IN THE CIRCUIT COURT FOR
Janet Watkins
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PCAC-09122018-PM-Transcript 1
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FOOD AND DRUG ADMINISTRATION
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CENTER FOR DRUG EVALUATION AND RESEARCH
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PHARMACY COMPOUNDING ADVISORY COMMITTEE (PCAC)
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Wednesday, September 12, 2018
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1:17 p.m. to 4:36 p.m.
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Afternoon Session
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FDA White Oak Campus
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Building 31, the Great Room
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10903 New Hampshire Avenue
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Silver Spring, Maryland
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A Matter of Record (301) 890-4188
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Meeting Roster
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ACTING DESIGNATED FEDERAL OFFICER (Non-Voting)
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Jay R. Fajiculay, PharmD
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Division of Advisory Committee and Consultant
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Management
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Office of Executive Programs, CDER, FDA
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PHARMACY COMPOUNDING ADVISORY COMMITTEE MEMBERS
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(Voting)
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Robin H. Bogner, PhD
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Professor
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University of Connecticut
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School of Pharmacy
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Department of Pharmaceutical Sciences
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Storrs, Connecticut
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Michael A. Carome, MD, FASHP
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(Consumer Representative)
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Director of Health Research Group
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Public Citizen
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Washington, District of Columbia
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Seemal R. Desai, MD, FAAD
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President and Medical Director
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Innovative Dermatology
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Plano, Texas
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Padma Gulur, MD (via phone)
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Vice Chair, Operations and Performance
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Duke University School of Medicine
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Department of Anesthesiology
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Duke University Medical Center
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Durham, North Carolina
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Stephen W. Hoag, PhD
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Professor
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Department of Pharmaceutical Science
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University of Maryland, Baltimore
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Baltimore, Maryland
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William A. Humphrey, BSPharm, MBA, MS
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Director, Pharmacy Operations
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St. Jude Children's Research Hospital
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Memphis, Tennessee
A Matter of Record (301) 890-4188
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Elizabeth Jungman, JD
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Director, Public Health Programs
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The Pew Charitable Trusts
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Washington, District of Columbia
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Kuldip R, Patel, PharmD
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Associate Chief Pharmacy Officer
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Duke University Hospital
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Durham, North Carolina
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Allen J. Vaida, BSc, PharmD, FASHP
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(Acting Chairperson)
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Executive Vice President
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Institute for Safe Medication Practices
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Horsham, Pennsylvania
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Jurgen Venitz, MD, PhD (via phone)
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Professor and Vice Chairman
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Virginia Commonwealth University
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School of Pharmacy, Department of Pharmaceutics
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Richmond, Virginia
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A Matter of Record (301) 890-4188
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Donna Wall, PharmD
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(National Association of Boards of Pharmacy
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Representative)
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Clinical Pharmacist
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Indiana University Hospital
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Indianapolis, Indiana
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PHARMACY COMPOUNDING ADVISORY COMMITTEE MEMBERS
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(Non-Voting)
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William Mixon, RPh, MS, FIACP
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(Industry Representative)
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Former Owner
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The Compounding Pharmacy
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Hickory, North Carolina
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Christopher J. Smalley, MS, MBA
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(Industry Representative)
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Compounding Pharmacy Consultant
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ValSource
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Downingtown, Pennsylvania
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TEMPORARY MEMBERS (Voting)
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Thomas Chelimsky, MD
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(Participation in alpha lipoic acid, coenzyme Q10,
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and creatine monohydrate discussion)
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Tenured Professor of Neurology
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Medical College of Wisconsin
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Milwaukee, Wisconsin
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Marc Gregory Ghany, MD, MHSc, FAASLD
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(Participation in alpha lipoic acid, coenzyme Q10,
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and creatine monohydrate discussion)
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Investigator
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Liver Diseases Branch
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National Institute of Diabetes and Digestive and
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Kidney Diseases
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National Institutes of Health
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Bethesda, Maryland
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Hrissanthi (Chris) Ikonomidou, MD, PhD
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(Participation in alpha lipoic acid, coenzyme Q10,
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creatine monohydrate, and pyridoxal 5 phosphate
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monohydrate discussion)
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Professor of Child Neurology (Tenured)
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Department of Neurology
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University of Wisconsin, School of Medicine and
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Public Health
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Madison, Wisconsin
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Sandeep Khurana, MBBS
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(Participation in alpha lipoic acid, coenzyme Q10,
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and creatine monohydrate discussion)
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Medical Director
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Liver Transplantation
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Geisinger Health System
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Danville, Pennsylvania
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Jeanne H. Sun, PharmD
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(U.S. Pharmacopeia Representative)
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Manager, Compounding
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U.S. Pharmacopeial Convention
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Rockville, Maryland
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FDA PARTICIPANTS (Non-Voting)
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Julie Dohm, JD, PhD
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Senior Science Advisor for Compounding
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CDER, FDA
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Frances Gail Bormel, RPh, JD
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Director
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Division of Prescription Drugs
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Office of Unapproved Drugs and
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Labeling Compliance (OUDLC), OC, CDER, FDA
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Rosilend Lawson, VMD, JD
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Lead Regulatory Counsel (Acting)
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Pharmacy Compounding Advisory Committee Team
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Division of Prescription Drugs
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OUDLC, OC, CDER, FDA
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Susan Johnson, PharmD, PhD
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Associate Director
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ODE IV, OND, CDER, FDA
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Ruey Ju, JD, PharmD
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Senior Advisor for Compounding
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Office of Compliance (OC), CDER, FDA
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Sara Rothman, MPH
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Senior Policy Advisor
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OUDLC, OC, CDER, FDA
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Charles Ganley, MD
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Director
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Office of Drug Evaluation IV (ODE IV)
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Office of New Drugs (OND), CDER, FDA
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A Matter of Record (301) 890-4188
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C O N T E N T S
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AGENDA ITEM
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SECTION 503A BULK DRUG SUBSTANCES LIST
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FDA Presentation
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Creatine monohydrate
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Susan Johnson, PharmD, PhD
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Clarifying Questions from the Committee
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Nominator Presentation
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A.J. Day, PharmD
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Clarifying Questions from the Committee
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Open Public Hearing
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Committee Discussion and Vote
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FDA Presentation
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Pyridoxal 5 phosphate monohydrate
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Susan Johnson, PharmD, PhD
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Nominator Presentation
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Tom Wynn, RPh
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Clarifying Questions from the Committee
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Committee Discussion and Vote
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C O N T E N T S (continued)
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AGENDA ITEM
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65 73 83 87
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A Matter of Record (301) 890-4188
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FDA Presentation
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Quercetin dihydrate
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Charles Ganley, MD
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Clarifying Questions from the Committee
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Nominator Presentation
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Paul Anderson, MD
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Clarifying Questions from the Committee
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Open Public Hearing
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Committee Discussion and Vote
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Adjournment
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P R O C E E D I N G S
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(1:17 p.m.)
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DR. VAIDA: We're going to get started with
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Susan Johnson, once again, for creatine
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monohydrate.
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FDA Presentation - Susan Johnson
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DR. JOHNSON: Well, good afternoon. I hope
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everyone had a nice lunch. Once again, my name is
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Susan Johnson, and I'm from the Office of Drug
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Evaluation IV in CDER's Office of New Drugs, and
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we're now discussing the nomination for creatine
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monohydrate.
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Again, I'd like to thank the review team and
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express their thanks to you for participating in
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this process and for reviewing the dense reviews
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that we put out to you. We prepare them with care,
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and we appreciate you paying attention to the
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details of them.
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Creatine monohydrate has been nominated for
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inclusion on the list of bulk drug substances for
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use in compounding under Section 503A. It's
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proposed for oral use in the treatment of
A Matter of Record (301) 890-4188
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mitochondrial disorders. We also evaluated it for
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use in the treatment of creatine deficiency
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syndromes, which were not proposed in the
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nomination.
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Creatine monohydrate and creatine are
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considered the same active pharmaceutical
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ingredient or API, and I'll be referring to them
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both as creatine. Creatine is a nonessential amino
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acid with a well characterized structure. It's
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slightly soluble in water.
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Based on published literature, we find it's
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likely to be stable at room temperature in solid
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dosage forms if kept away from moisture. Aqueous
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solution, including those intended for oral
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administration, are likely to be unstable.
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We are aware that the nominators may have
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more information about the stability of liquid
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formulations similar to the ALA scenario that we
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talked about this morning, and we will certainly
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take it, the committee's comments, and other public
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comments that we receive through the docket into
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consideration as we proceed through subsequent
A Matter of Record (301) 890-4188
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rulemaking.
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The synthesis of creatine as a bulk
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substance is illustrated here. In summary, we find
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creatine is well characterized and likely to be
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stable in solid oral dosage forms. In healthy
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humans, creatine is endogenously synthesized from
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other amino acids at a rate of up to approximately
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2 grams per day. The synthesis process involves
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the kidney, pancreas, and liver. Once synthesized,
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creatine is transported to other tissues in the
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body that use energy, including the brain.
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Creatine supply can also come from ingestion
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of animal products. Creatine helps to ensure the
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energy supply to muscle and other tissues. When
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muscles are at rest, the high energy phosphate bond
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from ATP is transferred to creatine, and creatine
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phosphate is then stored. During submaximal
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exercise, ATP is generated through aerobic
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glycolysis, and creatine is less involved. During
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intense exercise, creatine phosphate stores are
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used in the anaerobic glycogenolysis process.
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Pharmacokinetics from rodent models of oral
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dosing with creatine show that it's quickly
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absorbed but has low bioavailability that may be
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due to solubility issues. In humans, absorption is
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thought to be dependent on both -- we're on slide 8
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if folks want to proceed with the paper copies.
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Slide 8. Let me just begin again on slide
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8. Pharmacokinetics from rodent models of oral
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dosing with creatine show that it's quickly
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absorbed but has low bioavailability. In humans,
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absorption is thought to be dependent on both
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active and passive transport through the intestinal
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wall, although information about bioavailability is
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not available.
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Cellular uptake of creatine relies on a
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creatine transporter. Creatine storage in muscle
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is a saturable process. Excess creatine from
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dietary intake or supplementation is excreted in
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the urine. In muscle tissue, creatine is slowly
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converted to creatinine, released from the muscle,
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and eliminated in the urine. We found no
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information about the pharmacokinetics of creatine
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in patients with mitochondrial disorders or
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creatine deficiency syndromes.
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We're on slide 9. In a 15-day toxicity
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study in which rats and chickens were given
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creatine in their drinking water, no adverse event
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findings were noticed. In rodent models,
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conflicting findings have been observed. In one
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study, rats showed no adverse effects, while in
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another study, rats with existing kidney disease
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showed additional reduced renal function.
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Similarly, in adverse events of the liver,
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inflammatory changes were seen in liver studies of
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mice but not in rats. So both in hepatic and renal
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toxicity realms we have conflicting animal data.
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The standard Ames assay was negative for
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creatine. You may remember the public discussion
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about creatine as a component of meat being heated
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to high temperatures and becoming mutagenic. While
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that's unlikely to have relevance to pharmacy
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compounding, we mention it here because folks may
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actually remember the public discussion of creatine
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in that context. We found no developmental or
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reproductive toxicity and no carcinogenicity data
A Matter of Record (301) 890-4188
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for creatine.
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Moving to slide 10, with regard to clinical
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safety, the FAERS system contained four reports,
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including two serious cases. Given the animal
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toxicity data suggesting renal or hepatic safety
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issues, we're just providing some additional detail
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about these cases.
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One case reported the death of a 42-year-old
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male who experienced cardiac arrest while on
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hemodialysis due to acute renal failure. The
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patient had recently been diagnosed with diabetes
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and had been prescribed Metformin. He developed
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lactic acidosis, a known side effect of Metformin,
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and the reporters said it's unclear whether his
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renal failure may have been related to preexisting
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diabetic nephropathy, although some suspicion of
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the contribution of creatine was described in the
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report.
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A 38-year-old male who had been taking
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creatine supplements for several years was
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diagnosed with cholestatic hepatitis. Since he was
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also taking anabolic steroids, it was thought that
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those were most likely causal.
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Creatine is sold as a dietary ingredient in
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dietary supplement products often taken with the
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intent of increasing muscle strength. The CAERS
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database contained 139 reports, including 4 deaths
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that appear unrelated to creatine. No renal
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toxicity was reported among those cases.
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Moving on to slide 11, we found no reports
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of serious adverse events from studies of patients
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with mitochondrial disorders, and there were no
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studies in patients with creatine deficiency
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syndromes. We identified one case report of a
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patient with creatine deficiency syndrome who
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experienced urinary crystals at a dose of 800
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milligrams per kilogram per day -- I'm sorry,
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800 milligrams per day. I was correct the first
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time; 800 milligrams per kilogram per day. The
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condition resolved with a dose reduction.
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In another published case report, an 18-
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year-old male with mitochondrial disease and
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preexisting nephropathy experienced increased renal
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insufficiency with urea retention and reduced
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creatinine clearance. The patient admitted to
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having used creatine for a period of time during
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the decline of his condition. And because the
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decline was gradual, the reporting clinicians
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attributed it to his underlying disease but also
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cautioned about the potential for safety issues
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associated with the use of creatine in patients
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with mitochondrial disorders.
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In 2012, Gualano and colleagues undertook a
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review of the considerable volume of published
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information about creatine and renal toxicity. The
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review concluded that doses up to 5 grams per day
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over a period of months in healthy individuals
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appears to be safe. Doses higher than 5 grams per
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day were not recommended. And it was observed in
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their review that data in special populations,
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particularly those with disorders that may affect
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renal function, have not been well studied.
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With regard to the safety of creatine, we
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conclude that in healthy adults, it's generally
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safe. Urinary crystals may be associated with high
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prolonged dosing, but this was reported in patients
A Matter of Record (301) 890-4188
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with creatine deficiency syndrome. There's also
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sufficient information to support a clinical
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concern of the possibility of renal toxicity,
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particularly in patients at risk for renal
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impairment from their underlying disease. This
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includes patients with mitochondrial disorders.
