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1© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Post-marketing Safety Data CollectionPregnancy Exposure RegistriesC B I PAT I E N T R E G I S T R I E S S U M M I TJ A N U A R Y 2 7 , 2 0 1 6O R L A N D O , F L O R I D A
C AT H E R I N E S I G L E R , D V M M P H P H DE X E C U T I V E D I R E C T O RS A F E T Y, E P I D E M I O L O G Y, R E G I S T R I E S A N D R I S K M A N A G E M E N T
2© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Definition
Prospective observational study that actively collects information on medicinal product exposure during pregnancy and associated pregnancy outcomes.
Guidance for Industry – Establishing Pregnancy Exposure Registries US HHS, FDA, CDER & CBER August 2002 available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071639.pdf
Pregnancy Exposure Registry (PER)
3© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
1. Why are these data needed?
2. History and regulatory guidance
3. Does a medicinal product need one?
4. Major design features (fictitious case study)
5. PER Team and operations
6. Important recurring methodological details
Outline
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4© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Why These
Data are Needed and
Historic Examples
5© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
What is known about prenatal effects of in utero exposure?
Which is the safest therapeutic alternative for pregnant women who need to continue therapy?
Should I avoid getting pregnant?
Should I stop my medications? Have babies born following
fetal exposure been healthy?
Key Stakeholders Have Questions
Patients Prescribers
What is known about the product’s effects on birth outcomes?
6© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
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Lithium
Schou M, Goldfield MD, Weistein MR (1973) Lithium Babies. Br Med J 2:135-136.
Acylclovir
Andrews EB, Yankaskas BC, Cordero JF, Schoeffler K, Hampp S.(1992)
Acyclovir in pregnancy registry: six years' experience. The Acyclovir in Pregnancy Registry Advisory Committee. Obstet Gynecol. 1992 Jan;79(1):7-13.
Prozac (fluoxetine)
Goldstein DJ, Corbin LA, Sundell KL (1997) Effects of first-trimester fluoxetine exposure on the newborn. Obstet Gynecol 89:713-18.
History – Early One-Product PERs
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R I G H T S R E S E R V E D .
Antiepileptic Drug Pregnancy Registry
http://www.aedpregnancyregistry.org/
Antiretroviral Pregnancy Registry
http://www.apregistry.com/
Mycophenolate Pregnancy Exposure Registry
https://www.mycophenolaterems.com/PregnancyRegistry.aspx
History – Multi-sponsor PERs
8© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Antiepileptic Drug Pregnancy Registry
“AEDs such as valproate and phenobarbital were associated with a higher risk of major malformations than newer AEDs such as lamotrigine and levetiracetam. Topiramate was associated with an increased risk of cleft lip compared with that of a reference population”
Wyszynksi D.F., Nambisan M., Surve T., Alsdorf R.M., Smith C.R., Holmes L.B. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005; 64:961-965
Herndandez-Diaz, S., Smith, C.R., Shen, A., Mittendorf, R., Hauser, W.A., Yerby, M., Holmes L.B. Comparative Safety of Antiepileptic Drugs During Pregnancy. Neurology 2012 May 22;78(21):1692-9
Example of Important Reported Findings
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R I G H T S R E S E R V E D .
Regulatory Information
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R I G H T S R E S E R V E D .
1. Guidance for Industry. Establishing Pregnancy Exposure Registries, August 2002. http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthResearch/UCM133332.pdf
2. Reviewer Guidance. Evaluating the Risks of Drug Exposure in Human Pregnancies. April 2005. http://www.fda.gov/downloads/scienceresearch/specialtopics/womenshealthresearch/ucm133359.pdf
3. Guidance for Industry. Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products- Content and Format. June 2015 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm450636.pdf
Key FDA Regulatory Guidances
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R I G H T S R E S E R V E D .
