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

THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu

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: 978-0-309-67712-7
International Standard Book Number-10: 0-309-67712-2
Digital Object Identifier: https://doi.org/10.17226/25791
Library of Congress Control Number: 2020941544

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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.

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

JENNIFER HINNERS, Program Officer

ANNA SBEREGAEVA, Associate Program Officer (until May 2019)

ELIZABETH 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

Consultant

JOE ALPER, Science Writer

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 manuscript remain confidential to protect the integrity of the deliberative process.

We thank the following individuals for their review of this report:

Although the reviewers listed above provided many constructive comments 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 examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.

Preface

Across the history of medicine, preparation of a compounded medication by a physician or a 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 effectiveness to support treatment decisions. During this same time, therapeutic 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 patients with the disease.

This approach, leading to the development of U.S. Food and Drug Administration (FDA)-approved medications, and moving away from anecdotal 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, treatment 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 increase in supply and demand of cBHT has prompted the need for additional

data on the safety and effectiveness of these medications, as compounded medications are not reviewed for safety and efficacy nor approved by FDA.

The Committee on the Clinical Utility of Treating Patients with Compounded 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 multidimensional 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 societies. In addition, we received extensive correspondence from stakeholders, including that of patients and providers who use cBHT, compounding (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 reviewed, the committee became even more aware of strong preferences for individualized 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 recommendations 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

drugs, all of which have demonstrated clinical utility for treatment of symptoms 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 cheerfulness 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.

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Acknowledgments

The committee takes this opportunity to recognize the many individuals 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 associate; 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 acknowledge 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 executive office staff of the Health and Medicine Division, as well as Taryn 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 who generously contributed to this body of work. We extend our thanks to Phebe Hong

(Harvard Law School) and ChangWon C. Lee (Brigham and Women’s Hospital/Harvard Medical School) for their research and writing assistance. We thank Alliance for Natural Health, Alliance for Pharmacy Compounding, American Pharmacists Association, American Society for Reproductive Medicine, Endocrine Society, FDA, International Academy of Compounding Pharmacists, Massachusetts Board of Registration in Pharmacy, National Association of Boards of Pharmacy, National Community Pharmacists Association, National Women’s Health Network, Office of Tennessee Attorney General, Professional Compounding Centers of America, Reed Smith LLP, Dr. Loyd Allen (International Journal of Pharmaceutical Compounding), Drs. Avrum Bluming and Carol Tavris (Estrogen Matters), Dr. Al Bronstein and Ms. Heba Hashem (American Association of Poison Control Centers), Mr. Timothy Caulfield (University of Alberta), Dr. Wen Ying Sylvia Chou (National Cancer Institute), Dr. Rebecca Glaser (Millennium Wellness Center), Dr. Daniel Jiang (Reading Health System), Dr. Daved Rosensweet (The Menopause Method), 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 commissioned work, and Mark Goodin for his editorial assistance in preparing this report.

Contents

ACRONYMS AND ABBREVIATIONS

SUMMARY

1 INTRODUCTION

Study Charge

Study Scope

Key Definitions

Study Approach

Report Organization

References

2 AN OVERVIEW OF COMPOUNDING

Compounding: Types and Settings

The Complexity of Compounding

The Compounding Market: Supply and Demand

References

3 REGULATORY FRAMEWORK FOR COMPOUNDED PREPARATIONS

FDA-Approved Drug Products

Federal Regulation of Drug Compounding

Current Concerns with Federal Regulations for Compounded Drugs

Professional Standards of Drug Compounding

State Regulation of Drug Compounding

Financial Issues and Conflicts of Interest

References

4 REPRODUCTIVE STEROID HORMONES: SYNTHESIS, STRUCTURE, AND BIOCHEMISTRY

Reproductive Steroid Hormones

Structure and Biochemistry of Hormones Commonly Found in Compounded Bioidentical Hormone Preparations

Steroid Hormone Signaling

References

5 COMPOUNDED BIOIDENTICAL HORMONE PREPARATIONS

cBHT Preparations

Types of cBHT Preparations

cBHT Active Ingredients

Inactive Ingredients

References

6 BIOAVAILABILITY OF COMPOUNDED BIOIDENTICAL HORMONE THERAPY PREPARATIONS

Measuring Concentrations of Steroid Hormones

Bioanalytical Methods to Measure the Bioavailability of Steroid Hormones

Bioavailability of Compounded Bioidentical Hormone Therapy Preparations

Bioavailability of Traditionally Manufactured Bioidentical Hormone Therapy Products

Concluding Statements

References

7 THE SAFETY AND EFFECTIVENESS OF COMPOUNDED BIOIDENTICAL HORMONE THERAPY

Research Strategy

Estrogens and Progesterone Compounded Preparations

Testosterone Therapy in Men

Testosterone Therapy in Women

DHEA Therapy

cBHT Research Challenges

Summary of Research Findings

Adverse Event Reporting for cBHT

References

8 THE USE OF COMPOUNDED BIOIDENTICAL HORMONE THERAPY

The Women’s Health Initiative: Impact on the Current Use of Hormone Therapy

Bioidentical Hormone Therapy: Indications for Use

Professional Guidance and Clinical Practice Guidelines for the Use of cBHT

The Use of cBHT: Patterns and Trends

Factors Driving the Use of cBHT

Concluding Statements

References

9 CLINICAL UTILITY AND RECOMMENDATIONS

What Does “Clinical Utility” Mean?

