Two Years In: Lessons Learned 

with the Pregnancy and 

Lactation Labeling RuleApproaches to Human Data

CDER Prescription Drug Labeling Conference 2017

CDER SBIA REdI

Silver Spring, MD - November 1 & 2, 2017

Miriam Dinatale, DO, LCDR, USPHS

Division of Pediatric and Maternal Health

Center for Drug Evaluation and Research (CDER)

Food and Drug Administration (FDA)
2

Disclaimer

• The views and opinions expressed in this 

presentation represent those of the presenter, and 

do not necessarily represent an official FDA 

position.

• The labeling examples in this presentation are 

provided only to demonstrate current labeling 

development challenges and should not be 

considered FDA recommended templates.

• Reference to any marketed products is for 

illustrative purposes only and does not constitute 

endorsement by the FDA.
3

Overview

• Introduction

• Review of Draft PLLR Guidance Regarding 

Human Data

• Current Approaches to Inclusion of Human 

Data in Labeling

• Conclusion
4

Introduction
5

The Information Gap

• Human data about medical product safety in pregnancy 

at the time of market approval are limited or absent

– Pregnant women are usually actively excluded from 

clinical trials. 

– Women who become pregnant during clinical trials 

are discontinued but followed. 

• Consequently, almost all clinically relevant human data 

are collected post-approval

• Important goal of the PLLR conversion process is to 

have accurate and up-to-date labeling recommendations 

which reflect the post-approval experience
6

Human Data Sources for 

Pregnancy

• Clinical Trials

– Trials for drugs that specifically treat a pregnancyrelated condition

– Inadvertent pregnancy reported in clinical trials for a 

non-pregnancy-related condition

• Observational Studies

– Pregnancy Exposure Registries (Drug or Disease-based)

– Cohort Studies, Case-Control Studies

– Enhanced Pregnancy Surveillance Program

– Case Reports or Case Series
7

Draft PLLR Guidance regarding 

inclusion of Human Data in 

Subsection 8.1, Pregnancy
8

8.1 Pregnancy-Data, Human Data

• Must include the following elements:

– Data source (e.g., controlled clinical trials, ongoing or 

completed pregnancy exposure registries, other 

epidemiological or surveillance studies, case series)

– Number of subjects

– Study duration

– Exposure information (timing, duration, and dose of 

exposure)

• Limitations of the data, including potential confounders 

and biases, if known

• If available, data from the comparator or control group, 

and data confidence intervals and power calculations 

should also be included

From Draft PLLR Guidance 2014.
9

Challenges

• Most human data related to drug use during 

pregnancy and lactation do not come from 

adequate and well-controlled trials. 

• Ongoing discussions about what to do 

when:

– Data are limited

– Lack of a specific or consistent safety findings

– Whether to include case reports
Current Approach to the Inclusion 

of Human Data in Subsection 8.1
11

Key Considerations

• Quantity of Data

– none, limited, extensive 

• Quality of Data 

– Relevant and detailed information available

– Study design: case reports/series, observational studies

• Consistency/pattern of outcomes 

• Impact 

– None

• Risk Summary risk statement only

• Do not report under Human Data

– Triggers potential change in safety message

• Report under Human Data
12

No Data-No Impact

Often NMEs or New BLAs

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on TRADENAME 

use in pregnant women to inform a drugassociated risk of adverse developmental 

outcomes.
13

Some Data-No Impact

• Case reports only, with sparse details from clinical 

development program 

• Moderate number of case reports with no patterns or 

consistency of outcomes

• NMEs or New BLAs, rare disease drugs, newly 

marketed drug

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited available data with TRADENAME use in pregnant 

women are insufficient to inform a drug-associated risk of 

adverse developmental outcomes.
14

More Data - No Impact –

No Consistency

• Data from large epidemiologic studies reporting no clear 

association of adverse outcomes with drug use; no 

consistency or pattern 

• Does not necessarily establish or exclude absence of a 

risk

• Detailed description of every study is not the goal; 

however, a conclusion about the safety message from 

this data is most valuable

• This situation may only include simple statements in Risk 

Summary and Data. Any further description of data must 

be balanced and present meaningful information to the 

prescriber. 
15

Example 1

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The limited data with TRADENAME and drug 

name use in pregnant women are not sufficient 

to inform a TRADENAME-associated or 

drugname-associated risk for major birth defects 

and miscarriage. Published studies with 

drugname use during pregnancy have not 

reported a clear association with drug name and 

major birth defect or miscarriage risk [see Data].
16

Example 1 (cont’d)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

...

