Clinical Research and Epidemiology Robert S. Sandler, M.D., M.P.H. University of North Carolina

1. Clinical Research and Epidemiology Robert S. Sandler, M.D., M.P.H. University of North Carolina Chapel Hill, North Carolina

2. What is epidemiology? • Epidemiology • Study of the distribution and determinants of disease in populations • Clinical epidemiology • Science of making predictions about individual patients using the tools of epidemiology

3. History John Snow Map of cholera cases 1854

4. History

5. Epidemiology today N Engl J Med 2012;367:1704-13

6. Epidemiology today Williamsburg Crown Heights Borough Park N Engl J Med 2012;367:1704-13

7. IBD is a challenge for epidemiologists • Epidemiologic methods work great when • Acute onset illness – cholera, mumps • Point source – Broad Street pump, yeshiva • Rare illness cluster – angiosarcoma of the liver and vinyl chloride • IBD • Gradual onset in children and adults • Persists for years • No known etiology

8. Spectrum of epidemiologic research • Disease burden (how many/how much) • Etiology risk factors for disease) • Diagnosis (evaluation of medical tests) • Natural history/prognosis • What happens to people with disease • Risk factors for disease outcomes • Treatment effects • Intended • Unintended

9. Methods of clinical research • Observational Studies • Investigators just observe (measure) exposures and outcomes • Interventional Studies • Investigators assign exposure and measure outcomes (clinical trials of drugs or surgery)

10. Observational Studies “You can observe a lot just by watching.” - Yogi Berra • Descriptive • Analytical • Cross-sectional • Cohort • Case-control

11. Descriptive Studies Burden of Disease • Incidence – how many new cases/time • Prevalence – how many cases currently • Morbidity • Mortality • Costs • Days of work/school lost (disability days)

12. Incidence Prevalence Descriptive studies Prevalence ~ incidence x duration

13. Analytical studies Associations between exposures and outcomes • Is smoking (or diet) associated with risk of IBD? • Are specific genes associated with risk of IBD? • Are results of a diagnostic test associated with diagnosis of IBD? • Is treatment X associated with improvement in Crohn’s disease activity • Is treatment Y associated with a particular side effect? • Is diet (or other lifestyle factors) associated with IBD flares?

14. Cross-sectional studies Exposure and outcome measured at same time Outcome? Exposure? Source Population Sample

15. Cross-sectional • Assemble study population • Measure IBD status (yes/no) • Measure smoking (yes/no) • Find that people with Crohn’s more likely to smoke • i.e. smoking (exposure) is associated with CD (outcome) • Advantages: Quick and inexpensive • Disadvantages: • No temporality • Cannot differentiate cause and effect

16. Cross-sectional • CCFA Partners: Internet based research study • >12,000 individuals with IBD completed an online survey about steroid use and many patient outcomes

17. Cohort study Exposed Disease Baseline Measure exposure Unexposed Disease Time Study begins here

18. Cohort study • Assemble study population free of disease • Measure smoking (yes/no) • Follow study population for long time • Identify those who develop IBD • Compare incidence (# new cases) of IBD in smokers vs nonsmokers • Advantages: Can identify temporal relationship, assess causality, determine incidence • Disadvantages: • Long follow-up needed ($$$$$$$) • If outcome is rare (IBD), need very large population

19. NSAIDs and Aspirin Ananthakrishnan, Annals Internal Medicine, 2012 Nurses’ Health Study I is a prospective cohort of 121,700 U.S. female registered nurses, aged 30 to 55 years Aspirin/NSAID use ascertained by self-report Over 1,295,317 person-years of follow-up 123 cases of CD and 117 cases of UC

20. Case-control study Exposed? Disease Exposed? No Disease Time Study begins here

21. Case control study • Match cases (people with outcome (IBD)) to controls • Measure prior exposures • Compare exposures in cases and controls • Are IBD cases more likely to report low fiber intake in past than controls • Advantages: • Good for rare diseases • More efficient (time and sample size, ↓$$$$) • Can identify temporal relationships • Disadvantages: • Recall of exposure • Sample selection (cases and controls should arise from same population)

