post-marketing safety data pregnancy exposure1).pdf · case study polycystic ovarian disease ......

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



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)



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

3



Why These

Data are Needed and

Historic Examples



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?



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



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



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



Regulatory Information



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



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



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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



Case Study

Polycystic Ovarian

Disease (PCOS)



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?



Does The Product

Need a PER?



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



Major Design

Features



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



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)



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)



• Product uptake

• Marketing and HCP outreach

• Number of women of reproductive age exposed• Limited pool of potential subjects

Target Enrollment Considerations



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



PER Team and

Operations



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



• 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

25



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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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

30



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



Pharmacovigilance

• Reporting plan details responsibilities and processes• Adverse event reporting

• Medical information request

• Product Complaints• Coordination with registry sponsor



Details of Importance

to Pregnancy

Registries



• 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



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



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.



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?



• 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



Operational Details

• Highly sensitive data • Growth measurements quality• Registry Advisory Committee



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



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



Statistical Considerations

• Regulatory reporting requirements

• Experience with common problems

• Defining retrospective vs. prospective cases

• Adjudication of birth defects

• Analysis of complicated data



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

43



Thank you

post-marketing safety data pregnancy exposure1).pdf · case study polycystic ovarian disease ......

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