Data

Human Data 

Published data from post-marketing studies have not 

reported a clear association with drugname and major 

birth defects, miscarriage, or adverse maternal or fetal 

outcomes when drug name was used during 

pregnancy. However, these studies cannot definitely 

establish the absence of any drugname-associated 

risk because of methodological limitations, including 

small sample size and inconsistent comparator 

groups. 
17

• Varied findings from large epidemiologic 

studies of varied design (+/- pregnancy 

registry), with some reporting a potential 

association of adverse outcomes with drug 

use and others reporting no association; no 

consistency or pattern 

• Report details under Human Data

Quality Data - Potential ImpactInconsistent Findings
18

Example 2: 

Human Data Sources

• Two large retrospective cohort studies

– One with no increase of congenital malformations

– Second found association with congenital cardiac 

malformations

• One case-control study

– Finding of isolated cleft palate

• Several smaller observational studies

– No findings of adverse outcomes, but other 

limitations

– Too small to detect anything but a major teratogenic 

effect
19

Example 2

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data do not reliably inform the 

association of TRADENAME and adverse fetal 

outcomes. Published epidemiological studies on 

the association between drugname and fetal 

outcomes have reported inconsistent findings 

and have important methodological limitations 

hindering interpretation [see Data]. ...
20

Example 2 (cont’d)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

...

Data

Human Data

Methodological limitations of the epidemiology studies preclude a 

reliable evaluation of the potential risk of adverse fetal outcomes with 

the use of drugname in pregnancy. Two large retrospective cohort 

studies of drugname use in pregnancy have been published. In one 

study with 1,349 infants born to women who reported the use of 

drugname or received drugname prescription in the first trimester, no 

increased risk for major congenital malformations was seen in 

aggregate analysis. In this same study, however, a sub-analysis for 

specific malformations reported an association between drugname

exposure and cardiovascular defect (odds ratio (OR) 1.62 [95% CI 

(1.04, 2.14)]) and cardiac septal defect ( OR 2.05 [95% CI (1.19, 

3.28)]). 
21

Example 2 (cont’d)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

...

Data 

Human Data 

The second study examined 1970 women who received 

drugname prescription during pregnancy and reported no 

association between drugname exposure and major 

congenital malformations, miscarriage or stillbirth, and infants 

of low birth weight or small for gestational age. Important 

methodological limitations with these studies include the 

uncertainty of whether women who filled a prescription 

actually took the medication, the concomitant use of other 

medications or treatments, and other unadjusted confounders 

that may account for the study findings. 
22

Example 2 (cont’d)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

...

Data 

Human Data 

A case-control study evaluating associations between several common non- cardiac malformations and multiple antiemetic drugs reported an association 

between maternal use of drugname and isolated cleft palate (reported adjusted 

OR = 2.37 [95% CI (1.18, 4.76)]). However, this association could be a chance 

finding, given the large number of drugs-birth defect comparisons in this study. 

It is unknown whether drugname exposure in utero in the cases of cleft palate 

occurred during the time of palate formation (the palate is formed between the 

6th and 9th weeks of pregnancy) or whether mothers of infants with cleft palate 

used other medications or had other risk factors for cleft palate in the offspring. 

In addition, no cases of isolated cleft palate were identified in the 

aforementioned two large retrospective cohort studies. At this time, there is no 

clear evidence that drugname exposure in early pregnancy can cause cleft 

palate. 
23

Quality Data –

Clearly Identified Safety Finding

• Case reports/series with quality information 

to reasonably determine a risk; especially 

when a rare finding occurs at increased 

frequency with drug use

• Pregnancy registries or other quality 

epidemiologic studies report a specific 

increased risk

• Report details under Human Data
24

Example 3

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

TRADENAME can cause fetal harm when administered 

to a pregnant woman. In post-marketing reports, use of 

TRADENAME during pregnancy resulted in cases of 

oligohydramnios and of oligohydramnios sequence, 

manifesting as pulmonary hypoplasia, skeletal 

abnormalities, and neonatal death [see Data]. Apprise 

the patient of the potential risks to a fetus. 
25

Example 3 (cont’d)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

...

Data

Human Data 

In post-marketing reports, use of TRADENAME during pregnancy 

resulted in cases of oligohydramnios and of oligohydramnios 

sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal 

abnormalities and neonatal death. These case reports described 

oligohydramnios in pregnant women who received TRADENAME 

either alone or in combination with chemotherapy. In some case 

reports, amniotic fluid index increased after TRADENAME was 

stopped. In one case, TRADENAME therapy resumed after amniotic 

index improved, and oligohydramnios recurred. 
26

Pregnancy Exposure Registries

• May be required by FDA to collect more 

information on risk of adverse events in 

pregnancies exposed to specific drugs 

• Usually designed to assess risk of any 

adverse pregnancy outcome

From Lockwood Taylor presentation, Teratology Society meeting, June 28, 2016
27

Example 4

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 

Risk Summary 

Limited clinical data are available from the 

TRADENAME Pregnancy Registry. Excluding lost-to 

follow-up, data from the registry reports a rate of 5.6% 

for major birth defects with first trimester use of drug 

name in pregnant women with rheumatoid arthritis 

(RA), and a rate of 7.8% and 5.5% for major birth 

defects in the disease-matched and non-diseased 

comparison groups [see Data]. 
28

Example 4 (cont’d)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 

...

