CDER Prescription Drug Labeling Conference

December 4th and 5th 2019

The Pregnancy and Lactation Labeling Rule (PLLR): 

Four Years In- What’s Next?

Kristie Baisden, DO and Miriam Dinatale, DO

Division of Pediatric and Maternal Health

Office of Drug Evaluation 4/Office of New Drugs/CDER

December 4, 2019
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Disclaimer

• The views and opinions expressed in this presentation represent 

those of the speaker, 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.

www.fda.gov
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Learning Objectives

• To discuss the Agency’s key considerations for PLLR labeling 

conversion, including omission of clearly inapplicable or 

misleading information, and when to include labeling 

recommendations for pregnancy testing, contraception and 

infertility. 

• To discuss recently published guidances and the steps that the 

Agency is taking to increase research specific to pregnant and 

lactating women.

www.fda.gov
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Outline

• Introduction

• PLLR Implementation and Tracking 

• Submission of PLLR Compliant Labeling

• PLLR Content Considerations 

• New Guidances

• Efforts to Advance Research in Pregnant and Lactating Women

www.fda.gov
Introduction
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Division of Pediatric and Maternal Health (DPMH)

• Located within Office of New Drugs/Center for Drug Evaluation 

and Research(CDER)/FDA 

• Comprised of Maternal Health Team, Pediatrics Team, and 

Pediatrics Regulatory Team

• DPMH oversees quality initiatives which promote and necessitate 

the study of drug and biological products in the pediatric 

population and improve pregnancy and lactation-related 

information in prescription drug labeling.

www.fda.gov
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DPMH’s Role with PLLR

• To provide consultation to CDER and Center for Biologics 

Evaluation and Research (CBER) review divisions in issues related 

to maternal health, including pregnancy and lactation.

• To collaborate within the Agency for consistency of process 

(including revision of the draft PLLR guidance).

• To track the drug product labeling compliance with PLLR.

• To raise awareness of PLLR amongst external and internal 

stakeholders.

www.fda.gov
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PLLR Implementation

www.fda.gov
PLLR Implementation

ww

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w.fda.gov
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Tracking PLLR Converted Labeling*

• Between June 30, 2015 and June 30, 2019, >1300 applications 

approved with labeling that complies with PLLR 

• 2018 cohort: 

– ~294 were required to comply with PLLR format and content 

requirements

– 286 applications were submitted to comply with PLLR

• 208 applications were approved in PLLR format

• 78 applications are under review

– 8 applications were not submitted

*Applications (including NDA, BLA, and Efficacy Supplements) approved on or after June 30, 2001 required to comply with PLLR 

www.fda.gov
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Tracking PLLR Converted Labeling

• 2019 cohort: 

– ~730 applications were required to comply with PLLR format and 

content requirements

– 620 applications were submitted to comply with PLLR

• 335 applications were approved in PLLR format 

• 2020 cohort:

– ~367 are anticipated

www.fda.gov
Submission 

of PLLR Compliant Labeling
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PLLR Labeling Submission 

• Include labeling that complies with the PLLR content and format

• Include a review and summary of all available published literature regarding the drug 

and use in pregnant and lactating women and effects on male and female fertility

• Include a cumulative review and summary of relevant cases reported to your 

pharmacovigilance database (from the time of product development to present)

• Include a summary of drug utilization rates amongst females of reproductive potential 

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

• Include an interim report of an ongoing pregnancy registry or a final report on a closed 

pregnancy registry (if applicable)

• Include the updated PLLR labeling and supportive information in Module 1 of the 

submission

www.fda.gov
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Recommendation for Submission 

of PLLR Compliant Labeling

• Applicants should also review and update other sections of 

labeling pertinent to the PLLR (e.g., DOSAGE AND 

ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND 

PRECAUTIONS, CLINICAL PHARMACOLOGY, PATIENT COUNSELING 

INFORMATION) and Patient Labeling as necessary when updating 

the labeling to the PLLR format. 

www.fda.gov
PLLR Content Considerations
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Omissions*

• In some circumstances, applicants must omit certain subsections 

or specific information otherwise required under the PLLR 

because it is clearly inapplicable or misleading. 

• The applicant should provide the rationale and justification for 

any proposed PLLR labeling omissions. 