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Creatine deficiency syndromes are rare
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diseases caused by autosomal recessive inborn
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genetic errors. They are not considered
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mitochondrial disorders, and they result in a
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diminished brain pool of creatine.
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There are three creatine deficiency
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syndromes, and there are no FDA-approved treatments
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for any of them. No prospective clinical trials
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have been conducted, but there is evidence that for
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at least two of these syndromes, creatine has a
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beneficial effect. These two syndromes are
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associated with the deficiency of one of two
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enzymes in the creatine synthesis process.
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L-arginine-glycine amidotransferase
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deficiency, or AGAT deficiency, appears to be
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somewhat less common than guanidinoacetate
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methyltransferase deficiency or GAMT deficiency.
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Doses of up to 800 milligrams per kilogram per day
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have been shown to increase brain creatine levels
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and improve symptoms. A third syndrome in which
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there is a deficiency of the creatine transporter
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may respond to creatine supplementation in some
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cases, but the evidence is inconsistent.
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We found 3 placebo controlled trials that
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were crossover studies of creatine's use in
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mitochondrial disorders. One of these studies
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showed minor improvement on a subset of endpoints
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only under conditions of intense exercise. The
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2015 guidelines from the Mitochondrial Medicine
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Society do not provide a recommendation on the use
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of creatine.
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There's a small amount of clinical
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information that establishes that creatine is
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effective in treating AGAT or GAMT deficiencies.
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There are no compelling data we find that support
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the use of creatine treatment in mitochondrial
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diseases.
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Having said that, we are aware that creatine
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can be used in various mito cocktails, those mixes
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of vitamins and supplements that we've described
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that are tailored by clinicians to treat
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mitochondrial disease patients, but we were unable
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to find sufficient data to establish how long and
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to what extent creatine has been used in compounded
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products.
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In summary, creatine is well characterized
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and can be stable under normal conditions in solid
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oral dosage forms, and we expect to receive
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additional information about the use in aqueous
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forms. It is generally safe, however, there are
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data that suggest a concern that creatine can be
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associated with renal toxicity, particularly in
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patients with diseases that predispose them to
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renal impairment.
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Based on literature reports and clinical
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practice, creatine is effective in treating the
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rare disease creatine deficiency syndromes, AGAT
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deficiency, and GAMT deficiency. We have not found
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information about compounding with creatine, but we
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are aware that it is used in the treatment of
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mitochondrial disorders.
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A balancing of these factors weighs in favor
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of creatine monohydrate being added to the list of
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bulk drug substances that can be used in
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compounding under Section 503A. Thank you very
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much, and I'm happy to take questions.
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Clarifying Questions from the Committee
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DR. VAIDA: Thank you, Dr. Johnson.
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We'll now have opportunity for any
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clarifying questions from the committee. Yes, Dr.
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Ghany?
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DR. GHANY: Can you comment on the safety of
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the recommended dose of 3 to 5 milligrams in
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patients with renal insufficiency?
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DR. JOHNSON: The only safety information
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that we had that limits dosing -- and as I
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understand it, this is completely an empirical
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process and doses are titrated up until patients
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experience some relief of symptoms. The only
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experience we have with dose limiting is the
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urinary crystal toxicity.
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So we can't say what the optimal dose would
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be, and I think it's likely patient dependent.
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DR. VAIDA: Dr. Sun?
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MS. SUN: I noticed that there were some
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things in the FDA report that they were concerned
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about the stability in liquid formulations. Did
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you find any uses on any compounded formulations
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that were not solid oral dosage forms?
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DR. JOHNSON: If I could have the one backup
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slide that we prepared? I just want to go over the
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information that we have that was public at the
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time of the review. Based on published literature,
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stability concerns are most prominent at low pH's.
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And you'll note that these are very old references,
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so there isn't a lot of newer information in the
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literature. And that's why we're looking to the
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nominators to clarify.
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We also noted in these papers that
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degradation occurs in solution at higher pH's. The
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degradation process is slower, but it is relevant
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to compounded formulations. So we are recommending
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that we consider at this meeting solid oral dosage
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forms and that we use information that we received
A Matter of Record (301) 890-4188
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from the nominator, and elsewhere perhaps, to look
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at liquid formulations.
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Does that answer your question?
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MS. SUN: Yes. I guess in some of the case
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reports that you saw on efficacy and maybe even the
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adverse event reporting, were there any liquid
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formulations in there?
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DR. JOHNSON: I don't know if I can say that
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for sure. I will look back through the review as
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we're talking and see if I can find that, but I
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don't believe that in all cases the formulation was
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described.
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DR. VAIDA: Dr. Chelimsky?
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DR. CHELIMSKY: Just a dose clarification.
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So that was truly 800 milligrams per kilogram per
16
day, which translated for a 70-kilogram person
17
would be somewhere around 50 grams per day? That's
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10 times more than -- that's a good thing. If the
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only thing that happened was urine crystals, that
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means even at that dose, it seems reasonably safe.
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DR. VAIDA: Dr. Khurana?
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DR. JOHNSON: Let me make sure I have that
A Matter of Record (301) 890-4188
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accurate, and I will pull up the original paper
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just to make sure. Thank you.
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DR. VAIDA: Dr. Khurana?
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DR. KHURANA: I just have a couple of
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questions, ones directed to the speaker and for the
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FDA. One is that the two syndromes that are
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described for these enzyme deficiencies in the
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creatine synthesis process, what's the incidence of
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this disease? Even in comparison to other
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mitochondrial diseases, how rare are they?
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DR. JOHNSON: These are extremely rare.
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There were surveys done globally to assess the
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number of patients, and they identified families.
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In AGAT deficiency, a review was done in 2015
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looking globally at the number of patients, and
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they found 16 patients in 8 families. If there can
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be a rare-rare disease, that's the one. GMAT is
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slightly more common. There were 48 patients from
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38 families in a review done in 2014.
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DR. KHURANA: The other question is to the
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FDA. If anybody has looked at the supplements, the
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majority of the currently available over-the-
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counter supplements are not just pure isolated
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creatine supplements. They're invariably a
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cocktail of something added with caffeine and
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whatnot with it.
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So when we vote here, are we voting -- is
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that a vote to let that combination supplement
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stand or is this a vote purely for supplements on
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creatine alone? That's a concern because a lot of
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these supplements are overloaded with -- they say
10
creatine, but they are creatine plus with a lot of
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caffeine in it.
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DR. JOHNSON: You can clarify. But what
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we're voting on is whether solid oral dosage forms
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of creatine, starting with the compounding from a
15
bulk drug substance, can be added to the 503A list.
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We're not making a recommendation about the use of
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dietary supplements as creatine alone or with any
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other vitamins or supplements.
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DR. KHURANA: Great. Thank you.
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DR. HOAG: Steve Hoag. I have kind of a
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similar question. I might have heard you wrong,
22
but did I hear you say that the monohydrate and the
A Matter of Record (301) 890-4188
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anhydrous were the same, or did you say -- I didn't
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quite hear what you said.
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DR. JOHNSON: They're considered the same
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active pharmaceutical ingredient, and I'm going to
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let Dr. Zhang comment on that. We do an evaluation
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at the start of these reviews to understand how the
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literature can be amalgamated. So in some cases,
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we have to keep the substances separate, and in
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some cases we can use data from each.
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DR. HOAG: Yes. If you look at the USP,
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there are situations where a certain salt is needed
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for the product to be efficacious.
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DR. JOHNSON: Correct, yes.
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DR. ZHANG: Just to be clear -- this is Ben
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Zhang, FDA -- the monohydrate or non-hydros forms,
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they're just different polymorphisms. In this
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case, the active pharmaceutical
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moieties aren't the same. So in order to consider
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the medical indications and the efficacy, in this
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case, we consider them as the same.
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DR. VAIDA: All right. Thank you.
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We'll now move on to the presentation by the
A Matter of Record (301) 890-4188
29
1
nominator, and it's Dr. A.J. Day from Professional
2
Compounding Centers of America.
3
Nominator Presentation - A.J. Day
4
DR. DAY: Good afternoon. Once again, I'd
5
like to thank you for allowing me to address this
6
committee and the FDA regarding the use of creatine
7
monohydrate in compounded formulations for support
8
in patients with mitochondrial diseases. We're not
9
going to spend a lot of time going through all of
10
the different characterizations that Dr. Johnson
11
just went through.
12
Again, from the FDA's assessment, they do
13
note that while it's well characterized physically,
14
they do have a concern about aqueous stability.
15
They went through the safety data in depth. They
16
also mentioned concern regarding the amount of
17
literature and published peer-reviewed trials that
18
addresses the efficacy of creatine in patients with
19
mitochondrial disorders, and then the historical
20
use of compounding is not a concern.
21
So first let's start with the safety
22
concern. Again, we talked about level of evidence,
A Matter of Record (301) 890-4188
30
1
so when we get to the efficacy component, we'll
2
remember this stuff right before lunch, hopefully.
3
When we talk about the stability component of it,
4
FDA cited three studies. Two of them, which were
5
just shown on that slide, were from the 1920's,
6
1925 and 1928. They were looking at not the
7
stability of creatine or creatine monohydrate.
8
These studies were designed to find an equilibrium
9
point between creatine monohydrate and creatinine.
10
So they were intentionally trying to degrade
11
the creatine to force it to form an equilibrium
12
point with creatinine. It was not a stability
13
study to begin with.
14
FDA cites another study, Ganguly and
15
colleagues from 2003, where they found that the pH
16
had an impact on the stability, on the degradation
17
of creatine. And they showed that after 4 days,
18
they noted rapid degradation.
19
Something that is important to note is that
20
that study did not look at creatine monohydrate.
21
They use creatine citrate, which forms a weak acid,
22
forcing the pH into a more acidic environment.
A Matter of Record (301) 890-4188
31
1
This is not a form that we are nominating. This is
2
not a form that we have proposed for use in
3
compounding, and thus, we are not addressing
4
anything about those specific studies.
5
What we are addressing -- and this is some
6
data about the articles from the 1920's where they
7
found that equilibrium point. Their conclusion
8
that in alkaline to neutral environments, the
9
conversion to creatine is slowed. And at some
10
point in the alkaline environment, it forms an
11
almost irreversible formation of creatine.
12
Then we move on to some actual data on
13
creatine monohydrate. This is an independent test
14
result from an FDA-registered analytical laboratory
15
on a compounded formulation of creatine
16
monohydrate. This pharmacy that created this and
17
had this preparation tested is utilizing a 30-day
18
beyond-use date, which is a completely acceptable
19
and common shelf life in the world of compounding.
20
While it may be considered too unstable for typical
21
manufactured drugs, in the world of compounding,
22
that is a very reasonable beyond-use date.
A Matter of Record (301) 890-4188
32
1
They did this potency test. They stopped
2
the test after about 43 days because they got the
3
results that they needed to provide these
4
prescriptions for individual patients on a monthly
5
basis. They did note also -- let me go back to
6
that slide -- the pH of this formulation. It was
7
in the range of 4.9, 5.3 throughout the duration of
8
the study, and it was stored at a refrigerated
9
temperature.
10
When I read the FDA's briefing information
11
and we saw their concern regarding aqueous
12
stability of creatine monohydrate, and we saw the
13
specific notes within the studies, the primary
14
literature that looked at the effect of pH on that
15
conversion of creatine to creatinine, we wanted to
16
identify what is the likelihood of that happening
17
spontaneously in compounded formulations.
18
Just at a 1 percent concentration added into
19
purified water USP, the pH of creatine monohydrate
20
solution is between the range of 7.5 and 7.68. I
21
had to submit these slides last week, but it's 23
22
days. I checked with our analytical division this
A Matter of Record (301) 890-4188
33
1
morning. And at 23 days since we created that
2
solution, it's stable. The pH has stayed within
3
that narrow range, and there is not expected to be
4
any conversion.
5
There's, tangentially, a project going on
6
with an analytical laboratory, the same one that
7
conducted the initial trial, for that other
8
pharmacy to verify the stability of this under full
9
stability indicated forced degradation studies.
10
Further, there is data from a number of
11
dietary supplement manufacturers about the
12
stability of their formulations in an aqueous
13
environment. This set of data comes from one of
14
these dietary manufacturers, and their formulation
15
is buffered at a pH of 6.5 to 7.5, stored at room
16
temperature. You see their pH range. They do note
17
that when they get rid of that buffer and actually
18
put it into a more acidic buffer, that they get
19
degradation at the 3-day mark down to 80 percent,
20
so 20 percent degradation.
21
That same company that recommends their
22
product be stored at refrigeration when they keep
A Matter of Record (301) 890-4188
34
1
the pH around 6 to 7 notes remarkable stability.
2
Even beyond the 30-day mark, they're at greater
3
than 98 percent on their potency.
4
This is from yet another dietary supplement
5
manufacturer. I redacted the names of these
6
manufacturers per their request, but this is
7
creatine monohydrate in an aqueous liquid format,
8
and their buffer keeps the pH at an alkaline pH
9
greater than 7, less than 8. And they have
10
real-time testing as well as accelerated shelf-life
11
testing showing 36 and 48 months. You can see the
12
actual data that they have there.
13
So I present this simply to state that there
14
is data, while it may not be from a clinical trial,
15
showing that the formulations of creatine
16
monohydrate in an aqueous media are stable, at
17
least for the durations of therapy that we're
18
talking about for specific prescriptions in
19
compounding. A 30-day supply or even a 14-day
20
supply is very common for these formulas.
21
Next, we're going to look at the efficacy
22
data that FDA has identified. This is just a
A Matter of Record (301) 890-4188
35
1
screenshot from the FDA's briefing material. The
2
article from 1997 by Tarnopolsky, as you heard in
3
the previous open public hearing session on CoQ10
4
with Dr. Korson, some of this research is very
5
critical to the practice standards that we see out
6
in the real world.
