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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25791.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25791.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use. Washington, DC: The National Academies Press. doi: 10.17226/25791.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use Donald R. Mattison, Ruth M. Parker, and Leigh Miles Jackson, Editors Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy Board on Health Sciences Policy Health and Medicine Division A Consensus Study Report of PREPUBLICATION COPY—Uncorrected Proofs

THE NATIONAL ACADEMIES PRESS  500 Fifth Street, NW  Washington, DC 20001 This activity was supported by a contract between the National Academy of Sciences ­ and the U.S. Food and Drug Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/25791 Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2020 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2020. The clinical utility of compounded bioidentical hormone therapy: A review of safety, effectiveness, and use. Washington, DC: The National Academies Press. https://doi.org/10.17226/25791. PREPUBLICATION COPY—Uncorrected Proofs

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY—Uncorrected Proofs

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY—Uncorrected Proofs

COMMITTEE ON THE CLINICAL UTILITY OF TREATING PATIENTS WITH COMPOUNDED BIOIDENTICAL HORMONE REPLACEMENT THERAPY DONALD R. MATTISON (Chair), Chief Medical Officer, Senior Vice President Risk Sciences International, University of Ottawa RUTH M. PARKER (Vice Chair), Professor, Medicine and Pediatrics, Emory University School of Medicine LESLEY H. CURTIS, Professor and Chair of Population Health Sciences, Duke University School of Medicine SUSAN S. ELLENBERG, Professor, Biostatistics, Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine JENNIFER FISHMAN, Associate Professor, Biomedical Ethics Unit, Social Studies of Medicine, McGill University ADEL H. KARARA, Professor, Pharmaceutical Sciences, University of Maryland, Eastern Shore AARON S. KESSELHEIM, Professor, Harvard Medical School ROBERT B. MacARTHUR, Pharmacy Director, The Rockefeller University Hospital JOSÉ MANAUTOU, Professor, Toxicology, University of Connecticut NANCY KING REAME, Professor Emerita, School of Nursing, Columbia University DAVID R. RUBINOW, Professor and Chair, Department of Psychiatry, University of North Carolina School of Medicine RULLA TAMIMI, Associate Professor, Healthcare Policy and Research, Cornell University, Weill Cornell Medicine Study Staff LEIGH MILES JACKSON, Study Director ANNA SBEREGAEVA, Associate Program Officer (until May 2019) LIZ TOWNSEND, Associate Program Officer (from July 2019) ANDREW MARCH, Research Associate JUSTIN JONES, Senior Program Assistant DANIEL CESNALIS, Financial Officer (until June 2019) ANNA ISABEL CAMILO JAVIER, Financial Officer (until January 2020) VICTOR STEWART, Financial Officer (from February 2020) MIRIAM SHELTON, Program Coordinator (until August 2019) BRIDGET BOREL, Program Coordinator (from October 2019) ANDREW M. POPE, Senior Director, Board on Health Sciences Policy v PREPUBLICATION COPY—Uncorrected Proofs

Consultant JOE ALPER, Science Writer vi PREPUBLICATION COPY—Uncorrected Proofs

Reviewers This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manu- script remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of this report: GARNET ANDERSON, Fred Hutchinson Cancer Research Center JANE A. AXELRAD, Axelrad Solutions LLC SUSAN R. DAVIS, Monash University ANGELA DEROSA, Belmar Pharmacy KRIS ENSRUD, University of Minnesota DEBORAH GRADY, University of California, San Francisco JAMES LIU, Case Western Reserve University ALVIN M. MATSUMOTO, University of Washington School of Medicine ASHLEE MATTINGLY, University of Maryland School of Pharmacy LYNNETTE K. NIEMAN, National Institutes of Health NATHAN D. POPE, The University of Texas at Austin JEROME F. STRAUSS, Virginia Commonwealth University JANET WITTES, Statistics Collaborative vii PREPUBLICATION COPY—Uncorrected Proofs

viii REVIEWERS Although the reviewers listed above provided many constructive com- ments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by ELI Y. ADASHI, Brown University, and DAVID L. EATON, University of Washington. They were responsible for making certain that an independent examina- tion of this report was carried out in accordance with the standards of the N ­ ational Academies and that all review comments were carefully consid- ered. Responsibility for the final content rests entirely with the authoring ­ committee and the National Academies. PREPUBLICATION COPY—Uncorrected Proofs