*[21 CFR 201.56(a)(2) and 21 CFR 201.56(d)(3)]

www.fda.gov
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PLLR Omissions Example

• TRADENAME is a surfactant indicated for the rescue 

treatment, including the reduction of mortality and 

pneumothoraces, of Respiratory Distress Syndrome 

(RDS) in premature infants

• 8.1 Pregnancy and 8.2 Lactation were omitted from 

labeling because the information is clearly 

inapplicable.

www.fda.gov
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8.1 Pregnancy, Risk Summary

• Risk statement based on human data

• Determining whether pregnancy exposure data establish a drugassociated risk is a complex process that requires an assessment of the 

quality and quantity of available data. 

• Helps the prescriber to understand the benefit/risk of the drug

• The types of available data should be specified (e.g., pregnancy registry, 

cohort, case-control, case series, case reports, etc.).

• The focus is on evaluating the safety of drug use during pregnancy.

www.fda.gov
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8.1 Pregnancy, Risk Summary

• Risk statement based on animal data

• There are multiple considerations when determining potential human 

risks from animal data

• Does the adverse developmental outcome occur in more than one animal 

species?

• Is the adverse developmental outcome consistent across animal species?

• What is the relative animal to human exposure?

• Does the adverse developmental outcome occur in the absence of maternal 

toxicity?

• Are there positive signals in other drugs of the same class or with the same 

mechanism of action?

www.fda.gov
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8.1 Pregnancy, Risk Summary

• Risk statement based on pharmacology*

• When a drug has a well-understood pharmacologic mechanism of 

action that may result in adverse developmental outcomes, the Risk 

Summary must explain the mechanism of action and potential 

associated risks.

• A cross-reference should be provided to CLINICAL PHARMACOLOGY, 

where the pharmacologic data on which this Risk Summary is based are 

more fully described.

www.fda.gov

*21 CFR 201.57(c)(9)(i)(B)(3)).
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8.1 Pregnancy, Risk Summary-Example

8 USE IN SPECIFIC POPULATIONS 

8.1 Pregnancy 

Risk Summary 

Based on findings from animal studies and its mechanism of action [see Clinical 

Pharmacology (12.1)], TRADENAME can cause fetal harm when administered to a 

pregnant woman. Available human data are insufficient to inform the drug- associated risk of major birth defects, miscarriage, or adverse maternal or fetal 

outcomes. In animal reproduction studies in mice and rabbits, embryo and fetal 

toxicity were observed with administration of drug name at doses approximately 

0.33 and 0.18 times the human therapeutic dose, respectively (see Data). Advise 

pregnant women of the potential risk to a fetus.

www.fda.gov
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8.2 Lactation, Risk Summary*

• For drugs absorbed systemically by the mother, unless breastfeeding is 

contraindicated during drug therapy, the labeling under the Risk Summary 

heading must include the following risk and benefit statement at the end of the 

labeling under the Risk Summary heading: 

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 breastfed child from (name of drug) 

or from the underlying maternal condition.

www.fda.gov

*21 CFR 201.57(c)(9)(ii)(A)(3)]
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8.2 Lactation, Risk Summary

• When the drug is not contraindicated for use in breastfeeding 

women, but breastfeeding is not recommended during drug use 

because of the potential risk to the breastfed child (e.g., cytotoxic 

drugs), the labeling should include a statement describing the 

reason(s) to avoid breastfeeding. 

– Additionally, if breastfeeding is not recommended (e.g., cytotoxic drugs), the 

risk and benefit statement should be omitted because including such a 

statement may be misleading. 

• When human data are available, animal data must not be included 

unless the animal model is specifically known to be predictive for 

humans.*

www.fda.gov

*21 CFR 201.56(d)(4) and 21 CFR 201.56(a)(2)] 
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8.3 Females and Males of 

Reproductive Potential

• Pregnancy Testing

• Contraception

• Infertility

www.fda.gov
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8.3 Females and Males of 

Reproductive Potential, Pregnancy Testing*

• When FDA has determined that pregnancy testing is required 

or recommended, the labeling under the Pregnancy Testing 

heading must include this information. 

• Timing and frequency of pregnancy testing and the type of 

pregnancy test used should be individualized to the patient. 

• A statement regarding pregnancy testing should also be 

added to other sections of labeling, as applicable (e.g., 

DOSAGE AND ADMINISTRATION). 

www.fda.gov

*21 CFR 201.57(c)(9)(iii)
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8.3 Females and Males of 

Reproductive Potential, Contraception*

• When FDA has determined that contraception is required or 

recommended before, during, or after drug therapy for the 

appropriate use of a drug with potential risk of adverse 

developmental outcomes, the Contraception heading must 

include this information. 

