Download The Pregnancy and Lactation Labeling Rule (PLLR)

Volume 3 | June 2015
The Pregnancy and Lactation Labeling Rule (PLLR)
After nearly two decades of planning, the Food and Drug Administration (FDA) passed a legally
binding regulation on December 4, 2014 revising the content and format of the Pregnancy, Labor and
Delivery, and Nursing Mothers sections of the label for human drugs and biologics. The PLLR
requires the inclusion of much-needed additional information to help health care providers make
informed prescribing decisions. The result is a dramatically different format that contains increased
detail, but also increased complexity.
New Labeling Format for Use in Specific Populations
8.1 Pregnancy
1. Pregnancy Exposure Registry
2. Risk Summary
3. Clinical Considerations
4. Data
8.2 Lactation
1. Risk Summary
2. Clinical Considerations
3. Data
8.3 Females and Males of
Reproductive Potential
Implementation of PLLR Labeling Revisions
The PLLR takes effect on June 30, 2015 for all New Drug Applications (NDAs), Biologics License
Application (BLAs), and efficacy supplements. Importantly, labels approved from June 30, 2001 until
the present must also be revised under a staggered implementation schedule. Navigating the
complexity of the new labeling format will require advanced planning and a collaborative effort among
nonclinical, clinical, and regulatory experts.
“Pregnancy Categories” Are Removed and Replaced by “Risk Summaries”
A main feature of the PLLR is removal of the Pregnancy Categories A, B, C, D and X. While intended
to relate information on both risk and benefit, category meanings were often misinterpreted and there
was an overreliance on categories when making prescribing decisions. Accordingly, Pregnancy
Categories will be replaced by Risk Summaries, which are integrated statements of risk derived from
clinical experience (if any), animal data, and concerns related to the pharmacologic activity of the
drug. These risk summaries will cross-reference to more detailed descriptions of the data.
Importantly, the Risk Summary must also include the background risk of major birth defects and
miscarriage in the US, in order to put potential effects of the drug into perspective. For revision of
previously approved labels, a key challenge will be to incorporate clinical data generated in the
intervening years. This could include data from Sponsor-generated studies, pregnancy exposure
registries, and clinical/epidemiologic studies published in the scientific literature. Determining the
quality of studies, which studies to include, how results affect the risk summary, and navigating
conflicting results could be challenging for Sponsors accustomed to focusing primarily on animal data.
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Clinical Considerations Will Further Support a Risk-Benefit Analysis
One important feature of the Clinical Considerations subsection is a description of the disease state
to be treated by the drug, and its inherent risks to the mother or developing embryo. Understanding
risks inherent to the disease state will help prescribers weigh both the benefits and the risks of
prescribing the drug to women of child bearing potential, and will ultimately improve patient care.
However, how to relate disease risks in a consistent manner across the industry will be a key
challenge.
Additional information in this subsection addresses dose adjustments during pregnancy or
postpartum, maternal or fetal/neonatal adverse reactions, and potential effects of the drug on labor
or delivery. To adequately describe these data, cross-referencing other sections of the label (e.g.,
Clinical Pharmacology, Nonclinical Toxicology) will be important. Unlike the Risk Summaries,
Clinical Considerations is an optional section, which can be omitted if not applicable.
Lactation
As in the Pregnancy section of the label, a Risk Summary for Lactation is required, but inclusion of
Clinical Considerations is dependent on available information. The Risk Summary includes data on
the presence of the drug in milk, as well as potential effects on milk production and on the breastfed
child. Information should focus on human data, but may rely on animal data in the absence of
human data. However, these data (e.g., drug levels in milk) may not be routinely generated in
animal studies. Therefore, advanced planning and a customized approach will be crucial for
navigating this section.
Females and Males of Reproductive Potential Section – Added in Final Rule
Not present in the draft rule, this added section provides a consistent location for information related
to reproductive potential. Subsections include: Pregnancy Testing, Contraception, and Infertility,
any of which can be omitted if not applicable. The first two headings relate to drugs with high
concern for developmental toxicity (primarily teratogenicity), warranting a negative pregnancy test
or the use of contraception, respectively. Recommendations for contraception to protect partners of
male patients could also be included. The third subsection should contain statements about
potential risks of the therapeutic to human fertility. All three subsections should cross-reference
Pregnancy, Nonclinical Toxicology, Warnings and Precautions, or other sections of the label as
applicable.
