New FDA Pregnancy Categories Update 2020

Introduction

Pregnancy and Medication Use

• Six million pregnancies in US every year

• 50% of pregnant women reported taking at least one medication

• Pregnant women take an average of 2.6 medications at any time during pregnancy

• First trimester use of prescription medications has increased by more than 60%

• Use of 4 or more medications in the first trimester has tripled (9.9% to 27.6%)

The Food and Drug Administration (FDA) is proposing to amend its regulations concerning the format and content of the ‘‘Pregnancy’’, ‘‘Labor and delivery’’, and ‘‘Nursing mothers’’ subsections of the ‘‘Use in Specific Populations’’ section of the labeling for human prescription drug and biological products. The agency is proposing to require that labeling include a summary of the risks of using a drug during pregnancy and lactation and a discussion of the data supporting that summary. The labeling would also include relevant clinical information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy and/or lactation. The proposal would eliminate the current pregnancy categories A, B, C, D, and X. The ‘‘Labor and delivery’’ subsection would be eliminated because information on labor and delivery is included in the proposed ‘‘Pregnancy’’ subsection. The proposed rule is intended to create a consistent format for providing information about the effects of a drug on pregnancy and lactation that will be useful for decision making by women of childbearing age and d their health care providers.

Update 2020

In 2015 the FDA replaced the former pregnancy risk letter categories (see below) on prescription and biological drug labeling with new information to make them more meaningful to both patients and healthcare providers. The FDA received comments that the old five-letter system left patients and providers ill-informed and resulted in false assumptions about the actual meaning of the letters. The Pregnancy and Lactation Labeling Final Rule (PLLR) went into effect on June 30, 2015; however, the timelines for implementing this new information on drug labels (also known as the package insert) is variable. Prescription drugs submitted for FDA approval after June 30, 2015 will use the new format immediately, while labeling for prescription drugs approved on or after June 30, 2001 will be phased in gradually. The PLLR removes pregnancy letter categories – A, B, C, D and X. 

The Problem with Letters

• Pregnancy letter category system was overly simplistic

• Misinterpreted as a grading system

• A drug with adverse information in animals could be labeled as the same category as a drug with no animal information

– Example: Pregnancy Category C

– Animal reproduction studies have shown an adverse effect on the fetus, there are no AWC studies in humans, BUT the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks

– Studies in pregnant women and animals are not available

Intent of PLLR

• Provide the prescriber with relevant information for critical decision-making when treating pregnant or lactating women

• More complete statement of the known risks based on the available data

• Considerations of medical/disease factors

• Animal data put in context of human exposure

• Human data added when available

• Explicitly states when no data are available

The PLLR also requires the label to be updated when information becomes outdated. Below is a comparison of the current prescription drug labeling with the new PLLR labeling requirements.

8.1 Pregnancy

• Four headings

– Pregnancy Exposure Registry

– Risk Summary*

– Clinical Considerations

– Data

*Required heading

 8.1 Pregnancy- Pregnancy Exposure Registry

• Pregnancy Exposure Registry

“There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRADENAME during pregnancy.”

• Includes specific contact information

– Phone #

– Website

 8.1 Pregnancy- Risk Summary*

• No drug systemic absorption

“[TRADENAME] is not absorbed systemically

following (route of administration) and maternal use is not expected to result in fetal exposure to the drug.”

*Required heading(s)

8.1 Pregnancy- Risk Summary*

• Drugs with systemic absorption

– When use of a drug is contraindicated during pregnancy, that information must be stated first in the Risk Summary

– Risk statement based on human data*

– Risk statement based on animal data*

– Risk statement based on pharmacology

– Background risk information in general population*

– Background risk information in disease population

*Required

Example:

8.1 Pregnancy – Risk Summary - Risk Based on Animal Data

Risk Summary

There are no adequate and well-controlled studies of [TRADENAME] in pregnant women. The limited available information on [TRADENAME] use during pregnancy is not sufficient to inform a drug-associated risk of major birth defects or miscarriage. In animal reproduction studies, oral administration of [drug name] to pregnant rats and rabbits during the period of organogenesis at doses up to 40 and 20 times the maximum recommended human dose (MRHD), respectively, resulted in decreased fetal body weight gain and delayed skeletal ossification but no teratogenic effects were observed. Decreased fetal body weight and delayed skeletal ossification were not observed at doses up to 10 and 5 times the MRHD in rats and rabbits, respectively [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively.

