Guidance for Industry Establishing Pregnancy Registries

Guidance for Industry Establishing Pregnancy Registries

Pregnancy Registry Working Group

Pregnancy Labeling TaskforceMarch, 2000

Evelyn M. Rodriguez M.D., M.P.H.

OPDRA, CDER, FDA

OutlineOutline

Why A Guidance Document?Why A Guidance Document? What is a pregnancy registry?What is a pregnancy registry? Purpose of a pregnancy registry protocol.Purpose of a pregnancy registry protocol. Registry study design.Registry study design.

RecruitmentRecruitment Reporting sourceReporting source Follow-upFollow-up Comparison groupsComparison groups Data analysisData analysis Reporting resultsReporting results

Why a Pregnancy Registry Guidance Document?

Why a Pregnancy Registry Guidance Document?

To provide useful data to health care To provide useful data to health care providers in caring for their patientsproviders in caring for their patients

What is a Pregnancy Registry?What is a Pregnancy Registry?

Could have many designs Often hypothesis generating Hypothesis testing Design depends on the hypothesis and outcomes

of concern Ideally, prospective enrollment of subjects Actively collects information for providing

scientifically based outcome data

What is the Purpose of a Pregnancy Registry?

What is the Purpose of a Pregnancy Registry?

Determine risks associated with drug use during pregnancyMeasurement of this riskDetermine risk factors associated for

adverse outcomeCould provide margins of

reassurance regarding lack of risk

Limitations of Current Data SourcesLimitations of Current Data Sources

Population-based surveillance systems - no linkage of maternal exposures and fetal outcome is available

Spontaneous Reports - bias in reporting and no incidence estimate available

Clinical Trials - Lack of meaningful data

What is the Purpose of aPregnancy Registry Protocol?

What is the Purpose of aPregnancy Registry Protocol?

To assure quality & validity of data elements collected

To assure documentation and consistency of research methods

What are Pregnancy Registries?

What are Pregnancy Registries?

Observational (non-experimental) studies that actively enroll subjects

Registration is ideally prospectiveEarly in pregnancy Drug exposure prior to or during

pregnancy

What are Pregnancy Registries? (continued)

What are Pregnancy Registries? (continued)

Determine rates of outcome among mothers exposed to drug

Comparison Groups Known background population rates Concurrently enrolled unexposed mothers

with or without underlying disease of interest

Pregnancy Registry StudiesPregnancy Registry Studies

Baseline information is collected at enrollment

Prospective subjectsSubject enrollment during pregnancy with

unknown fetal outcome to provide risk estimate

Retrospective subjects - case seriesSubject enrollment after abnormal fetal

results or adverse infant outcome are known

Considerations for Design of a Pregnancy Registry

Considerations for Design of a Pregnancy Registry

What is the feasibility of successfully completing the study?

Anticipate patterns of product use relative to fetal development

Definition and identification of outcomes

What Products are Good Candidates?

What Products are Good Candidates?

Products used frequently where inadvertent exposures are apt to occur

Products initiated or continued during pregnancy as therapy

What Products are Good Candidates? (continued)

What Products are Good Candidates? (continued)

When available information suggests a need: Pharmacologic class Animal reproductive data Structure/activity relationships Human case reports

When in a Medical Product’s Lifetime should a Registry be Established?

When in a Medical Product’s Lifetime should a Registry be Established?

A pregnancy registry should be established when the need is perceived Most likely at the time of approval Possibly with a new indication When a postmarketing signal is

observed

What are the Elements to Consider in the Pregnancy Registry Design?

What are the Elements to Consider in the Pregnancy Registry Design?