Preface Across the history of medicine, preparation of a compounded medica- tion by a physician or pharmacist has been central to treating a variety of disorders. Historically, a compounded medication was formulated to treat an individual patient, and the science supporting the use of that compounded preparation was anecdotal. Over the past century, clinicians increasingly sought to improve and rely on the evidence of safety and effective­ ess to support treatment decisions. During this same time, thera- n peutic data evolved away from information on a single patient treated with a medication specifically formulated to treat that individual patient to data that reflect how safe and effective the medication is for treating most p ­ atients with the disease. This approach, leading to the development of U.S. Food and Drug Administration (FDA)-approved medications, and moving away from anec- dotal evidence, decreased the demand for custom-compounded medications and substantially increased the use of medications tested and approved for treatment and prevention of specific diseases. More recently, over the past several decades, it has been observed that in certain instances, treat- ment needs to be individualized, producing a resurgence in the use of compounded medications. Treatment of menopause is one clinical area where the use of compounded bioidentical hormone therapy (cBHT) has been increasing. cBHT is marketed as a personalized and natural approach to enhanced wellness using tailored preparations that address a myriad of symptoms, including those associated with menopause and aging. The in- crease in supply and demand of cBHT has prompted the need for additional ix PREPUBLICATION COPY—Uncorrected Proofs

x PREFACE data on the safety and effectiveness of these medications, as compounded medications are not reviewed for safety and efficacy or approved by FDA. The Committee on the Clinical Utility of Treating Patients with Com- pounded Bioidentical Hormone Replacement Therapy was formed at the request of FDA to assess the clinical utility of cBHT. We, the members of this committee, began our work by defining clinical utility as a multi­ dimensional construct that reflects evidence about safety, effectiveness, therapeutic need, and patient preference concerning benefit–risk balance. We then turned to explore existing evidence related to the attributes of cBHT from the perspective of clinical utility. We evaluated findings from a literature search of peer-reviewed evidence and gray literature (e.g., research reports, books for a lay audience) and held several open listening sessions to obtain input from various stakeholders. We heard presentations by researchers, clinicians, health advocates, representatives from government agencies, attorneys, and members of professional medical and pharmacy s ­ocieties. In addition, we received extensive correspondence from stake- holders, including that of patients and providers who use cBHT, compound- ing (503A) pharmacists, and members of a coalition of (503B) pharmacists. In our deliberations, we worked to garner data for an evidence base relating to safety and effectiveness of cBHT, as these are two critical attributes of our definition of clinical utility. In the course of the public meetings and based on the materials ­ eviewed, r the committee became even more aware of strong preferences for indi­ vidualized treatment among certain individuals who use cBHT. As such, our work was guided by our collective commitment to keep patient autonomy as a core value. However, the committee also grappled with the concern that for the large patient population using cBHT, it is currently impossible for their clinicians to provide evidence-based guidance on the effectiveness or safety of each unique formulation. Therefore, the committee remained mindful that safety and effectiveness data are required for understanding risks and benefits for all therapeutics, and they are fundamental to how we practice medicine in this country. We thus worked to listen, collect, review, and assess the best available evidence regarding cBHT preparations in order to evaluate their clinical utility. We recognize that not all parties will be in agreement with this report’s recommendations. Should further data from high-quality, well-controlled clinical trials become available, such evidence could be evaluated and the clinical utility of cBHT preparations could be reassessed. Our hope is that our findings, conclusions, and recommenda- tions will inform patients, health care providers, and regulatory bodies to ensure patients have accessible and understandable information based on the best available evidence needed to support their decision making. It was our responsibility and honor to chair this committee. Our efforts focused on evaluating cBHT within the context of current, FDA-approved PREPUBLICATION COPY—Uncorrected Proofs

