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2/18/2016 An Overview of the FDA Pregnancy and Lactation Labeling Rule Jamie Ridley Klucken, Pharm.D, MBA, BCPS, CDE Assistant Professor of Pharmacy Practice Department of Clinical Sciences Bernard J Dunn School of Pharmacy Shenandoah University Ashburn Campus Conflict of Interest Disclosure Jamie relevant financial relationships to disclose Kristina Luong No relevant financial relationships to disclose Originally developed presentation Presentation originally developed by: Kristina Luong PharmD Candidate, 2016 VCU School of Pharmacy Objectives Ridley Klucken No Pre-quiz Explain the rationale behind the FDA pregnancy labeling changes When did the new FDA Pregnancy and Lactation Labeling Rule (PLLR) take effect? Identify changes to the FDA pregnancy and lactation information on prescription drug labeling a. December 15, 2015 b. May 30, 2015 c. June 30, 2015 d. August 1, 2015 Describe how the implementation of the Pregnancy and Lactation Rule will impact newly approved medications and current medications Pre-quiz Pre-quiz What of the following is not one of the categories that will be found in drug labeling, in accordance with the PLLR? Which is not a subsection that will be found under Clinical Considerations under the Pregnancy section? a. Pregnancy b. Labor and Delivery c. Lactation d. Females and Males of Reproductive Potential a. Maternal Adverse Reactions b. Drug-Drug interactions c. Dose adjustments during pregnancy and the postpartum period d. Fetal/Neonatal adverse reactions 1 2/18/2016 Pre-quiz When must all pregnancy categories be removed from drug labeling? a) June 30, 2015 b) December 30, 2016 c) January 1, 2018 d) June 30, 2018 Background A 2011 study using U.S. data from 1976-2008 reported that about 90% of women take at least one medication during pregnancy Over the last 30 years 70% take at least one prescription medication First trimester use of prescription medications has increased more than 60% First trimester use of 4 or more medications tripled Use of 4 or more medications anytime during pregnancy more than doubled Origins Under sections 502 and 505 of the Food, Drug, and Cosmetic Act, the FDA has responsibility for ensuring that prescription drug and biological products have labeling that summarizes scientific information concerning their safe and effective use In 1979, FDA issued labeling for use during pregnancy, labor and delivery, and nursing to be found in the “Precautions” section of drug labeling Rule revised January 2006 Increased use of prescription medications during pregnancy has reinforced need for better labeling Overview of Physician Labeling Rule Rationale Behind FDA Pregnancy Labeling Changes Pregnancy subsection: Commonly referred to as the “Physician Labeling Rule” Subsections on labeling for pregnancy, labor and delivery, and nursing mothers moved from “Precautions” to “Use in Specific Populations” portion of drug labeling Overview of Physician Labeling Rule Nursing mothers subsection: Drug’s teratogenic effects Excretion of drug in human milk Effects on reproduction and pregnancy Effects on nursing infant Available data regarding later growth, development, and functional maturation of the child Description of pertinent adverse effects observed in animal offspring A, B, C, D, or X categories Standard statements depending on whether drug was known to be excreted in human milk and whether it was associated with serious adverse reactions Labor and Delivery subsection: Effect of drug on mother and fetus Duration of labor and delivery Effect of drug on later growth, development, and functional maturation of the child Sections were only present if drug was absorbed systemically 2 2/18/2016 Review of Pregnancy Categories A • No risk in controlled human studies B • No risk in other studies C • Risk not ruled out D • Positive evidence of risk X • Contraindicated in Pregnancy Development of Proposed Changes May 2008: the FDA proposed a revision of the pregnancy and lactation labeling on prescription drug and biological products Part of a broad effort to improve content and formatting of prescription drug labeling Goal was to provide information for healthcare professionals to make an educated decision Eliminate pregnancy categories Development of Proposed Changes FDA received feedback on the 1979 regulations In response to feedback, FDA held public hearings, conducted focus groups, and convened two advisory committees Feedback provided: Labeling lacked clarity Failed to provide meaningful clinical information about drug exposure Did not address potential maternal and fetal consequences of discontinuing needed maternal drug therapy during pregnancy Pregnancy categories often misinterpreted Misinterpretation of Pregnancy Categories Clinicians and patients often believed that Category A represents lowest risk whereas Category X represents highest risk Drugs in the same category have the same level of risk or that data supporting classification is similar Assumption that drugs within the same category share the same extent of risk for congenital disorders Mental Models