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The new US Food and Drug Administration pregnancy and lactation labeling rules: Their impact on clinical practice
The new US Food and Drug Administration pregnancy and lactation labeling rules: Their impact on clinical practice Melissa J. Danesh, BS,a and Jenny E. Murase, MDa,b San Francisco and Mountain View, California ermatologists should be aware that the US Food and Drug Administration (FDA) will soon abolish pregnancy category letters and that drug labeling will have specific evidence cited—the quantity of which may appear uncomfortably meager to both patients and physicians. The FDA has recently released the Pregnancy and Lactation Labeling Rule (PLLR), which goes into effect on June 30th, 2015. The PLLR introduces new drug labeling to help physicians better communicate the risks and benefits of pharmacologic treatment to patients during pregnancy and lactation. This rule will immediately apply to all drugs approved after June 30th; labels for products approved between 2001 and the PLLR effective date will have a staggered phase-in, and those approved before 2001 must be amended within 3 years. Labels for over the counter medications will not be affected by the PLLR. The new drug labeling rule is described herein, including a discussion of its potential impact on clinical practice. The most notable change of the PLLR is that it will abolish pregnancy labeling categories for pharmaceuticals (ie, A, B, C, D, and X), which have been applied since 1979. In place of these labeling categories will be individualized narrative summaries for each medication that include ‘‘risks of using a drug during pregnancy and lactation, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation.’’1 Other select revisions are included. First, the 3 subsections of populations for whom risks were separately described have now been collapsed into 2 subsections—the old subsections of ‘‘Pregnancy’’
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and ‘‘Labor and Delivery’’ are now a single umbrella subsection (‘‘Pregnancy’’), and the old subsection of ‘‘Nursing Mothers’’ is now ‘‘Lactation.’’ In addition, an altogether new subsection has been created to describe risks to ‘‘Females and Males of Reproductive Potential.’’ Second, the ‘‘Pregnancy’’ subsection will include a required (previously recommended) pregnancy exposure registry for drugs approved for use during pregnancy and a summary of available data on any particular developmental outcome specific to gestational timing of exposure (previously not reported). Third, the ‘‘Lactation’’ subsection will provide additional information regarding the amount of the drug transferred to breast milk and the specific potential effects on the breastfed infant. Finally, the ‘‘Females and Males of Reproductive Potential’’ subsection will discuss the need for pregnancy testing, contraception recommendations, and infertility associated with use of the drug. The PLLR has several promising implications for clinical practice. In place of the lettering system— which many considered to be overly simplistic, ambiguous, and incomplete2-4—detailed risk profiles will provide more comprehensive information. This information will, ideally, facilitate more careful and individualized riskebenefit analysis by patients and physicians. In addition, the new labeling system will likely reduce the ‘‘innocent until proven guilty’’ bias, where untested drugs with no known harmful side effects were perceived to be safer (eg, Category B) than tested drugs with known side effects (eg, Category C). The PLLR also poses challenges. The new system is more explicit about the sources of data on the label, and it is likely to further expose how little human data exist for most drugs that are available in
From the Departments of Dermatology at the University of California, San Francisco,a San Francisco, and the Palo Alto Foundation Medical Group,b Mountain View. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Jenny E. Murase, MD, Department of Dermatology, Palo Alto Foundation Medical Group, 701 E El
Camino Real (31-104), Mountain View, CA 94040. E-mail: [email protected]. J Am Acad Dermatol 2015;73:310-1. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.04.026
