RTI Health SolutionsRTI Health Solutions

Practical and Methodological Issues in

Long-Term Follow-Up Studies

Practical and Methodological Issues in

Long-Term Follow-Up Studies

Elizabeth B. Andrews, Ph.D.Vice President, RTI Health Solutions

Methodologic IssuesMethodologic Issues

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Why Conduct Long-Term Follow-Up Studies?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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Start with the Goal in MindStart 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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Start with the Goal in MindStart 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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Surveillance Study vs. Etiologic StudySurveillance 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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Surveillance Study – ExampleSurveillance 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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Comparison Groups – Points to ConsiderComparison 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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Study with Comparison Group – ExampleStudy 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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Potential Study DesignsPotential Study Designs

Longitudinal Follow-Up Study

Case-Control Study

Variations on either

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Longitudinal Follow-Up StudyLongitudinal 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

EventComparison Patients

No event

Time

Event

No event

Examples: RAAR, patient registries, large simple trials

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Case-Control StudyCase-Control StudyCase-control study: Groups identified based on events and compared for antecedent factors

Measure of exposure: Exposure odds or rate

Measure of effect: Odds ratio

ExposureCases

ExposureControls

No Exposure

Time

No Exposure

Examples: Studies of Agranulocytosis, Severe Cutaneous Reactions,Vaginal Cancer (DES), Neural Tube Defects (Folic Acid)

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Study Population – Points to ConsiderStudy 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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Exposure Measurement – Points to ConsiderExposure 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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Outcome Measurement – Points to ConsiderOutcome 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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Potential Confounders – Points to ConsiderPotential 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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Analysis IssuesAnalysis 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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Ideal DesignIdeal 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?

Practical ConsiderationsPractical Considerations

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Selecting the General ApproachSelecting 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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General ConsiderationsGeneral 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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Follow-Up MethodsFollow-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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Study RetentionStudy Retention

Retention includes 2 components Tracking

Can patient be located?

Participation

Will patients voluntarily continue in the study?

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Patient TrackingPatient 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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Study ParticipationStudy 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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Other Practical ConsiderationsOther 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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ConclusionsConclusions

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