• This information should also be included in other sections of 

labeling (e.g., PATIENT COUNSELING INFORMATION)

www.fda.gov

*21 CFR 201.57(c)(9)(iii)
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8.3 Females and Males of 

Reproductive Potential, Contraception*

• If data from nonclinical studies or mechanism of action raise 

concerns about mutagenesis

• A summary of this information and its clinical implications must appear under 

the Contraception heading. 

• When pertinent, a cross-reference to the NONCLINICAL TOXICOLOGY section 

should be included for a detailed discussion of the nonclinical studies. 

• If data from the nonclinical studies do not raise concern with respect 

to mutagenesis

• Information should be described only in the NONCLINICAL TOXICOLOGY 

section. 

www.fda.gov

*21 CFR 201.57(c)(9)(iii)
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8.3 Females and Males of 

Reproductive Potential, Contraception*

• If there are pharmacokinetic studies of semen that inform the 

need for contraception recommendations, 

• A summary statement of pertinent findings and recommendations 

should be included under the Contraception heading

• There should be a cross-reference to the Pharmacokinetics subsection 

of the CLINICAL PHARMACOLOGY section for a more detailed study 

description.

www.fda.gov

*21 CFR 201.57(c)(9)(iii)
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8.3 Females and Males of 

Reproductive Potential, Contraception*

• If there is an interaction between the drug and hormonal 

contraception, a summary statement concerning the interaction 

and a recommendation to use a nonhormonal or additional 

method of contraception could be included.

– A cross-reference to the DRUG INTERACTIONS section (and, if 

applicable, to other relevant sections of labeling) should be included for 

a more detailed description of the interaction

www.fda.gov

*21 CFR 201.57(c)(9)(iii)
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8.3 Females and Males of 

Reproductive Potential, Infertility*

• Describe the availability of human data that demonstrate adverse 

effects on male or female fertility

• Include a description of what is known about the potential 

reversibility of the adverse effect(s). 

• If there are no available human fertility data, then no statement 

is needed. 

www.fda.gov

*21 CFR 201.57(c)(9)(iii)
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8.3 Females and Males of 

Reproductive Potential, Infertility*

• If data from animal studies or mechanism of action raises concerns 

aboutimpairment of human fertility,

– Include a summary of this information and its clinical implications under the 

Infertility heading. 

– When pertinent, cross-reference to the NONCLINICAL TOXICOLOGY section 

for a detailed discussion of the animal studies. 

• If data from the animal studies do not raise concerns with respect to 

impairment of human fertility,

– Information should be described only in subsection 13.1 Carcinogenesis, 

Mutagenesis, Impairment of Fertility. 

www.fda.gov

*21 CFR 201.57(c)(9)(iii)
What’s Next?
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PLLR Research 

• Project: “PLLR End User Testing to Improve Health Communications”

• Aims:

-Identify gaps in HCP understanding of the PLLR content in labeling to 

improve risk communication between HCP and pregnant women.

-Develop approaches for the presentation of pregnancy information 

in labeling (e.g., graphical representations) to improve risk 

communication. 

www.fda.gov
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New Guidances
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• Published May 9, 2019 • Replaces 2002 Pregnancy Registry Guidance • Reflects recommendations from 

2014 FDA public meeting of 

stakeholders on how to best collect 

safety data in pregnant women 

after a drug is approved

• Guidance available at: 

https://www.fda.gov/regulatory- information/search-fda-guidance

- documents/postapproval- pregnancy-safety-studies-guidance

- industry

www.fda.gov
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Highlights of Draft Guidance

• Expands on previous pregnancy registry guidance to also include 

other types of epidemiologic studies (e.g., electronic healthcare 

data studies) and pregnancy surveillance programs.