PREFACE xi drugs, all of which have demonstrated clinical utility for treatment of symp- toms of menopause. We want to thank our fellow committee members; without them, their perseverance, effort, and good humor, this consensus report would not have been possible. We also want to thank individuals who took time to come to the public sessions to share their experiences, insights, and compassion for those individuals seeking safe and effective treatment. Our work could not have been accomplished without the concerted efforts of the committee members who did their work sensibly with cheer- fulness and open minds. The committee’s able and fearless staff, Andrew March, Elizabeth Townsend, Justin Jones, and led by the understanding and knowledge of Leigh Miles Jackson, could not have been more wonderful to work with or more essential to the committee’s task. Donald R. Mattison, Chair Ruth M. Parker, Vice Chair Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy PREPUBLICATION COPY—Uncorrected Proofs

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Acknowledgments The committee takes this opportunity to recognize the many indi­ iduals v and organizations who so generously gave their time and expertise to inform its work. To begin, the committee would like to thank the sponsor of this study, the U.S. Food and Drug Administration (FDA), for its guidance and support. The committee also greatly benefited from the discussions with individuals who attended and made public presentations (see Appendix A). The committee is thankful for the many contributions of these individuals. The committee could not have done its work without the support and guidance provided by the National Academies project staff: Leigh Miles Jackson, study director; Elizabeth Townsend, associate program officer; Anna Sberegaeva, associate program officer; Andrew March, research asso­ ciate; and Justin Jones, senior program assistant. We appreciate Victor Stewart for his financial assistance on this project, are indebted to Jennifer Hinners for her research and writing contributions, and gratefully acknowl- edge Carolyn Shore and Andrew Pope of the Board on Health Sciences Policy for the guidance they provided throughout this important study. Many other staff within the National Academies provided support to this project in various ways. The committee would like to thank the execu­ ive office staff of the Health and Medicine Division, as well as Taryn t Young and Bettina Seliber for the management of the report review and publication process. We would like to thank Jorge Mendoza-Torres and the National Academies Research Center staff for their assistance in the committee’s research efforts, as well as the National Academies Press staff. This committee is grateful to the research consultants that generously contributed to this body of work. We extend our thanks to Phebe Hong xiii PREPUBLICATION COPY—Uncorrected Proofs

xiv ACKNOWLEDGMENTS (Harvard Law School) and ChangWon C. Lee (Brigham and Women’s H ­ ospital/Harvard Medical School) for their research and writing assistance. We thank FDA, Professional Compounding Centers of America, National Association of Boards of Pharmacy, Massachusetts Board of Registration in Pharmacy, Office of Tennessee Attorney General, National Women’s Health Network, American Society for Reproductive Medicine, Alliance for Pharmacy Compounding, Endocrine Society, National Community Pharmacists Asso­iation, International Academy of Compounding Phar- c macists, American Pharmacists Association, Alliance for Natural Health, Reed Smith LLP, Dr. Rebecca Glaser (Millennium Wellness Center), Dr. Daved Rosensweet (The Menopause Method), Dr. Loyd Allen (Interna- ­ tional Journal of ­ harmaceutical Compounding), Dr. Daniel Jiang (Reading P Health System), Dr. Wen Ying Sylvia Chou (National Cancer Institute), Mr. Timothy Caulfield (University of Alberta), Dr. Al Bronstein and Ms. Heba Hashem (American Association of Poison Control Centers), Drs. Avrum Bluming and Carol Tavris (Estrogen Matters), and the hundreds of patients, clinicians, and pharmacists for their generous submission of testimony, data and resources, and for the context and perspective they provided. Finally, the committee is indebted to Joe Alper for his valuable com- missioned work, and Mark Goodin for his editorial assistance in preparing this report. PREPUBLICATION COPY—Uncorrected Proofs

