Pregnancy Registries’ Contribution to Informed Clinical Practice

Third Annual International Conference for Individualized Pharmacotherapy in Pregnancy

Indianapolis, IndianaJune 7, 2010

Kristine Shields MSN, MPHGlobal Safety, Merck

Course Objectives

To understand the processes in place for evaluating the safety profile of pharmaceutical products used during pregnancy

To appreciate how Pregnancy Registries contribute to the evaluation of pregnancy exposures in the post-marketing environment

To encourage health care provider participation in product safety evaluation

Course Outline

Sources of pregnancy data Pregnancy Registries Signal detection vs signal

investigation Other sources for data analyses and

their uses, strengths and limitations Risk Management

Background About 64% of pregnant women are prescribed

one or more drugs during pregnancy (excluding vitamins/minerals)

Chronic health problems that require continuous or intermittent medicine use

Acute or new problems that arise during pregnancy

50% of pregnancies are unplanned Inadvertent exposures

For most drugs, there are little or no data about use during pregnancy.

Source of data

Animal testing Clinical Trials Post-marketing surveillance

“ The true picture of a product’s safety actually evolves over the months and years that make up the product’s lifetime” - FDA

Routine Pregnancy Surveillance

Required Not a pregnancy registry

Definition Pregnancy Registries are prospective active

data collections in systems which can facilitate the early detection of teratogenicity and other serious adverse experiences in patients who inadvertently or purposefully use a drug during pregnancy. Useful information about the outcome of exposure in pregnancy can best be obtained by the careful collection and analysis of postmarketing surveillance data.

merckpregnancyregistries.com

FDA and Pregnancy Exposure Registries

FDA Guidance for Industry (August 2002): Establishing pregnancy exposure registries

“the ultimate goal of pregnancy exposure registries is to provide clinically relevant human data that can be used in a product’s labeling…”

Pregnancy Registry Evolution

Voluntary Phase IV Commitment Risk Management Plans

Pregnancy Registries

There are different kinds of registries

Single drug

Multiple drugs Sponsor-managed vs. contract

organization

Purpose

Primary Signal detection of teratogen or other

serious adverse events

Purpose

Secondary Help patients and providers to make

informed decisions Avoid consequences of poor information

Patients denied treatment Termination of wanted pregnancies

Encourage Participation

FDA website Product label Publications Universal Call Center Miscellaneous

Data

Prospective Reports Learn about the exposure before the

outcome of pregnancy is known

Retrospective Reports Learn about the exposure and the

outcome of pregnancy at the same time

Registry Strengths and Limitations

Strengths Real time Information to

women Prospective reports New products Low cost

Limitations Low numbers Reporting bias Variable report

quality No comparator Loss to follow-up

Risk Management

Surveillance, signal detection Monitoring reports, literature, studies Consultant teratologist review, advisory

committee Sources of additional information

Risk Management

Signal investigation Case reports, literature Registries, call centers Large databases Case-control studies

Data Sources and Strengths

New

products Low cost

Real time

Prospec-tive

Data quality

Denom-inator

Com-parator

Large #s

Rare Outcomes

Hypothesis testing

Case Reports

++

++

++//--

++

Call Centers,

Registries

++

++//--

++

++

++//--

++//--

++//--

Large databases

++

++

++

++

++

++

++

Case-control

++

++

++

++//--

++

++

Risk Management Provide human data in label Change pregnancy category

Acyclovir; Budesonide (C to B) Efavirenz; mycophenolate mofetil and

mycophenolic acid (C to D)

Provide information in periodic reports to regulatory agencies

Provide information in interim reports to health care providers

Risk Management

Maternal and fetal outcomes Pediatric medical record review, long-

term follow-up Other information

Causes of inadvertent exposure Product confusion Use patterns

Benefit-Risk Relationship

Changes throughout product life cycle Depends on whether drug is

preventive, cosmetic, symptomatic, or curative

Related to risk of non-treatment Comparative to alternative products

Questions?

Resources

Proposed Pregnancy and Lactation Labeling Rule: CDER Pregnancy and Lactation Labeling

http://www.fda.gov/CDER/regulatory/pregnancylabeling/default.htm

Pregnancy Registries webpage, FDA Office of Women’s Health http://www.fda.gov/womens/registries/defa

ult.htm

Back-up Slides

Proposed rule: 8.1 PregnancyRequired labeling elements

Pregnancy registry contact information (when available) - encouragement to enroll

Standard statement about background population risk of fetal abnormalities

Three main parts Fetal risk summary Clinical considerations Data

Sifontis et al. Transplantation 2006 Dec 27; 82(12): 1698-1702

Overall, 25 transplant recipients with 33 pregnancy outcomes:

15 spontaneous abortions (45%) all first trimester (3 – 9 weeks gestation)

18 live births/ 4 with malformations (22%) 1 infant with multiple anomalies (including microtia) and

death at one day of age

Two infants with microtia (one preterm)

Two infants with cleft lip/palate

One preterm infant with hypoplastic nails and short 5th fingers.

Rates of SAB and malformations increased over background rates (general and transplant recipients)

Call Centers, Registries Examples

Pregnancy outcome following maternal use of the new serotonin reuptake inhibitors Kulin et al, JAMA 1998 (OTIS)

Pregnancy outcomes following systemic prenatal acyclovir exposure Stone et al, BDRA 2004 (GSK)

Measles, Mumps, and Rubella MMWR 1998 (CDC)

Immunosuppression in pregnancy Drugs 2002 (Nat’l Transplantation Preg

Registry)

Large Database Examples

Spina bifida in infants of women treated with carbamazepine during pregnancy Rosa, NEJM 1991 (Medicaid)

Exposure to NSAIDS during pregnancy and risk of miscarriage Li, BMJ 2003 (Kaiser Permanente)

Congenital malformation after the use of inhaled budesonide in early pregnancy Kallen et al, OB/GYN 1999 (SMBR)

Retrospective Case-control Examples

Folic acid antagonists during pregnancy and the risk of birth defects Hernandez-Diaz et al, NEJM 2000 (Slone)

Evaluation of an association between loratadine and hypospadias – U.S., 1997-2001 Werler et al, MMWR 2004 (NBDPS)

No teratogenic effect after clotrimazole therapy during pregnancy Czeizel et al, Epidemiology 1999 (HCCSCA)