7
They used 5 grams of creatine monohydrate
8
twice daily for 2 weeks, followed by 2 grams orally
9
twice a day for 1 week. They also had a placebo
10
control in this study. They concluded that
11
creatine's effects were limited to high intensity
12
aerobic and anaerobic activities, and there is no
13
effect on lower intensity aerobic activities.
14
When we look at the specific demographics of
15
the patients that were included in this study, the
16
phenotype of mitochondrial disorder that they all
17
had, or for the most part all had, is MELAS.
18
Again, they specifically state that creatine seems
19
to have the most benefit in high intensity
20
activities such as sports and manual labor, and
21
it's not necessarily about activities of daily
22
living. They do also say that it may possibly be
A Matter of Record (301) 890-4188
36
1
very effective or beneficial in weaning from a
2
ventilator an already fatigued patient.
3
The type of activity that we're looking at
4
and the type of measurements that clinical trials
5
are primarily studying should be really focused on
6
the types of activity that utilize creatine as a
7
primary source of ATP generation. And I'm really
8
glad that the projector is working right now
9
because in the slide, this color doesn't come out
10
all that well.
11
The utilization of creatine as a source for
12
the generation of ATP is in a very specific time
13
line, and it's more highly utilized for specific
14
types of muscle utilization. So we need to keep
15
that in mind when we look at these other studies
16
and what kinds of biomarkers, what kinds of
17
activities they were looking at in assessing the
18
efficacy of creatine in these patient populations.
19
Here we have a publication by Hagenfeldt
20
from 1994. Usually, I don't include letters to the
21
editor in these presentations and these discussions
22
here, however, I think that this one in particular
A Matter of Record (301) 890-4188
37
1
is notable because we have a 25-year-old patient
2
who was diagnosed with MELAS at the age of 5. So
3
it's well established in this patient. He's had a
4
number of different therapies. His present
5
treatment before starting creatine involved a
6
carbamazepine, aspirin, dipyridamole, carnitine,
7
CoQ10, thymine, and vitamins K1 and vitamin C.
8
Creatine was given orally at 5 grams twice a
9
day for 2 weeks and 2 grams twice daily thereafter,
10
so a similar loading-dose protocol as we saw in the
11
previous study by Tarnopolsky. The patient and his
12
family reported reduced headaches, less weakness,
13
better appetite, and an improved general well being
14
during treatment.
15
They went through the graded exercise test.
16
They talk about the level of improvement that this
17
patient was able to experience at the 3-month mark
18
with creatine and how that improvement was able to
19
have an impact on his quality of life.
20
Again, another patient with MELAS. This one
21
was cited by Dr. Johnson in her presentation just a
22
moment ago. In the safety evaluation, this
A Matter of Record (301) 890-4188
38
1
18-year-old male patient with MELAS had two
2
previous episodes of cerebral stroke.
3
Prior to the patient's degradation, which
4
was gradual due to the severity of his disease and
5
the kidney disease that he had preexisting, they
6
noted that after 7 days of creatine
7
supplementation, the symptoms of psychomental
8
regression and aggressive behavior improved
9
significantly, and they had disappeared completely
10
after 4 weeks of treatment when the patient had
11
regained all his previous mental abilities. Six
12
months later, there was a clear improvement in his
13
vocabulary, his concentration, and alertness.
14
Next, FDA brought to the table the article
15
by Komura and colleagues in 2003. This is an
16
interesting study specifically because of the way
17
that they designed it. Note the phenotypes that
18
were chosen for this study are a little bit
19
different. They're not all MELAS patients, but
20
these have a variety of different phenotypes of
21
mitochondrial disorders.
22
From the discussion part of the study, they
A Matter of Record (301) 890-4188
39
1
also note, patient 1, they did an on/off trial.
2
They noted specifically that when they removed the
3
creatine, the improvements that they got
4
disappeared. And when they re-initiated creatine
5
supplementation at double the dose, the impact that
6
they were able to observe on their ergometry
7
doubled. When they reduced the dose down to the
8
original dose, the impact on the outcomes reduced
9
as well. They saw a similar dose outcome
10
relationship in patient number 2 and 3.
11
Here, we have another case study. This is
12
yet another phenotype of mitochondrial disorder.
13
That says Leigh syndrome patient. This was a
14
toddler who was not fully able to stand up
15
independently, or when they were, they had their
16
legs splayed quite broadly.
17
Soon after the initiation of vitamin B1 and
18
B2 therapy, she was able to walk up and down a
19
slope. Three months after starting creatine
20
therapy, she was able to climb up and down stairs;
21
fine motor function. She was initially only able
22
to put a small ball into a hole if her wrist was
A Matter of Record (301) 890-4188
40
1
fixed so as to prevent involuntary movements, but
2
after 3 months of creatine therapy, she could put
3
2 balls into the hole without needing to have her
4
wrist fixed.
5
Komura had a follow-up article in
6
2006 -- sorry. This case study was the follow-up
7
article from 2006, and again, the conclusion of
8
this article is that creatine monohydrate
9
supplementation improved gross and fine motor
10
skills and respiratory and cardiac function in the
11
present Leigh syndrome patients.
12
Next, FDA assessed two different trials that
13
looked at creatine. What we noticed about these
14
patients is that, for the most part, the phenotype
15
of mitochondrial disorder was all CPEO.
16
When we look at the conclusion and the
17
discussion of these articles from Klopstock in
18
2000, creatine supplementation is most effective in
19
subjects with low endogenous muscle creatine
20
concentrations. As these concentrations are normal
21
in CPEO patients, these patients may benefit less
22
than patients with other mitochondrial diseases.
A Matter of Record (301) 890-4188
41
1
They go on to talk about the specific
2
measures, the outcome measures that they had in
3
their study design. Their study, most variables
4
measured low-intensity exercise, which may be more
5
relevant for daily life, however, creatine, again,
6
does not necessarily impact those types of
7
activities. So the authors also conclude that we
8
cannot exclude an effect of creatine in
9
high-intensity exercise.
10
These outcomes are supported by the results
11
of the Kornblum study, where again they studied
12
primarily patients with CPEO, and they noted that
13
the failure to improve muscle energy metabolism in
14
our patients with mitochondrial disorders may
15
therefore be attributed to the inefficacy of
16
creatine supplementation to increase intramuscular
17
phosphocreatine contents.
18
They weren't actually measuring the
19
activities of daily living or the high-intensity
20
muscle exercise. They were measuring
21
phosphocreatine in the muscle. So they were
22
looking for a biomarker rather than a clinical
A Matter of Record (301) 890-4188
42
1
outcome.
2
As blood concentrations of creatine
3
significantly increase under oral creatine
4
treatment, disturbances of creatine uptake into
5
muscle cells should be considered. Creatine is
6
transported into the cells by a specific creatine
7
transporter.
8
So again, the impact that they're looking at
9
here, again, within the CPEO patients has to do
10
with the level of endogenous creatine that might be
11
intramuscular as well as a transport mechanism when
12
you have normalized endogenous creatine levels in
13
these CPEO patients.
14
Another article that the FDA addressed in
15
their briefing information is Rodriguez trial from
16
2007, and they talk about how difficult this study
17
is to assess the specific therapy or outcomes of
18
the utilization of creatine. It's an article to
19
utilize a combination of creatine, CoQ10, and alpha
20
lipoic acid. I would like to point out that this
21
is one of the most clinically relevant studies
22
because this is more realistic to how patients are
A Matter of Record (301) 890-4188
43
1
treated in the real world.
2
Again, the cocktail of medications, the
3
cocktail of therapies that these patients are
4
typically on is multimodal, and it's not just
5
creatine, nor is it just coenzyme Q10 or alpha
6
lipoic acid. These are patients who are on
7
combination therapies to help address the various
8
modalities that contribute to the lack of
9
mitochondrial function.
10
Also, when we look at this study, they had
11
the most broad subset of phenotypes of
12
mitochondrial disorders. It wasn't just CPEO, it
13
wasn't just Leigh patients, it wasn't just MELAS
14
patients. But they had a cross section from a
15
variety of these phenotypes.
16
Here's a table that summarizes the primary
17
literature that FDA cited, as well as PCCA cited in
18
our nomination. You can see that all of those in
19
green are the ones that showed positive clinical
20
outcomes. While the studies were not necessarily
21
designed specifically to look at the safety of
22
creatine in the human population, they do talk
A Matter of Record (301) 890-4188
44
1
about the adverse event profile of the patients
2
that were involved, and they were universally
3
pretty well tolerated.
4
The Klopstock and the Kornblum study, both
5
of them were primarily focused on patients with
6
CPEO phenotype of mitochondrial disease. And even
7
they noted that it was primarily well tolerated, a
8
few incidences of muscle cramps or flatulence being
9
a primary side effect profile. And then of course
10
the Rodriguez study that looked at a multimodal
11
approach for these patients.
12
So that's the primary literature. Again,
13
similar to coenzyme Q10, we also look at the
14
guidelines and expert opinions that have been
15
published on this topic. In 2009, the
16
Mitochondrial Medicine Society had a publication
17
that stated, based on our clinical experience and
18
judgment, we agree that a therapeutic trial of
19
CoQ10co along with other antioxidants should be
20
attempted.
21
In their chart, of those other antioxidants,
22
they specifically mentioned creatine at a dose of
A Matter of Record (301) 890-4188
45
1
0.1 grams, or 100 milligrams per kilogram, orally
2
daily, up to a maximum dose of 10
3
milligrams -- sorry, 10 grams per day, and then
4
they also give adult dosage along with adverse
5
effects to watch out for and specific comments
6
about its utilization.
7
The 2015 study that Dr. Johnson and the FDA
8
noted did specifically say that there's a general
9
lack of consensus regarding which agents should
10
use, although most physicians prescribe CoQ10
11
levocarnitine, creatine, ALA, and certain B
12
vitamins. The citation that they actually point
13
to, that's citation number 146, simply goes back to
14
the survey that they conducted in 2013, where
15
again, 75 percent of respondents stated that they
16
do utilize compounded creatine for their patients.
17
Here we have the physician's guide to the
18
treatment and follow-up of metabolic disease, where
19
again they specifically state that administration,
20
metabolizing cofactors such as riboflavin,
21
ubiquinone, carnitine, and creatine are utilized.
22
And the starting dose of creatine; again, they give
A Matter of Record (301) 890-4188
46
1
you a loading dose as well as a therapeutic
2
maintenance dose.
3
So in conclusion, I hope that you have seen
4
that there is stability data about aqueous
5
formulations of creatine monohydrate. Again, these
6
are packaged in amber plastic prescription bottles
7
kept in a refrigerated temperature, and they can be
8
stable for at least 40 days.
9
Typically, pharmacies will utilize a 14-or a
10
30-day beyond-use date for those preparations. The
11
pH in the vehicles that that is compounded in is
12
greater than or equal to 4.9. You've seen the data
13
from the dietary supplement manufacturers as well.
14
Creatine monohydrate has shown more efficacy
15
in certain phenotypes of mitochondrial disorders,
16
such as MELAS and KSS, than other phenotypes due to
17
intrinsic differences such as endogenous, creatine
18
levels. Creatine monohydrate may benefit more in
19
high intensity activities simply due to the way
20
that our bodies utilize different sources of ATP
21
generation for different types of activities.
22
Thank you very much.
A Matter of Record (301) 890-4188
47
1
Clarifying Questions from the Committee
2
DR. VAIDA: Thank you, Dr. Day.
3
We'll now have an opportunity for some
4
clarifying questions from the committee. Dr.
5
Carome?
6
DR. CAROME: Mike Carome. So I have a
7
question both for Dr. Day and also maybe for FDA.
8
As a nephrologist, I have a particular interest in
9
the renal toxicity issued here.
10
Dr. Day, you said FDA had no safety
11
concerns. I'm not sure that accurately reflects
12
FDA's position. FDA raised concerns about possible
13
kidney toxicity, noting, though, that there have
14
been safe doses identified for healthy adults.
15
In the nomination, I believe the proposed
16
dose was up to 20 grams per day. Is that correct?
17
That's for Dr. Day. Then for FDA, when you say
18
that safe doses have been identified for healthy
19
adults, what doses are you talking about?
20
DR. DAY: Well, the nomination data is
21
there, so I'll let FDA address the specific
22
questions.
A Matter of Record (301) 890-4188
48
1
DR. JOHNSON: Creatine monohydrate was
2
nominated for use in oral formulations in divided
3
doses of up to 20 grams per day.
4
Your next question was have we identified a
5
safe dose? No. In the review from Gualano, who
6
looked back through all the renal toxicity data,
7
starting with 3 cases in the 1990s of bodybuilders
8
essentially, who are trying to lose weight very
9
rapidly.
10
There were three cases in which these
11
individuals died, and at least one of them was on
12
creatine. And apparently, that's how it got
13
started that creatine may be associated with renal
14
toxicity. And since then, cases have propagated.
15
It was never clear whether the original ones were
16
real.
17
So this review was undertaken, and their
18
assessment of the data was that 5 grams per day for
19
a prolonged period of time in healthy individuals
20
is safe. Above that, they didn't have safety
21
recommendations. They suggested that the data may
22
actually support use even in type 2 diabetics who
A Matter of Record (301) 890-4188
49
1
at present had no renal impairment, that again, 5
2
grams might be safe. But doses higher than that
3
really hadn't been established. They didn't
4
particularly point to creatine deficiency syndromes
5
or mitochondrial disorders, but we note that we
6
just don't have that sort of information.
7
I will say -- and this is reflective of all
8
of the rare diseases -- these patients are
9
monitored very, very closely. And in the one case
10
report that I showed, they picked up on the renal
11
dysfunction very early on in its course and then
12
monitored it for a while. The thing that they
13
didn't know was that the patient was also taking
14
creatine, and they did attribute it to his
15
underlying disorder
16
Did you have another question? Was there
17
one?
18
DR. CAROME: Just for Dr. Day. What types
19
of doses are actually routinely being used?