Contents ACRONYMS AND ABBREVIATIONS xxiii SUMMARY 1 1 INTRODUCTION 17 Study Charge, 18 Study Scope, 20 Key Definitions, 20 Study Approach, 21 Report Organization, 23 References, 25 2 AN OVERVIEW OF COMPOUNDING 29 Compounding: Types and Settings, 30 The Complexity of Compounding, 31 The Compounding Market: Supply and Demand, 36 References, 39 3  REGULATORY FRAMEWORK FOR COMPOUNDED PREPARATIONS 43 FDA-Approved Drug Products, 44 Federal Regulation of Drug Compounding, 46 Current Concerns with Federal Regulations for Compounded Drugs, 57 Professional Standards of Drug Compounding, 60 xv PREPUBLICATION COPY—Uncorrected Proofs

xvi CONTENTS State Regulation of Drug Compounding, 64 Financial Issues and Conflicts of Interest, 67 References, 70 4 REPRODUCTIVE STEROID HORMONES: SYNTHESIS, STRUCTURE, AND BIOCHEMISTRY 75 Reproductive Steroid Hormones, 76 Structure and Biochemistry of Hormones Commonly Found in Compounded Bioidentical Hormone Preparations, 79 Steroid Hormone Signaling, 84 References, 87 5 COMPOUNDED BIOIDENTICAL HORMONE PREPARATIONS 91 cBHT Preparations, 92 Types of cBHT Preparations, 95 cBHT Active Ingredients, 102 Inactive Ingredients, 110 References, 113 6 BIOAVAILABILITY OF COMPOUNDED BIOIDENTICAL HORMONE PREPARATIONS 117 Measuring Concentrations of Steroid Hormones, 118 Bioanalytical Methods to Measure the Bioavailability of Steroid Hormones, 122 Bioavailability of Compounded Bioidentical Hormone Therapy Preparations, 123 Bioavailability of Traditionally Manufactured Bioidentical Hormone Therapy Products, 130 Concluding Statements, 131 References, 132 7 THE SAFETY AND EFFECTIVENESS OF COMPOUNDED BIOIDENTICAL HORMONE THERAPY 137 Research Strategy, 138 Estrogens and Progesterone Compounded Preparations, 141 Testosterone Therapy in Men, 170 Testosterone Therapy in Women, 172 DHEA Therapy, 173 cBHT Research Challenges, 175 Summary of Research Findings, 176 Adverse Event Reporting for cBHT, 177 References, 182 PREPUBLICATION COPY—Uncorrected Proofs

CONTENTS xvii 8 THE USE OF COMPOUNDED BIOIDENTICAL HORMONE THERAPY 189 The Women’s Health Initiative: Impact on the Current Use of Hormone Therapy, 190 Bioidentical Hormone Therapy: Indications for Use, 193 Professional Guidance and Clinical Practice Guidelines for the Use of cBHT, 204 The Use of cBHT: Patterns and Trends, 212 Factors Driving Use of cBHT, 219 Concluding Statements, 227 References, 227 9 CLINICAL UTILITY AND RECOMMENDATIONS 233 What Does “Clinical Utility” Mean?, 233 The Clinical Utility of cBHT and Related Considerations, 235 Recommendations, 238 APPENDIXES A Study Approach 245 B Study Methods 255 C Glossary 263 D Biosketches 269 E 503A and 503B Distribution Supplement 279 F Compounded Bioidentical Hormone Therapy Formulations with a Single Active Ingredient 281 G Compounded Bioidentical Hormone Therapy Formulations with Two or More Active Ingredients 305 H Boxed Warnings on U.S. Food and Drug Administration– Approved Estrogen and Testosterone Products 325 PREPUBLICATION COPY—Uncorrected Proofs

