine will stop heroin addicts from using heroin.

7. Tested Positive for Heroin Tested Negative for Heroin Risk of Using Heroin Tested Positive for Heroin Tested Negative for Heroin Risk of Using Heroin Relative Risk Total Total 79 79 79 79 90 90 90 90 Bupe Bupe 79% 79% 79% 79% 79 79 79 79 21 21 21 21 100 100 100 100 or or or or 100 100 100 100 No Bupe Tested Positive for Heroin Tested Negative for Heroin Risk of Using Heroin Tested Positive for Heroin Tested Negative for Heroin Risk of Using Heroin Relative Risk Relative Risk Total Total Bupe Bupe No Bupe No Bupe Review of Lesson 3-2 Trial 1 Trial 2 Nothing Trial 3 Trial 4

8. Tested Positive for Heroin Tested Negative for Heroin Risk of Using Heroin Tested Positive for Heroin Tested Negative for Heroin Risk of Using Heroin Relative Risk Total Total 79 79 79 79 79 90 90 90 90 90 Bupe Bupe 79% 79% 79% 79% 79% 79 79 79 79 79 21 21 21 21 21 100 100 100 100 100 or or or or or 100 100 100 100 100 No Bupe Tested Positive for Heroin Tested Negative for Heroin Risk of Using Heroin Tested Positive for Heroin Tested Negative for Heroin Risk of Using Heroin Relative Risk Relative Risk Total Total Bupe Bupe No Bupe No Bupe 94 90 38 90 94% 94 6 100 or 38% 38 62 100 or 100 100 Review of Lesson 3-2 Trial 1 Trial 2 1 Nothing Nothing There is no association between Bupe and heroin use. Trial 3 Compared to what? Trial 4 .84 2.08 Bupe is associated with an increase in heroin use. Bupe is associated with a decrease in heroin use.

9. Relative Risk Relative Risk Type Association Interpretation 1 None Exposure is not associated with the outcome. Greater than 1 (>1) Positive Exposure is associated with a greater likelihood of the outcome. Less than 1 (<1) Negative Exposure is associated with a lower likelihood of the outcome. Relative Risk: The ratio of the risk of an outcome among the exposed to the risk of the outcome among the unexposed.

10. We conducted a randomized, placebo controlled, multi-center trial to evaluate the safety and efficacy of a sublingual-tablet formulation of buprenorphine and naloxone in an office-based setting.

11. Citation Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, Collin J, Raisch D, Casadonte P, Goldsmith RJ, Ling W, Malkerneker U, McNicholas L, Renner J, Stine S, Tusel D. Office-based treatment of opiate addiction with a sublingual-tablet formulation of Buprenorphine and Naloxone. New England Journal of Medicine 2003;349:949-58.

12. Features of a Randomized Controlled Trial • A significant health problem with evidence of a potential solution • Subject selection - diagnostic criteria • Ethics - informed consent, independent review • Defined, measurable treatment (exposure) • Random assignment into treatment and control groups • Defined, measurable study result (outcome) • Procedures for conduct of study • Blinding, double blinding • Ethics - data safety monitoring

13. Significance of Health Problem Potential Solution Addiction to opiates, usually to heroin, remains a continuing problem in the United States and is increasing in Europe. Opiate-substitution pharmacotherapy reduces the use of illicit opiates and the high-risk and criminal behaviors associated with it.

14. Subject Selection - Diagnostic Criteria Men and women who met the diagnostic criteria for opiate dependence according to the Diagnostic and Statistical Manual for Mental Disorders, who were seeking opiate-substitution pharmacotherapy, … were eligible to participate.

15. Criteria for Substance Dependence Diagnostic and Statistical Manual - IV • DSM-IV Substance Dependence Criteria • Substance dependence is defined as a maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring any time in the same 12-month period: 1. Tolerance, as defined by either of the following: (a) A need for markedly increased amounts of the • substance to achieve intoxication or the desired effect or (b) Markedly diminished effect with • continued use of the same amount of the substance. • Withdrawal, as manifested by either of the following: (a) The characteristic withdrawal syndrome for the • substance or (b) The same (or closely related) substance is taken to relieve or avoid withdrawal symptoms. • 3. The substance is often taken in larger amounts or over a longer period than intended. • 4. There is a persistent desire or unsuccessful efforts to cut down or control substance use. • A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover • from its effects. • 6. Important social, occupational, or recreational activities are given up or reduced because of substance use. • The substance use is continued despite knowledge of having a persistent physical or psychological problem • that is likely to have been caused or exacerbated by the substance (for example, current cocaine use • despite recognition of cocaine-induced depression or continued drinking despite recognition that an ulcer • was made worse by alcohol consumption). • American Psychiatric Association. 1994. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. • Washington D.C.: American Psychiatric Association. (pp. 181-183)

16. Ethics - Informed Consent All subjects provided written informed consent.

17. Principles of Informed Consent • The participant must be COMPETENT to begin the informed consent process  • The research team must DISCLOSE all relevant information to the potential participant • The participant must COMPREHEND the information • The participant must AGREE to the proposed intervention in the research study • The participant's agreement must be VOLUNTARY and free from coercion • Finally, participants must be informed that even after they have made a voluntary agreement to participate in the study, they may WITHDRAW such agreement at any time without penalty

18. Code of Federal Regulations Basic elements of informed consent (paraphrased from Code of Federal Regulations, 45CFR.46.116) • A statement that the study involves research, an explanation of the purposes and expected duration of participation, a description of procedures, and identification of any experimental procedures • A description of any reasonably foreseeable risks or discomforts • A description of any benefits to the subject or to others which may reasonably be expected • A disclosure of appropriate alternative procedures or treatment, if any, that might be used • A statement describing the extent of maintaining confidentiality of identifiable subject records • For research involving more than minimal risk, statements about possible compensation for injury and where to obtain further information further information may be obtained; • Statement of whom to contact for any questions • Statement about voluntary nature of participation and freedom to withdraw without penalty

19. Ethics - Independent Review The study was approved by the Human Rights Committee of the Veterans Affairs Cooperative Studies Program Coordinating Center…and by the institutional review boards of participating sites and was conducted in accordance with the Declaration of Helsinki. Declaration of Helsinki

20. Defined Treatment (Exposure) …, subjects were … assigned to daily treatment with buprenorphine in combination with naloxone, buprenorphine alone, or placebo.

