pregnancy registries’ contribution to informed clinical practice third annual international...
TRANSCRIPT
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
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Call Centers,
Registries
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Large databases
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Case-control
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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)