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Boxes, Figures, and Tables BOXES 1-1 Statement of Task, 19 1-2 Identified Themes in the Literature on Clinical Utility, 21 1-3 Key Definitions, 22 1-4 Information-Gathering Process, 24 2-1 Allowable Compounding Under the Federal Food, Drug, and Cosmetic Act, 32 2-2 Master Formulation Record According to USP <795> for Compounded Nonsterile Preparations, 33 3-1 FTC and Deceptive Advertising, 56 3-2 Large-Scale Compounding Operations at 503A Compounding Pharmacies, 58 3-3 Illustrative Findings from Select Compounding Pharmacy Inspections, 61 3-4 United States Pharmacopeia General Chapters Related to Compounding, 62 5-1 Labeling of FDA-Approved Hormone Products and Boxed Warnings, 94 5-2 FDA Policy and Guidance on Products Combining Multiple Drugs, 101 5-3 Difficult to Compound List, 109 xix PREPUBLICATION COPY—Uncorrected Proofs

xx BOXES, FIGURES, AND TABLES 5-4 Inactive Ingredients in Estrace Cream, an FDA-Approved Product, 111 7-1 FDA-Approved Hormone Therapy Indications, 138 FIGURES 3-1 Geographic distribution of 503B outsourcing facilities throughout the United States, 49 3-2 Comparison of select steps within the statutory and regulatory processes for FDA-approved drug products and compounded drug preparations, 52 3-3 Variability in state requirements for 503A compounding pharmacy compliance with USP Chapter <795> and <797> standards, 64 4-1 Biosynthetic pathway of steroid hormones, 77 4-2 Production of bioidentical hormones from plant-produced compounds, 78 4-3 Chemical structure of estrone (E1), 79 4-4 Chemical structure of estradiol (E2) and estradiol cypionate, 80 4-5 Chemical structure of estriol (E3), 81 4-6 Chemical structure of pregnenolone, 81 4-7 Chemical structure of progesterone, 82 4-8 Chemical structure of testosterone, testosterone cypionate, and testosterone propionate, 83 4-9 Chemical structure of dehydroepiandrosterone (DHEA), 84 5-1 Comparing the strength of various compounded progesterone capsule formulations to two FDA-approved capsule strengths, 99 6-1 Correlation between salivary testosterone (T) and serum free (T) (nmol/L), 120 6-2 Steady-state serum estradiol concentration time course, 124 6-3 Serum testosterone concentrations in 12 female patients 4 weeks after therapy with a 100 mg testosterone implant, 126 8-1 Use of bioidentical hormone therapy, 194 8-2 Age differentials in users of bioidentical hormone therapy: compounded formulations versus FDA-approved drug products, 213 8-3 Sample prescription pad from deidentified compounding pharmacy’s online advertising for cBHT, 222 PREPUBLICATION COPY—Uncorrected Proofs

BOXES, FIGURES, AND TABLES xxi B-1 Literature search and article selection process flowchart for literature on the safety and effectiveness of cBHT, 256 H-1 Boxed warning included with FDA-approved estrogen-containing products, 326 H-2 Boxed warning included with FDA-approved topical testosterone products, 326 TABLES 5-1 FDA-Approved Drug Products and Availability of Medication Guides and Boxed Warnings, 94 5-2 Summary of Dosage Forms Available for FDA-Approved Bioidentical Hormone Products and Compounded Bioidentical Hormone Preparations, 97 5-3 Available Dosage Forms for Single Active Ingredient cBHT Preparations and FDA-Approved BHT Products, 98 5-4 Contributing Factors and Absorption Classifications of Bioidentical Hormones, 103 5-5 Inactive Ingredients in Estrace Cream and Their Function, 111 6-1 Examples of the Bioanalytical Methods Used to Analyze Bioidentical Hormones in Blood/Serum/Plasma from Subjects Who Were Administered cBHT, 123 6-2 Progesterone Median Bioavailability Parameters Following Daily Application of 80 mg Progesterone Custom-Compounded Cream or Gel, 128 7-1 Overview of 13 Studies Reviewed by the Committee with Relevance to the Safety and Effectiveness of cBHT, 142 7-2 Adverse Events Discovered During an FDA Inspection, 181 8-1 Common Indications and Contraindications for FDA-Approved Bioidentical Hormone Therapy Products, 196 8-2 Professional Medical Guidance on Use of cBHT, 205 8-3 Data from the 2015 NHS2 Questionnaire (n = 87,677) on Hormone Therapy Use, 215 8-4 Frequency of Types of Hormones Among Women Reporting Use of BHT (n = 1,534), 215 8-5 2017–2018 Production Levels of Select Hormones Used in Compounded Preparations by 503B Outsourcing Facilities, 218 PREPUBLICATION COPY—Uncorrected Proofs

