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Suggested Citation:"Appendix A: Study Approach." 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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Appendix A

Study Approach

Responding to a request by the U.S. Food and Drug Administration (FDA), the National Academies of Sciences, Engineering, and Medicine’s Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy was charged with reviewing use patterns of compounded bioidentical hormone therapy (cBHT), the physiochemical properties of cBHT, and the available evidence on the safety and effectiveness of cBHT preparations.

COMMITTEE EXPERTISE

The National Academies appointed a 12-member committee of experts to address objectives in the Statement of Task. The resulting committee included experts in a variety of disciplines and fields, including drug research and development, pharmacology, toxicology, endocrinology, epidemiology, health literacy, pharmaceutical compounding and manufacturing, health risk mitigation, and health policy.

MEETINGS AND INFORMATION-GATHERING ACTIVITIES

The committee deliberated from March 2019 to April 2020, during the course of which it held five in-person meetings (March, May, June, August, and November) and four virtual meetings (one in September, two in January, and one in April). The March, May, June, and November meetings included portions open to the public. One of the January virtual

Suggested Citation:"Appendix A: Study Approach." 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.
×

meetings was open in its entirety. All other meetings were closed to support the committee’s private deliberations.

In the open session meetings, the committee heard presentations from invited content experts on a wide variety of topics related to the committee’s charge. These open-session meetings also included periods of public comment, to provide an additional opportunity to present the committee with relevant information. The agendas for the five open-session meetings are presented here.

First Committee Meeting

Open Session Agenda

Tuesday, March 5, 2019
National Academies Keck Center
500 Fifth Street, NW, Washington, DC 20001

Part I
Sponsor Briefing: Discussion of the Committee’s Charge

1:15 p.m. Welcome and Introductions
JEROME (JERRY) STRAUSS III, M.D.
Committee Chair
1:20 p.m. Sponsor Perspective on Charge to the Committee
RUEY JU, PHARM.D., J.D., Study Sponsor
U.S. Food and Drug Administration
LESLEY FURLONG, M.D., Study Sponsor
U.S. Food and Drug Administration
2:00 p.m. Discussion with Committee
2:45 p.m. BREAK

Part II
Additional Context for the Study

3:00 p.m. Key Stakeholder Perspectives
BARBARA EXUM, PHARM.D., Director
Center for Compounding Practice and Research
Virginia Commonwealth University
Suggested Citation:"Appendix A: Study Approach." 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.
×
  TIMOTHY MCPHERSON, PH.D., Professor [REMOTE]
Department of Pharmaceutical Sciences
Southern Illinois University, Edwardsville
NESE YUKSEL, PHARM.D., Professor
Faculty of Pharmacy and Pharmaceutical Sciences
University of Alberta
4:00 p.m. Discussion with Committee
4:45 p.m. Public Comments
5:00 p.m. ADJOURN

Second Committee Meeting

Open Session Workshop Agenda

Monday, May 6, 2019
National Academies Keck Center
500 Fifth Street, NW, Washington, DC 20001

9:00 a.m. Introductions
LEIGH MILES JACKSON, PH.D., Study Director
Board on Health Sciences Policy
Health and Medicine Division
DONALD MATTISON, M.D.
Committee Chair
RUTH PARKER, M.D.
Committee Vice Chair

Session I
Context for the Current Study

9:10 a.m. Overview Session
CYNTHIA STUENKEL, M.D.
University of California, San Diego
BRANT HARRELL, J.D.
Office of Tennessee Attorney General
Suggested Citation:"Appendix A: Study Approach." 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.
×
  SARA ROTHMAN, M.P.H.
U.S. Food and Drug Administration
9:55 a.m. Discussion and Q&A

Session II
Consumer Engagement, Education, and Medical Care

10:40 a.m. Perspectives from Consumers, Educators, and Medical Care Providers
Consumer Education Perspectives
PHYLLIS GREENBERGER, M.S.W.
Healthy Women
CINDY PEARSON, M.D. [REMOTE]
National Women’s Health Network
LYN HOGREFE, M.S. [REMOTE]
Happy Hormone Cottage
Provider Perspectives
NANETTE SANTORO, M.D. [REMOTE]
University of Colorado Denver
ADRIAN SANDRA DOBS, M.D., M.H.S.
Johns Hopkins University School of Medicine
WANDA DYSON, M.D.
Change for Life Wellness & Aesthetics
DAVED ROSENSWEET, M.D.
The Menopause Method
12:40 p.m. LUNCH BREAK