Guideline on the Exposure to Medicinal Products during Pregnancy: Need for Post-Authorisation Data November 2005
European Medicines Agency Committee for Medicinal Products for Human Use
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/11/WC500011303.pdf
European Pregnancy Registry Guideline
12© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
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63 Entries as of January 2016
• Epilepsy
• Influenza prevention
• HIV
• Multiple Sclerosis
• Autoimmune Disorders
• Mental Heath Disorders
• Hepatitis C
• Sleep Disturbances
• Asthma
• Cancer
• HIV/AIDS
• Transplants
• Type 2 Diabetes
• Fibromyalgia
Example indications in FDA per Website
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R I G H T S R E S E R V E D .
Case Study
Polycystic Ovarian
Disease (PCOS)
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R I G H T S R E S E R V E D .
Female hyperandrogenic/insulin resistance disorder that may include:• Cystic ovaries
• Acne
• Weight gain & difficult to lose weigh
• Extra hair on face and body
• Thinning hair on scalp
• Irregular periods
• Fertility problems
What is PCOS?
15© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Does The Product
Need a PER?
16© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Considerations in planning a PER
Indication
• Use in women of reproductive age
• Chronic therapy
• Underlying disease may confer additional risk
Product
• Animal studies find adverse fetal effects
• In a drug class with known fetal effects
• New chemical entity
• Pregnancy should be avoided per label
17© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Major Design
Features
18© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Study Characteristics
Pregnancy Exposure Registries
No site enrollment
Multiple reporters
Central data collection
Might be REMS mandated
May include Root Cause analysis
Observational Studies
Real world data collection
Marketed products
Usual care
Varying time points
Limited exclusions
Flexibility a must
19© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Design: Prospective, longitudinal, observational cohort
Location: US
Objectives:
• To estimate the risk of major congenital anomalies or in offspring of women exposed to Drug X during pregnancy
• To estimate the risk of other adverse pregnancy outcomes (spontaneous abortion, stillbirth, preterm delivery, small for gestational age) in offspring of women exposed to Drug X during pregnancy
Fictitious PER Case Study: Drug X in Women with Polycystic Ovarian Disease (PCOS)
20© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
What about the secondary objectives?
Driven by existing data (animal and human)
Consider:
• Spontaneous abortion
• Stillbirth
• Preterm delivery
• Small for gestational age
Case Study: Pregnancy Exposure Registry (PER)
21© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
• Product uptake
• Marketing and HCP outreach
• Number of women of reproductive age exposed• Limited pool of potential subjects
Target Enrollment Considerations
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R I G H T S R E S E R V E D .
Prospective data of pregnancy exposure are data acquired prior to the knowledge of the pregnancy outcome or prior to the detection of a congenital malformation at prenatal examination (e.g., foetalultrasound, serum markers).
Retrospective data of pregnancy exposure are data acquired after the outcome of the pregnancy is known or after the detection of a congenital malformation on prenatal test.
Cases are classified as prospective or retrospective
23© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
PER Team and
Operations
24© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Approaches that Lead to Success
• Low loss to follow-up
• Streamlined case report form
• Flexible data collection
• Strong relationships developed with patients and HCPs
• Unique analytical approaches
• Automated alerts for follow-ups
• Adverse event triggers, coordinate with pharmacovigilance departments
• Registry Advisory Committee organization and management
25© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
• May create and use a study name and logo• Keeps study “top of mind” with HCP and serves as a visual reminder of
reporting requirements• Useful for publications and presentations• Brand all materials
Patient Recruitment and Retention
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R I G H T S R E S E R V E D .
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R I G H T S R E S E R V E D .
