Marion F. Gruber, Ph.D., Director

Office of Vaccines Research and Review

Center for Biologics Evaluation and Research

Food and Drug Administration

Examples of How Regulators Approach Maternal Immunization:

US Regulatory Perspective

September 25, 2012

Maternal Immunization: Challenges and Opportunities September 24 - 26, 2012

Les Pensières, Annecy, France

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Outline

• General Considerations

• Guidelines for Vaccinating Pregnant Women

• Labeling provisions

- Pregnancy subsection

- Proposed Pregnancy and Lactation Labeling Rule

• Post marketing initiatives to obtain safety data from immunization

during pregnancy

- VAMPPS (Vaccines and Medications in Pregnancy Surveillance

System)

- PRISM (Post-licensure Rapid Immunization Safety Monitoring)

- Pregnancy Registries

• Pre-licensure Clinical trials

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Maternal Immunization

• Important health benefits for mother and newborn infant

- Important disease prevention strategy (e.g., neonatal tetanus)

• Current US licensed vaccines are not labeled for use during pregnancy

- No adequate and well-controlled pre-licensure studies in pregnant

women to establish the safety and effectiveness of the vaccine as

required under 21 CFR 314.126

- Data from published literature often do not meet the bar of adequate

and well-controlled studies as described in 21 CFR 314.126

- Pregnant women are excluded from pre-licensure clinical trials,

because they are considered a vulnerable subject population and are

therefore not exposed to investigational biologics and drug products

However…

Vaccination programs frequently include pregnant women (e.g., influenza)

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Guidelines for Vaccinating Pregnant Women Modified after: Advisory Committee on Immunization Practices (ACIP)

CDC, July 2012

Hepatitis A May be used if benefits outweigh risks

Hepatitis B Recommended in some circumstances

Human Papillomavirus (HPV) Not recommended

Influenza (Inactivated) Recommended

MCV4, PCV 13, PPS23 Inadequate data for specific recommendation

Polio May be used if needed

Td Should be used if otherwise indicated

TdaP Recommended

Varicella, LAIV, MMR, Zoster Contraindicated

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Maternal Immunization with Inactivated Flu Vaccines:

Evidence from Published Literature

• Inactivated influenza vaccine is well tolerated in pregnant women with no

adverse effects on infant outcome

• Deinard et al., Am. J. Obstet. Gynecol.:1981;140:240 • Heinonen et al., Int J Epidemiol.:1973;2:229

• Murray et al., J. Clin. Microbiol.:1979;10:184 • Munoz, FM, et al., Am J Obstet Gynecol.:2005;192:1098

• Sumaya et al.,J . Inf. Dis.:1979;140:141 • Yeager et al., Am. J. Perinatol.:1999;16:283,

• Tamma et al, Am. J. Obstet. Gynecol.:2009;547 • Moro et al, Am. J. Obstet. Gynecol.:2011;146.e1

• Maternal antibodies to influenza vaccines are transmitted across the placenta

from the vaccinated mother to the fetus • Englund JA, et al. J Infect Dis.:1993;168:647 • Reuman PD, Pediatr Infect Dis J.:1987;6:398 • Naleway et al., Epidemiol Rev.:2006;28:47

• Immunization with influenza vaccine of pregnant women reduces influenza

illness in infants < 6 months old, e.g

• Zaman, K, et al., N. Engl. J. Med.:2008;359:1555

• Eick, A, et al., Arch. Ped. Adolesc. Med.:2011;165:104

• Poehling K, et al., Americ. J. Obst. Gynecol.:2011

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Recommendations for Use of Inactivated

Influenza Vaccine: ACIP and ACOG

• Vaccination with inactivated influenza vaccine is recommended by ACIP

for women who will be pregnant during the influenza season.

(2004: changed to any trimester)

• Inactivated influenza vaccination is considered an essential element of

prenatal care.

ACOG Committee Opinion, No. 305, Obst. Gynecol 104:1125-6,

2004

• Inactivated influenza vaccine is recommended for infants 6 months of age

and older.

• FDA supports ACIP recommendations that pregnant women receive

inactivated seasonal and pandemic flu vaccine.

Live attenuated influenza vaccine is not recommended for use in

pregnancy

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ACIP recommendation and FDA approved indication

• Vaccines recommended by ACIP when

pregnant women are at risk for serious

consequences from disease (e.g.

influenza).