Session III
Pharmaceutical Sciences and Compounding Panel

1:45 p.m. Perspectives from Compounding Pharmacists
A. J. DAY, PHARM.D., R.PH. [REMOTE]
Professional Compounding Centers of America
GUS BASSANI, PHARM.D.
Professional Compounding Centers of America
Suggested Citation:"Appendix A: Study Approach." 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.
×
  JIM HRNCIR, R.PH.
Las Colinas Pharmacy
LOYD ALLEN, JR., PH.D., R.PH. [REMOTE]
International Journal of Pharmaceutical Compounding
3:15 p.m. Discussion with Committee
4:00 p.m. Public Comments
4:15 p.m. ADJOURN

Third Committee Meeting

Open Session Agenda

Thursday, June 27, 2019
National Academies Keck Center
500 Fifth Street, NW, Washington, DC 20001

12:45 p.m. Welcome and Introductions
DONALD MATTISON, M.D.
Committee Chair
RUTH PARKER, M.D.
Committee Vice Chair
12:50 p.m. Presentations from Invited Speakers
LOYD ALLEN, JR., PH.D., R.PH.
International Journal of Pharmaceutical Compounding
JANE AXELRAD, J.D.
Axelrad Solutions LLC
REBECCA GLASER, M.D.
Millennium Wellness Center
2:45 p.m. Public Comments
3:00 p.m. ADJOURN
Suggested Citation:"Appendix A: Study Approach." 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.
×

Sixth Committee Meeting

Open Session Agenda

Tuesday, November 12, 2019
National Academies Keck Center
500 Fifth Street, NW, Washington, DC 20001

12:45 p.m. Doors Open
1:00 p.m. Introductions
LEIGH MILES JACKSON, PH.D., Study Director
Board on Health Sciences Policy
Health and Medicine Division
DONALD MATTISON, M.D.
Committee Chair
RUTH PARKER, M.D.
Committee Vice Chair
1:05 p.m. Perspectives from Professional Associations and Organizations
THOMAS MENIGHAN, B.S.PHARM., M.BA., SC.D. (HON), FAPHA
Executive Vice President and Chief Executive Officer
American Pharmacists Association
RONNA B. HAUSER, PHARM.D.
Vice President
Policy & Government Affairs Operations
National Community Pharmacist Association
1:30 p.m. Q&A and Discussion (moderated by committee members)
1:45 p.m. Perspectives from Providers
GARY S. DONOVITZ, M.D., FACOG
Founder
BioTE Medical, LLC
PAMELA SMITH, M.D., M.P.H., M.S.
Founder and Director
Center for Personalized Medicine
Suggested Citation:"Appendix A: Study Approach." 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.
×
2:15 p.m. Q&A and Discussion (moderated by committee members)
2:45 p.m. BREAK
3:00 p.m. Perspectives from Compounding Pharmacists
PETER KOSHLAND, PHARM.D.
Chief Executive Officer
Koshland Pharmacy
GINA BESTEMAN, R.PH.
Director
Compounding and Dispensing
Women’s International Pharmacy
3:30 p.m. Q&A and Discussion (moderated by committee members)
4:00 p.m. Public Comments
4:30 p.m. ADJOURN

Seventh Committee Meeting

Open Session Agenda

Tuesday, January 14, 2019
National Academies Keck Center
500 Fifth Street, NW, Washington, DC 20001

12:00 p.m. Introductions
LEIGH MILES JACKSON, PH.D., Study Director
Board on Health Sciences Policy
Health and Medicine Division
DONALD MATTISON, M.D.
Committee Chair
RUTH PARKER, M.D.
Committee Vice Chair
12:05 p.m. Perspectives from Invited Speakers
RACHEL PONTIKES, J.D.
Partner
Reed Smith LLP
Suggested Citation:"Appendix A: Study Approach." 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.
×
  ANGELA DEROSA, D.O., M.B.A.
Medical Director
Belmar Pharmacy & Belmar Select Outsourcing
DOUG CAMMANN, R.PH.
Vice President
Operations
AnazaoHealth Corporation
DONALD PRENTISS
President
Operations
Carie Boyd’s Prescription Shop
THOMAS C. KUPIEC, PH.D.
President and Chief Executive Officer
ARL BioPharma, Inc., DNA Solutions, Inc., The Kupiec Group, LLC
1:20 p.m. Q&A and Discussion (moderated by committee members)
1:40 p.m. Public Comments
2:00 p.m. ADJOURN

RESOURCES SUBMITTED BY STAKEHOLDERS

Recognizing the limited information available addressing the use, safety, effectiveness, and patient perspectives of cBHT, the committee also made concerted efforts to collect and review relevant anecdotal, survey, and (when possible) quantitative data from national stakeholders to supplement their research efforts. For example, relevant data were submitted by stakeholders, including 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, representatives of 503A compounding pharmacies and 503B outsourcing facilities; an editor-in-chief of a leading compounding journal; nonprofit medical and pharmaceutical societies and organizations; compounding advocacy organizations; and nonprofit wellness organizations; women’s health advocacy groups; and medical prescribers and researchers of cBHT. Several testimonies, position statements, and letters were also submitted by Alliance for Natural Health, Alliance for Pharmacy Compounding, American Pharmacists Association,

Suggested Citation:"Appendix A: Study Approach." 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.
×

American Society for Reproductive Medicine, Endocrine Society, International Academy of Compounding Pharmacists, National Community Pharmacists Association, Reed Smith LLP, Senator Lamar Alexander, Congressman Mark Pocan and Chris Stewart, and thousands of patients and professional advocates of cBHT.