xxii BOXES, FIGURES, AND TABLES 8-6 Published Statements and Professional Guidance on the Marketing of Compounded Bioidentical Hormone Therapy, 220 9-1 Summary of Key Conclusions Related to the Clinical Utility of cBHT Preparations, 236 E-1 Distribution of 503B Outsourcing Facilities by State, 280 PREPUBLICATION COPY—Uncorrected Proofs

Acronyms and Abbreviations ACCP American College of Clinical Pharmacy ACOG American College of Obstetricians and Gynecologists API active pharmaceutical ingredient BHRT bioidentical hormone replacement therapy BHT bioidentical hormone therapy cBHT compounded bioidentical hormone therapy CDC Centers for Disease Control and Prevention CGMP current good manufacturing practice CMC chemistry, manufacturing, and controls CNS central nervous system CPG Compliance Policy Guide DHEA dehydroepiandrosterone DMF Drug Master File DQSA Drug Quality and Security Act E1 estrone E2 estradiol E3 estriol FAERS FDA Adverse Event Reporting System FDA U.S. Food and Drug Administration FDAMA Food and Drug Administration Modernization Act xxiii PREPUBLICATION COPY—Uncorrected Proofs

xxiv ACRONYMS AND ABBREVIATIONS FDCA Federal Food, Drug, and Cosmetic Act FSD female sexual dysfunction FTC Federal Trade Commission GABA γ-amino butyric acid HHS U.S. Department of Health and Human Services HSDD hypoactive sexual desire disorder IND investigational new drug LC-MS/MS liquid chromatography–mass spectrometry MFR Master Formulation Record MHT menopausal hormone therapy MOU Memorandum of Understanding NABP National Association of Boards of Pharmacy NAMSA North American Menopause Society NDA new drug application NECC New England Compounding Center NF National Formulary NHS2 Nurses’ Health Study 2 PCAB Pharmacy Compounding Accreditation Board PCCA Professional Compounding Centers of America POI primary ovarian insufficiency PSA prostate-specific antigen RCT randomized controlled trial SERM selective estrogen receptor modulator USP United States Pharmacopeia USPSTF U.S. Preventive Services Task Force WHI Women’s Health Initiative PREPUBLICATION COPY—Uncorrected Proofs

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The U.S. Food and Drug Administration (FDA) has approved dozens of hormone therapy products for men and women, including estrogen, progesterone, testosterone, and related compounds. These products have been reviewed for safety and efficacy and are indicated for treatment of symptoms resulting from hormonal changes associated with menopause or other endocrine-based disorders. In recent decades, an increasing number of health care providers and patients have turned to custom-formulated, or compounded, drug preparations as an alternative to FDA-approved drug products for hormone-related health concerns. These compounded hormone preparations are often marketed as “bioidentical” or “natural” and are commonly referred to as compounded bioidentical hormone therapy (cBHT).

In light of the fast-growing popularity of cBHT preparations, the clinical utility of these compounded preparations is a substantial public health concern for various stakeholders, including medical practitioners, patients, health advocacy organizations, and federal and state public health agencies. This report examines the clinical utility and uses of cBHT drug preparations and reviews the available evidence that would support marketing claims of the safety and effectiveness of cBHT preparations. It also assesses whether the available evidence suggests that these preparations have clinical utility and safety profiles warranting their clinical use and identifies patient populations that might benefit from cBHT preparations in lieu of FDA-approved BHT.

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