Andrews 3/27/00 SP1 Pregnancy Follow-up Studies Lessons from Glaxo Wellcome Experience

Andrews 3/27/00 SP 1

Pregnancy Follow-up Pregnancy Follow-up StudiesStudies

Lessons from Glaxo Lessons from Glaxo WellcomeWellcome

ExperienceExperience


OutlineOutline

Historical case studyHistorical case study Lessons learnedLessons learned Future possibilitiesFuture possibilities Key issues Key issues

Points to Consider in Deciding When to Establish a Pregnancy Follow-up

Study

Points to Consider in Deciding When to Establish a Pregnancy Follow-up

Study

Likelihood of 1st trimester exposureLikelihood of 1st trimester exposure Potentially large exposed population Potentially large exposed population

of sexually active women Ages 15-44of sexually active women Ages 15-44 Animal data and relationship toAnimal data and relationship to

effect on human fetuseffect on human fetus Underlying medical conditionUnderlying medical condition Medication’s mechanism of actionMedication’s mechanism of action FDA pregnancy category ratingFDA pregnancy category rating


Case-study: AcyclovirCase-study: AcyclovirBackgroundBackground

Antiviral medicine to treat Antiviral medicine to treat

herpes simplex virus infections herpes simplex virus infections Pregnancy registry established in Pregnancy registry established in

1984 due to:1984 due to:• Potential for unintentional 1st trimester Potential for unintentional 1st trimester

exposure to new chemical entityexposure to new chemical entity

• Historic precedent of less specific Historic precedent of less specific

antiviral agents for toxic effectsantiviral agents for toxic effects


Acyclovir Study - OriginsAcyclovir Study - Origins

Acyclovir Study established 1984Acyclovir Study established 1984

– Part of broad epidemiologic safety programPart of broad epidemiologic safety program

– Joint effort with CDCJoint effort with CDC

– Objective: Monitor for risks of birth defects Objective: Monitor for risks of birth defects following antenatal acyclovir exposurefollowing antenatal acyclovir exposure

– Duration: Use registry approach until other, Duration: Use registry approach until other, more efficient, methods could address the more efficient, methods could address the questionquestion


Design Considerations Design Considerations (1)(1)

Exposures of potential Exposures of potential interestinterest– Oral acyclovirOral acyclovir– IV acyclovirIV acyclovir– Topical acyclovirTopical acyclovir

– Maternal Maternal exposuresexposures

– Paternal exposuresPaternal exposures

– Trimester Trimester 11, 2, 3, 2, 3

Outcomes of potential Outcomes of potential interestinterest– Overall major birth Overall major birth

defectsdefects– Specific birth Specific birth

defectsdefects– Minor events Minor events – Delayed developmentDelayed development– Maternal Maternal

complicationscomplications– Spontaneous abortionSpontaneous abortion



Objective: Estimate risk of major birth Objective: Estimate risk of major birth defectsdefects

Cohort study neither ethical nor Cohort study neither ethical nor feasible because outcomes are too rarefeasible because outcomes are too rare

Case-control not feasible Case-control not feasible – Exposures too rareExposures too rare– No No a prioria priori hypotheses hypotheses

No existing data resources available No existing data resources available and sufficientand sufficient



Exposure registration and followup study Exposure registration and followup study – Prospective enrollment requiredProspective enrollment required– Birth defect comparator needed (population Birth defect comparator needed (population

rate)rate)– Outcomes: birth defects consistent with CDC Outcomes: birth defects consistent with CDC

definitionsdefinitions– Other outcomes not within scope (e.g., Other outcomes not within scope (e.g.,

maternal events, spontaneous abortion) maternal events, spontaneous abortion) because because • different / more data neededdifferent / more data needed• methods not appropriatemethods not appropriate

Inclusion CriteriaInclusion Criteria

Trimester 1 Trimester 2

Trimester 3

Birth

Ultrasound16 weeks

PROSPECTIVE (included)Case reported before outcome known

RETROSPECTIVE(excluded) Case reported after outcome known


Method - Data CollectionMethod - Data Collection

Initial data collected at enrollment Initial data collected at enrollment – Exposure, timing, EDD, prenatal testingExposure, timing, EDD, prenatal testing– Potential confounders specific to the studyPotential confounders specific to the study

Basic information from single reporter Basic information from single reporter – Likely to be motivatedLikely to be motivated– Likely to have exposure and outcome Likely to have exposure and outcome

informationinformation– Will not require additional stepsWill not require additional steps

Methods - Follow-UpMethods - Follow-Up Follow-Up:Follow-Up:

– Form sent to health professional Form sent to health professional at EDDat EDD

– Monthly reminders until data Monthly reminders until data obtainedobtained

– Patient identifiers (not names) Patient identifiers (not names) used and deleted at completionused and deleted at completion

– Thank you letter with Thank you letter with encouragement to register other encouragement to register other exposures, and to solicit longer exposures, and to solicit longer term outcomes, if knownterm outcomes, if known


Targeted Follow-UpTargeted Follow-Upof Birth Defectsof Birth Defects

Initiated by registry staffInitiated by registry staff Targeted to specific birth defect Targeted to specific birth defect

cases reportedcases reported Based on CDC teratology reviewBased on CDC teratology review Could include questions from GW Could include questions from GW

Drug Surveillance M.D. Drug Surveillance M.D.

Methods - AnalysisMethods - Analysis

Separate prospective/retrospective Separate prospective/retrospective reportsreports

Estimate birth defect risk Estimate birth defect risk (proportion) from prospective (proportion) from prospective reportsreports

Compare risk against “expected” Compare risk against “expected” riskrisk

Evaluate specific birth defectsEvaluate specific birth defects Analyze defects for evidence of Analyze defects for evidence of

patterns or uniquenesspatterns or uniqueness Review of all data by Advisory Review of all data by Advisory

CommitteeCommittee


RecruitmentRecruitment

Challenge: Encourage enrollment without Challenge: Encourage enrollment without communicating an inappropriate message communicating an inappropriate message – Avoid implying drug should be used in Avoid implying drug should be used in

pregnancy pregnancy – Avoid suggesting a known risk existsAvoid suggesting a known risk exists

Options:Options:– Use existing health information linesUse existing health information lines– Referrals from TIS, CDC, FDAReferrals from TIS, CDC, FDA– Medical newsletters, journals, MMWRMedical newsletters, journals, MMWR– Scientific meetings, presentationsScientific meetings, presentations– Package insertPackage insert


Sources of Calls and Referrals

Sources of Calls and Referrals

RegistryRegistry

CDC CDC Health CareProviders

Health CareProviders PatientsPatients Clinical TrialsClinical Trials

Operating Companies

Operating Companies

InternationalSources

InternationalSources

GeneticCounselors

GeneticCounselors

Company Sales Force

Company Sales Force

Teratogen Information

Services

Teratogen Information

Services

Other Manufacturers

Other Manufacturers

Advisory CommitteeAdvisory Committee

Reviewed dataReviewed data Assisted in disseminating informationAssisted in disseminating information Members representedMembers represented

- Centers for Disease Control and Centers for Disease Control and PreventionPrevention

- Academic medical Academic medical practitioners/epidemiologistspractitioners/epidemiologists

- Glaxo Wellcome medical departmentGlaxo Wellcome medical department- Could be expanded to include other Could be expanded to include other

disciplines, groupsdisciplines, groups Expertise in STDs, Obstetrics, Expertise in STDs, Obstetrics,

Teratology, Pediatrics, EpidemiologyTeratology, Pediatrics, Epidemiology


Acyclovir Registry -- Acyclovir Registry -- Prospective Prospective Reports Reports

June 1984 - April 1999June 1984 - April 1999

EarliestTrimester ofExposure

Outcomes

with Birth

Defects

Live Births

Without Birth

Defects

Spont.

Pregnancy

Losses

Induced

Termina-

tions

Total

Unspecified 0 1 0 1 2

First 19 577 b 77 83 756

Second 2 194 c 0 1 197

Third 7 282d 2 0 291

Total 28 1054 79 85 1246

b Includes 7 sets of twins.c Includes 2 sets of twins.d Includes 3 sets of twins.


Results: Birth Defects

Results: Birth Defects

First -Trimester Exposure: First -Trimester Exposure: 19/59619/596

3.2% (95% CI: 2.0%, 5.0%)3.2% (95% CI: 2.0%, 5.0%)

Any Trimester Exposure: Any Trimester Exposure: 28/108228/1082

2.6% (95% CI: 1.8%, 3.8%)2.6% (95% CI: 1.8%, 3.8%)

Does not differ from general Does not differ from general populationpopulation


ConclusionsConclusions

No pattern among prospectively or No pattern among prospectively or retrospectively reported birth defectsretrospectively reported birth defects

Potential limitations should be Potential limitations should be recognized (underreporting, recognized (underreporting, differential reporting, losses to follow-differential reporting, losses to follow-up) up)

Despite these limitations, these Despite these limitations, these results are useful in the course ofresults are useful in the course of counseling women following counseling women following inadvertent prenatal exposureinadvertent prenatal exposure