20
DR. DAY: Yes. Thank you for that, and
21
Dr. Carome. It was something I wanted to expand
22
upon.
A Matter of Record (301) 890-4188
50
1
So up to 20 grams in divided doses, that was
2
the maximum dose that I was able to ascertain from
3
the practitioners out in the field that I consulted
4
with as we put together the nomination because we
5
want it to be as transparent as possible. And the
6
statement was, "I once had a patient getting a dose
7
that high." That is clearly an outlier.
8
Typically the doses are going to be less
9
than 10 grams per day, however, because I did
10
receive that information, I didn't feel the need to
11
include that in the nomination.
12
DR. JOHNSON: And I would just add that we
13
talked about the reviews that were done of AGAT and
14
GAMT on a global basis, and the dose range that
15
they found in AGAT was 100 to 800 milligrams per
16
kilogram per day.
17
DR. VAIDA: Dr. Ghany?
18
DR. GHANY: Thanks. Marc Ghany. Two
19
questions, one for Dr. Day and one for Dr. Johnson.
20
So first, Dr. Day, in some of the nomination
21
letters to the FDA, one of the utilities of this
22
compound was in autism spectrum disorders, but we
A Matter of Record (301) 890-4188
51
1
haven't heard any data on the effectiveness in that
2
population.
3
For Dr. Johnson, does the FDA recommendation
4
to support this mean that you endorse a
5
20-milligram dose per day? And if so, how was that
6
decision arrived at if there's no data? Twenty
7
grams; sorry. How was that decision arrived at if
8
there's no data to support that dose?
9
DR. DAY: So I guess I'll go first. In my
10
research and in my discussions with the
11
practitioners who specialize in both autism
12
spectrum disorders as well as mitochondrial
13
disorders and other inborn genetic disorders, I
14
asked specifically if patients on the autism
15
spectrum, or specifically with diagnosis of autism,
16
have a need, if it's a common or well-known
17
supplements or it's just something that is used
18
occasionally in the autism spectrum disorders.
19
The information that I received is that it's
20
not that common unless the patient who has autism
21
spectrum disorders also has a mitochondrial
22
component, in which case they will try creatine.
A Matter of Record (301) 890-4188
52
1
They'll monitor for progress, and they always
2
monitor renal function.
3
Not to answer on behalf of the FDA, but my
4
understanding is that no specific dosing or
5
indication is endorsed by FDA by going through this
6
process. They can clarify more, I'm sure.
7
DR. JOHNSON: So to build on that a little
8
bit, we have a process whereby we evaluate the
9
nominations and look at the proposed uses as well
10
as the information that's been submitted. And our
11
review of the nominations was such that we found
12
that use in mitochondrial disorders was supported
13
in the nomination and use in autism spectrum
14
disorders was not adequately supported in
15
literature.
16
We do have a process that's ongoing, a
17
contract with an external clinical expertise group
18
to look at autism spectrum for all of the nominated
19
substances. They're working bit by bit on various
20
substances, but they're going to be giving us
21
feedback, and we'll be publishing more information
22
about what types of non-approved substances are
A Matter of Record (301) 890-4188
53
1
useful in autism spectrum disorder.
2
DR. GHANY: Could you comment on the dose?
3
DR. JOHNSON, We didn't, for the purposes of
4
this review, look at autism spectrum disorder.
5
DR. GHANY: I meant the dose of 20 grams.
6
DR. JOHNSON: Oh, I'm sorry. For the
7
purposes of the creatine deficiency syndrome, doses
8
of 100 up to 800 milligrams per kilogram per day
9
have been used, and that's largely in infants. It
10
may or may not total 20 milligrams or 20 grams.
11
DR. VAIDA: Dr. Chelimsky?
12
DR. CHELIMSKY: Can I make a comment or is
13
it only clarification questions? I just want to do
14
that anecdotally I've used creatine with many, many
15
of my patients, hundreds. And probably about half
16
a dozen -- I typically use 5 grams a day, and about
17
half a dozen, I've had to lower the dose due to a
18
rise in creatinine, which I monitor pretty closely.
19
DR. VAIDA: Dr. Jungman?
20
DR. JUNGMAN: Dr. Day, it would be helpful
21
for me to understand how much -- your best
22
understanding of how much component is currently
A Matter of Record (301) 890-4188
54
1
solid oral dosage forms versus aqueous solution.
2
DR. DAY: My understanding of the
3
compounding need for creatine in this patient
4
population is that it's primary oral liquids due to
5
the dose that's required. When you're talking
6
about even 1 gram, putting that into capsules or
7
solid oral dosage forms for a child to swallow or
8
for children with multiple other medications
9
especially is not really feasible. So they do
10
typically utilize it into an oral liquid dosage
11
forms.
12
In terms of how those are prepared, being
13
are they aqueous at the time they leave the
14
pharmacy or are they in a powder format, a dry
15
format that then gets reconstituted at the time of
16
administration by the caretaker or the parents or
17
something like that, there's a split. There's a
18
bit of variance in there. But in terms of how the
19
patient actually takes it, the vast majority is
20
going to be as an oral liquid.
21
Open Public Hearing
22
DR. VAIDA: With that, I'll now move on to
A Matter of Record (301) 890-4188
55
1
the open public hearing, and we have one speaker.
2
DR. KORSON Thank you. My name is Mark
3
Korson, and I'm a biochemical geneticist with VMP
4
Genetics of Atlanta. You will notice that this is
5
very close to the one offered earlier for
6
coenzyme Q10.
7
This is not an oversight. It is due to the
8
fact that we are dealing with a wide range of
9
defects and complex biosynthetic pathways of ATP or
10
cellular energy, and the nature of mitochondrial
11
disease and what we know of them is such that good
12
studies have not been possible that include large
13
numbers of patients with clear or distinct
14
phenotypes to test each new supplement and monitor
15
for efficacy and side effects. But this
16
presentation focuses on creatine monohydrate, and
17
since our approach with CoQ10 proved to be helpful
18
clinically, we followed the same approach for
19
creatine, looking for improvement and watching for
20
creating specific side effects.
21
Identifying the patient for whom creatine is
22
appropriate is still a challenge, but comparable to
A Matter of Record (301) 890-4188
56
1
coenzyme Q10 synthesis defects as they apply to
2
coenzyme Q10, with creatine synthesis defects, the
3
biochemistry defines the problem, the treatment is
4
clear, and the patients can show a response.
5
Although, depending on the defect and the status of
6
the patient, the response may be variable.
7
Remember, there are hundreds of different
8
mitochondrial disorders. The benefit of creatine
9
is not always clear. These patients are in need of
10
energy from wherever they can get it. Different
11
from other supplements, though creatine provides
12
another source of ATP as well as acting as an
13
antioxidant, offering a neuroprotective effect.
14
Are all these patients then candidates for
15
creatine? No, but again, there are a few therapies
16
for this cluster of diseases that address the root
17
problem. And here, creatine provides a clear
18
alternative source of energy. These disorders have
19
a dramatic impact on functioning of quality of
20
life, and there's a relatively low incidence and
21
transient nature of the side effects, so many of
22
these patients are offered to trial.
A Matter of Record (301) 890-4188
57
1
I support a trial of creatine in patients
2
with disease when it is associated with fatigue or
3
weakness that impacts functioning. Again, self
4
care, home life, learning at school, or work, and
5
so on. Studies have looked mostly at aerobic
6
activities, but from a practical perspective, it is
7
perhaps more important that one look at common even
8
basic activities in these patients' lives that are
9
less energy demanding, but which still may utilize
10
creatine as an energy source.
11
In my practice, we have treated over 250
12
patients, patients with documented mitochondrial
13
disease or who have significant evidence to support
14
a diagnosis. But because of possible renal
15
concerns, we have not provided creatine to patients
16
with any history or evidence of kidney disease.
17
This dosing, it was obtained from consensus
18
reports of mitochondrial disease provider
19
practices. The patients are provided a trial of
20
creatine for at least 3 months, given the time it's
21
needed, to assess improvement and/or side effects.
22
And since a cocktail usually involves more than one
A Matter of Record (301) 890-4188
58
1
supplement, it is impractical to provide a separate
2
period of introduction of more than a few months.
3
Again, we try to appreciate the benefits to
4
the patients since providing a supplement is a
5
burden for patients and families that are already
6
saddled with the medical, psychological, and
7
financial burdens of the disease itself. We try to
8
rely on uninformed observers. You see a lot of
9
children or patients in their clinical practices
10
from an industry perspective: physical and
11
occupational therapists, teachers, activity leaders
12
who can distinguish who stands out from the norm,
13
but who have also followed the patient over time.
14
Again, someone who sees a patient several
15
times a month or several times a week may be in a
16
position to better assess a change in strength or
17
stamina -- may be able to better assess a change in
18
strength or stamina than a physician who sees a
19
patient every 6 months or so, especially if highly
20
specialized research technologies are not
21
available.
22
Again, we monitor for improvement
A Matter of Record (301) 890-4188
59
1
prospectively after starting the supplement, but
2
again, sometimes the benefit is not observed after
3
starting the supplement, but only when it is taken
4
away. The improvement is more apparent in
5
retrospect.
6
Sometimes if an obvious benefit is unclear,
7
we have also recommended periods of time off the
8
supplement, again, without informing observers in
9
the community of the switch, to determine if there
10
has been a change this time in reverse.
11
GI upset, abdominal pain, and flatulence has
12
been reported. Regarding the abdominal pain,
13
though, the question is, again, is it due to the
14
supplement itself or is it due to the presence of
15
pills or powder in the stomach that doesn't empty
16
properly since gastroparesis or slow gastric
17
emptying is a common symptom in patients with
18
mitochondrial disease.
19
Creatine is almost never prescribed as a
20
solitary supplement. Following recommendations
21
like the ones of Tarnopolsky, et al., the
22
Mitochondrial Medicine Society often includes
A Matter of Record (301) 890-4188
60
1
cocktails that include supplements that impact
2
different aspects of the energy production pathway.
3
Thank you.
4
Committee Discussion and Vote
5
DR. VAIDA: Thank you. We will now proceed
6
with the vote. The question is, the FDA is
7
proposing that creatine monohydrate solid oral
8
dosage forms be included on the 503A bulks list.
9
Should creatine monohydrate solid oral dosage forms
10
be placed on the list?
11
We'll now open up for any discussion before
12
we vote. Any discussion from the committee?
13
(No response.)
14
DR. VAIDA: Hearing none, we'll take the
15
vote. Please vote either yes, no, or abstain.
16
(Voting.)
17
DR. FAJICULAY: For the record, the results
18
are 17, yes; zero, no; and zero abstain.
19
DR. VAIDA: Thank you. We'll go around the
20
table from the committee and state your name, your
21
vote, and in any comments. We'll start here on my
22
right-hand side with Dr. Ghany.
A Matter of Record (301) 890-4188
61
1
DR. GHANY: Marc Ghany. I voted yes. I do
2
have one comment. The reason I voted yes was,
3
again for the disorders under question, there is no
4
effective therapy. And while the evidence is weak
5
that this compound does work, there is some
6
suggestion that some patients do benefit.
7
The comment I have is I would strongly urge
8
the FDA to look into the safety data for renal
9
toxicity and perhaps consider what might be a safe
10
upholdment [ph] of dosage that you all would
11
approve.
12
DR. CHELIMSKY: Tom Chelimsky. I voted yes,
13
and I actually echo the comments of my colleague.
14
DR. KHURANA: Sandeep Khurana. I voted yes
15
for the similar comments.
16
DR. IKONOMIDOU: Chris Ikonomidou. I voted
17
yes. I agree with all that has been said. And in
18
addition, I think it's important to have access to
19
this compound for the treatment of creatine
20
biosynthesis disorders.
21
MS. SUN: Jeanne Sun, I voted yes. I would
22
suggest or recommend that we look at this bulk drug
A Matter of Record (301) 890-4188
62
1
substance without the qualifications, similar to my
2
recommendations for ALA. Similar to the discussion
3
that went on, there are stability data for other
4
dosage forms. And it seems like even the questions
5
asked today, there's some inconsistencies on how
6
the substances are nominated. Some say a route of
7
administration, some say the dosage form, and some
8
do not any at all if you look at the previous
9
meetings.
10
So my recommendation would be to add the
11
bulk substance to the list without the
12
qualifications of the dosage form or route of
13
administration.
14
DR. DESAI: Seemal Desai. I also voted yes
15
for the reasons previously stated.
16
DR. JUNGMAN: Elizabeth Jungman from Pew. I
17
voted yes. I had some hesitance about the AEs and
18
high doses, but I thought the balance of factors
19
was in favor of inclusion on the list given the
20
limited options for these patients.
21
DR. WALL: Donna wall. I voted yes for the
22
reasons that they've stated, but it also should be
A Matter of Record (301) 890-4188
63
1
emphasized that this is the drug in which both the
2
prescriber and the pharmacist really need to
3
closely monitor these patients to make sure that we
4
do not encounter the ADEs, or if we do, we can
5
address them.
6
DR. CAROME: Mike Carome. I voted yes. I
7
think from a safety perspective, this drug
8
substance rarely can cause some renal injury, but I
9
think those risks are outweighed by the benefits
10
for the patients who have these very metabolic
11
disorders.
12
DR. BOGNER: Robin Bogner. Similar to
13
Jeanne, I vote yes without any dosage form
14
constraints. If you need further evidence, Ted
15
Labuza's article out of his group in 2009, Drug
16
Development in Industrial Pharmacy, has a very
17
clear temperature pH activity of water data on the
18
stability of creatine monohydrate in water.
19
DR. VAIDA: Allen Vaida. I voted yes,
20
although I had some concerns over what is the real
21
dose or the correct dose of the drug.
22
DR. PATEL: Kuldip Patel. I voted yes. I
A Matter of Record (301) 890-4188
64
1
did have some concerns about the efficacy data but
2
also realize that there are a subset of patients
3
that will benefit from having this available.
4
MR. HUMPHREY: William Humphrey, I voted
5
yes. I felt like it met the inclusion criteria.