References
FDA 21 CFR Part 201. Content and Format of Labeling for Human Prescription Drug and Biological Products;
Requirements for Pregnancy and Lactation Labeling. Federal Register, 79(233), 04Dec2014, 72064‐72103.
FDA Draft Guidance for Industry, Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription
Drug and Biological Products – Content and Format. Dec 2014.
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For More Information, Please Contact:
Tacey E.K. White, Ph.D.
(215) 594-8849 • [email protected]
John M. DeSesso, Ph.D.
(571) 227‐7261 • [email protected]
www.exponent.com
How Exponent Can Assist
Exponent’s Nonclinical Services
Exponent’s Center for Toxicology and Mechanistic Biology provides the highest quality
technical, regulatory, and safety assessment services to assist our clients with issues related to
pharmaceutical and biotechnology products, with a particular focus on nonclinical development
and regulatory support.
We have several in‐house staff with direct pharmaceutical experience, coming to Exponent from
both large and small pharmaceutical and biotechnology companies. Our unique range of skills
and experience in drug development helps our clients maximize the value of their research and
development efforts in bringing medications to the market.
Aspects of the nonclinical developmental process for which Exponent is posed to assist
include:
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Development of customized nonclinical testing strategies to reduce costs and maximize
the likelihood of moving your candidate into the clinic and beyond
Identification of appropriate animal models for nonclinical safety assessment
Expertise in small and large molecules, and other novel therapeutics
CRO selection, study design and management, including toxicity, safety pharmacology
and toxicokinetic evaluations
Appropriate dose selection for nonclinical safety testing (including carcinogenicity
testing) and first-in-human studies
Nonclinical issues research and resolution
Particular expertise in developmental / reproductive toxicology, juvenile and genetic
toxicology
Data analysis and regulatory document preparation
Preparation of pregnancy and lactation labeling content
Regulatory support in preparation of Investigational New Drug (IND) applications and
New Drug Applications (NDAs)
Knowledge of global regulatory requirements, and responses to regulatory questions
Representation during meetings with the FDA and other regulatory bodies
Environmental impact assessments for US and EU regulatory authorities.
Beyond Nonclinical
Exponent is positioned to provide guidance across the entire product lifecycle for clients.
Examples of areas beyond nonclinical in which Exponent can assist include the selection and
prioritization of therapeutic indications and the development of target product profiles; defining
the commercial strategy or competitive landscape; streamlining the regulatory approval process
through the incorporation of biomarkers and tools for managing patients; the design of post‐
marketing surveillance strategies; and economic modeling to prioritize pipeline assets and
provide predictions regarding success. We also have expertise in development of devices and
device‐drug combination products. We provide these services by leveraging the knowledge and
experience of more than 90 technical disciplines across our firm.
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Our Nonclinical Support Staff
John DeSesso, Ph.D., DABFM, DABFE,
FACFEI, Fellow ATS
(571) 227‐7261 • [email protected]
Dr. DeSesso has over 35 years of
experience in the areas of developmental
and reproductive toxicology, general
toxicology, risk assessment, and human
health effects and has published widely in
these areas. He has assisted companies
with assessment of data needs; design and
interpretation of studies to meet regulatory
requirements; preparation of INDs and
NDAs for pharmaceutical substances; and
preparation for and attendance at various
FDA and Advisory Panel meetings. He is an
adjunct professor of Biochemistry and
Molecular Biology at Georgetown University
School of Medicine, where he has been a
faculty member for more than 30 years.
Bhaskar Gollapudi, Ph.D.
(989) 486‐8782 • [email protected]
Dr. Gollapudi specializes in genetic and
molecular toxicology/chemical
carcinogenesis. He has over 30 years of
research and issue management experience
at a major multinational industry addressing
the safety of a diverse portfolio of
substances. He is widely published in the
area of genotoxicity and risk assessment, is
an adjunct Associate Professor at the
University of Michigan School of Public
Health, and serves on a number of scientific
committees, including the OECD Expert
Committee on Genetic Toxicology Guidelines
and the Committee on Toxicology of the U.S.