Prescriber Outreach
• Target prescribers by understanding their workflow
• Letters will contain
• Information about the registry
• FAQs including:
• Eligibility criteria
• Brief description of participation involvement and data collection time points by the UBC Coordinating Center
• Minimum of 2 mailings
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29© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
30© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Data Collection via Phone
Call Center for Registry ProgramsSpecific experience with PER
21 CFR Part 11 compliant systems
PER Hours of operation: 8:00AM – 5:00PM ET from Monday – Friday
Well-trained staff must balance regulatory program needs with positive customer-friendly interactions
High touch service
Multi-lingual capabilities
Experience with PERs
21 CFR Part 11 compliant systems
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31© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Pregnantpatient
Health Care Provider (HCP)
OR
Reportspregnancy
Call Center documents on Pregnancy Report
Form
HCP sent signed RMI
HCP sent brochures and notified of verbal
consent
Patient receives study information and RMI
Patient providesverbal consent
Call Center follows up with patient and HCP per
protocol
32© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Pharmacovigilance
• Reporting plan details responsibilities and processes• Adverse event reporting
• Medical information request
• Product Complaints• Coordination with registry sponsor
33© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Details of Importance
to Pregnancy
Registries
34© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
• Registry Advisory Committees
• Comparison Group Considerations
• Lost to follow-up is of critical importance
• Retrospective/prospective classification case definitions
• Birth defect coding
• Creation of proportions and rates – numerator and denominator (twins, live births, and abortions)
• Growth calculations taken in the field
Details of Importance
35© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Methodological Details
• Birth defect adjudication for proper coding • Size for gestational age (varies with age estimates)• Classification of cases into retrospective and prospective
important as prospective are used for key comparisons• Construction of proportions and rates
36© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Details - Comparison Group Considerations
General Population Rates
• Estimate risk of major malformations – MACDP published rates1
• Other adverse pregnancy outcomes – US vital statistics and US National Survey of Family Growth2-4
• Size for gestational age – use published growth curves5
1. Correa et al Birth Defects Res A Clin Mol Teratol 2007; 79:65-186.2. Ventura et al Natl Vital Stat Rep 2008;56(15):1-25.3. Zhang et al BJOG 2014 Sep;121(10):1229-1236.4. Hamilton et al Pediatrics 2013 131(3):548-558.5. Fenton et al BMC Pediatrics 2013 13:59.
37© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Details - Comparison Group Considerations (cont’d)
Women with PCOS
Also compare to published birth outcome rates among infants born to women with polycystic ovarian disease
Is the disease state associated with an increased risk of adverse birth outcomes?
What birth outcome data are available in women not treated with Drug X?
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R I G H T S R E S E R V E D .
• Drives Small for Gestational Age, Large for Gestational Age
• Drives head circumference
• Influences coding (example of Ventricular Septal Defect)
• Difficult to pin down• LMP
• Capture on forms
• Ultrasound best
• May have conflicting information in multiple places so may need review and decision
Details – Gestational Age
39© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Operational Details
• Highly sensitive data • Growth measurements quality• Registry Advisory Committee
40© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Registry Advisory Committee (RAC) andAdjudication of CasesRegistry Advisory Committee (RAC) and Adjudication• RAC – an experienced, multidisciplinary group of experts
providing scientific oversight, e.g.:• Perinatologist• Obstetrician• Epidemiologist• Endocrinologist
• Meet periodically for data review and to provide a consensus opinion
• UBC manages following a written charter• Clinical reviewer adjudicates individual cases to properly
categorize birth defects into the Metropolitan Atlanta Congenital Defects Program coding scheme
• Complicated cases will require full RAC review
41© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Data Management
Start-Up
• Design eCRF
• Edit Specifications (develop, program, validate
• Draft DMP
• Timelines
• Coding Conventions
• Database UAT
• Draft Data Completion/Entry Guidelines
Maintenance
• Ongoing DM Review of EDC forms and datasets
• Data Review Listings (if applicable)
• Coding activities
• AE reconciliation
• Reporting
• Status, Metrics
• Data Transfers to BMS
Finalization
• Final Dataset review
• Coding Approval
• Final AE Reconciliation
• Database Lock Checklist
• Final Database Transfer
• Decommission database
• Archival
Electronic data capture platform created for registries greatly improves the quality of the study. Accommodates real-life physician office work flows
42© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
Statistical Considerations
• Regulatory reporting requirements
• Experience with common problems
• Defining retrospective vs. prospective cases
• Adjudication of birth defects
• Analysis of complicated data
43© C O P Y R I G H T 2 0 1 5 E X P R E S S S C R I P T S H O L D I N G C O M P A N Y . A L L
R I G H T S R E S E R V E D .
How a Successful PER?
Experienced staff, attuned to the factors required for success
Teamwork & communication
Safety a core focus
Ability to attain high retention rates
Quality programs & deliverables
Regulatory and Design
Technology Platforms
Focus on Retention
&
Annual Reports
Staff Experience
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