SKS Drug Safety Evaluation in Pregnancy and Lactation

Drug safety evaluation in pregnancy
and lactation
By
Prof. Satish Sharma, Dean, School of Pharmacy
Background
 Pregnant women represent an important segment of the population
 Pregnant women may have chronic conditions, such as diabetes, seizure
disorders, or asthma, that need to be treated during pregnancy
 Pregnant women may develop acute or serious medical conditions during
pregnancy that require treatment.
 During clinical development of most drugs and biological products,
pregnant women are actively excluded from trials, and if pregnancy does
occur during a trial, the usual procedure is to discontinue treatment and
monitor the women to assess pregnancy outcomes
 There are no or limited human data to inform the safety of a drug or
biological product taken during pregnancy
Factors in evaluating the effects of product
exposure in pregnancy
 A detailed description of the adverse pregnancy outcome
 A detailed description of the exposure including the specific
medication, the dose, frequency, route of administration, and
duration
 The timing of the exposure in relation to the gestational age
 The maternal age, medical and pregnancy history, and use of
concomitant medications, supplements, and other substances
 Exposures to known or suspected environmental teratogens
Lactation study added on to a
pregnancy registry
There is also often a need to collect lactation data to
provide information on the safety of drugs and
biological products during breast-feeding.
Pregnancy registries can be used to recruit and
enroll breast-feeding women in lactation studies.
Some women enrolled in a pregnancy registry are
already taking a drug or biological product during
pregnancy, and because they may be likely to
continue treatment after delivery, these women are
an ideal population in which to study
Methods to Identify Pregnancies
Sponsors should consider the implications of limiting

a study population to that of only live births, because
birth defects likely to result in non-live birth outcomes
would not be captured.
Failure to include non-live births in a study
population primarily affects study generalizability
Without a reasonable estimate of gestational age, a
reliable assessment of pregnancy exposure is
difficult unless the investigator has access to
ultrasound or laboratory data.
The Risk of Birth Defects
Teratogenicity—the risk of congenital anomaly

(malformations at birth)—is a major concern with
regard to the safety of medicines during pregnancy.
 During the first trimester of pregnancy, the foetus
undergoes a period of organogenesis, the formation
and differentiation of organs and organ systems
during embryonic development.
This period extends from approximately the end of
the second week through the twelfth week of
gestation in humans
The Risk of Birth Defects
 Consequently,
pregnant women
should be careful
about their medication
use during this period.
Late exposure may
also cause
neurodevelopmental
effects, which is of
increasing concern
Medicines used during Pregnancy-Why
action is needed
 Birth defects, stillbirth and death are a harrowing experience for
both women and their families
 The safe use of medication during pregnancy is an unmet
medical and societal need. There is little information available
to determine the risks to both mother and child
 Approximately 90% of medications currently have no
information about their potential to cause birth defects
 Most medicines have not been tested in pregnant women
 When a medicine receives its marketing authorisation,
information about reproductive toxicity is only available from
animal studies, which are limited in their ability to predict human
teratogenesis.
Recommendations for a comprehensive
pharmacovigilance System
The findings of EUROmediCAT and its

recommendations inform current regulatory practice,
pharmacovigilance, research, health policy and
practice in order to:
Improve future pharmacovigilance
Inform future drug safety measures
Raise the level of reproductive
pharmacovigilance to meet women’s expectations
Pregnancy registries
A pregnancy registry actively collects information on
drug or biological product exposure during pregnancy
and associated pregnancy outcomes, which can be
used to conduct a prospective observational study
(women are enrolled before the pregnancy outcome).
Pregnancy registries depend on the voluntary
participation of women who have been exposed to a
specific drug or a biological product during pregnancy
and unexposed women who enroll into the
comparator
Pregnancy registries
 Pregnancy registry data are prospectively collected by maternal
interview and medical record documentation and may include
results of the clinical examination of the newborn
 Because of the prospective design of pregnancy registries,
they may support assessment of multiple maternal, obstetrical,
fetal, and infant outcomes, including pregnancies that do not
result in a live birth
Strength of pregnancy registries
 By enrolling women exposed to the product of interest,
pregnancy registries can be an efficient way to collect data on
the effects of rare exposures during pregnancy
 Have the potential to obtain accurate information about whether
exposure occurred and the timing of the exposure in relation to
gestational age, dose, frequency, and duration of the exposure
 A pregnancy registry can potentially collect data on a variety of
pregnancy and infant outcomes, including postnatal outcomes
PHARMACOVIGILANCE — CASE REPORTS
 Good pharmacovigilance practice involves the collection of

comprehensive data on adverse pregnancy outcomes to detect
safety signals and develop a case series for analysis.
 Sources can include spontaneous reports submitted to the
sponsor and FDA, as well as case reports from the medical
literature or clinical studies.
 Well-documented and informative case reports can be used to
identify a signal, particularly if the pregnancy outcome is rare in
the absence of drug exposure.
The new EU clinical trials regulation
 The new EU Clinical Trial Regulation (No 536/2014) aims to

create an environment that is favorable to conducting clinical
trials in the EU with the highest standards of ethical and safety
protection for participants
 It contains new rules for the inclusions of pregnant and
breastfeeding women in clinical studies under strict protective
measures.
 The Regulation, which becomes law in 2016, sets out the legal
provisions under which clinical trials will have to be conducted
in Europe in the future. Article 33, Chapter V defines the
conditions for including pregnant and/or breastfeeding women
in clinical trials
Benefits of breastfeeding
 Reduced infection
 Protection against 72% hospital
admissions due to diarrhea
 9% reduction in asthma
 24% reduction in Type II
Diabetes
 Higher IQ
 Shorter hospital stay
 Breast cancer prevention
 Ovarian cancer prevention
Drugs that preclude breastfeeding
Methotrexate (long-term)
Ergot Alkaloids (cabergoline, methylergonovine)
 Anticancer drugs: Cisplatin, Doxorubicin, Carboplatin
Tamoxifen
Drugs of Abuse: Cocaine, Phencyclidine, Marijuana
Metals: High mercury, High lead
Radioactive: 131Iodine
What might preclude choice to breastfeed
Medication use
Short term vs. long term Toxicity of drug
Exceedingly high dose of drug
Drugs that might suppress lactation
Drug-drug interactions
Drugs with cardiovascular side effects
Challenges
 New drugs come out faster than information on lactation safety
 Many studies have only small samples of breastfeeding
mothers
 Physicians recommending without exploring how to make
breastfeeding and medication compatible
 Physician Desk Reference still used by many healthcare
providers
 Packaging inserts may be inaccurate or incomplete in
communicating drug information to mothers and health care
providers

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Drug safety evaluation in pregnancy

Sponsors should consider the implications of limiting

Teratogenicity—the risk of congenital anomaly

The findings of EUROmediCAT and its

 Good pharmacovigilance practice involves the collection of

 The new EU Clinical Trial Regulation (No 536/2014) aims to

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