National Research Council. Dr. Gollapudi is
a recent recipient of the 2014 Arnold J.
Lehman Award from the Society of
Toxicology in recognition of his contributions
to the field of risk assessment and chemical
regulation. Karyn Hentz, MSPH, RAC, DABT
(571) 227‐7208 • [email protected]
Ms. Hentz is Regulatory Affairs Certified
(RAC) in U.S. FDA regulations and provides
regulatory support for a range of healthcare
products. She assists companies with the
identification of data gaps in their regulatory
submissions, and collaboration in the
conduct of studies or development of a
rationale for waiving specific requirements.
When studies have been needed, she has
performed study monitoring on behalf of her
clients, to ensure compliance and timely
preparation of reports to meet regulatory
deadlines. She has provided regulatory
support for proprietary drug substances,
generics, and excipients, leading to the
submission of INDs, ANDAs and NDAs.
Jane Staveley, MSPH
(919) 228‐6480 • [email protected]
Ms. Staveley has over 35 years of
experience in environmental toxicology,
ecological risk assessment, and product
stewardship. She has conducted
environmental assessments of
pharmaceuticals, both for human and
animal use, for submission to the U.S. FDA
and European regulatory authorities. This
work has involved the placement,
monitoring, and interpretation of ecotoxicity
and environmental fate studies, as well as
the development of novel exposure
assessment approaches, including a
watershed-level assessment. Ms. Staveley
served as the moderator of a U.S.
Congressional Briefing in 2010 on the topic
of “Pharmaceuticals in Our Water:
Concerns and Responses.” She also served
on the steering committee of a 2011
workshop sponsored by SETAC and Health
Canada on “The Top Research Questions
on Pharmaceuticals and Personal Care
Products in the Environment.”
www.exponent.com
Tacey White, Ph.D.
(215) 594‐8849 • [email protected]
Amy Williams, Ph.D., DABT
(571) 227‐7226 • [email protected]
Dr. White has over 16 years of experience in
pharmaceutical drug development of small
and large molecules, with emphasis on
developmental and reproductive toxicology
(DART), and juvenile and general toxicology.
She advises pharmaceutical and biotech
companies on nonclinical safety assessment
strategies throughout the entire drug
development process, including planning
customized nonclinical strategies, placing
and monitoring studies, developing human
risk assessments for toxicology issues,
addressing regulatory questions, and
contributing to regulatory documents (IBs,
INDs, Briefing Books, PIPs/PSPs, NDAs).
Within the pharmaceutical industry, she has
had extensive experience as a Study
Director, safety assessment project team
representative, and lead investigator on
developmental toxicity mode-of-action studies
for a diverse range of pharmaceutical
products. She is currently Vice President
of the Teratology Society.
Dr. Williams is a board-certified toxicologist
with more than 20 years of experience in the
evaluation of pharmaceuticals, as well as
chemical and physical agents, for potential
adverse effects on human health. She
specializes in general toxicology,
developmental and reproductive toxicology,
and endocrine disruption. Dr. Williams has
assisted companies in the design, monitoring,
and interpretation of preclinical safety studies,
in the evaluation of excipients, and in the
preparation of NDAs for regulatory
submission. Dr. Williams also has significant
experience communicating health risks to the
public.
Recent Publications
Alyea RA, Gollapudi BB, Rasoulpour RJ.
Are we ready to consider transgenerational
epigenetic effects in human health risk
assessment? Environ Mol Mutagen 2014;
55:292–298.
DeSesso JM. Chapter 6: Comparative
gestational milestones in vertebrate development.
In Developmental and Reproductive Toxicology:
A Practical Approach, 3rd Ed. Hood RD (Ed.).
Informa Healthcare, London, pp. 93‐138, 2012.