6
And I also recommend that the alternative dosage
7
form be considered.
8
DR. HOAG: Steve Hoag. I voted yes for the
9
reasons considered. Also, I thought it was good
10
that they specified the state of the monohydrate
11
because I think you need to pay attention to that,
12
especially in situations where there's not a
13
monograph. Also, I think the FDA should look at
14
other dosage forms and examine the stability
15
issues.
16
DR. VAIDA: Our two committee members on the
17
phone starting with Dr. Venitz.
18
DR. VENITZ: Jurgen Venitz. I voted yes,
19
and I have nothing to add.
20
DR. VAIDA: Dr. Gulur?
21
DR. GULUR: Padma Gulur. I voted yes. I
22
will echo the concerns with dosage and renal
A Matter of Record (301) 890-4188
65
1
considerations, but other than that, feel like it
2
should be useful for a small subgroup of patients.
3
DR. VAIDA: Okay. Thank you. Why don't we
4
just take a 5-minute break, and we'll reconvene
5
after 5 minutes.
6
(Whereupon, at 2:21 p.m., a recess was
7
taken.)
8
DR. VAIDA: If committee members could get
9
back to their seats, in just another minute, we
10
will begin.
11
I'd also just like to mention that
12
Dr. Ghany, Chelimsky, and Khurana, that were with
13
us for the first three items will not be with us
14
for the next two. They were just here for
15
temporary members for that and that Dr. Ikonomidou
16
had to leave for her flight, but she will be
17
calling in for the next item on the agenda.
18
We want to begin with Dr. Johnson, talk
19
about the next substance that's up, pyridoxal 5
20
phosphate monohydrate.
21
FDA Presentation - Susan Johnson
22
DR. JOHNSON: Once again, my name is Susan
A Matter of Record (301) 890-4188
66
1
Johnson, and I'm from the Office of Drug Evaluation
2
IV in CDER'S Office of New Drugs. And the
3
substance that we'll be discussing now is
4
pyridoxal 5 phosphate monohydrate. And reflecting
5
back to creatine monohydrate, we do discriminate
6
between salts. These different crystalline forms
7
are things that we can generally consider as the
8
same substances. So this is a similar scenario to
9
the last substance that we discussed.
10
Again, I'd like to express my thanks to the
11
review team and to Dr. Philip Sheridan, who
12
couldn't be here today, from OND's Division of
13
Neurologic Products.
14
Pyridoxal 5 phosphate monohydrate has been
15
nominated for inclusion on the list of bulk drug
16
substances for use in compounding under 503A. It's
17
proposed for oral and intravenous use in the
18
treatment of epilepsy and seizure disorders. It
19
was not associated with the dose in the nomination.
20
Pyridoxal 5 phosphate monohydrate and
21
pyridoxal 5 phosphate are considered the same
22
active pharmaceutical ingredient, as with the last
A Matter of Record (301) 890-4188
67
1
scenario. And I'll be referring to both of them as
2
PLP. PLP has a well characterized structure and is
3
soluble in water. I know that's a relief to
4
everybody.
5
(Laughter.)
6
DR. JOHNSON: In aqueous formulations, PLP
7
is most stable between a pH of 5 and 8. PLP is
8
also stable in solid form. PLP can be synthesized
9
in manufacturing from pyridoxamine. So in summary,
10
PLP is well characterized and likely to be stable
11
in the proposed oral and intravenous dosage forms.
12
Vitamin B6 is a term which is used to refer
13
to any one of 6 vitamers or a mix of those
14
vitamers. These 6 vitamers include pyridoxal and
15
its phosphorylated ester PLP. Pyridoxine and
16
pyridoxamine, and both of their phosphorylated
17
esters comprise the 6 vitamers. These 6 vitamers
18
can be inter converted in the body, and it's
19
notable that PLP is the one metabolically active
20
form of vitamin B6.
21
PLP is a essential cofactor in numerous
22
enzymatic reactions and can be found in various
A Matter of Record (301) 890-4188
68
1
animal food sources. FDA has set a recommended
2
tolerable upper limit of dose of 100 milligrams per
3
day in food that does not necessarily pertain to
4
drugs, but that's a guideline that we have.
5
We did not find any animal pharmacokinetic
6
data for PLP. When humans ingest PLP or other
7
phosphorylated, they're usually hydrolyzed by
8
intestinal phosphatases, and the non phosphorylated
9
forms are then rapidly absorbed. After absorption,
10
each vitamer can be phosphorylated again and then
11
converted to PLP.
12
The enzyme that converts phosphorylated
13
pyridoxine and pyridoxamine to PLP is PNPO. At
14
high doses, PLP is absorbed without being
15
hydrolyzed that reduces the body's dependence on
16
PNPO to convert PNP and PMP to PLP. To say that
17
again, pyridoxamine and -- now I'm getting myself
18
confused. Pyridoxine and pyridoxamine are
19
phosphorylated once absorbed and then are
20
ultimately converted to PLP. At high doses, PLP
21
when taken orally can be absorbed intact and does
22
not need to be re-phosphorylated once absorbed.
A Matter of Record (301) 890-4188
69
1
Most of the super physiologic oral dose of
2
the vitamers will be excreted unchanged in the
3
urine, although a small portion of the vitamers are
4
metabolized to pyridoxic acid. Drug interactions
5
can occur between the vitamers and drugs like
6
isoniazid or L-dopa that react with carbonyl
7
groups.
8
We found no animal toxicity data specific to
9
PLP, so we reported on information from the study
10
of vitamin B6. Neuronal damage and sensory and
11
motor effects have been seen across many different
12
species when exposed to prolonged high doses. In
13
reproductive toxicity studies, vitamers had been
14
shown to cross the placental barrier and reach the
15
fetus. And although no teratogenicity was seen,
16
high doses were associated with a decrease in body
17
weight of pups. We found no genotoxicity or
18
carcinogenicity studies for PLP or for vitamin B6.
19
In the FAERS database, there were 20 cases
20
in which PLP use was reported. In 12 cases, the
21
event was likely related to the underlying disease
22
or to concomitant medication. In 8 reported cases,
A Matter of Record (301) 890-4188
70
1
including 6 deaths, there was insufficient
2
information to determine whether there was a causal
3
association with PLP. There were 98 reports in the
4
CAERS database in which PLP was reported, but each
5
was confounded by use of multi ingredients
6
supplements. We found no clinical studies designed
7
specifically to assess safety.
8
There are literature reports of neuronal
9
damage with high-dose vitamin 6, and one could
10
expect similar events with PLP. We do not have
11
specific information about the cutoff of doses at
12
which you might begin to see neuronal damage.
13
In addition, at high doses, PLP can
14
interfere with platelet function. PLP has also
15
been associated with dermatologic,
16
gastrointestinal, and hepatic adverse events,
17
including two reports of cirrhosis in PNPO
18
deficient patients. And I should emphasize that
19
those were pediatric patients. Although PLP is
20
generally safe and well tolerated, with long-term
21
high dosing, it may be associated with peripheral
22
nerve injury. Other types of events, including
A Matter of Record (301) 890-4188
71
1
hepatotoxicity, have been infrequently reported.
2
PNP and PMP are converted, as we said, to
3
the metabolically active form PLP via the oxidase
4
PNPO. But a rare inborn error of metabolism can
5
result in a deficiency of PNPO oxidase. The onset
6
of PNPO deficiency is usually observed within the
7
first two weeks of life and is characterized by
8
monoclonic seizures that can progress to status
9
epilepticus. These seizures are not controlled by
10
anticonvulsants.
11
In some patients, it's theorized that there
12
may be residual PNPO activity, and treatment with
13
pyridoxine may be sufficient to sustain the
14
production of PLP. Some of these patients may have
15
onset of seizures later in life, and there is much
16
current activity going on to identify genotypes and
17
phenotypes where this may be the case. But
18
patients with essentially no PNPO activity are
19
dependent on PLP therapy.
20
This condition of PLP-dependent epilepsy was
21
first observed in the early 2000S. A cessation of
22
seizure activity with the administration in PLP in
A Matter of Record (301) 890-4188
72
1
the face of treatment failure with pyridoxine
2
administration and anticonvulsants helps to
3
establish the distinct condition. And as we said
4
earlier, administration of high-dose oral PLP will
5
allow for PLP to be absorbed with its phosphate
6
group intact and bypass the need for PNPO activity.
7
We conclude that PLP is effective for
8
treating PLP-dependent efficacy in neonates and
9
infants. PLP has been compounded in various dosage
10
forms since at least 2010. It's known to be
11
compounded to treat PLP-dependent epilepsy, but
12
there's insufficient information on which to assess
13
the extent of use for this or other conditions.
14
In summary, PLP as well characterized and
15
can be stable under normal storage conditions in
16
oral and intravenous formulations. It is generally
17
safe but may cause peripheral nerve damage if used
18
at high doses for prolonged periods. There are
19
also literature reports of rare adverse events,
20
including hepatotoxicity.
21
Based on literature reports and clinical
22
practice, PLP is effective in treating the rare
A Matter of Record (301) 890-4188
73
1
disease PLP-dependent epilepsy and has been
2
documented to be compounded for this purpose. A
3
balancing of these factors weighs in favor of
4
pyridoxal 5 phosphate monohydrate being added to
5
the list of bulk drug substances that can be used
6
in compounding under Section 503A. Thank you, and
7
I'm happy to take questions.
8
DR. VAIDA: Thank you. Are there any
9
clarifying questions from the committee for
10
Dr. Johnson?
11
(No response.)
12
DR. VAIDA: All right. Seeing none, we will
13
now have a presentation by our nominator, Mr. Tom
14
Wynn from Fagron.
15
Nominator Presentation - Tom Wynn
16
MR. WYNN: Thank you very much for having us
17
today, and thank you to the FDA for a great
18
discussion about pyridoxal 5 phosphate monohydrate.
19
Pyridoxal 5 phosphate is considered the most
20
important member of the vitamin B6 group, which was
21
already stated. It is an active coenzyme for more
22
than a hundred enzymes, including glutamic acid
A Matter of Record (301) 890-4188
74
1
decarboxylase, an enzyme involved in gamma
2
aminobutyric acid synthesis.
3
I'll talk a little bit about glutamic acid -
4
decarboxylase. It synthesizes GABA or
5
gamma-aminobutyric acid. GABA's the principal
6
inhibitory neurotransmitter in the cerebral cortex
7
and maintains the inhibitory tone that
8
counterbalances the neuronal excitation that goes
9
on in the brain. P5P is needed for glutamic acid
10
decarboxylase as the coenzyme for the synthesis of
11
GABA.
12
When we talk about pyridoxine-dependent
13
seizures, and oftentimes that's what they're going
14
to call them, even though we're actually using a
15
pyridoxal 5 phosphate to treat, it's a condition
16
caused by autosomal recessive inborn error of
17
metabolism, and affected patients are dependent
18
upon regular pharmaceutical doses of pyridoxine or
19
pyridoxal 5 phosphate, which the FDA has mentioned
20
is the more potent form of pyridoxine to help treat
21
that condition.
22
Untreated, the disorder results in death
A Matter of Record (301) 890-4188
75
1
from status epilepticus. In most instances, the
2
institution of either parenteral or oral pyridoxine
3
rapidly results in seizure control and improvement
4
of the encephalopathy. And again, here we're using
5
pyridoxine, but we know -- and I'll have an article
6
to come up later in my talk -- the pyridoxal 5
7
phosphate is the more active and form that we're
8
going to use in this case. But the diagnosis for
9
this type of seizure is by clinical observation
10
where an infant with anticonvulsant resistant
11
seizures offered a trial of pyridoxine, or P5P,
12
that results in often a dramatic cessation of these
13
events.
14
This is just one particular case report, and
15
in this one, it was a male infant born at 35 weeks
16
who promptly responded to oral administration of
17
PLP. This particular patient neurological outcome
18
at 21 months is favorable and illustrates the
19
importance of standardized vitamin trials in an
20
acute setting of therapy-resistant neonatal
21
seizures. If you look more into this, it's showing
22
that this particular patient, again, at a very
A Matter of Record (301) 890-4188
76
1
early age was not responding to other therapies.
2
But when the PLP was administered, it did result in
3
cessation of those seizures.
4
A positive outcome, again, of the early
5
diagnosis within 12 hours, irritability and erratic
6
myoclonic jerks involving all 4 extremities were
7
noted. The first EEG recorded 2 hours after the
8
onset of symptoms showed a suppression burst
9
pattern with synchronized bursts of bilateral,
10
moderate amplitude spike and waves. These seizures
11
are resistant to phenobarbital, phenytoin, and
12
vigabatrin. And again, we're still talking about
13
this same 35-week a child here.
14
Profound authority in hypertonia were
15
noticed over the following 3 weeks. PLP was
16
administered every 6 hours at a dose of 35
17
milligrams per kilogram per day, and anticonvulsant
18
therapy withdrawn. After 5 week, the infant was
19
discharged with mild hypertonia and adequate bottle
20
feeding. So in this particular case study, again,
21
the other normal, let's say, or commercially
22
available options weren't working, so the PLP was
A Matter of Record (301) 890-4188
77
1
administered and was able to control the seizures,
2
and the child was discharged with pretty much
3
normal activity.
4
This one here does get into pyridoxal
5
phosphate is better than pyridoxine for controlling
6
idiopathic intractable epilepsy. Again, it gets
7
into more about the P5P. Among 574 children with
8
active epilepsy, 94 were diagnosed with idiopathic
9
intractable epilepsy for more than 6 months. And
10
then the conclusion was that PLP could replace
11
pyridoxine in the treatment of intractable
12
childhood epilepsy, particularly in the treatment
13
of infantile spasms, which is what we're really
14
looking at here today, is the infantile spasms.
15
In that study, after the first attempt and
16
to treat West Syndrome -- and West syndrome is
17
another name for what they have for infantile
18
spasms -- with high-dose vitamin B6, was
19
recognized, the treatment dose, for that syndrome.