• Describes three general approaches used in postmarketing 

setting to evaluate drug or biological product safety during 

pregnancy

– Pharmacovigilance

– Pregnancy registries

– Complementary data sources

www.fda.gov
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• Published May 9, 2019 • Replaces draft guidance published in 2005 • This guidance provides information to facilitate 

the conduct of lactation studies. Such studies can 

inform breastfeeding with drug use 

recommendations included in the Lactation 

subsection of labeling

• Guidance available at: 

https://www.fda.gov/regulatory-

information/search-fda-guidance-

documents/clinical-lactation-studies-

considerations-study-design

www.fda.gov
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Highlights of Draft Guidance

• Describes specific study designs that can be considered (e.g., milk 

only study; milk/plasma study; mother-infant pair study)

• Clinical pharmacology considerations

– Milk sampling methods

– Pharmacokinetic analyses

– Calculation of estimates of infant dosage

• Infant safety considerations

www.fda.gov
Efforts to Advance Research in Pregnant and 

Lactating Women
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Task Force on Research Specific to Pregnant 

and Lactating Women (PRGLAC)

• Required under the 21st Century Cures Act of 2016

• Objectives: Identify and address gaps in knowledge and research 

regarding safe and effective therapies for pregnant women and 

lactating women

• Phase I: PRGLAC Task Force prepared a report of 15 

recommendations to the Secretary of the Department of Health 

and Human Services (completed September 2018)

www.fda.gov
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Task Force on Research Specific to Pregnant 

and Lactating Women (PRGLAC)

• Phase II: HHS reauthorized PRGLAC Task Force to continue work 

on implementation of recommendations (Task Force charter 

extended to 3/2021)

– FDA representation on the PRGLAC Task Force, including representatives 

from DPMH

– Four working groups (Research/Training, Regulatory, Communication 

and Discovery) were established to develop a plan for implement the 

recommendations

For more information, visit https://www.nichd.nih.gov/about/advisory/PRGLAC

www.fda.gov
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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/guidancecomplianceregulatoryinformation/guidanc

es/ucm425398.pdf

• Pregnancy and Lactation Labeling Final Rule 

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

g/ucm093307.htm

• Prescription Drug Labeling Resources

https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources

www.fda.gov
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Where to find product labeling 

and other resources

• FDALabel: Full-Text Search of Drug Labeling

https://www.fda.gov/scienceresearch/bioinformaticstools/

ucm289739.htm

• Drugs @FDA http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.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/WomensHealthResearch/ucm

251314.htm

www.fda.gov
Thank You
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Challenge Question 1

Question #1: True/False: In some circumstances certain 

subsections or specific information that is otherwise required 

under PLLR must be omitted because it is clearly inapplicable or 

misleading.

www.fda.gov
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Challenge Question 1

• Answer: True

www.fda.gov
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Challenge Question 2

Question #2: What are the main topics discussed in the Clinical 

Lactation Studies Guidance? 

A. Clinical lactation studies can inform breastfeeding with drug use 

recommendations included in the Lactation subsection of labeling 

B. It describes specific study designs that can be considered (e.g., milk only 

study; milk/plasma study; mother-infant pair study)

C. It describes clinical pharmacology considerations (milk sampling methods, 

pharmacokinetic analyses, calculation of estimates of infant dosage)

D. It describes infant safety considerations

E. All of the above

www.fda.gov
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Challenge Question 2

• Answer E: All of the above

www.fda.gov
Back-up Slides
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PRGLAC Recommendations

1. Include and integrate pregnant/lactating women in the clinical research agenda

2. Increase the quantity, quality, and timeliness of research involving therapeutic 

products used by pregnant/lactating women

3. Expand the workforce of clinicians and research investigators with expertise in 

obstetric and lactation pharmacology

4. Remove regulatory barriers to research in pregnant women

5. Create a public awareness campaign to engage the public and healthcare 

providers in research on pregnant/lactating women

6. Develop and implement evidence based communication strategies with health 

care providers on information relevant to research on pregnant/lactating women

www.fda.gov
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PRGLAC Recommendations

7. Develop programs to study products used off-patent in 

pregnant/lactating women using NIH Best Pharmaceuticals for 

Children Act as a model

8. Reduce liability to facilitate research in women who are or may 

become pregnant and in lactating women

9. Implement a proactive approach to protocol development and study 

design to include pregnant/lactating women in research

10.Develop programs to drive discovery/development of new 

therapeutics for conditions specific to pregnant/lactating women

www.fda.gov
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PRGLAC Recommendations

11.Utilize and improve existing resources for data to inform the 

evidence and provide a foundation for research on 

pregnant/lactating women

12.Leverage established and support new infrastructures/collaborations 

to perform research in pregnant/lactating women

13.Optimize registries for pregnancy and lactation

14.Extend the charter for the Taskforce (extended 3/2019 to 3/2021)

15.Establish an Advisory Committee to monitor and report on the 

implementation of the Taskforce recommendations (Deferred)

www.fda.gov