Boxall AB, Rudd MA, Brooks BW, Caldwell DJ,
Choi K, Hickmann S, Innes E, Ostapyk K,
Staveley JP, Verslycke T, et al. Pharmaceuticals and personal care products in the
environment: what are the big questions?
Environ Health Perspect 2012; 120:1221‐1229.
DeSesso JM, Jacobson CF, Williams AL.
Chapter 2: Anatomical and physiological
parameters that influence gastrointestinal
absorption. In Encyclopedia of Drug Metabolism
and Interactions, Volume 2. Lyubimov A. (Ed.).
John Wiley and Sons, New York, pp. 43‐78,
2012.
Cavagnaro J, Berman C, Kornbrust D, White
T, Campion S, Henry S. Considerations for
assessment of reproductive and
developmental toxicity of oligonucleotidebased therapeutics. Nucleic Acid Ther 2014;
24:313–325.
DeSesso JM, Williams AL, Ahuja A, Bowman
CJ, and Hurtt ME. The placenta, transfer of
immunoglobulins, and safety assessment of
biopharmaceuticals in pregnancy. Crit Rev
Toxicol 2012; 42:185‐210.
www.exponent.com
Geter DR, Bhat VS, Gollapudi BB, Sura R,
Hester SD. Dose‐response modeling of
early molecular and cellular key events in
the CAR‐mediated hepatocarcinogenesis
pathway. Toxicol Sci 2014; 138:425–445.
Gollapudi BB, Johnson GE, Hernandez
LG, Pottenger LH, Dearfield KL, Jeffrey AM,
Julien E, Kim JH, Lovell DP, MacGregor JT,
Moore MM, van Benthem J, White PA,
Zeiger E, Thybaud V. Quantitative
approaches for assessing dose‐ response
relationships in genetic toxicology. Environ
Molec Mutagen 2013; 54:8–18.
Gollapudi BB, Lynch AM, Heflich RH ,
Dertinger SD, Dobrovolsky VN, Froetschle
R, Horibata K, Kenyon MO, Kimoto T, Lovell
D, Stankowski Jr. LF, White PA, Witt KL,
Tanir JY. The in vivo Pig‐a assay: A report
of the International Workshop on
Genotoxicity Testing (IWGT) Workgroup.
Mutat Res (in press).
Hentz KL. Safety assessment of
pharmaceuticals. In: Reference Module in
Biomedical Sciences, Elsevier. Current as
of 1 December 2014, ISBN
9780128012383.http://dx.doi.org/10.1016/B
978‐0‐12‐801238‐3.01942‐5.
Holson JF, Stump DG, Pearce LB, Watson
RE, DeSesso JM. Absence of developmental
toxicity in a canine model after infusion of a
hemoglobin‐based oxygen carrier:
Implications for risk assessment. Reprod
Toxicol 2015 (In press).
Johnson GE, Slob W, Doak S, Fellows M,
Gollapudi B, Heflich RH, Rees B,
Soeteman‐ Hernández LG, Verma J, Wills J,
Jenkins G, White P. New Approaches to
Advance the use of Genetic Toxicology
Analyses for Human Health Risk
Assessment and Regulatory Decision‐
Making, Toxicology Res 2014 (In Press).
Johnson GE, Soeteman‐Hernández LG,
Gollapudi BB, Bodger OG, Dearfield KL,
Heflich RH, Hixon JG, Lovell DP, MacGregor
JT, Pottenger LH, Thompson CM, Abraham
L, Thybaud V, Tanir JY, Zeiger E, van
Benthem J, White PA. Derivation of point of
departure (PoD) estimates in genetic
toxicology studies and their potential
applications in risk assessment. Environ Mol
Mutagen 2014; 55:609‐623.
Kimmel CA, Garry MR, DeSesso JM.
Relationship between bent long bones, bent
scapulae, and wavy ribs: malformations or
variations? Birth Defects Res B Dev Reprod
Toxicol (In Press).
Lamb JC IV, Boffetta P, Foster WE, Goodman
JE, Hentz KL, Rhomberg LR, Staveley J,
Swaen G, Van Der Kraak G, Williams AL.