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the United States (92.9% of pharmaceutical drugs obtain pregnancy data from animal studies; 5.2% have human pregnancy data).5,6 The detailed information in the new narrative summaries may also make the decision-making process between patients and physicians more complex and time consuming. Previously, physicians used pregnancy categories as simple surrogates for risk stratification, with A being considered the safest and X the most dangerous.7 The new labels will require physicians to not only read and understand the potential risks of a medication but also interpret a summary of the literature that support these risks. Physicians must then formulate a concise way of explaining risks to patients before a decision is made about starting a medication. The challenge of explaining probabilities to patients in risk communication is well known, and there is no universally accepted format for doing so (eg, frequencies, percentages, risk reduction, graphs, etc).8 These obstacles will likely push physicians to develop new ways of coherently and efficiently engaging patients in difficult decisions. Yet these obstacles also represent far-reaching opportunities to advance patient care. If physicians develop the requisite communication skills, they are likely to find that the new labeling system better equips them to help patients make decisions that accurately reflect their values and risk tolerance. We recommend that all physicians familiarize themselves with the new labeling rules—available at http://federalregister.gov/a/2014-28241—before they come into effect in order to promote a smoother transition. For a condensed version of the PLLR,
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please see http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guid ances/UCM425398.pdf; drug labels may be found at http://dailymed.nlm.nih.gov/dailymed/index.cfm. The authors thank William Feldman, DPhil, for his comments on an earlier draft of this paper. REFERENCES 1. Food and Drug Administration, HHS. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. Final rule. Fed Regist. 2014;79:72063-72103. 2. Addis A, Sharabi S, Bonati M. Risk classification systems for drug use during pregnancy: are they a reliable source of information? Drug Saf. 2000;23:245-253. 3. Boothby LA, Doering PL. FDA labeling system for drugs in pregnancy. Ann Pharmacother. 2001;35:1485-1489. 4. Doering PL, Boothby LA, Cheok M. Review of pregnancy labeling of prescription drugs: is the current system adequate to inform of risks? Am J Obstet Gynecol. 2002;187: 333-339. 5. Mazer-Amirshahi M, Samiee-Zafarghandy S, Gray G, van den Anker JN. Trends in pregnancy labeling and data quality for US-approved pharmaceuticals. Am J Obstet Gynecol. 2014;211: 690.e1-690.e11. 6. Chambers CD. Evaluating the impact of FDA’s pregnancy and lactation labeling rule. Dermatology News. December 16, 2014. Available at: http://www.edermatologynews.com/views/ single-view/evaluating-the-impact-of-fdas-pregnancy-andlactation-labeling-rule/0c73d9cc718200951776403b0a9d 8760.html. Accessed March 25, 2015. 7. US Food and Drug Administration website. Summary of comments from a public hearing and model pregnancy labeling based on recommendations. Published May 20, 1999. Available at: http://www.fda.gov.ucsf.idm.oclc.org/ohrms/dockets/ac/99/ transcpt/3516r1.doc. Accessed March 25, 2015. 8. Visschers VH, Meertens RM, Passchier WW, de Vries NN. Probability information in risk communication: a review of the research literature. Risk Anal. 2009;29:267-287.
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and ‘‘Labor and Delivery’’ are now a single umbrella subsection (‘‘Pregnancy’’), and the old subsection of ‘‘Nursing Mothers’’ is now ‘‘Lactation.’’ In addition, an altogether new subsection has been created to describe risks to ‘‘Females and Males of Reproductive Potential.’’ Second, the ‘‘Pregnancy’’ subsection will include a required (previously recommended) pregnancy exposure registry for drugs approved for use during pregnancy and a summary of available data on any particular developmental outcome specific to gestational timing of exposure (previously not reported). Third, the ‘‘Lactation’’ subsection will provide additional information regarding the amount of the drug transferred to breast milk and the specific potential effects on the breastfed infant. Finally, the ‘‘Females and Males of Reproductive Potential’’ subsection will discuss the need for pregnancy testing, contraception recommendations, and infertility associated with use of the drug. The PLLR has several promising implications for clinical practice. In place of the lettering system— which many considered to be overly simplistic, ambiguous, and incomplete2-4—detailed risk profiles will provide more comprehensive information. This information will, ideally, facilitate more careful and individualized riskebenefit analysis by patients and physicians. In addition, the new labeling system will likely reduce the ‘‘innocent until proven guilty’’ bias, where untested drugs with no known harmful side effects were perceived to be safer (eg, Category B) than tested drugs with known side effects (eg, Category C). The PLLR also poses challenges. The new system is more explicit about the sources of data on the label, and it is likely to further expose how little human data exist for most drugs that are available in
