Clinical Research and Epidemiology Robert S. Sandler, M.D., M.P.H. University of North Carolina Chapel Hill, North Carolina
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
History John Snow Map of cholera cases 1854
Epidemiology today N Engl J Med 2012;367:1704-13
Epidemiology today Williamsburg Crown Heights Borough Park N Engl J Med 2012;367:1704-13
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
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
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)
Observational Studies “You can observe a lot just by watching.” - Yogi Berra • Descriptive • Analytical • Cross-sectional • Cohort • Case-control
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)
Incidence Prevalence Descriptive studies Prevalence ~ incidence x duration
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?
Cross-sectional studies Exposure and outcome measured at same time Outcome? Exposure? Source Population Sample
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
Cross-sectional • CCFA Partners: Internet based research study • >12,000 individuals with IBD completed an online survey about steroid use and many patient outcomes
Cohort study Exposed Disease Baseline Measure exposure Unexposed Disease Time Study begins here
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 ($$$$$$$) • If outcome is rare (IBD), need very large population
NSAIDs and Aspirin Ananthakrishnan, Annals Internal Medicine, 2012 Nurses’ Health Study I is a prospective cohort of 121,700 U.S. female registered nurses, aged 30 to 55 years Aspirin/NSAID use ascertained by self-report Over 1,295,317 person-years of follow-up 123 cases of CD and 117 cases of UC
Case-control study Exposed? Disease Exposed? No Disease Time Study begins here
Case control study • Match cases (people with outcome (IBD)) to controls • Measure prior exposures • Compare exposures in cases and controls • Are IBD cases more likely to report low fiber intake in past than controls • Advantages: • Good for rare diseases • More efficient (time and sample size, ↓$$$$) • Can identify temporal relationships • Disadvantages: • Recall of exposure • Sample selection (cases and controls should arise from same population)
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
What do statistics tell us? • Magnitude of effect • Precision of results • Statistical significance - role of chance • Statistical significance not clinical significance
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
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
Confounding Direct Effect Exposure (smoking) Outcome (ulcer) Indirect Effect Confounder (alcohol)
Intervention ‘A’ Outcome Standardized Follow-up & Co-interventions Study population Intervention ‘B’ Outcome Clinical trial
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!
Clinical trial • 526 patients randomly assigned to receive intravenous ustekinumab or placebo • Primary outcome (end point) was a clinical response at 6 weeks
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
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
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?
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?
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
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
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
Hospitalization for Infection No difference in hospitalizations for infection Mean age 58 (versus 35 in SONIC)
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?
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