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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. www.exponent.com 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. ------------------------------------------------------------------------------------------------------------------------------- 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: 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. www.exponent.com 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. ------------------------------------------------------------------------------------------------------------------------------- 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