PLLR Labeling and Process 

Considerations

Jane Liedtka, MD

Medical Officer, Maternal Health Team

Division of Pediatric and Maternal Health

Center for Drug Evaluation and Research (CDER)

Food and Drug Administration (FDA)

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CDER Prescription Drug Labeling Conference 2017

CDER SBIA REdI

Silver Spring, MD - November 1 & 2, 2017
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Disclaimer

• The views expressed in this presentation are those of the 

speaker, and do not necessarily represent an official FDA 

position.

• The labeling examples included in this presentation are provided 

only to demonstrate current labeling development challenges 

and should not be considered FDA recommended labeling 

templates. 
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OVERVIEW

• Process Considerations

• Content Considerations

• Format Considerations

• Summary
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Best Practice for Submission 

of PLLR Compliant Labeling

• The submitted labeling should:

– comply with the PLLR format

– reflect an integrated assessment of known risks relevant to 

pregnancy, lactation and infertility based on available 

information/data

– be accompanied by a summary and review of the available 

relevant information/data that supports labeling content

• Locate labeling and supportive information in Module 1 of 

submission
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Process Considerations (1)

• Applicant must be aware of requirement for labeling to 

comply with PLLR format 

– includes new 505 (b)(2) and biosimilar applications

• Agency is informing applicants through pre-BLA/pre-NDA 

meetings, external conferences, FDA website and other 

methods of communications

• No waivers of PLLR requirement

• Deferral requests will be reviewed on a case-by-case 

basis

• Potential Refuse to File issue
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Process Considerations (2)

• If submission lacks information/data to support 

labeling content 

– Review division may issue information request (IR)

– Applicant should consider the amount of supporting 

information that needs to be prepared and the time 

needed to respond to the IR

– Response to an IR could be considered a major 

amendment
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Supportive Information

• Assessment should generally include (when applicable):

– a review and summary of available nonclinical information, including 

published literature 

– a review and summary of all available published literature regarding 

[drug name] use in pregnant and lactating women and the effects of 

[drug name] on male and female fertility (include search parameters and 

a copy of each reference publication)

– a cumulative review and summary of relevant cases reported in your 

pharmacovigilance database (from the time of product development to 

present)

– a summary of drug utilization rates amongst females of reproductive 

potential (e.g., aged 15 to 44 years) calculated cumulatively since initial 

approval

– interim report from an ongoing pregnancy registry or final report from a 

closed pregnancy registry (if applicable)
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Content Considerations (1)

• Clinical Considerations:

Disease-Associated Maternal and/or Embryo/Fetal Risk

– This subheading should not include an exhaustive textbook 

review of the untreated disease/condition and pregnancy 

outcomes

– Limit information contained in this subheading to a brief 

description of any serious known or potential risk of the 

underlying disease/condition on pregnancy outcomes that is 

well-established
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Example of 8.1 Pregnancy, 

Clinical Considerations

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

...

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Poorly controlled diabetes in pregnancy increases the 

maternal risk for diabetic ketoacidosis, pre-eclampsia, and 

delivery complications. Poorly controlled diabetes increases 

the fetal risk for major birth defects, still birth, and 

macrosomia-related morbidity. 
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Content Considerations (2)

8.2 Lactation 

• Required risk and benefit statement unless 

breastfeeding is not recommended, then 

required statement may be omitted

“The developmental and health benefits of 

breastfeeding should be considered along with the 

mother's clinical need for [name of drug] and any 

potential adverse effects on the breast-fed child from 

[name of drug] or from the underlying maternal 

condition”
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Example of Subsection 8.2 – When 

Breastfeeding is Not Recommended

8 USE IN SPECIFIC POPULATIONS

...

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIVinfected mothers in the United States not breastfeed their infants to 

avoid risking postnatal transmission of HIV infection. 

There is no information available on the presence of drugname in 

human milk, the effects of the drug on the breastfed infant, or the 

effects of the drug on milk production. When administered to lactating 

rats, drugname was present in milk (see Data). Because of the 

potential for (1) HIV transmission (in HIV-negative infants), (2) 

developing viral resistance (in HIV-positive infants) and (3) serious 

adverse reactions in a breastfed infant, instruct mothers not to 

breastfeed if they are receiving TRADENAME. 
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Content Considerations (3)

8.3 Females and Males of Reproductive Potential

• Use the following headings as required 

– Pregnancy Testing

o Intent is to determine the woman’s pregnancy status in time to prevent 

or minimize embryo/fetal exposure to a drug with embryo-fetal toxicity. 

o Section 2 Dosage and Administration should identify any specific safety 

monitoring procedures that should be implemented before initiating 

therapy (i.e., the need to test to rule out pregnancy).

– Contraception

o Intent is to prevent embryo/fetal exposure.

– Infertility 

• If there is embryo-fetal toxicity that supports recommendations for pregnancy 

testing and contraception use, a Warning & Precaution is generally included

• If there are drug interactions that require the use of alternative contraception 

methods, these should be included under the heading Contraception and crossreferenced to Section 7 Drug Interactions
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Example of 8.3 Females and Males 

of Reproductive Potential (1)

• When there is embryofetotoxicity:

8 USE IN SPECIFIC POPULATIONS

...

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior 

to initiating TRADENAME treatment.