Research Classifications based on levels of evidence 65%-70% of all prescription drugs are assigned to Pregnancy Category C but have drastically different supporting evidence and risks Research Findings FDA contracted third-party to conduct a Mental Models Research study in 2009 Findings consistent with feedback the FDA received Established risk analysis using structured interviews to evaluate decision-making process Showed pregnancy categories relied on almost to exclusion of other information found in labeling Purpose: to understand how healthcare providers used FDA prescribing information to influence treatment decisions for pregnant and lactating women with chronic conditions Providers often relied on secondary sources to find the pregnancy category rather than product labeling Suggestions from interviewees were provided 54 healthcare providers interviewed Improved prescribing information Simplifying information presented Centralizing relevant information Making information on label clinically relevant 3 2/18/2016 Final Rule Pregnancy and Lactation Labeling Final Rule Overview of Section Changes Pregnancy Labor and Delivery Nursing Mothers Pregnancy FDA published the Pregnancy and Lactation Labeling Rule on December 3, 2014 New labeling effective June 30, 2015 Labeling will remain under “Use in Specific Populations” section of labeling for prescription drug products Replaces letter categories with detailed subsections describing risks within real-world context of caring for pregnant women or those planning on getting pregnant Draft guidance for industry also issued to help manufacturers comply with new rule and format requirements Final Rule 3 subsections: “Pregnancy”, “Lactation”, and “Females and Males of Reproductive Potential” “Pregnancy” and “Lactation” categories will have three subheadings Lactation Females and Males of Reproductive Potential Pregnancy Subheadings Pregnancy Exposure Registry Risk Summary Clinical Considerations Data Risk Summary replaces the pregnancy categories Risk Summary Clinical Considerations Data Clinical Considerations and Data are required only to extent of relevant information available Pregnancy Exposure Registry required under “Pregnancy” if a registry exists Pregnancy Exposure Registry Required under Pregnancy subsection if there is a scientifically acceptable pregnancy exposure registry for the drug Requires contact information needed to enroll in or obtain information about the registry FDA is hoping that since this data will be easy accessible, this will encourage participation in registries, improving data collection in pregnant women 4 2/18/2016 Pregnancy: Risk Summary Risk statement based on risk of adverse developmental outcomes based on all relevant human data, animal data, and the drug’s pharmacology Any contraindications must be stated first If the drug is systemically absorbed: % range of pregnancies in U.S. that end in miscarriage Must be specifically stated Provides information to further inform healthcare provider Counseling information about use during pregnancy Required Subheadings: Differs from previous rule When applicable, risk statements must include a cross-reference to the Data subheading Any scientific data for information presented in the Risk Summary or Clinical Considerations Subsections Human Data Animal Data Lactation: Risk Summary If the drug is not systemically absorbed Pregnancy: Data Pregnancy: Clinical Considerations Contraindications Systemic absorption Presence in human milk: concentration in milk or estimated daily dose for infant fed exclusively with human milk Effects on breast-fed child: systemic/local adverse reactions Effects on milk production: amount, milk composition, effects of drug or its active metabolites For drugs systemically absorbed, a risk-benefit statement must appear at the end of the Risk Summary, unless the drug is contraindicated If drug is not absorbed systemically and not present in milk, the label must also state this Disease-associated maternal and/or fetal risk Dose adjustments during pregnancy and the postpartum period Maternal adverse reactions Fetal/Neonatal adverse reactions Labor or delivery (effects) Lactation Subheadings Risk Summary Clinical Considerations Data Lactation: Clinical Considerations and Data Ways to minimize exposure in breast-fed child When applicable, describe ways to minimize child’s oral intake of topical drugs “Monitoring for adverse reactions” Must describe available interventions for monitoring or mitigating adverse reactions Data: Describes data that provide scientific basis for the information presented in the Risk Summary and Clinical Considerations subheadings 5 2/18/2016 Females and Males of Reproductive Potential: Subheadings Pregnancy Testing Contraception Infertility Recommendations/requirements for pregnancy testing and/or contraception before, during, or after drug therapy Human and/or animal data suggesting drugassociated effects on fertility Omit if none of the subheadings are applicable Draft guidance Implementation of Changes Implementation Along with the final Pregnancy and Lactation Labeling Rule, the