- Risk for disease exposure is high

- Infection poses a special risk to mother

and fetus

- Vaccine unlikely to cause harm

• FDA approved indication is based on

adequate and well-controlled pre-

licensure safety and effectiveness studies

• ACIP recommendations and FDA

approved indication based on different

considerations

• Example: Fluarix

- No prelicensure safety and

effectiveness studies

- Fluarix label “Safety and

effectiveness have not been

established in pregnant women”

- Pregnancy category B “…Fluarix

should be given to a pregnant

women only if clearly needed.”

- Inactivated influenza vaccines

are recommended during all

stages of pregnancy

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Applicable US Laws Pertaining to Vaccines

Section 351 of the Public Health Service Act

• Approval of vaccines if data show that the product is safe, pure and

potent

• Only those vaccines that are demonstrated to be safe and effective will

be licensed by the FDA

21 CFR 56/57

• Labeling provisions require that prescribing information must summarize

essential information needed for safe & effective use

• For biological products, indications listed must be supported by

substantial evidence of effectiveness

• No implied indications or uses

• Labeling must not contain false or misleading claims

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Pregnancy Subsection of Product Labeling for US licensed Vaccines

• Requirements for pregnancy, labor and delivery, and nursing mothers labeling first described in 1979 (21 CFR 201.57)

(44 Federal Register 37434; 6/26/1979)

• A drug's pregnancy category is identified at the beginning of its pregnancy

labeling subsection

• Regulation require that each product be classified under one of five pregnancy categories (A, B, C, D, or X)

A: Controlled studies in humans

B: Human data reassuring (animal positive) OR animal studies show no risk and no human data (i.e., adequate and well-controlled studies)

C: No human data (i.e., adequate and well-controlled studies); animal studies positive OR not done

D: Human data show risk, benefit may outweigh risk

X: Animal or human data positive

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Pregnancy Subsection of Product Labeling for US licensed Vaccines

• Prescribing information for US licensed vaccines (with some exceptions)

carry either

Category B (no human data & animal data reassuring)

Category C (no human data & no animal data)

21 CFR 201.57(c)(9)(i)

• Category B & C allow vaccination of pregnant women if the benefits

from the use of the vaccine in pregnant women may be acceptable

despite its potential risk and there is determination that the vaccine is

clearly needed

• Most US licensed vaccines not contraindicated for use in pregnant

women

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Limitations of Current Pregnancy Categories

• Labeling language that accompanies the letter categories is prescribed by

regulation

Ex. FLUARIX (Category B)

"Because animal reproduction studies are not always predictive of

human response, FLUARIX should be given to a pregnant woman

only if clearly needed."

• Categories are seen as a grading system where risk increases from

A→B →C →D →X

• Do not distinguish between the types of supporting data (non-clinical vs.

clinical)

• Do not adequately address inadvertent exposure

• Heavily relied on by clinicians but often misinterpreted

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Pregnancy Lactation and Labeling Proposed Rule (May 29, 2008)

• Revises the content and format of pregnancy and nursing mothers

labeling subsections for prescription drugs and biologicals to

- Remove letter categories

- Include a narrative summary of the risks of using a drug during pregnancy and lactation

- Based on human and animal data

- Include a discussion of the data supporting that summary

- Inclusion of relevant clinical information to help health care

professionals advise women about the use of drugs during pregnancy

and lactation

• Proposed rule seeks to make drug labeling a better communication tool

in order to present the scientific information available for each drug and

biological

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Comparison: Current vs Proposed Pregnancy Section

8.1 Pregnancy

(A) Teratogenic effects

Pregnancy Category A, B, C, D, or X

(B) Nonteratogenic effects

8.2 Labor and Delivery

8.3 Nursing Mothers

8.1 Pregnancy

Pregnancy Exposure Registry

Risk Summary

Clinical Considerations

Data

8.2 Lactation

Risk Summary

Clinical Considerations

Data

8.3 Females and Males of Reproductive Potential

Current Format of Pregnancy Labeling Proposed Rule for Pregnancy and Lactation

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Proposed Rule: Required Labeling Elements

8.1 Pregnancy

• Pregnancy Exposure Registry Contact Info

• Risk Summary

Human data*

Animal data

• Clinical considerations

Inadvertent exposure

Prescribing decisions

Labor and delivery

• Data

Human

Animal

*Human data may come from clinical trials,

pregnancy exposure registries, other large scale epidemiologic studies, or case series reporting a rare event

8.2 Lactation

• Risk summary

Effects on milk production

Presence of drug in milk

Adverse effects in breast-fed

child

• Clinical considerations

• Data

The proposed rule is in the process of

being finalized.

Comments from stakeholders have

been addressed and guidance will be

provided on how to implement this

rule when in effect.

