Guidance for Industry Establishing Pregnancy Registries

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Guidance for Industry Establishing Pregnancy
Registries

• Pregnancy Registry Working Group
• Pregnancy Labeling Taskforce
• March, 2000
• Evelyn M. Rodriguez M.D., M.P.H.
• OPDRA, CDER, FDA

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Outline

• Why A Guidance Document?
• What is a pregnancy registry?
• Purpose of a pregnancy registry protocol.
• Registry study design.
• Recruitment
• Reporting source
• Follow-up
• Comparison groups
• Data analysis
• Reporting results

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Why a Pregnancy Registry Guidance Document?

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

Pregnancy Registry Guidance
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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

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What is the Purpose of a Pregnancy Registry?

• Determine risks associated with drug use during
  pregnancy
• Measurement of this risk
• Determine risk factors associated for adverse
  outcome
• Could provide margins of reassurance regarding
  lack of risk

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Limitations 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

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What is the Purpose of aPregnancy Registry
Protocol?

• To assure quality validity of data elements
  collected
• To assure documentation and consistency of
  research methods

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What are Pregnancy Registries?

• Observational (non-experimental) studies that
  actively enroll subjects
• Registration is ideally prospective
• Early in pregnancy
• Drug exposure prior to or during pregnancy

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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

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Pregnancy Registry Studies

• Baseline information is collected at enrollment
• Prospective subjects
• Subject enrollment during pregnancy with unknown
  fetal outcome to provide risk estimate
• Retrospective subjects - case series
• Subject enrollment after abnormal fetal results
  or adverse infant outcome are known

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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

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What Products are Good Candidates?

• Products used frequently where inadvertent
  exposures are apt to occur
• Products initiated or continued during pregnancy
  as therapy

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What Products are Good Candidates? (continued)

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

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When in a Medical Products 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

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

• Protocol should assure consistency in data
  collection and analysis
• Consult FDA in design

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Registry 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

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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

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Research Design Recruitment

• Announcements may appear
• Professional journals
• Womens magazines
• Professional and maternal/infant advocacy group
  newsletters
• Internet sites
• Mailings to specialists
• Lectures
• Informational booths at professional meetings

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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

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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

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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

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Research Design Reporting Source

• Sources of baseline and follow-up information
• Subjects
• Health Care Providers
• Both

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Research Design Reporting Source-Subjects

• May minimize loss to follow-up
• Facilitates multiple follow-up contacts and
  enhance infant data collection
• Facilitates informed consent
• May need medical record validation
• May be more expensive due to more frequent and
  extensive follow-up

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Research Design Reporting Source - Health Care
Providers

• Health Care Providers
• Convenient, good source of medical data
• Economical, requires fewer contacts
• Data collection on maternal and infant events may
  be incomplete
• Loss to follow-up may be substantial lack of
  motivation

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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

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Research 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

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Research 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

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Research Design Comparators

• Selection of unexposed comparison group(s)
• Matching on medical condition
• Exposure to another product
• Multiple comparison groups

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Research Design Statistical Considerations

• Adequate sample size
• Estimate rates of suspected outcomes of
  scientific interest
• Estimate power

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Research Design Data Analysis

• Separate prospective and retrospective cases
• Pregnancy outcome, fetal abnormalities
• Describe subjects lost to follow-up, and compare
  to study subjects
• Calculate incidence point estimate and 95
  confidence interval
• Compare to population background rates

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Regulatory 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.

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Additional Information

• References
• Suggested Data Elements for Pregnancy Registries
• Sample Size Determinations by Adverse Pregnancy
  Outcomes

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Thank You