22. Case control study of potential risk factors for IBD Cases with CD (n = 364) and UC (n = 217), ages 18-50 yr Controls were drawn from Manitoba Health Subjects were administered a multi-item questionnaire Bernstein, Am. J. Gastro, 2006

23. What do statistics tell us? • Magnitude of effect • Precision of results • Statistical significance - role of chance • Statistical significance not clinical significance

24. Potential pitfalls: validity and bias • Internal validity: degree to which the study findings reflect the truth • Bias: Systematic difference between observed findings and the truth • Chance • Statistics assess role of chance, but do not address bias • External validity: degree to which the study findings are applicable to other populations

25. Types of bias • Selection/referral bias • Distortion in the results due to a difference b/t subjects who participated and those who did not • Measurement bias • Distortion in results due to error in measurement of the exposure, outcome or both

26. Confounding Direct Effect Exposure (smoking) Outcome (ulcer) Indirect Effect Confounder (alcohol)

27. Intervention ‘A’ Outcome Standardized Follow-up & Co-interventions Study population Intervention ‘B’ Outcome Clinical trial

28. What does randomization accomplish? • If treatments are assigned at random, then: • Treatments are unrelated to patient characteristics • Achieves balance among different treatment groups (same mix of smokers, disease severity, across groups) • No confounding • Even if confounder not known or measured!

29. Clinical trial • 526 patients randomly assigned to receive intravenous ustekinumab or placebo • Primary outcome (end point) was a clinical response at 6 weeks

30. Clinical trial

31. Clinical trial

32. Why Placebo? • If patients know they are getting a study medication, they may feel better • If doctors know their patients are getting a medication, they may perceive them as doing better • “Double-blind, placebo-controlled” • All subjects get something • Neither subjects nor investigators know what • Randomization and concealed allocation required to prove efficacy • Required by FDA

33. Ethical considerations • Honest disagreements exist about the preferred treatment of the condition (equipoise) • Neither intervention/treatment should be considered inferior, or potentially harmful • The RCT must produce results which are convincing enough to resolve the dispute • Makes the patients’ participation is worthwhile

34. Comparative Effectiveness Research • If all we have is placebo controlled trials, then we don’t know • What medicines are more effective than others • What medicines are safer than others • We need head-to-head comparisons, but • Pharma often not willing to take the risk • FDA not require it • Observational studies?

35. Clinical Effectiveness Research • Patients who enroll in clinical trials are: • Young to middle aged adults • Free of co-morbidity (other health problems) • Cared for at large research hospitals • What about. . . • Kids • Elderly • Those with other health conditions • Observational studies?

36. Safety • Clinical trials too small to assess medication safety • 51% of drugs have label changes due to major safety issues discovered after marketing • 20% of drugs get new “black box” warnings after marketing • 4% of drugs are ultimately withdrawn for safety reasons

37. 5000 4000 3000 2000 1000 1/10 1/100 1/1000 Too Small Probability of detection 99% 95% Number of exposed 90% Lymphoma REACH n=212 CERTIFI n=526 Incidence

38. Safety research Grijalva, JAMA, 2011 Objective: To determine whether initiation of TNF- antagonists compared with immunomodulators is associated with an increased risk of serious infections requiring hospitalization Methods: • Cohort study using de-identified data from insurance companies • For IBD, TNF- antagonist initiators compared to 6MP/AZA initiators, matched by propensity score

39. Hospitalization for Infection No difference in hospitalizations for infection Mean age 58 (versus 35 in SONIC)

40. What makes a good study • Is there a primary research question? • Is the research question important? • Is the study design appropriate to the research question? • Are the investigators qualified? • Is the study population well-defined? • Are exposures and outcomes well-defined? • Feasible? • Sample size needed relative to time and budget? • Barriers for recruitment • Burden (for patients and providers) • Pool of eligible subjects • Competing studies • Ethical?

41. Review

42. Conclusion • Broad spectrum of clinical and epidemiological research: burden, etiology, diagnosis, prognosis, treatment effects • Many study designs • Advantages and disadvantages to each • Focused and highly relevant clinical question essential • Many pitfalls to be considered • Bias • Ethics • Practical considerations