 8.1 Pregnancy- Clinical Considerations

• Clinical Considerations (five optional subheadings)

– Disease-Associated Maternal and/or Embryo/Fetal Risk

– Dose Adjustments During Pregnancy and the Post- Partum Period

– Maternal Adverse Reactions

– Fetal/Neonatal Adverse Reactions

– Labor or Delivery

 • Data

 8.1 Pregnancy- Data

 – Detailed description of the data that provide the scientific basis for the summary information presented in the Risk Summary and Clinical Considerations headings

– The applicant provides to the Agency a comprehensive review of relevant published literature, their pharmacovigilance database, and pregnancy exposure registry (if applicable) to support updated language for this section of labeling.

– Sections

• Human Data

• Animal Data

 8.2 Lactation

• Three headings:

– Risk Summary*

– Clinical Considerations

– Data

*Required heading

 8.2 Lactation- Risk Summary*

• No drug systemic absorption

“[TRADENAME] is not absorbed systemically by the mother following (route of administration) and breastfeeding is not expected to result in exposure of the infant to [drug name].”

*Required heading

 8.2 Lactation – Risk Summary

• Systemic drug absorption

– Presence of drug in milk*

• Concentration in milk

• Actual or estimated infant daily dose

– Effects of drug on the breastfed infant*

– Effects of the drug on milk production*

– Risk/Benefit Statement

8.2 Lactation –

Clinical Considerations and Data

• Clinical Considerations

– Minimizing exposure to the breastfed infant

– Monitoring the breastfed infant for Adverse Reactions

• Data - Include only when information are available

– The applicant will provide a comprehensive review of published literature and their pharmacovigilance database to update this section.

– Description of clinical lactation study/data

– Description of animal lactation study (only if there are no human data)

 

8.3 Females and Males of Reproductive Potential

• Include when there are requirements or recommendations for pregnancy testing and/or contraception and/or when human and/or animal data suggest drug effects on fertility

• Three headings

– Pregnancy Testing

– Contraception

– Infertility

 

8.3 Females and Males

of Reproductive Potential

• Dedicated labeling section consolidates information from other areas of labeling

– Moves recommendations for contraception and pregnancy testing from section 8.1, Pregnancy and section 13, Nonclinical Toxicology

– Moves human fertility study descriptions and infertility considerations from section 13, Nonclinical Toxicology

– Animal fertility study descriptions remain in section 13, Nonclinical Toxicology

 

Example:

8.3 Females and Males of Reproductive Potential

Based on its mechanism of action, TRADENAME can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Female patients of reproductive potential should have a negative pregnancy test …

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment and for at least 2 weeks after the last dose of TRADENAME. Advise patients that TRADENAME can reduce the effectiveness of oral contraceptives and to use alternative effective contraception during treatment with TRADENAME [see Warnings and Precautions (5.x), Drug Interactions (7.x), Clinical Pharmacology (12.x)].

Infertility

Females

Decreased fertility and ovarian toxicity were observed in female rats treated with DRUGNAME. Advise female patients of reproductive potential …

Males

Effects on spermatogenesis have been observed in animals treated with DRUGNAME. Advise male patients of the potential risk…

PLLR Summary

• PLLR implementation is a gradual process that will take another 2 to 4 years.

• ALL prescription drug labeling will be required to remove pregnancy letter categories.

• PLLR provides clearer communication of available data to assist the prescriber with critical decision-making when treating pregnant or lactating women

• PLLR notes when there is no available data

PLLR – Changes to Labeling

*Required heading. See draft guidance: Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products- Content and Format.

Conclusion

The PLLR provides a more structured approach to labeling to help more clearly describe available data that can be used to aid in complex risk/benefit discussions between prescribers and their patients.

PLLR includes required statements when data are not available. Hopefully, all stakeholders will work together to proactively seek information to fill the gaps.

The former pregnancy categories, which still may be found in some package inserts, were as follows:

Category A

Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).

Category B

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Category C

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Category D

There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Category X

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Reference :

https://www.fda.gov/media/100406/download