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US licensed Vaccines:

Considerations

• From a public health perspective, studies in pregnant women to

evaluate the safety, immunogenicity & effectiveness of US

licensed vaccines in current use and recommended by ACIP are

important to obtain additional information with regard to:

Pregnancy outcomes

Immunogenicity in mother/infants

Effectiveness in mother/infants

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Studies with Preventive Vaccines in Pregnant Women

Postmarketing studies in pregnant Women

Commonly used approach since

Data from nonclinical studies available

Safety data from non-pregnant women enrolled in premarketing

trials available

Some data from pregnant women inadvertently immunized during

premarketing trials may be available

Supportive data from published literature

Premarketing

Phase 1 Phase 2 Phase 3 Licensing

Phase 4

Postmarketing

FDA Postmarketing Surveillance Systems • VAERS

• National vaccine passive safety surveillance program co-sponsored by CDC and FDA

• Collects information about adverse events that may occur after the administration of vaccines licensed for use in the US

• FDA Sentinel Initiative/Mini-Sentinel

• Active surveillance system that uses electronic healthcare data from multiple sources to actively monitor the safety of medical products continuously and in real time

• PRISM (Post-licensure rapid immunization safety monitoring)

• A new national system for active vaccine safety surveillance within Mini-Sentinel.

• Addresses key gaps in existing vaccine safety monitoring capabilities in the United States by assembling a nation-wide surveillance population with very large size and statistical power, and by capturing data from sources outside traditional health care systems

• Pregnancy exposure registries

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FDA Postmarketing Initiatives to Obtain Safety Data Following Use of Influenza Vaccines in Pregnancy

• Development of innovative systems for evaluating vaccine safety in

pregnancy, e.g.,

FDA/CBER is launching a project to evaluate the ability to conduct

surveillance for pregnancy outcomes after vaccination in the Post-

licensure Rapid Immunization Safety Monitoring (PRISM) program

as part of the FDA's Sentinel Initiative

• Pregnancy Registries, e.g., prospective cohort studies

FDA Guidance for Industry: “Establishing Pregnancy Registries”

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Post-licensure Rapid Immunization Safety

Monitoring (PRISM) program

• PRISM is the Mini-Sentinel program

dedicated to vaccine safety

• PRISM is the largest active

surveillance system worldwide with

more than 100 million individuals

under surveillance

• Claims-based system with access to

medical records to validate

exposures and outcomes

• Started during the 2009 H1N1

influenza pandemic

• Integrated into Mini-Sentinel in 2010

• More than 20 active vaccine safety

projects

• Mini-Sentinel’s PRISM program has 2

initiatives aimed at improving

postlicensure safety surveillance for

vaccines among pregnancy women.

• Infrastructure building activity

• Methods development project

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Post-licensure Rapid Immunization Safety

Monitoring (PRISM) program

• Overall PRISM Goal with regard to maternal immunization: enable

observational retrospective safety studies to be conducted for

pregnancy safety

• Will develop new data linkages between Mini-Sentinel distributed

database and state-based birth certificate registries and fetal death

registries

• Will create new electronic algorithms to identify infant-mother pairs to

assess maternal exposure with birth outcomes

• Will enhance capture of timing of vaccine exposure, pregnancy

outcomes of interest, and key confounders (i.e. smoking, multivitamin

use, drug and alcohol abuse, etc.)

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Example of Vaccine Safety Program under PRISM Maternal Immunization with Influenza Vaccine

• FDA is also supporting the evaluation and development of new

epidemiologic study designs to analyze pregnancy safety (e.g. case-

time-control methods).

• One evaluation will analyze cleft-lip and palate.

• Second evaluation will analyze spontaneous abortions.

• Both are designed to test the methods for assessing these pregnancy

outcomes (and not to follow up any particular safety signal after

influenza vaccination).

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Pregnancy Registries

• The goal of pregnancy exposure registries is to provide clinically

relevant human data that can be used in a product’s labeling to provide

medical care providers with useful information for treating or counseling

patients who are pregnant or anticipating pregnancy.

• FDA believes that pregnancy registries are an important mechanism for

the collection of clinically relevant data concerning the effects of

exposure to drugs during pregnancy.

• Under the proposed Pregnancy and Lactation labeling rule, FDA is

requiring that the pregnancy subsection of prescription drug labeling

include contact information necessary to enroll in a pregnancy exposure

registry if one exists for the drug or biological product.