20
The 574 children with active epilepsy were referred
21
to a pediatric neurology department. After
22
appropriate management, 219 had medically
A Matter of Record (301) 890-4188
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1
intractable epilepsy; again, 94, age between
2
8 months or 15 years, were defined as having those
3
type of infantile spasm were enrolled in this
4
study. 11 of 94 responded dramatically to
5
intravenous infusion, achieving seizure-free
6
status. The 11 responded to the dose of
7
10 milligram per kilogram per day. The other 8
8
needed a dose of 50 milligrams per kilogram per
9
day.
10
Our present study, PLP was effective
11
controlling up to 46 percent of the patients with
12
intractable infantile spasms. In conclusion, our
13
data suggests that PLP is more effective than
14
regular pyridoxine in some children with idiopathic
15
intractable epilepsy, particularly children with
16
infantile spasms. And I think those are the ones
17
that we're really looking at here. The infantile
18
spasms are the ones that it really helps out more.
19
Looking at this year, it's pyridoxine
20
oxidase deficiency treatable cause of neonatal
21
epilepsy with burst suppression. This is a case
22
report. They reported on a patient with myoclonic
A Matter of Record (301) 890-4188
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1
and tonic report on a patient with myoclonic and
2
tonic seizures at the age of one hour. P5P was
3
started on the first day of life and seizures
4
stopped at the age of 3 days. The encephalopathy
5
persisted for 4 weeks. They had normal neuro
6
development outcome, and age 12 pyridoxal 5
7
monotherapy was the only therapy that they had for
8
that child.
9
So looking more into that particular study,
10
again, 41 percent of patients with pyridoxine 5
11
phosphate oxidase deficiency were treated with
12
pyridoxine supplementation, 30 milligrams per
13
kilogram per day. Of those patients, 71 percent
14
were seizure free; 42 percent had normal neuro
15
developmental outcome for pyridoxal monotherapy.
16
Pyridoxine 5 phosphate and pyridoxine
17
supplementation therapy are the only treatments,
18
and untreated oxidase deficiency results in early
19
death. Dose range is from 30 milligrams per
20
kilogram per day to 100 milligrams per kilogram per
21
day given through a neogastric tube.
22
As far as stability, I know that the FDA
A Matter of Record (301) 890-4188
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1
already talked about that they had found that
2
pyridoxal 5 phosphate is found to be stable. This
3
was just one -- it wasn't really a study, but they
4
were looking at the hydrolysis that could occur
5
with pyridoxine 5 phosphate, and looking at ways
6
that can be minimized. Part of it was they talked
7
about the pH temperature, and then they also found
8
that adding metabisulfite can also help stabilize
9
those solutions even more.
10
So I do feel that they can be stabilized for
11
the length of time that we need to utilize that,
12
whether it'd be an IV or in some type of
13
suspension. And this was just another study, if
14
you will, that was looking at ways to kind of
15
combat what can happen as far as degradation with
16
it
17
So in clinical safety, I know the FDA has
18
already mentioned that they found no issues in the
19
literature that I looked over. I too could not
20
find any issues with safety. They did mention
21
sometimes that there could be high doses, that they
22
were having some issues with some possible
A Matter of Record (301) 890-4188
81
1
neuropathy or a neuro type damage could occur.
2
Seizure breakthrough was the only thing that I saw
3
in the studies that I looked at of the few that I
4
presented today.
5
I did want to talk about one in particular.
6
It mentioned in one of the studies, they actually
7
went through a review, and they looked at right
8
around 50 of the current cases that they saw where
9
P5P was actually utilized to help with infantile
10
spasms. And of those, 50 they were looking at did
11
they actually do any therapy at all, did they not,
12
and the different dosage range that they did.
13
The doses did vary anywhere from 10
14
milligram per kilogram up to 100 milligram per
15
kilogram per day. And I think the dosing is
16
adjusted to -- they're trying to control the
17
seizures, so they'll start out at a lower dose and
18
work up if they have to just to get them under
19
control.
20
But the most interesting thing that I saw
21
was that in those studies, whenever they did not do
22
anything, it resulted in death. And when they
A Matter of Record (301) 890-4188
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1
actually add the P5P, there was always an outcome
2
of either mild seizures or none at all. So
3
definitely, there is something to that in these
4
infantile spasms, if we do not treat, I think the
5
outcome is not good. And usually within less than
6
a week, this was actually resulting in death.
7
So again, the main points is that the
8
commercially available options have limited effect,
9
if anything at all, in infantile spasms.
10
Definitely, that seems to be true. Pyridoxal 5
11
phosphate seems to be superior to pyridoxine.
12
There were no severe adverse effects reported, and
13
even the ones that the FDA had mentioned becomes a
14
risk-benefit at that point.
15
If we know that if the infantile spasms are
16
not treated and the current commercially available
17
options aren't working as far as treatment, that it
18
results in early death, I think we need to weigh
19
out the risk-benefit of the possible neuropathy
20
that could occur compared to the outcome if we
21
don't treat at all.
22
Clarifying Questions from the Committee
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1
DR. VAIDA: All right. Thank you. Any
2
clarifying questions?
3
DR. IKONOMIDOU: I have more of a comment.
4
Thank you very much for the presentation. I think
5
information you presented on the efficacy of
6
pyridoxal 5 phosphate on infantile spasms and also
7
the lack of other therapies for infantile spasms is
8
misleading. That is not the case. Pyridoxal 5
9
phosphate is not the treatment of choice for
10
infantile spasms. There are other therapies. ACTH
11
is a first line therapy followed by steroids and
12
vigabatrin.
13
The only scenario where pyridoxal 5
14
phosphate could be of use is if the infantile
15
spasms are the expression of a mild form of
16
pyridoxal 5 phosphate dependent epilepsy, which
17
starts later during the first year of life. So I
18
think this information cannot stand as was
19
presented here.
20
I think that pyridoxal 5 phosphate does
21
indeed have a place in the treatment of pyridoxal 5
22
phosphate dependent epilepsy, and we are definitely
A Matter of Record (301) 890-4188
84
1
dependent on this medication. Also, oftentimes in
2
refractory neonatal seizures, we do pursue clinical
3
or therapeutic trials with these compounds until we
4
have the diagnosis. But I do not agree with the
5
infantile spasm presentation. Thank you.
6
DR. VAIDA: Any other questions? Dr. Sun?
7
DR. SUN: This may be more of a question for
8
FDA. I know one of the case reports had talked
9
about dosing through the nasal neogastric tube. So
10
would that still qualify under the oral dosage
11
form?
12
DR. GANLEY: Yes, that would be oral.
13
DR. VAIDA: I have one question, too. Back
14
in 2014, the organizations, it was only the oral
15
capsules, and then just this year when you did the
16
confirmation, you asked for the IV also, the IV was
17
never mentioned in any of the original nominations
18
from all three organizations.
19
So was that because there's been more IV
20
used in the last few years? What was the change?
21
MR. WYNN: Sure. It's been more -- as we
22
went to reclarify and we started looking at the
A Matter of Record (301) 890-4188
85
1
ways that it could be used to help with seizures,
2
sometimes you're dealing with such small children
3
that it may not be feasible to always give an oral
4
dose.
5
Sometimes you want to get those seizures
6
stopped more quickly, so doing an IV would be the
7
better way to go. And looking at the studies that
8
I had, they were doing IV as well as oral therapy.
9
They were doing both, and the ones who had this
10
deficiency be able to [indiscernible] the P5P and
11
make that decarboxylase enzyme.
12
DR. VAIDA: Okay. But I'm also taking for
13
granted that a lot of that has been made by the
14
compounders -- I'm sorry, all of that, that the
15
intravenous is now being made by the compounders
16
all of a sudden.
17
MR. WYNN: I'm sorry?
18
DR. VAIDA: That the intravenous is now
19
being made by the compounders versus the oral.
20
MR. WYNN: Well, this is something, yes,
21
that has come more recently. As I mentioned, it's
22
just been since 2000 that there's been kind of a
A Matter of Record (301) 890-4188
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1
rise in awareness.
2
DR. VAIDA: I'm just thinking of the ability
3
to produce the IV versus the oral. That's fine.
4
MR. WYNN: Okay.
5
DR. VAIDA: Any other questions?
6
(No response.)
7
DR. VAIDA: Then we'll move on to the open
8
public hearing, and we have -- Dr. Johnson?
9
DR. JOHNSON: This is Sue Johnson. I just
10
wanted to reiterate that the development of
11
hepatotoxicity associated with the treatment of
12
PLP-dependent epilepsy is new, and they're thinking
13
that this might be an actual new genotype. I read
14
recently that PNPO deficiency may in time prove to
15
be a suitable candidate for consideration of
16
therapeutic liver transplantation in select
17
patients.
18
So I don't want us to lose track of the fact
19
that there could be serious consequences to
20
administering PLP, but as the nominator has said,
21
this is life-saving therapy in this genetic
22
disorder. But I just wanted to make sure that that
A Matter of Record (301) 890-4188
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1
didn't get lost in the conversation.
2
Committee Discussion and Vote
3
DR. VAIDA: All right. We'll proceed to the
4
vote, and the vote -- for the record, there are no
5
presenters for the open public hearing, and we'll
6
now proceed to the vote. The vote that's up is the
7
FDA is proposing that pyridoxal 5 phosphate
8
monohydrate, intravenous and oral dosage forms, be
9
included on the 503A bulks list.
10
Should pyridoxal 5 phosphate monohydrate
11
intravenous and oral dosage forms be placed on the
12
list? I'll open it up for the committee for any
13
discussion before the vote. Dr. Patel?
14
DR. PATEL: I just wanted a clarification.
15
We had a panel member, Hrissanthi, who mentioned
16
there are other treatment alternatives or standard
17
of care has -- she listed a list of agents.
18
Can I get a clarification that for infantile
19
spasms, that that is indeed the standard of care,
20
that there are options available before going to
21
PLP?
22
DR. JOHNSON: PLP-dependent epilepsy is a
A Matter of Record (301) 890-4188
88
1
very specific disorder, so we're talking about a
2
subset within other sets. Infantile spasms is a
3
larger set. I think at some places, it intersects
4
with PLP dependency. And in some cases of PLP-
5
dependent epilepsy, you may see some efficacy with
6
other things. But she was talking about infantile
7
spasms being a broader disorder than actual
8
PLP-dependent epilepsy.
9
Did I make it worse?
10
(Laughter.)
11
DR. JOHNSON: So, yes, there are other
12
treatments for infantile spasms, but you would go
13
through the process of eliminating any
14
antiepileptic therapy and pyridoxine, and then you
15
would be able to establish whether or not this was
16
truly PLP-dependent epilepsy.
17
DR. VAIDA: Any other questions?
18
DR. PATEL: One more follow-up question. On
19
the study, Wang and colleagues, it appears that the
20
investigators claimed that PLP was effective in
21
controlling up to 46 percent of the patients, but
22
actually they started off with 574 patients. And
A Matter of Record (301) 890-4188
89
1
toward the end, only 3 responded. In addition to
2
that, they said 94 percent of patients responded
3
dramatically. But then during that course of time,
4
the patients were also on other antiepileptic
5
medications, which were later tapered off.
6
Is that correct?
7
Is your question --
8
DR. PATEL: To the nominator.
9
DR. JOHNSON: I can take a stab at that. My
10
understanding of these cases -- and I think our
11
pediatric geneticist had to leave for another
12
meeting. But my understanding is that this is a
13
completely empirical field, and there is a
14
protocol -- or several protocols, many -- followed
15
by the neurologists where each sequential treatment
16
is tried.
17
In the absence of genetic testing, which
18
identifies exactly what the condition is, they work
19
through each of these. PLP is one of the later or
20
latest parts of this protocol. They don't try that
21
until they've failed regular anticonvulsants and
22
pyridoxine.
A Matter of Record (301) 890-4188
90
1
DR. VAIDA: All right. We'll now vote,
2
either yes, no, or abstain. Please hold down the
3
button for at least 15 seconds.
4
DR. FAJICULAY: For the record, the results
5
are 14, yes; zero, no; and zero, abstain.
6
DR. VAIDA: I'll start to my right here with
7
Dr. Sun. If you'll state your name, vote, and any
8
comment.
9
DR. SUN: Jeanne Sun. I voted yes. I think
10
the presentations illustrate that it's well
11
characterized and it's well supported for efficacy
12
and safety.
13
DR. DESAI: Seemal Desai, I also voted yes.
14
I also thought that this clearly has a role in a
15
very rare combination set of diseases. We think we
16
have a theme today in talking about rare diseases,
17
but this one in particular on the infantile
18
population, it really seemed like this could be a
19
life or death benefit for PLP-deficient epilepsy,
20
as Susan clarified a moment ago.
21
DR. JUNGMAN: Elizabeth Jungman from Pew. I
22
voted yes for the same reasons.
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1
DR. WALL: Donna Wall. I voted yes for the
2
same reasons.
3
DR. CAROME: Mike Carome. I voted yes for
4
the exact same reason.
5
DR. BOGNER; Robin Bogner. Yes; same
6
reasons.
7
DR. VAIDA: Allen Vaida. I voted yes,
8
although I do have to say I'm a little concerned if
9
the indications are going to start to wander off
10
because back in '14, too, along with just oral, it
11
was only indicated for the PLP dependent. Then in
12
'18, they talked about a lot more indications.
13
That's my only concern with that, although I voted
14
yes.
15
DR. PATEL: Kuldip Patel. I also voted yes
16
for the same reasons that are already described.
17
MR. HUMPHREY: William Humphrey. I voted
18
yes for the same reasons.
19
DR. HOAG: Steve Hoag. I voted yes, and I
20
agree with what was said previously.
21
DR. VAIDA: Members o the phone? Dr. Gulur?
22
DR. GULUR: Dr. Gulur.
A Matter of Record (301) 890-4188
92
1
DR. VAIDA: Right.
2
DR. GULUR: I voted yes for the reasons
3
already stated.