FDA issued a draft guidance Application holders required to remove pregnancy category designation by June 30, 2018 Intended to help manufacturers to develop and revise professional labeling that meets the new format requirements Content and format changes required for drugs for which an application was approved on or after June 30, 2001 One in a series of guidances the FDA is developing to assist applicants with content and format FDA proposed phased-in implementation plan that would stagger required dates for when labeling with new pregnancy/lactation content must be submitted to the FDA for approval Others include adverse reactions, dosage and administration, etc. Implementation plan: New or Pending Applications Implementation plan: Approved Applications Application Submit Date Time by Which Labeling with New Pregnancy/Lactation Content Must Be Submitted to FDA for Approval Application Approval Date Time by Which Labeling with New Pregnancy/Lactation Content Must Be Submitted to FDA for Approval On or after the effective date of final rule Time of submission June 30, 2001–June 29, 2002 June 30, 2005-June 29, 2007 3 years after the effective date of pregnancy final rule June 30, 2007–June 30, 2015 Pending on the effective date of final rule 4 years after the effective date of pregnancy final rule or at time of approval, whichever is later 4 years after the effective date of pregnancy final rule June 30, 2002-June 29, 2005 5 years after the effective date of pregnancy final rule Table 1: Implementation Plan; FDA PLLR Final Rule Table 1: Implementation Plan; FDA PLLR Final Rule 6 2/18/2016 Exercise 1 Go to http://www.accessdata.fda.gov/scripts/cder/drug satfda/ to search for FDA approved drug labels Look up drug labeling for thalidomide (NDA 020785) and Yaz (NDA 021676, 2010 label) Compare pregnancy information on each label Category Data supporting the category Exercise 1 Thalidomide labeling Exercise 1 Exercise 1 Thalidomide labeling Labeling for Yaz Exercise 1 Exercise 2 Both thalidomide and Yaz were both pregnancy category X Thalidomide is contraindicated in pregnancy because it has shown to cause embryo-fetal harm, death, and developmental malformations with documented cases and studies in animals Yaz was considered pregnancy category X because the designation is based on the fact that it lacked efficacy in preventing pregnancy (its FDA labeled indication) in a woman already pregnant Lack of human data Findings of congenital disorders in animal studies Go to http://www.accessdata.fda.gov/scripts/cder/drug satfda/ to search for FDA approved drug labels Look up Entresto (NDA 207620) Read through the “Pregnancy” section of the labeling information only Would you recommend this medication to a pregnant patient? 7 2/18/2016 Review: Outline of Drug Labeling Review: Outline of Drug Labeling Pregnancy Data Pregnancy Exposure Registry Human Data Risk Summary Animal Data Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Lactation Risk Summary Clinical Considerations Data Dose adjustment during pregnancy and the postpartum period Maternal adverse reactions Fetal/Neonatal adverse reactions Pregnancy Testing Labor or delivery Contraception Infertility Exercise 2 Females and Males of Reproductive Potential Resources Mitchell, Allen A., Suzanne M. Gilboa, Martha M. Werler, Katherine E. Kelley, Carol Louik, Díaz. "Medication Use during Pregnancy, with Particular Focus on Prescription Drugs: 1976-2008." American Journal of Obstetrics and Gynecology 205.1; 2011. Accessed September 16, 2015. "FDA Issues Final Rule on Changes to Pregnancy and Lactation Labeling Information for Prescription Drug and Biological Products." http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm 425317.htm; December 3, 2014. Accessed September 1, 2015. FDA, U.S. Department of Health and Human Services (HHS). Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. www.gpo.gov/fdsys/pkg/FR-2008-05-29/pdf/E8-11806.pdf; May 29, 2008. Accessed September 1, 2015. "Labeling for Human Prescription Drug and Biological Products – Implementing the PLR Content and Format Requirements." Http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryI nformation/Guidances/ucm075082.pdf. Accessed September 9, 2015. Resources Singh, Amrita, Gregory Hughes, and Nissa Mazzola. "New Changes in Pregnancy and Lactation Labeling." USPharmacist. http://www.uspharmacist.com/content/c/51060/; October 16, 2014. Accessed September 15, 2015. Entresto (sacubitril/valsartan) package insert. East Hanover, NJ: Novartis; 2015 http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Ori g1s000lbl.pdf. Accessed September 17, 2015. Thalomid (thalidomide) package insert. Summit, NJ : Celgene; August 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020785s05 1lbl.pdf. Accessed September 17, 2015. Feibus, Karen B. "FDA’s Proposed Rule for Pregnancy and Lactation Labeling: Improving Maternal Child Health through Well-informed Medicine Use." Journal of Medical Toxicology J. Med. Toxicol. 4.4 (2008): 284-88. Accessed September 7, 2015. Drugs@FDA: FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed September 16, 2015. 8