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Examples of Routinely Recommended Vaccines with Pregnancy Registries

* contraindicated for use in pregnancy women

Vaccine Pregnancy Category Pregnancy Registry

Human Papilloma-

virus vaccines

B Yes

Inactivated influenza

vaccines

B or C Some

Meningococcal

conjugate vaccines

C Yes

TdaP C Yes

Varicella* C Yes

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Postmarketing Initiatives to obtain Safety Data Ex.: Use of Influenza Vaccines in Pregnancy

Vaccines & Medications in Pregnancy Surveillance System (VAMPSS)

• 5 year post-marketing surveillance conducted by OTIS, AAAAI &

SEC consisting of 2 study designs to enhance pregnancy

surveillance

Prospective, observational study (OTIS)

Retrospective case-control study (SEC)

• Both methods are strengthened by source record validation, patient

interviews to collect key confounder data, and the availability of

internal comparison groups

Schatz et al, AJOG (2011) “Safety of influenza immunizations and treatment during

pregnancy: the Vaccines and Medications in Pregnancy Surveillance System”

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Postmarketing Initiatives to Obtain Safety Data Ex.: Use of Influenza Vaccines in Pregnancy

• CBER continues to support VAMPSS and has encouraged

manufacturers to consider this novel system to meet their pregnancy

safety surveillance needs

• Key examples of ongoing VAMPSS studies for pregnancy safety

- 2009 H1N1 influenza vaccine and antiviral medications

• To monitor and evaluate the fetal and maternal risks with

respect to H1N1 vaccine, seasonal influenza vaccines and

antiviral medications

• Identify specific pregnancy outcomes following exposure of

pregnant women to influenza vaccine

- CSL’s Afluria trivalent influenza vaccine

- Novartis’s Menveo meningitis vaccine

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Postmarketing Initiatives to obtain Safety Data Following Use of Vaccines in Pregnancy

• FDA has determined that safety data from well-designed post-licensure

studies evaluating vaccines in pregnant women (such as

epidemiological studies) may be included in product labeling (i.e.

prescribing information) provided that

FDA has access to primary data

FDA conducts its own review & analysis of data

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Studies with Preventive Vaccines

in Pregnant Women

Premarketing studies in pregnant Women

• An evaluation of safety and effectiveness of the particular vaccine in

clinical maternal immunization trials to include data in product labeling

Investigational vaccines (e.g., GBS)

Currently licensed vaccines (e.g., influenza)

• Maternal immunization studies in pregnant women to obtain a labeled indication

Premarketing Postmarketing

Phase 1 Phase 2 Phase 3 Licensing

Phase 4

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Maternal Immunization Studies

Safety Considerations & Evaluations

• Product safety should be tested directly in mother/infants

AE monitoring in mother (local/systemic)

Pregnancy outcomes, perinatal events

Postnatal events (infant growth & development)

Infant immune response to vaccination

Potential for unexpected clinical adverse events

Rare adverse event(s) may not be detectable in pre-licensure clinical trials

• Safety data for currently US licensed vaccines generated in

nonpregnant subjects may be supportive

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Maternal Immunization Studies Effectiveness Considerations & Evaluations

• Product effectiveness should be

tested directly in mother/infants

Challenge: Who will conduct

these studies?

• Ideally, trials are randomized and

controlled

Standard of care influences study

design

• Endpoints/specific outcomes

• Clinical endpoint (e.g., culture

confirmed influenza) in

mother/infant

• Immunological endpoint (inferred

efficacy) in mother/infant ?

- No accepted immunologic

correlate of protection

• Evidence needed to demonstrate

that vaccination during pregnancy

protects mothers & infants < 6

months of age

• Risk/benefit assessment difficult in

the absence of clinical data

demonstrating protection of the

mother and infant from disease

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Maternal Immunization Studies

Immunogenicity Considerations & Evaluations

• Persistence of immune response in the mother

• Efficiency of placental transport of antibodies

• Persistence of maternal antibody in the infant

Cord blood titer, correlation with maternal antibody

• Clinical immunogenicity studies in infants

Evaluation of immune interference

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Summary

• Immunization of pregnant women with preventive vaccines have the

potential to be of benefit to the mother and infant.

• FDA is revising current pregnancy labeling regulations to provide a

framework to clearly communicate available data on the potential risks of

drug & biological use during pregnancy and lactation.

• FDA supports ongoing initiatives to obtain postmarketing information on

safety and immunogenicity for US vaccines in current use (e.g. influenza

vaccines).

• Maternal immunization studies are needed to establish effectiveness of

preventive vaccines to protect mother and infants from disease and to

describe, in product labeling, safety and effectiveness of the vaccine

administered during pregnancy.