From the Departments of Dermatology at the University of California, San Francisco,a San Francisco, and the Palo Alto Foundation Medical Group,b Mountain View. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Jenny E. Murase, MD, Department of Dermatology, Palo Alto Foundation Medical Group, 701 E El
Camino Real (31-104), Mountain View, CA 94040. E-mail: [email protected]. J Am Acad Dermatol 2015;73:310-1. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.04.026
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the United States (92.9% of pharmaceutical drugs obtain pregnancy data from animal studies; 5.2% have human pregnancy data).5,6 The detailed information in the new narrative summaries may also make the decision-making process between patients and physicians more complex and time consuming. Previously, physicians used pregnancy categories as simple surrogates for risk stratification, with A being considered the safest and X the most dangerous.7 The new labels will require physicians to not only read and understand the potential risks of a medication but also interpret a summary of the literature that support these risks. Physicians must then formulate a concise way of explaining risks to patients before a decision is made about starting a medication. The challenge of explaining probabilities to patients in risk communication is well known, and there is no universally accepted format for doing so (eg, frequencies, percentages, risk reduction, graphs, etc).8 These obstacles will likely push physicians to develop new ways of coherently and efficiently engaging patients in difficult decisions. Yet these obstacles also represent far-reaching opportunities to advance patient care. If physicians develop the requisite communication skills, they are likely to find that the new labeling system better equips them to help patients make decisions that accurately reflect their values and risk tolerance. We recommend that all physicians familiarize themselves with the new labeling rules—available at http://federalregister.gov/a/2014-28241—before they come into effect in order to promote a smoother transition. For a condensed version of the PLLR,
Danesh and Murase 311
please see http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guid ances/UCM425398.pdf; drug labels may be found at http://dailymed.nlm.nih.gov/dailymed/index.cfm. The authors thank William Feldman, DPhil, for his comments on an earlier draft of this paper. REFERENCES 1. Food and Drug Administration, HHS. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. Final rule. Fed Regist. 2014;79:72063-72103. 2. Addis A, Sharabi S, Bonati M. Risk classification systems for drug use during pregnancy: are they a reliable source of information? Drug Saf. 2000;23:245-253. 3. Boothby LA, Doering PL. FDA labeling system for drugs in pregnancy. Ann Pharmacother. 2001;35:1485-1489. 4. Doering PL, Boothby LA, Cheok M. Review of pregnancy labeling of prescription drugs: is the current system adequate to inform of risks? Am J Obstet Gynecol. 2002;187: 333-339. 5. Mazer-Amirshahi M, Samiee-Zafarghandy S, Gray G, van den Anker JN. Trends in pregnancy labeling and data quality for US-approved pharmaceuticals. Am J Obstet Gynecol. 2014;211: 690.e1-690.e11. 6. Chambers CD. Evaluating the impact of FDA’s pregnancy and lactation labeling rule. Dermatology News. December 16, 2014. Available at: http://www.edermatologynews.com/views/ single-view/evaluating-the-impact-of-fdas-pregnancy-andlactation-labeling-rule/0c73d9cc718200951776403b0a9d 8760.html. Accessed March 25, 2015. 7. US Food and Drug Administration website. Summary of comments from a public hearing and model pregnancy labeling based on recommendations. Published May 20, 1999. Available at: http://www.fda.gov.ucsf.idm.oclc.org/ohrms/dockets/ac/99/ transcpt/3516r1.doc. Accessed March 25, 2015. 8. Visschers VH, Meertens RM, Passchier WW, de Vries NN. Probability information in risk communication: a review of the research literature. Risk Anal. 2009;29:267-287.