Data

Human Data 

In a prospective cohort pregnancy exposure registry 

conducted in the U.S. and Canada between 2004 and 

2013, 74 women with RA treated with drugname at 

least during the first trimester, 80 women with RA not 

treated with drug name and 218 women without RA 

(non-diseased) were enrolled. Excluding lost-to-follow- up, the rate of major defects in the drugname-exposed 

pregnancies (N=72), disease-matched (N=77), and 

non-diseased comparison groups (N=201) was 5.6%, 

7.8% and 5.5%, respectively. 
29

Example 4 (cont’d)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 

...

Data

Human Data 

However, this study cannot definitely establish the 

absence of any risk because of methodological 

limitations, including small sample size and nonrandomized study design. Data from the Crohn’s 

disease portion of the study is in the follow-up 

phase and the analysis is ongoing. 
Regulation and Draft PLLR 

Guidance: Inclusion of Data in 

Subsection 8.2-Lactation
31

8.2 Lactation-Data

• When relevant human and/or animal lactation 

data are available, the Risk Summary must 

include a cross-reference to the Data portion of 

the Lactation subsection where the details of 

the data are presented (§ 201.57(c)(9)(ii)(A)). 

• Data may come from a clinical lactation 

study(s) or from other sources (e.g., published 

literature, lactation databases). 

• Applicants should evaluate the quality and 

quantity of data available with respect to what 

information warrants inclusion in labeling. 

From Draft PLLR Guidance 2014
32

8.2 Lactation-Data

• Even less clinical data available on drug use 

while breastfeeding

• Published clinical studies often not best 

quality, no information on effects on 

breastfed infant, and raw data not available 

for review

• Greater contribution of case reports to risk 

determination
33

8.2 Lactation-Data

• Data - Include only when information are 

available

– Description of clinical lactation study/data

– Description of animal lactation study (only if there 

are no human data)

• Note: If considered meaningful for information 

on concentration in breast milk or adverse 

reactions in infants, information from case 

reports may be reflected briefly under the Risk 

Summary or Data headings
34

Example 1

8 USE IN SPECIFIC POPULATIONS

...

8.2 Lactation

Risk Summary 

Limited data from case reports in the published literature 

describe the presence of drugname in human milk at infant 

doses of 0.1% to 1% of the maternal serum level. There 

are no reports of adverse effects of drugname on the 

breastfed infant and no effects on milk production. The 

developmental and health benefits of breastfeeding should 

be considered along with the mother’s clinical need for 

TRADENAME, and any potential adverse effects on the 

breastfed child from TRADENAME, or from the underlying 

maternal condition.
35

Example 2

8 USE IN SPECIFIC POPULATIONS

...

8.2 Lactation 

Risk Summary 

Small amounts of drugname have been detected in the 

milk of lactating women. A pharmacokinetic study in 

lactating women detected drugname in breast milk at 

average steady state concentrations approximately 76% of 

those in maternal plasma. The estimated average daily 

infant dose of drugname from breast milk (assuming mean 

milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, 

which on a mg/kg basis would be approximately 7% of the 

maternal dose [see Data]. The study did not evaluate the 

effects of TRADENAME on milk production or the effects of 

TRADENAME on the breastfed infant... 
36

Example 2 (cont’d)

8 USE IN SPECIFIC POPULATIONS

...

8.2 Lactation 

...

Data

A pharmacokinetic study in ten lactating women, who were at least 12 

weeks postpartum, evaluated the concentrations of drugname in 

plasma and breast milk. TRADENAME 150 mg oral capsule was given 

every 12 hours (300 mg daily dose) for a total of four doses. Drugname

was detected in breast milk at average steady-state concentrations 

approximately 76% of those in maternal plasma. The estimated 

average daily infant dose of drugname from breast milk (assuming 

mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which 

on a mg/kg basis would be approximately 7% of the maternal dose. 

The study did not evaluate the effects of TRADENAME on milk 

production. Infants did not receive breast milk obtained during the 

dosing period, therefore, the effects of TRADENAME on the breast fed 

infant were not evaluated. 
37

Conclusion

• The goal of PLLR is to accurately communicate known 

information about the risks with prescription drug use in 

pregnant and lactating women 

• PLLR format improves presentation of currently available 

data, but does not help when there are poor quality or 

sparse data

• Determination of adequate data is based on clinical review

• It is important to have the applicant’s input on the available 

data and rationale for updates to safety messaging in the 

labeling

• The FDA continues to think about how to include human 

data into labeling that is both accurate and meaningful to 

the prescriber