# Presentation: 308552

## RTI Health Solutions

**RTI Health Solutions**

*   ** **Practical and Methodological Issues in Long-Term Follow-Up Studies*

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

*Methodologic Issues*

## 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

## 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?

## 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?

## 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

## 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.

## 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)

## 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

## Potential Study Designs

- Longitudinal Follow-Up Study
- Case-Control Study
- Variations on either

## 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

## 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)

## 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?

## 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?

## 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

## 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

## Analysis Issues

- Analytic methods need to handle time-dependent measures
- Patient characteristics at enrollment
- Medication exposures
- Potential confounders
- Unanticipated practice pattern changes

## 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?***

## Practical Considerations

## 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

- *

- *

- *

## 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?

## 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

## Study Retention

- Retention includes 2 components
- Tracking
- Can patient be located?
- Participation
- Will patients voluntarily continue in the study?

## 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

## 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

## 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?

## 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