Information useful to patients and Information useful to patients and physiciansphysicians

Useful to GW in evaluation of safetyUseful to GW in evaluation of safety Information included in product labelInformation included in product label Changed label from Category C to BChanged label from Category C to B Study data informed the CDC STD Study data informed the CDC STD

Treatment GuidelinesTreatment Guidelines

Value of the StudyValue of the Study

Pregnancy Follow-up Studies

Pregnancy Follow-up Studies

Acyclovir -- June 1984 (now closed)Acyclovir -- June 1984 (now closed) AntiretroviralsAntiretroviralsaa -- 1 Jan 1989 -- 1 Jan 1989 Lamotrigine -- 1 Sept 1992Lamotrigine -- 1 Sept 1992 Valacyclovir -- Jan 1995 (now closed)Valacyclovir -- Jan 1995 (now closed) Sumatriptan -- 1 Jan 1996Sumatriptan -- 1 Jan 1996 NA AED Pregnancy RegistryNA AED Pregnancy Registryaa -- Nov -- Nov

19961996 Bupropion -- 1 Sept 1997Bupropion -- 1 Sept 1997 Naratriptan -- 1 Oct 1997Naratriptan -- 1 Oct 1997

aa Multi-company sponsored studiesMulti-company sponsored studies


Lessons Lessons

Design must be targeted to the Design must be targeted to the questionsquestions

Simplicity is essential in data gatheringSimplicity is essential in data gathering Voluntary recruitment of sufficient Voluntary recruitment of sufficient

numbers of relevant exposures is numbers of relevant exposures is difficultdifficult

Follow-up is a challengeFollow-up is a challenge Ideal must be balanced by practicalityIdeal must be balanced by practicality


Ideal study Ideal study designdesign

Probability Probability of of obtainingobtaining

useful useful datadata

Probability Probability of of obtainingobtaining

useful useful datadata

MEDICATION SAFETY STUDIESMEDICATION SAFETY STUDIES


Broad surveillance for increased risks of major birth defects ?

Basic Approach

Monitoring for specific birth defect?

Case-control study

Monitoring for subtle or delayed event?

Targeted follow up study

Yes

NO

Basic Approach

Yes

TAILOR DESIGN TO THE QUESTION


SELECT THE METHOD APPROPRIATE SELECT THE METHOD APPROPRIATE TO THE OUTCOMES OF INTERESTTO THE OUTCOMES OF INTEREST

Basic registry designed to evaluate Basic registry designed to evaluate risk of major birth defectsrisk of major birth defects

Other outcomes can be better studied Other outcomes can be better studied with different methodswith different methods– spontaneous abortionspontaneous abortion– maternal outcomesmaternal outcomes– infant outcomes requiring long-term infant outcomes requiring long-term

follow-upfollow-up– infant outcomes requiring medical infant outcomes requiring medical

examination for confirmationexamination for confirmation


Selecting the Right Selecting the Right ApproachApproach

High

Low

Sam

ple

Siz

e Com

ple

xi

ty

Nature of Information

Frequency of majorbirth defects

Delayed effectsCross-drugcomparisonFrequency

of all birth defects in first year


Impact of Methods on Impact of Methods on Case Capture and Case Capture and

Follow-upFollow-up

Consent required

Number of Referral steps

Complexity of data collection

Duration of follow-up

100%

? 50 %


Other ApproachesOther Approaches

Large linked databases offer promise Large linked databases offer promise Identification of all exposures within a Identification of all exposures within a

populationpopulation Not dependent on voluntary reporting Not dependent on voluntary reporting Follow-up information collected for Follow-up information collected for

other purposesother purposes Sample size may be achievable if Sample size may be achievable if

multiple populations can be usedmultiple populations can be used

Case-Control studies remain usefulCase-Control studies remain useful


Issues Issues New consent/IRB considerations must balance New consent/IRB considerations must balance

individuals’ interests with impediments to individuals’ interests with impediments to conducting voluntary registries. Regulations conducting voluntary registries. Regulations should facilitate, not hinder, public health should facilitate, not hinder, public health monitoring functionsmonitoring functions

Adverse event reporting should follow study Adverse event reporting should follow study guidelines, not spontaneous guidelines guidelines, not spontaneous guidelines

Value and use of information need to be Value and use of information need to be better understood (confirm safety & identify better understood (confirm safety & identify new signals) new signals)

Documents

Andrews 3/27/00 SP1 Pregnancy Follow-up Studies Lessons from Glaxo Wellcome Experience