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RTI Health Solutions Practical and Methodological Issues in Long-Term Follow-Up Studies Elizabeth B. Andrews, Ph.D. Vice President, RTI Health Solutions
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Methodologic Issues
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3 Why Conduct Long-Term Follow-Up Studies? Adverse events may not manifest until months or years after treatment Adverse events which were ambiguous during short-term courses of therapy may manifest clearly with long-term therapy Adverse events may be infrequent and require larger sample size than possible in clinical trials
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4 Start with the Goal in Mind Key questions for today Are these drugs associated with cancer at a level that would warrant modification of current prescribing recommendations? What is the baseline level of risk of skin cancer and lymphoma in the pediatric population? What is the estimated increase in risk that must be detected for safety assurance?
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5 Start with the Goal in Mind Should the potential increase in risk for the adverse event, as compared to background, be measured by relative risk or risk difference? If baseline 10-year risk is 2/10,000 and observed risk is 10/10,000 Relative risk is 5 Risk difference is 8/10,000 (roughly 1 new case per 1,000 exposed, over 10 years) What potential increase has public health/policy significance? What level of increased risk would be acceptable to patients/families?
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6 Surveillance Study vs. Etiologic Study What is the goal of the study? Reduce the uncertainty about a possible increased risk? (Surveillance approach) Use standard study designs, in general Consider analytic methods to evaluate information as it emerges Detect or rule out small increase in risk? (Etiologic approach) Use standard study design Power study to achieve predicted outcome
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7 Surveillance Study – Example Acyclovir Pregnancy Registry Patient exposure to acyclovir during pregnancy registered and followed Outcomes captured (e.g., pregnancy outcomes, birth defects) Frequency of birth defects compared to population expected data (collected using similar methods) Concluded that overall frequency of birth defects was similar in acyclovir and general population (3–4%) Determined that study had ability to detect a 7-fold increase in risk of events that occur 1/1,000.
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8 Comparison Groups – Points to Consider What is the goal of the study? Detect possible signal? Reduce uncertainty relating to possible increased risk? Single arm registry Can identify incidence of events over follow-up period in exposed patients Can identify if and when event rate exceeds threshold of “expected” risk Need well-defined data on “expected” risk Study with concurrent comparison group Can establish whether the incidence of events is similar between exposed and comparison groups Can explore role of potential confounders Can help assess signal from exposed group (e.g., 2 cases out of 5,000 over 3 years)
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9 Study with Comparison Group – Example Rheumatoid Arthritis Azathioprine Registry (RAAR) Enrollment over 10 years through rheumatologists of patients starting AZA (n=420) or other DMARD (n=1006) therapy Follow-up for exposures and serious events (e.g., lymphoma, all cancers) for 5+ years per patient Follow-up excluded basal cell and squamous cell carcinomas because of potential detection bias and underascertainment Sample size designed to enable detection of increased risk of 2.5–3-fold with full follow-up
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10 Potential Study Designs Longitudinal Follow-Up Study Case-Control Study Variations on either
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11 Longitudinal Follow-Up Study Cohort study: Two or more groups identified based on exposure, followed over time, and compared for events of interest Measures of frequency of event: incidence, risk Measure of comparative risk: risk or rate ratio Exposed Patients Event Comparison Patients No event Time Event No event Examples: RAAR, patient registries, large simple trials
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12 Case-Control Study Case-control study: Groups identified based on events and compared for antecedent factors Measure of exposure: Exposure odds or rate Measure of effect: Odds ratio Exposure Cases Exposure Controls No Exposure Time No Exposure Examples: Studies of Agranulocytosis, Severe Cutaneous Reactions, Vaginal Cancer (DES), Neural Tube Defects (Folic Acid)
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13 Study Population – Points to Consider Methods for identifying patients (e.g., referral centers, direct patient recruitment) Will methods select typical patients or highly skewed cohort? Will patients be newly treated or already on therapy? Inclusion criteria (e.g., indication, severity, exposure level) Will study maximize ability to detect risk if true risk exists? Should study represent “typical” use patterns? Comparison group Will this group have same baseline risk as exposed group? If not, how will they differ? What analytic methods will be used in comparison?
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14 Exposure Measurement – Points to Consider What minimum exposure dose and duration are sufficient for inclusion? What level of ongoing exposure information is necessary? Drug Dose Duration Site What periodicity of follow-up is necessary?
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15 Outcome Measurement – Points to Consider How would outcomes be identified? Patient self-report Record abstraction from treating physician Required physical exams Link with cancer registry and/or other files What level of detail is required? What biases might be expected? Greater detection in calcineurin inhibitor group if drugs are suspected to be associated with outcome
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16 Potential Confounders – Points to Consider Other treatments for atopic dermatitis Other conditions related to atopic dermatitis (e.g., asthma) and treatment Other variables not yet understood at time of study planning
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17 Analysis Issues Analytic methods need to handle time- dependent measures Patient characteristics at enrollment Medication exposures Potential confounders Unanticipated practice pattern changes
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18 Ideal Design Subject Selection: Exposed and unexposed group with same baseline risk Exposure Measurement: Dose and duration of all relevant treatments and potential confounders Outcome Measurement: Complete ascertainment of outcomes in both groups Follow-up: Complete follow-up for sufficient time to observe outcomes (10 years?) Power: Ability to detect or rule out an increased risk of X over the expected or observed in the unexposed group But … is the ideal practical?
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Practical Considerations
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20 Selecting the General Approach Complexity Size Small (1,500) Large (10,000+) Simple (e.g., mail) Highly Complex (e.g., Routine physician exams) Major Public Health Trials (e.g.,WHI) Pivotal RCTs Large Safety Studies ** *
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21 General Considerations Cost of study Opportunity costs (to regulators, sponsors, physicians, patients) Indirect impact of study on treatment choices (physicians, patients) When is it reasonable to do such a study? What are benchmarks? What is standard practice in these circumstances?
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22 Follow-Up Methods High retention rate over multiple years is essential Tools to help maximize follow-up Enrollment of child and family Routine contact with child/family to update contact details Tracking Incentives Minimize study burden
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23 Study Retention Retention includes 2 components Tracking Can patient be located? Participation Will patients voluntarily continue in the study?
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24 Patient Tracking Tracking can locate patients when they move, change status, change address Some examples of studies using tracking show >90% of study patients can be successfully located over periods of 10–20 years (e.g., Piedmont Health Survey of the Elderly, with 99% location rate at 10 years) Special considerations exist in following pediatric patients into adulthood
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25 Study Participation Participation varies with Mode of data collection Periodicity of contact Interest of patient (family) in study objectives Incentives Burden to participant(s) Special considerations in pediatrics Patient and parent participation Changes in consent and data collection over time Plan for annual attrition based on study methods selected
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26 Other Practical Considerations IRB/HIPAA privacy issues Treatment cannot ethically be conditioned on participation in research (e.g, mandatory registry is probably not an option) Who will give assent/consent, when, how often? What IRB approvals will be needed? Will HIPAA waivers be needed for access to records?
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27 Conclusions Study requires epidemiologic expertise in design and analytic methods Key focus must be on long-term retention Study must minimize burden on participants Successful design will be a compromise between the ideal and the practical Study design must be tailored to the ultimate goal of the study
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