COMMITTEE REQUEST FOR INFORMATION ON CBHT PREFERENCE AND USE

A “Dear Stakeholder” letter was emailed to a diverse group of study stakeholders in the summer of 2019.1 The letter invited the stakeholders to disseminate questionnaire links to their membership networks and/or followers in order to gather public input on the use of cBHT from three relevant populations: consumers, providers, and pharmacists and compounders.

A total of 3,370 respondents who self-identified as consumers initiated the questionnaire, and 2,068 completed it; 327 respondents who self-identified as prescribers started the questionnaire, and 180 finished it; and 386 respondents who self-identified as pharmacists or compounders began the questionnaire with 166 completing it. Although the majority of responses came from the United States, a portion of the overall input was received from the international community.

The questionnaire was not designed to capture a nationally representative sample of consumers, prescribers, or compounders, and therefore, likely has a high risk of selection bias. As a result of this confound, the questionnaire cannot be used to provide quantitative data to inform the conclusions on the use of cBHT. Instead, the committee used the qualitative responses as testimonial evidence to better understand overall perspectives on cBHT use and preference, evidence that is difficult to derive from the current evidence base.

Summary of Responses

Respondents Who Identified as Consumers

Respondents to the consumer questionnaire reported first learning about options for cBHT use from sources that included their physician and through word of mouth from other sources. Similarly, respondents reported relying on their physicians, as well as Internet sources, books,

___________________

1 Stakeholders included medical societies, wellness centers and organizations, women’s health organizations, pharmacy associations, compounding organizations, government agencies, and education and research institutions.

Suggested Citation:"Appendix A: Study Approach." 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.
×

and scientific literature, for information related to the potential safety and effectiveness of both cBHT and FDA-approved hormone therapy. Certain respondents expressed a lack of concern for the quality, safety, or effectiveness of cBHT preparations, while at the same time, also expressing concern for the quality, safety, and effectiveness of FDA-approved hormone therapy. Respondents who were satisfied with their use of cBHT tended to describe their satisfaction in terms of a preference for natural medications, overall improved well-being, and little to no adverse reactions.

Respondents Who Identified as Prescribers

Respondents who responded to the prescriber questionnaire specialized in fields including family medicine, obstetrics and gynecology, and wellness. Similarly, respondents represented various medical professions, including doctors of medicine (M.D.), doctors of osteopathy (D.O.), and nurse practitioners. Certain respondents expressed a lack of concern for the safety, product labeling, or quality of cBHT preparations, and reported a reliance on clinical trial data, professional experience, and patient response for evaluations on the safety and effectiveness of cBHT. Respondents varied widely in the types of circumstances they believed were appropriate to prescribe cBHT, in lieu of FDA-approved hormone therapy products. Certain respondents reported that they would prescribe only cBHT to their patients, while others described a narrow set of circumstances that would lead them to prescribe cBHT, in lieu of FDA-approved hormone therapies.

Respondents Who Identified as Pharmacists or Compounders

The respondents to the pharmacist and compounder questionnaire described a reliance on both published literature and professional experience for evidence on the potential safety and effectiveness of cBHT preparations. Resources for patients who describe the safety of cBHT formations varied—some respondents only provided oral instructions for use, others shared resources from compounding trade organizations, and still others distributed written information and instructions that were developed in house. Some respondents expressed having minimal concerns with the safety, labeling, or quality of cBHT preparations, while others stated that all hormones have risks.

Suggested Citation:"Appendix A: Study Approach." 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.
×
Page 229
Suggested Citation:"Appendix A: Study Approach." 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.
×
Page 230
Suggested Citation:"Appendix A: Study Approach." 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.
×
Page 231
Suggested Citation:"Appendix A: Study Approach." 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.
×
Page 232
Suggested Citation:"Appendix A: Study Approach." 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.
×
Page 233
Suggested Citation:"Appendix A: Study Approach." 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.
×
Page 234
Suggested Citation:"Appendix A: Study Approach." 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.
×
Page 235
Suggested Citation:"Appendix A: Study Approach." 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.
×
Page 236
Suggested Citation:"Appendix A: Study Approach." 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.
×
Page 237
Suggested Citation:"Appendix A: Study Approach." 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.
×
Page 238
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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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