Protocol should assure consistency in data collection and analysis

Consult FDA in design

Registry Design: ProtocolRegistry Design: Protocol

Background Section Animal reproductive toxicity studies Relevant pharmacologic and toxicolgic

studies Any human experience from spontaneous

reports or earlier human studies Estimate of risk in human pregnancy

Registry Design: Research Methods

Registry Design: Research Methods

Description of Research Methods Patient Recruitment - Active enrollment

strategies and follow-up plans Draft of registry announcements of

informational pieces containing contact number, website

Product label containing contact information

Research Design: RecruitmentResearch Design: Recruitment

Announcements may appear: Professional journals Women’s magazines Professional and maternal/infant advocacy group

newsletters Internet sites Mailings to specialists Lectures Informational booths at professional meetings

Research Design: Recruitment(continued)

Research Design: Recruitment(continued)

However, unless specifically approved for use during pregnancy, any recruitment effort should not promote the use of the product during pregnancy

Research Design: Recruitment(continued)

Research Design: Recruitment(continued)

All product specific promotional materials must be submitted to FDA at the time of first use

Review prior to use not necessary UNLESS product was approved under expedited approval regulations

Research Design: Recruitment(continued)

Research Design: Recruitment(continued)

Protocol should include scripts that will be used in response to registry announcements and to recruit subjects

To increase awareness, sponsors are encouraged to work with FDA, CDC, Organization of Teratogen Information Services, and other organizations

FDA website will list known pregnancy registries

Research Design: Reporting Source

Research Design: Reporting Source

Sources of baseline and follow-up information SubjectsHealth Care Providers Both

Research Design: Reporting Source-Subjects

Research Design: Reporting Source-Subjects

May minimize loss to follow-upFacilitates multiple follow-up

contacts and enhance infant data collection

Facilitates informed consentMay need medical record validationMay be more expensive due to more

frequent and extensive follow-up

Research Design: Reporting Source - Health Care ProvidersResearch Design: Reporting

Source - Health Care Providers

Health Care ProvidersConvenient, good source of medical

dataEconomical, requires fewer contactsData collection on maternal and

infant events may be incompleteLoss to follow-up may be substantial

lack of motivation

Research Design - Patient Follow-up

Research Design - Patient Follow-up

Patient follow-up: Describe follow-up procedures in protocol Update drug exposure & risk factor information Obtain results of any diagnostic tests Collect information on spontaneous abortions, elective

terminations and the medical reasons for these events Consistent, similar follow-up for all women to avoid

bias Specify criteria to define subjects that are pending and

those lost to follow-up

Research Design: Study OutcomesResearch Design: Study Outcomes

Case definitions for all outcomes: maternal, labor & delivery, major categories of anomalies

Confirm outcomes: autopsy & pathology results, birth and death infant records, expert evaluation of infant, long-term follow-up

Feasibility of obtaining outcome data from different sources

Research Design: MiscellaneousResearch Design: Miscellaneous

Define outcomes of concern and hypothesis Define characteristics of the exposed

population Define biologic impact of the treated medical

condition(s) Describe what is known about drug exposure

during pregnancy Anticipate likelihood of discontinuing

treatment upon diagnosis of a pregnancy

Research Design: ComparatorsResearch Design: Comparators

Selection of unexposed comparison group(s):Matching on medical conditionExposure to another productMultiple comparison groups

Research Design: Statistical Considerations

Research Design: Statistical Considerations

Adequate sample sizeEstimate rates of suspected outcomes of scientific interest

Estimate power

Research Design: Data Analysis Research Design: Data Analysis

Separate prospective and retrospective casesPregnancy outcome, fetal abnormalitiesDescribe subjects lost to follow-up, and

compare to study subjects Calculate incidence point estimate and 95%

confidence intervalCompare to population background rates

Regulatory ReportingRegulatory Reporting

Registry reports are considered information derived during active solicitation of information from patients.

Should be handled as safety information obtained from a study (1997 FDA Interim Report Guidance)

FDA Postmarketing Safety Reporting Regulations are in the process of being updated.

Additional InformationAdditional Information

ReferencesSuggested Data Elements for

Pregnancy RegistriesSample Size Determinations by

Adverse Pregnancy Outcomes