Critical comments on the WHO‐UNEP state of
the science of endocrine disrupting chemicals
–2012. Regul Toxicol Pharmacol 2014; 69:22‐
40.
LeBaron MJ, Geter DR, Rasoulpour RJ,
Gollapudi BB, Thomas J, Murray J, Kan HL,
Wood AJ, Elcombe C, Vardy A, McEwan J,
Terry C, Billington R. An integrated approach
for prospectively investigating a mode‐of‐
action for rodent liver effects. Toxicol Appl
Pharmacol 2013; 20:164–173.
LeBaron MJ, Schisler MR, Torous DK,
Dertinger SD, Gollapudi BB. Influence of
counting methodology on erythrocyte ratios in
the mouse micronucleus test. Environ Molec
Mutagen 2013; 54:222–228.
Metcalfe C, Boxall A, Fenner K, Kolpin D,
Servos M, Silberhorn E, Staveley J. Chapter
4: Exposure assessment of veterinary
medicines in aquatic systems. In: Veterinary
Medicines in the Environment. Crane M, Boxall
ABA, Barrett K (Eds.). CRC Press, Taylor &
Francis Group, 2009.
Posobiec LM, Bushdid PB, Laffan SB, Clark
RL, White TEK. Dihydroartemisinin (DHA)
treatment causes decreased proliferation and
apoptosis in rat embryonic erythroblasts in
whole embryo culture. Birth Defects Res B Dev
Reprod Toxicol 2013; 98:445–458. [Recipient
of the 2014 Teratology Society Wilson Award
for best paper.]
www.exponent.com
Schisler MR, Moore MM, Gollapudi BB. In
vitro mouse lymphoma (L5178Y Tk (+/‐) ‐
3.7.2C) forward mutation assay. Methods in
Molecular Biology 2013; 1044:27–50.
Stump DG, Holson JF, Harris C, Pearce LB,
Watson RE, DeSesso JM. Developmental
toxicity in rats of a hemoglobin‐based oxygen
carrier results from impeded function of the
inverted visceral yolk sac. Reprod Toxicol
2015 (In press).
Zhang F, Bartels MJ, LeBaron MJ, Schisler
MR, Gollapudi BB, Moore NP. A novel
approach for concurrent quantitation of
glutathione, glutathione disulfide, and 2‐
hydroxyethylated glutathione in lungs of mice
exposed to ethylene oxide, using liquid
chromatography‐positive electrospray
tandem mass spectrometry. Biomed
Chromatogr. 2015 (In Press).
Zhang F, Bartels MJ, LeBaron MJ, Schisler
MR, Jeong YC, Gollapudi BB, Moore NP.
LC‐MS/MS simultaneous quantitation of 2‐
hydroxyethylated, oxidative, and unmodified
DNA nucleosides in DNA isolated from
tissues of mice after exposure to ethylene
oxide. J Chromatogr B Analyt Technol
Biomed Life Sci. 2015 (In Press).
Zeiger E, Gollapudi B, Aardema MJ,
Auerbach S, Boverhof D, Custer L, Dedon
P, Honma M, Ishida S, Kasinski AL, Kim JH,
Manjanatha MG, Marlowe J, Pfuhler S,
Pogribny I, Slikker W, Stankowski LF Jr,
Tanir JY, Tice R, van Benthem J, White P,
Witt KL, Thybaud V. Opportunities to
integrate new approaches in genetic
toxicology: An ILSI‐HESI workshop report.
Environ Mol Mutagen. 2014 (In Press).
Ziejewski, MK, Solomon HM, Stanislaus D,
Clark RL, White TEK, Apostoli AR. The
potential role for corticosterone in the
induction of cleft palate in mice after
treatment with a selective NK‐1 receptor
antagonist, Casopitant (GW679769B). Birth
Defects Res B Dev Reprod Toxicol 2011;
95:54–62.
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About Exponent
Exponent is a leading engineering and scientific consulting firm. Our team of scientists, physicians,
engineers, and regulatory consultants performs investigations in more than 90 technical
disciplines. We analyze failures and accidents to determine their causes and we evaluate complex
human health and environmental issues to find cost-effective solutions.
www.exponent.com