The New Labeling System, Pre- and Post-Marketing ...media-ns.mghcpd.org.s3.amazonaws.com/pllr2017/2017-pllr...The New Labeling System, Pre- and Post-Marketing Reproductive Pharmacovigilance,

The New Labeling System,

Pre- and Post-Marketing Reproductive Pharmacovigilance,

and Science

Leyla Sahin, MD, FACOG Division of Pediatric and Maternal Health

Center for Drug Evaluation and Research, Office of New Drugs US FDA

Pharmacovigilance, Reproductive Safety, and PLLR Meeting

4-28-2017

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I do not have any financial disclosures to report

Pharmacovigilance, Reproductive Safety, and PLLR Meeting April 28, 2017

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Objectives

• Overview of the New Labeling System

• Pre-and Post-Marketing Reproductive Pharmacovigilance

• Science

Pharmacovigilance, Reproductive Safety, and PLLR Meeting

April 28, 2017

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New Labeling System

The Pregnancy

and

Lactation

Labeling Rule (PLLR)


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Evidence Based ?


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Intent of the New Labeling System

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

• Focus on human data • 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 • States when no human data available


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Implementation schedule

• Pregnancy and Lactation Labeling Rule (PLLR) came into effect on June 30, 2015

• ALL prescription drugs will no longer have pregnancy letter categories by June 30, 2018

• All drugs approved since June 30, 2001 will be in the new format by June 30, 2020


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Comparison of New Labeling with Old Labeling


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New Format


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8.1 Pregnancy • Pregnancy Exposure Registry Contact Info

(if available)

• Risk Summary

– Narrative description of risk

– Background risk information

– Background risk information in disease population (if available)


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8.1 Pregnancy (continued)

• Clinical Considerations – Disease-associated risk

– Dose adjustments

– Maternal adverse reactions

– Fetal/neonatal adverse reactions

– Labor or delivery

• Data

– Human

– Animal


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New Format


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Example of Approved Lactation Labeling in the new format

Suboxone (buprenorphine-naloxone) 2-2017

Risk Summary

Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk and available data have not shown adverse reactions in breastfed infants. There are no data on the combination product buprenorphine/naloxone in breastfeeding, however oral absorption of naloxone is limited. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SUBOXONE sublingual film and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Clinical Considerations

Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.


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Suboxone (buprenorphine-naloxone) (continued) Data

Data were consistent from two studies (N=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose.

In a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight‐adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent).

Data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (Cavg) of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the study data, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight‐adjusted dose.


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PLLR Take-aways

• Human data will be added if it informs or changes the risk profile

• Need to communicate data in a factual way that is meaningful for the healthcare provider


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Pre and post marketing Pharmacovigilance;

Science


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Pre and post marketing Pharmacovigilance

• Need data to inform labeling – Pregnant women are mostly excluded from drug development

trials

– Data collection on safety in pregnancy are collected in the post marketing phase

• FDA Amendments Acts 2007 – Authority to require post-approval studies to assess serious risks

(risk of an adverse drug experience that results in a birth defect, death or risk of death, incapacity, hospitalization, or requires a medical or surgical intervention to prevent one of these outcomes)∗

– Pregnancy registries are the most common type of post-marketing requirement (PMR)/post-marketing commitment (PMC)


∗See FDA Guidance Postmarketing studies and clinical trials-Implementation of Section 505 (o) 3 of the FD&C Act

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Science

• Observational study methods are evolving

– Pregnancy registries are still the “gold standard”

– Complementary methods with different study designs

– Both have advantages and disadvantages


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Science • 2014 FDA Public Meeting

– Input from experts

– ACOG and all stakeholders emphasized the need for data

– FDA review of 59 products from 38 pregnancy registries listed on FDA Pregnancy Registry Webpage

• ½ of all registries were PMR/PMC

• Key messages from 2014 public meeting: – A combination of approaches overcome the limitations of

individual study designs and increase confidence in the findings

– Multi-product or disease based approaches have generally been more successful for collection of data and sustainability of the registry


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Example of multiproduct Pregnancy Registry- Antiretroviral Pregnancy Registry (APR)*


2016

Number of drugs included in the registry

53

Number of sponsors 27

Number of countries participating 70

Number of evaluable prospective cases 17,371

Number of 1st trimester exposures 8,227

U.S. reports 76.6%

*data from December 2016 APR Interim Report

21 Pharmacovigilance, Reproductive Safety, and PLLR Meeting April 28, 2017

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Summary

• The changes in the format and content of pregnancy and lactation labeling provide a more structured and informative approach to describe available data to inform prescribing and risk benefit decision making.

• Data are needed to populate labeling

• Data collection in pregnant women is a shared responsibility among all stakeholders


Documents

The New Labeling System, Pre- and Post-Marketing ...media-ns.mghcpd.org.s3.amazonaws.com/pllr2017/2017-pllr...The New Labeling System, Pre- and Post-Marketing Reproductive Pharmacovigilance,