Contraception 

Females 

Based on its mechanism of action and animal data, TRADENAME can 

cause fetal harm when administered to a pregnant woman [see Use 

in Specific Populations (8.1)]. Advise females of reproductive 

potential to use effective contraception during treatment with 

TRADENAME and for at least X months after the last dose. 
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Example of 8.3 Females and Males of 

Reproductive Potential (2)

• When embryofetotoxic drug is present in semen:

8 USE IN SPECIFIC POPULATIONS

...

8.3 Females and Males of Reproductive Potential

Contraception 

Males

Drugname is present in semen [see Clinical Pharmacology (12.3)]. It is 

not known if the amount of drugname in semen can cause embryofetal harm. Advise male patients to use condoms, even after a 

vasectomy, to avoid potential drug exposure to pregnant partners and 

female partners of reproductive potential during treatment with 

TRADENAME and for at least X months after the last dose. Advise 

males not to donate semen during treatment with TRADENAME and 

for at least X months after the last dose.
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Example of 8.3 Females and Males 

of Reproductive Potential (3)

• When there are drug-contraceptive interactions

8 USE IN SPECIFIC POPULATIONS

...

8.3 Females and Males of Reproductive Potential

Contraception

Use of TRADENAME may reduce the efficacy of combined 

hormonal contraceptives. Advise patients using 

combined hormonal contraceptives to use an effective 

alternative contraceptive method or an additional barrier 

method of contraception [see Drug Interactions (7.3)]. 
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Example of 8.3 Females and Males of 

Reproductive Potential (4)

8 USE IN SPECIFIC POPULATIONS

...

8.3 Females and Males of Reproductive Potential

...

Infertility

Females

Based on findings from animal studies, female fertility may be 

compromised with TRADENAME [see Nonclinical Toxicology(13.1)].

Males

Based on animal studies, TRADENAME can lead to inhibition of 

spermatogenesis and may impair fertility in males of reproductive 

potential. The long-term effects of TRADENAME on male fertility 

have not been studied [see Nonclinical Toxicology (13.1)].
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Format Considerations

• Formatting of titles for headings and 

subheadings within subsections should be 

consistent throughout the labeling

• Combination products must address 

information known about each individual 

component, as well as the combined product
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Example of Subsection 8.1 Labeling 

for a Combination Product (1)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data with TRADENAME, 

component1 or component2 in pregnant women to 

inform a drug associated risk for adverse developmental 

outcomes. There are clinical considerations of risks [from 

the underlying disease] in pregnancy (see Clinical 

Considerations).

For component1 , rats and rabbits were exposed in 

animal reproduction studies at X times (rat) and X times 

(rabbit) the human exposure of 0.75 U/kg/day. No 

adverse outcomes were observed for pregnant animals and 

offspring (see Data).
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Example of Subsection 8.1 Labeling 

for a Combination Product (2)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

For component2, animal reproduction studies identified 

increased adverse developmental outcomes from exposure 

during pregnancy. Component2 exposure was associated with 

. . . some fetal abnormalities in pregnant rats administered 

component2 during organogenesis at doses that approximate 

clinical exposures at the maximum recommended human 

dose (MRHD) of 1.8 mg/day. . .[see Data]. 

The estimated background risk of major birth defects for 

women . . .
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Example of Section 8.1 Labeling for 

a Combination Product (3)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Data

Animal Data 

Component1

Component1 was investigated in studies covering fertility, embryofetal development and pre- and post-natal development in rats 

and during the period of embryofetal development in rabbits. . . . 

Component2

Female rats given subcutaneous doses of 0.1, 0.25 and 1.0 

mg/kg/day component2 beginning 2 weeks before mating, during 

mating and the period of organogenesis, through gestation day 17 

had estimated systemic exposures 0.X, X, and XX-times the human 

exposure at the MRHD based on plasma AUC comparison. . . .
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Summary

– The submitted labeling should comply with PLLR requirements 

and be accompanied by a summary and review of the available 

relevant information/data

– Additional Recommendations:

– Refer to the Draft Guidance for Industry

– Refer to the Selected Requirements of Prescribing 

Information (SRPI)

– Review recent PLLR conversions, especially those in similar 

drug class or for similar patient population
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PLLR Resources

• Draft Guidance for Industry: Pregnancy, Lactation, and 

Reproductive Potential: Labeling for Human Prescription 

Drug and Biological Products — Content and Format 

http://www.fda.gov/downloads/drugs/guidancecomplianc

eregulatoryinformation/guidances/ucm425398.pdf

• Pregnancy and Lactation Labeling Final Rule 

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/

DevelopmentResources/Labeling/ucm093307.htm

• Physician’s Labeling Rule Requirements for Prescribing 

Information 

http://www.fda.gov/Drugs/GuidanceComplianceRegulato

ryInformation/LawsActsandRules/ucm084159.htm
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Where to find product labeling 

and other resources

• Drugs @FDA 

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/in

dex.cfm

• Daily Med (National Library of Medicine)

http://dailymed.nlm.nih.gov/dailymed/about.cfm

• LactMed (National Library of Medicine) 

http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

• CDC (Centers for Disease Control) 

http://www.cdc.gov/pregnancy/meds/index.html

• FDA Office of Women’s Health Pregnancy Registry Website 

https://www.fda.gov/ScienceResearch/SpecialTopics/Wom

ensHealthResearch/ucm251314.htm
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THANK YOU