4
DR. VENITZ: Jurgen Venitz. I voted yes;
5
same reasons.
6
DR. IKONOMIDOU: This is Chris Ikonomidou.
7
I voted yes because pyridoxal 5 phosphate is the
8
only available treatment for pyridoxal-dependent
9
epilepsy.
10
DR. VAIDA: All right. Thank you.
11
Why don't we just skip this break and move
12
on to the next topic. The next topic, we'll hear
13
from the FDA, Dr. Ganley, on the quercetin
14
dihydrate.
15
FDA Presentation - Charles Ganley
16
DR. GANLEY: Good afternoon. Thank you.
17
I'm Charlie Ganley from the Office of New Drugs,
18
and I'm just going to give a brief summary of the
19
quercetin dihydrate nomination. This slide just
20
shows the review staff involved in the review. I
21
wanted to acknowledge their efforts here and also
22
acknowledge the many people behind the scenes who
A Matter of Record (301) 890-4188
93
1
have not been acknowledged in any of these slides.
2
There are a lot of people that go in putting these
3
meetings together, and we appreciate their efforts.
4
Just to go through this quickly, quercetin
5
dihydrate has been nominated for inclusion on the
6
list of bulk drug substances for use in compounding
7
under Section 503A. We listed the proposed uses
8
that we have reviewed, and these are the proposed
9
routes of administration.
10
Quercetin -- and I think it's important to
11
note that in a lot of this, I'm going to be talking
12
about quercetin, although the nominated substance
13
is quercetin dihydrate. And it becomes very
14
important to understand that distinction as I go
15
through the talk because there are very great
16
differences between different forms of quercetin.
17
Quercetin is a naturally occurring flavonol
18
found in fruits and vegetables. It is a yellow
19
crystalline solid chemical with a well
20
characterized structure. The structure shown here
21
is for quercetin. If there were 2 water molecules
22
shown, it would be the dihydrate form. And I want
A Matter of Record (301) 890-4188
94
1
you to take note of the hydroxyl side chains off of
2
the ring structure because they are important in
3
understanding the forms of quercetin present in
4
foods, and they also are important in understanding
5
how the molecule is metabolized by the body. We'll
6
be getting to that in a few slides.
7
Quercetin exists in different crystalline
8
forms based on the degree of hydration. It is
9
stable in its solid form and protected from oxygen.
10
Quercetin dihydrate is the most thermodynamically
11
stable hydrate form, which may contribute to its
12
lower bioavailability. And again, I want to make
13
note of that because you'll see later on when I
14
present some pharmacokinetic data, there is a
15
difference between these different forms of
16
quercetin.
17
In aqueous solutions, because of rapid
18
oxidation and other degradations, under basic
19
condition, it is unlikely to be stable when
20
compounded in aqueous solutions. Now, I don't
21
mention on this slide here the aqueous solubility,
22
but I just want to point out an error that I've
A Matter of Record (301) 890-4188
95
1
noted in the page 4 of the memo. The memo stated
2
that quercetin is soluble in water. Well,
3
quercetin dihydrate is not very soluble in water.
4
In fact, it has a very poor solubility. And in one
5
literature article that I found, it was shown to be
6
2.5 milligrams per liter.
7
Now, other forms of quercetin may be more
8
soluble, but we're not talking about those. We're
9
talking about quercetin dihydrate today. The
10
possible synthetic route is extraction from plant
11
tissues, rapid extraction from powdered quercetin
12
bark with dilute ammonia and boiling of the extract
13
with sulfuric acid. Once you obtain the quercetin,
14
it's probably recrystallized with water. Again, we
15
don't know what the source of the bulk substance
16
manufactured is.
17
In summary, quercetin is a naturally
18
occurring, well characterized flavonol. The
19
extraction and synthesis are well developed. It is
20
likely to be stable in a solid form when protected
21
from oxygen but not in aqueous formulations. And
22
again, I noted that a dihydrate form is not very
A Matter of Record (301) 890-4188
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1
soluble in water. Quercetin dihydrate is most
2
thermodynamic, stable, hydrated forum, which may
3
affect its bioavailability.
4
With regard to the general pharmacology, the
5
average quercetin dietary intake from food sources
6
for humans ranges from 25 to 205 milligrams per
7
person per day. But in some individuals who have
8
high intakes of fruit and vegetables, you could get
9
up to as much as 1250 milligrams per day, and that
10
doesn't include all the other flavonoids that are
11
in food.
12
Examples of foods that contain quercetin are
13
many, and I'll just mention a few: onions,
14
berries, and tea. And there'll be different forms
15
of it, not the dihydrate form. In its natural form
16
in food, quercetin exists as a quercetin glycoside
17
or rutinoside. And I want to highlight this point
18
because the form of quercetin impacts on the
19
absorption of quercetin into the body for reasons
20
that are not entirely clear.
21
There are approximately 150 glycosides of
22
quercetin that have been described and include
A Matter of Record (301) 890-4188
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1
mono- di-, and oligosaccharides. The structure
2
shown here is quercetin-3-glucoside. If I can
3
show, there is the glucose hanging off of the
4
hydroxyl group.
5
In the gut, quercetin glycosides are
6
converted to quercetin aglycone and sugar moieties.
7
It's important to note that the term "aglycone" is
8
a general term applied to quercetin without any
9
side chains bound to the hydroxyl groups. That
10
would include quercetin dihydrate because there are
11
no groups bound to the hydroxl group. This is
12
important because quercetin is lipophilic, while
13
glycoside forms are polar. Quercetin glycosides
14
are more polar and were more soluble in aqueous
15
solution.
16
Based on the in vitro and in vivo models,
17
quercetin may act as an antioxidant,
18
anti-inflammatory, antiproliferative, and
19
anti-angiogenic agent, and many of these models are
20
conducted with quercetin aglycone and not quercetin
21
metabolites. And that's important to understand,
22
and we'll get to that in a few minutes.
A Matter of Record (301) 890-4188
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1
The bioavailability of quercetin is
2
generally poor and variable. The solid dosage
3
formulations -- the chemical form of quercetin
4
makes for solid dosage forms. The form of
5
quercetin seat makes a difference. In a study
6
comparing absorption of quercetin from quercetin
7
dihydrate and onionskin extract, the
8
bioavailability of quercetin was greater with the
9
extract.
10
In this study, the amount of quercetin in
11
the onion extract was 163 milligrams and a
12
dihydrate forum was 134 milligrams. The values in
13
the slide were normalized to the amount of
14
quercetin administered. And as you can see with
15
the onionskin extract form, the AUC and Cmax is
16
about fivefold greater for the extract form versus
17
the dihydrate form.
18
Now, this is very difficult to explain
19
because when they actually do the analysis of
20
quercetin that is present in the onion extract,
21
they characterize it as the aglycone, meaning that
22
there's no side chain, but 95 percent is the
A Matter of Record (301) 890-4188
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1
aglycone and about 5 percent have different
2
glycosides. And again, this is the dihydrate form,
3
so it gets back to this issue of thermal stability
4
I think, the absorptive capacity of one form versus
5
another one when they're both characterized as the
6
aglycone form.
7
The elimination of quercetin is via
8
conjugation reactions or ring fission to eventually
9
produce benzoic acid, which is excreted in the
10
kidneys. Conjugation occurs quickly in the
11
intestinal cell. The aglycone form undergoes
12
glucuronidation, sulfation, and methylation. And
13
these are the primary forms of circulating
14
quercetin.
15
When we're eating food and it has a
16
quercetin glycoside, there are brush border enzymes
17
on the luminal cells that cleave that, and that
18
forms an aglycone. The aglycone is absorbed into
19
the intestinal luminal cell and almost immediately
20
undergoes conjugation.
21
This also raises question about the
22
bioavailability, and it also raises question that
A Matter of Record (301) 890-4188
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1
when you're looking at these studies of in vitro or
2
cell studies that talk about the antioxidative or
3
anti-inflammatory effects, they're not talking
4
about necessarily the conjugates, which is the
5
predominant form that circulates in the body.
6
There have been some studies that look at
7
conjugated forms and their activity, and it's
8
somewhat all over the place. Many of them have
9
little or no activity, though.
10
The other thing to note is the conjugated
11
form is excreted in the bile fluid and can undergo
12
enterohepatic circulation. And you can see it in
13
this slide. I can't see it very well from here,
14
but the dark value here shows a biphasic curve.
15
It's this little dip and then increase. You can go
16
and look at individual patients, and you can see
17
that second peak. So what's happening is the
18
conjugated form is being excreted in the bowel.
19
That conjugate is cleaved, and it's reabsorbed.
20
Now, this is a part of a slide from your
21
background memo. What I've done is I've taken off
22
the -- originally there were two, the quercetin
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1
glycoside and the quercetin rutinoside. Their side
2
chains are cleaved, and they form an aglycone. And
3
very quickly, this aglycone, in the luminal cell
4
and also in the liver, is converted to the
5
conjugated forms, a glucuronide, a sulfate, a
6
methylated form. All these reactions occur very
7
quickly, so most of the quercetin that circulates
8
in our body after we eat food that contains
9
quercetin is in the conjugated form.
10
Various foods and drinks can affect
11
quercetin absorption. We've listed some of them in
12
the background memo. There are potential drug
13
interactions through different mechanisms.
14
Quercetin interacts with different CYP450s that
15
have not been fully characterized. Some of these
16
are from different in vitro studies.
17
In another, I believe it was a cell study
18
where quercetin may enhance or inhibit the
19
transport of P-glycoprotein substrate, and the
20
example was been vincristine depending on the
21
concentration quercetin. That's one of the issues
22
when you're looking at the literature of these in
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1
vitro and cellular studies and they're defining a
2
certain concentration. We don't know what
3
concentration is going to be at the cellular level.
4
With regard to the nonclinical safety, there
5
is limited data on the acute toxicity of quercetin.
6
Observational studies were limited to animal
7
symptoms without histopathology. For repeat dose
8
toxicity, there were no toxicity seen in rabbits
9
for orally-fed quercetin at 1 percent for 410 days.
10
In a 2-year rat carcinogenicity study, there
11
was increased severity of chronic nephropathy,
12
slight increase in focal hyperplasia of the renal
13
tubule epithelium, an increased incidence of
14
parathyroid hyperplasia seen in males at 10,000
15
parts per million, which is essentially a 1 percent
16
feed. A 6-month interim report for 2-year study
17
showed reduction in body weight among females at
18
40,000 parts per million or 4 percent feed and
19
increases in relative kidney and liver weights in
20
both sexes at 4 percent feed.
21
With regard to genotoxicity, there have been
22
positive genotoxic toxic signals for in vitro
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1
studies, including Ames chromosome aberrations and
2
sister chromosome aberrations. There were negative
3
genotoxic signals for in vivo studies, specifically
4
micronuclei and sister chromatid genes. The
5
developmental and reproductive toxicity, there were
6
no adverse effects reported in the literature.
7
With regard to carcinogenicity, oral administration
8
of quercetin 0.1 percent in a diet for 540 days in
9
rats did not increase the incidence of tumor
10
formation when compared to concurrent controls.
11
With regard to clinical safety for the FDA
12
adverse reporting system, there were 7 reports
13
submitted to FDA for an FDA-approved drug that
14
included the concomitant use of quercetin. These
15
were reports for other drugs, which quercetin just
16
happened to be being used by the individual. The
17
attribution to quercetin is not possible because of
18
multiple concomitant drugs or limited information,
19
but there was one report of a possible interaction
20
with apremilast, which is Otezla. The brand name
21
was Otezla.
22
Now, apremilast is metabolized by cytochrome
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1
P450s, and subsequently glucuronide. If you read
2
the package insert, there's a drug interaction with
3
rifampin, and this is because rifampin induces
4
CYP3A. What happened in this individual is that
5
the adverse event was related to a lack of
6
effectiveness. In the next slide, I'm going to
7
show that there is at least one study that shows
8
that quercetin can induce a CYP3A. So there is a
9
possible drug interaction here.
10
With regard to CFSAN adverse event reporting
11
system, there were 20 reports; 7 were
12
hospitalizations but none appeared directly related
13
to quercetin. The majority of cases were
14
confounded by multiple medications and their
15
underlying disease, and there was insufficient
16
information for assessment.
17
There were no adverse events reported in
18
clinical trials for orally administered, and also
19
there were no specific case reports for orally
20
administered. Serious adverse events occurred
21
after the administration of high-dose intravenous
22
quercetin to patients with cancer, including pain
A Matter of Record (301) 890-4188
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1
at the site of injection at greater than 60
2
milligrams per meter squared, dyspnea at greater
3
than 1400 milligrams per meter squared, and
4
vomiting greater than 1700 milligrams per meter
5
squared. There was significant renal toxicity
6
noted at greater than 630 milligrams per meter
7
squared, and in some patients, they had residual
8
renal injury after the treatment was stopped.
9
There were some drug-drug interaction
10
studies. As I noted and I mentioned earlier with
11
apremilast, quercetin significantly induced CYP3A
12
activity to the substrate midazolam, and this was
13
partly related to CYP3A5 genotype. Quercetin is
14
also present in St. John's wort and has been shown
15
to inhibit activities of cytochrome 1A2, 2C19, and
16
2D6.
17
With regard to clinical effectiveness for
18
cancer prevention and treatment, there are
19
mechanistic in vitro studies in the literature,
20
there are sporadic small clinical studies, and
21
extensive literature on purported mechanisms for
22
treating a wide variety of cancers, but no
A Matter of Record (301) 890-4188
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1
compelling clinical studies evaluating
2
effectiveness. For prevention, there are no
3
clinical studies, and most information is based on
4
dietary intervention with multiple dietary
5
ingredients, none of which is supportive abuse to
6
prevent cancer.
7
With regard to allergy, most clinical
8
studies conducted to date have evaluated
9
combinations or mixtures of ingredients either in
10
the form of an herbal product or in a food
11
substance. There is insufficient data from
12
clinical studies to support the effectiveness of
13
quercetin in the treatment of allergy.