21. O E O Assigned Heroin Addicts Volunteer Heroin Addicts O E O Time Review - Flow Diagram in Lesson 3-2 … subjects were … assigned to ….

22. + B&N _ + + Assigned B _ _ P Flow Diagram in Actual Controlled Trial Volunteer Heroin Addicts … subjects were … assigned to ….

23. Review - 2x2 Table in Lesson 3-2 Tested Positive for Heroin Tested Negative for Heroin Tested Risk of Using Heroin Relative Risk Total 79 Bupe 79% 79 21 100 or 100 a b c d .84 94 No Bupe 94 6 100 94% or 100

24. Actual Controlled Trial Tested Positive for Heroin Tested Negative for Heroin Tested Risk of Using Heroin Relative Risk Total or a b c d or …, subjects were … assigned to daily treatment with buprenorphine in combination with naloxone, buprenorphine alone, or placebo.

25. 3x2 Table in Actual Controlled Trial Tested Negative for Heroin Tested Positive for Heroin Tested Risk of NOT Using Heroin Relative Risk Total or or or … assigned to …buprenorphine in combination with naloxone, buprenorphine alone, or placebo.

26. Buprenorphine Placebo Buprenorphine & Naloxone Placebo Controlled All the tablets were identical in appearance and taste and were provided by Reckitt Benckiser Healthcare ….

27. Random assignment into treatment and control groups …, subjects were randomly assigned to daily treatment with buprenorphine in combination with naloxone, buprenorphine alone, or placebo.

28. Review - Lesson 3-2 Assign Volunteers to 2 Groups

29. Randomly Assigned Randomly Assign Volunteers to Three Groups

30. Randomization Allocation of individuals to groups by chance. Randomization should not be confused with haphazard assignment. Random allocation follows a predetermined plan that is usually devised with the aid of a table of random numbers.

31. Randomly Assigned Study Flow Diagram + B&N _ + Volunteer Heroin Addicts B _ Non-predictability of the next assignment + P _

32. + B&N _ + + Randomly Assigned B _ _ P Randomly Assigned Increase the likelihood that the groups are comparable in regard to characteristics that may affect the outcome Volunteer Heroin Addicts Non-predictability of the next assignment

35. RANDOMLY ASSIGNED Base-line demographics data were similar in all three treatment groups.

38. Exposure Tested Negative for Heroin Tested Positive for Heroin Tested Risk of NOT Using Heroin Relative Risk Total Bupe & Naloxone or Bupe or Placebo or

39. Exposure Tested Negative for Heroin Tested Positive for Heroin Tested Risk of NOT Using Heroin Relative Risk Total Bupe & Naloxone or 109 Bupe or 105 Placebo or 109

40. PRIMARY OUTCOMES The primary outcome measures in the double-blind trial were the percentage of opiate-negative urine samples and subjects’ self-reported craving for opiates.

41. PRIMARY OUTCOMES Both the buprenorphine-based treatments reduced opiate use; the percentages of urine tests that were opiate-negative were 17.8 percent in the combined- treatment and 20.7 percent in the buprenorphine group

42. PRIMARY OUTCOMES Both the buprenorphine-based treatments reduced opiate use; the percentages of urine tests that were opiate-negative were 17.8 percent in the combined- treatment and 20.7 percent in the buprenorphine group as compared with 5.8 percent in the placebo group.

43. Study Results Regarding Negative Urine Tests Tested Negative for Heroin Tested Positive for Heroin Tested Risk of NOT Using Heroin Relative Risk Total Bupe & Naloxone 17.8% 109 20.7 % Bupe 105 5.8% Placebo 109 … urine tests that were opiate-negative were 17.8 percent in the combined- treatment and 20.7 percent in the buprenorphine group as compared with 5.8 percent in the placebo group.

44. Relative Risks Compared to the Placebo Group Tested Negative for Heroin Tested Positive for Heroin Tested Risk of NOT Using Heroin Relative Risk Total Bupe & Naloxone 17.8% 3.1 109 20.7 % 3.6 Bupe 105 5.8% Placebo 109 Urine tests were opiate negative 3.1 times as frequently in the combination group compared to the placebo group Urine tests were opiate negative 3.6 times as frequently in the Buprenorphine group compared to the placebo group

45. Inference Tested Negative for Heroin Tested Positive for Heroin Tested Risk of NOT Using Heroin Relative Risk Total Bupe & Naloxone 17.8% 3.1 109 20.7 % 3.6 Bupe 105 5.8% Placebo 109 Urine tests were opiate negative 3.1 times as frequently in the combination group compared to the placebo group Urine tests were opiate negative 3.6 times as frequently in the Buprenorphine group compared to the placebo group

46. BLIND During the double-blind trial ….

47. Blind A study in which the observer and / or subjects are kept ignorant of the group to which they are assigned.

48. Blind

49. DATA AND SAFETY MONITORING BOARD

50. Data and Safety Monitoring Board An independent group of experts that periodically reviews and evaluates study data. It is interested in safety of participants, study conduct and progress, and preliminary findings. It can make recommendations about continuation, modification, or termination of the study.