The Clinical Utility of cBHT and Related Considerations

Recommendations

APPENDIXES

A Study Approach

B Study Methods

C Glossary

D Biosketches

E 503A and 503B Distribution Supplement

F Compounded Bioidentical Hormone Therapy Formulations with a Single Active Ingredient

G Compounded Bioidentical Hormone Therapy Formulations with Two or More Active Ingredients

H Boxed Warnings on U.S. Food and Drug Administration–Approved Estrogen and Testosterone Products

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Boxes, Figures, and Tables

BOXES

1-1 Statement of Task

1-2 Identified Themes in the Literature on Clinical Utility

1-3 Key Definitions

1-4 Information-Gathering Process

2-1 Allowable Compounding Under the Federal Food, Drug, and Cosmetic Act

2-2 Master Formulation Record According to USP <795> for Compounded Nonsterile Preparations

3-1 FTC and Deceptive Advertising

3-2 Large-Scale Compounding Operations at 503A Compounding Pharmacies

3-3 Illustrative Findings from Select Compounding Pharmacy Inspections

3-4 United States Pharmacopeia General Chapters Related to Compounding

5-1 Labeling of FDA-Approved Hormone Products and Boxed Warnings

5-2 FDA Policy and Guidance on Products Combining Multiple Drugs

5-3 Difficult to Compound List

5-4 Inactive Ingredients in Estrace Cream, an FDA-Approved Drug Product

7-1 FDA-Approved Hormone Therapy Indications

FIGURES

3-1 Geographic distribution of 503B outsourcing facilities throughout the United States

3-2 Comparison of select steps within the statutory and regulatory processes for FDA-approved drug products and compounded drug preparations

3-3 Variability in state requirements for 503A compounding pharmacy compliance with USP Chapter <795> and <797> standards

4-1 Biosynthetic pathway of steroid hormones

4-2 Production of bioidentical hormones from plant-produced compounds

4-3 Chemical structure of estrone (E1)

4-4 Chemical structure of estradiol (E2) and estradiol cypionate

4-5 Chemical structure of estriol (E3)

4-6 Chemical structure of pregnenolone

4-7 Chemical structure of progesterone

4-8 Chemical structure of testosterone, testosterone cypionate, and testosterone propionate

4-9 Chemical structure of dehydroepiandrosterone (DHEA)

5-1 Comparing the strength of various compounded progesterone capsule formulations to two FDA-approved capsule strengths

6-1 Correlation between salivary testosterone (T) and serum free (T) (nmol/L)

6-2 Steady-state serum estradiol concentration time course

6-3 Serum testosterone concentrations in 12 female patients 4 weeks after therapy with a 100 mg testosterone implant

8-1 Use of bioidentical hormone therapy

8-2 Age differentials in users of bioidentical hormone therapy: compounded formulations versus FDA-approved drug products

8-3 Sample prescription pad from deidentified compounding pharmacy’s online advertising for cBHT

B-1 Literature search and article selection process flowchart for literature on the safety and effectiveness of cBHT

H-1 Boxed warning included with FDA-approved estrogen-containing products

H-2 Boxed warning included with FDA-approved topical testosterone products

TABLES

5-1 FDA-Approved Drug Products and Availability of Medication Guides and Boxed Warnings

5-2 Summary of Dosage Forms Available for FDA-Approved Bioidentical Hormone Therapy (BHT) Products and Compounded Bioidentical Hormone Therapy (cBHT) Preparations

5-3 Available Dosage Forms for Single Active Ingredient cBHT Preparations and FDA-Approved BHT Products

5-4 Contributing Factors and Absorption Classifications of Bioidentical Hormones

5-5 Inactive Ingredients in Estrace Cream and Their Function

6-1 Examples of the Bioanalytical Methods Used to Analyze Bioidentical Hormones in Blood/Serum/Plasma from Subjects Who Were Administered cBHT

6-2 Progesterone Median Bioavailability Parameters Following Daily Application of 80 mg Progesterone Custom-Compounded Cream or Gel

7-1 Overview of 13 Studies Reviewed by the Committee with Relevance to the Safety and Effectiveness of cBHT

7-2 Adverse Events Discovered During an FDA Inspection

8-1 Common Indications and Contraindications for FDA-Approved Bioidentical Hormone Therapy Products

8-2 Professional Medical Guidance on the Use of cBHT

8-3 Data from the 2015 NHS2 Questionnaire on Hormone Therapy Use (n = 87,677)

8-4 Frequency of Types of Hormones Among Women Reporting Use of BHT (n = 1,534)

8-5 2017–2018 Production Levels of Select Hormones Used in Compounded Preparations by 503B Outsourcing Facilities

8-6 Published Statements and Professional Guidance on the Marketing of Compounded Bioidentical Hormone Therapy

9-1 Summary of Key Conclusions Related to the Clinical Utility of cBHT Preparations

E-1 Distribution of 503B Outsourcing Facilities by State

Acronyms and Abbreviations