14
With regard to hypertension, there was a
15
meta-analysis published I think in 2016 that looked
16
at the available randomized control trials
17
evaluating the impact of quercetin on blood
18
pressure. The author suggested a statistically
19
significant effect of quercetin supplement in the
20
reduction in blood pressure when used at doses
21
greater than 500 milligrams per day. However, I
22
will add that the authors noted in their summary
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1
that further studies are necessary to investigate
2
the clinical relevance of these results, and the
3
possibility of quercetin application as an add-on
4
to in anti-hypertensive therapy.
5
Now, in these 7 studies, several of them
6
were the dihydrate, several were just characterized
7
as the aglycone form, and one of them had an
8
anhydride form. We looked at all 7 studies, and in
9
evaluating each study in the meta-analysis, we did
10
not find a single study that showed a significant
11
effect on blood pressure compared to placebo, and
12
placebo was present in many of these studies.
13
I should note here -- and I should have
14
pointed out earlier -- that this was an effect on
15
blood pressure, so not all these individuals in
16
these studies had high blood pressure. There were
17
some studies where individuals had high blood
18
pressure.
19
If you read just the abstracts of these
20
studies, some of them report a statistically
21
significant effect s on blood pressure, but the
22
authors really conducted a within-treatment
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1
comparison, which was baseline minus the in-study
2
visit and not a between-treatment comparison, even
3
though there was a placebo group available. And
4
the change in blood pressure for quercetin versus
5
placebo did not show a significant difference. So
6
we disagree with any suggestion that it does
7
improve hypertension.
8
With regard to asthma, there are no clinical
9
studies where quercetin was administered and
10
evaluated for the treatment for asthma. Clinical
11
effectiveness, our conclusion is there is
12
insufficient data to support the effectiveness of
13
quercetin dihydrate in the treatment of cancer,
14
allergy, hypertension, or asthma.
15
With regard to the historical use in
16
compounding, quercetin dihydrate is available as a
17
dietary supplement, but its historical use in
18
compounding is unclear. There is insufficient
19
information available to determine how long
20
quercetin dihydrate has been used in pharmacy
21
compounding. Insufficient data are available from
22
which to draw conclusions about the extent of use
A Matter of Record (301) 890-4188
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1
of quercetin dihydrate in compounded drug products.
2
Quercetin dihydrate is not listed in the British,
3
European, or Japanese pharmacopeia.
4
So with regard to our recommendation, with
5
regard to chemistry, quercetin dihydrate is well
6
characterized and stable in a solid dosage form if
7
protected from oxygen. It is likely to be unstable
8
in aqueous solutions and rarely undergoes
9
oxidation, but also add that the dihydrate form is
10
insoluble in aqueous solutions.
11
With regard to safety with the oral
12
administration, there appear to be no serious
13
adverse events. For intravenous administration,
14
serious adverse events include dyspnea, vomiting,
15
and kidney toxicity. Oral absorption is poor and
16
variable. There is rapid metabolism to glucuronide
17
and sulfates, which raise questions about the
18
bioavailability of quercetin dihydrate.
19
There are potential interactions with
20
cytochrome enzymes that have not been fully
21
explored, which raise concerns about potential drug
22
interactions if used with approved drug products
A Matter of Record (301) 890-4188
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1
that are metabolized by cytochrome enzymes, and
2
there also may be some interaction with
3
transporters.
4
With regard to effectiveness, there is
5
insufficient data to support the effectiveness of
6
quercetin dihydrate in the treatment of cancer,
7
allergy, hypertension, or asthma. With regard to
8
the historical use in compounding, insufficient
9
data are available from which to draw conclusions
10
about the extent of use of quercetin dihydrate in
11
compounded drug products.
12
So overall, our recommendation after
13
balancing the 4 evaluation criteria, it weighs
14
against quercetin dihydrate being added to the list
15
of bulk drug substances that can be used in
16
compounding under Section 503A. Thank you.
17
Clarifying Questions from the Committee
18
DR. VAIDA: Thank you. We'll now entertain
19
any clarifying questions from the committee. Dr.
20
Desai?
21
DR. DESAI: I was curious about your comment
22
with the drug-drug interaction with apremilast. I
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1
haven't seen -- and apremilast is a fairly new
2
drug. It's FDA approved for moderate to severe
3
plaque psoriasis, so obviously I use that
4
frequently in my practice as a dermatologist. I
5
haven't heard of many CYP interactions with
6
apremilast. Can you comment a little bit more
7
about that?
8
DR. GANLEY: The only one that I saw listed
9
in the package insert had to do with rifampin
10
induction.
11
DR. DESAI: Right.
12
DR. GANLEY: That was the only one. I
13
pointed that out. I'm not here to review
14
apremilast. I pointed it out because there was
15
evidence of a clinical study where they looked at
16
cytochrome 3A and suggested that quercetin could
17
induce that. So the adverse event was limited in
18
the amount of information. I didn't see
19
information on what the specific details are
20
regarding to the dose of quercetin or things like
21
that, or how it was administered, or what form it
22
was and things like that.
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1
DR. DESAI: And that was just one report
2
that you found?
3
DR. GANLEY: We hardly had any -- again,
4
that was from 7 reports for quercetin in the drug
5
adverse event, so we're not going to expect a lot
6
from there.
7
DR. VAIDA: Any other questions? Hearing
8
none, we'll now hear from --
9
DR. GANLEY: She has a question over here.
10
DR. SUN: Thank you. I just have a quick
11
question about the safety and efficacy data. Was
12
that based on compounded preparations or the
13
dietary supplements?
14
DR. GANLEY: Well, we don't know. I'm not
15
sure what specific safety data you're referring.
16
When we look at safety data that comes
17
into -- presumably if it's coming into the CAERS,
18
the CFSAN database, that was a dietary supplement.
19
If it's coming into the FAERS, which is the drug
20
adverse event reporting system, that could be a
21
dietary supplement also. We don't get granular
22
information on these things.
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1
DR. SUN: Yes. I was referring to those two
2
databases.
3
DR. GANLEY: Right.
4
DR. VAIDA: All right. We're now hear from
5
Dr. Paul Anderson.
6
DR. LOUVEN: [Inaudible - off mic]. My name
7
is Bob Louven from the Division of
8
Pharmacovigilance. I think the case of the
9
reported drug interaction, if I'm not mistaken, if
10
it's the same case we're discussing, there's one
11
report we found in FAERS that the patient taking
12
apremilast with a dermatologic condition reported
13
lack of effect, they suspected a lack of effect.
14
There's really no other information. It was
15
just sort of a very brief comment that the patient
16
had expected a better result, did not have
17
efficacy, and mentioned that they were suspecting,
18
just theoretically, there might be an interaction,
19
but there's no objective data.
20
In general, it's important to know that lack
21
of effect type of AE is the most commonly reported
22
in FAERS, so it's really very hard to interpret
A Matter of Record (301) 890-4188
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1
that case.
2
DR. GANLEY: No. I don't disagree. I'm
3
just pointing out that we already have data that
4
this drug can induce CYP3A just like rifampin. In
5
most drug interactions, we're speculating.
6
I'm just raising that there is a connection of the
7
dots here, and there's a lot of interactions,
8
potential interactions, through cytochromes that we
9
don't fully understand related to this specific
10
ingredient.
11
DR. VAIDA: All right. Now we're hear from
12
Dr. Paul Anderson from Anderson Medical Specialty
13
Associates with the nominator presentation.
14
Nominator Presentation - Paul Anderson
15
DR. ANDERSON: Thank you. I know we're at
16
the end, so a few things is based on the prior
17
testimony by the FDA. All of the primary concepts
18
and many of the data I was going to present our
19
similar, so what I will do is just spend the little
20
time I have on the differences and a little bit of
21
preliminary data and information around modern uses
22
other than oral that are currently going on and
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1
some related to an ongoing trial.
2
So, obviously we've already gone through the
3
nominated indications. And what I would say is
4
that -- of course there's over 16,000 references.
5
So having a short time, I'd just like to mostly
6
review just to show what was, what was being done,
7
whether through a meta or a regular review.
8
So in asthma and allergy, as was mentioned
9
prior, what you really have as opposed to really
10
hardcore, good single agent studies are a lot of
11
mechanistic studies, a lot of mechanistic studies
12
that speak to changes in cytokines, et cetera.
13
Many of these mention traditional use.
14
Traditional use is hard to tease out with
15
quercetin. In the 30 years I've been around
16
people, physicians who have used quercetin, it is
17
commonly used really in the asthma-allergy setting
18
and for a few other purposes that I will mention.
19
I think one thing that's really important
20
and in almost every study mentioned, and certainly
21
just about every study that I'm going to briefly go
22
through, one of the points always made is it's
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1
generally an add-on therapy. It's never really a
2
monotherapy. Now, there may be exceptions to that,
3
but generally it is as an add-on therapy as either
4
a synergist or some other type of add-on effect.
5
So I think that's important to mention.
6
The other problem in looking at the
7
particular nominated substance, which is likely the
8
very best for compounding, as was just brought up,
9
is it's not always the substance that was used in
10
the trials that are mentioned. And then when you
11
get either the metas or the reviews, you've got
12
this mixture of that going on. So in that respect,
13
I would also completely agree with the data you've
14
already been given, so I won't go deeply into that
15
because it's going to be the same information.
16
But I think when you look at the totality of
17
the asthma-allergy, it is not being certainly
18
promoted and the traditional use is not as a
19
replacement for most standard asthma or allergy
20
medications. It is usually used as a synergist in
21
either children or adults to either lower their
22
dependence on some of their background medications
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1
or to decrease their antigenicity, allergenicity.
2
Most of these have been gone through, and
3
most of the reviews have statements in them, if you
4
read through the whole paper, that are very hopeful
5
and promising with respect to quercetin, but again,
6
as a agent that we need to study more to figure out
7
the mechanisms more deeply. Then the other things
8
which were already brought up, which revolve around
9
absorption, et cetera, are kind of common themes in
10
almost every paper that you look at.
11
This is one that did get a little bit more
12
deeply into activities, so talking about alteration
13
of IL-8 and that it's comparable or better than
14
cromolyn, then IL-6 and calcium level changes
15
shifting as well. So there are some studies
16
looking into actual cytokine shifts and changes.
17
In oncology, again, I've not ever seen
18
anything, either in traditional use or published,
19
where quercetin itself was purported to be a
20
monotherapy, but in a trial that's currently going
21
on -- and I apologize it didn't get in the slide,
22
but I'll read it into the record, so it's there.
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1
Clinical trial NCT02494037, which is a prospective
2
human trial on 4 types of cancer. The question is,
3
being used in a very multimodal, multifactoral
4
treatment protocol that is individualized for the
5
patient. So that is ongoing right now. It's
6
2 years its 5 years, and a fair amount of quercetin
7
has been used in that, and I'll be talking about
8
that in a little bit.
9
Again, as was discussed earlier, I'm going
10
to just move this phase 1 trial forward because FDA
11
used that to speak specifically about parenteral
12
use quercetin, so I'll move that to the parenteral
13
safety coming up later. This was, again, I believe
14
a 1996 trial. It was a phase 1 trial where they
15
were doing the best that they could to solubilized
16
quercetin so it could be infused, which, as was
17
mentioned, it's not a water soluble component. So
18
as a phase 1 trial, they learned a lot of things
19
the hard way, so we'll talk about that coming up.
20
This is a low-dose in vitro mechanism, and
21
something interesting in the oncology data as you
22
read through it. And it's the same as with
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1
asthma-allergy, et cetera. You have certainly in
2
vitro studies. You've got a lot of animal,
3
proof-of-concept, and mechanism studies. And then
4
you've got some observational studies with human.
5
You find statements -- and I believe this is a
6
little hard to see from the side here, but you find
7
statements like this. And one study will say,
8
well, we had to get to very large oral doses to
9
achieve an effect, and then other studies will say
10
we were able to achieve effect at smaller doses.
11
One of the other things that I think is
12
confounding to the discussion is that the delivery
13
mechanisms for oral, especially use, have been
14
quite varied as was brought up in the FDA
15
presentation. What we have seen over time is as
16
delivery mechanisms are more stable and better
17
absorbed, meaning it's not just plain quercetin or
18
even the quercetin being mentioned here, but
19
normally it's complex with something to either get
20
past the brush border enzymes or enhance
21
absorption, you get very different treatment
22
effects.
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1
So as was brought up earlier by FDA, you
2
cannot homogeneously extract from every study that
3
quercetin in one is at all like quercetin in
4
another. So we want to be up front about that as
5
well.
6
There are a lot of mechanistic studies and
7
reviews that show, essentially, if you look at all
8
of these -- and you've already had them. But if
9
you look at all of them together, what most of
10
those papers around oncology say is this obviously
11
is not going to be a monotherapy, but it may be a
12
therapy that would help in either
13
chemosensitization or potentially in improving
14
quality of life, et cetera.
15
Similar to the way that the drug, LipoCure,
16
which is a version of a curcuminide [ph] molecule,
17
which is in final trials right now as being used as
18
a chemosensitizing and improving of certain aspects
19
of quality of life, that's kind of the theme of all
20
of those particular studies.
21
When it comes to hypertension, both FDA and
22
myself have comment on the same review, of the
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1
papers that were already mentioned because my
2
colleague went into good depth on that one. I
3
won't go into a whole lot of depth there. What I
4
can say is from particular -- if you take, as I
5
said, the 30 years I've been watching the clinical
6
use of quercetin, I do not see hypertension as an
7
extremely common use for it unless it's used as a
8
synergist or an add-on. I see quercetin used in
9
asthma-allergy, and I see it used in oncology,
10
primarily.
11
I want to mention a few things just about
12
administration and safety because this is another
13
thing that's highly, highly variable over time. If
14
we go back to that first paper that was mentioned
15
with respect to parenteral administration and all
16
of those side effects that came out, which is in
17
the briefing document, et cetera, that goes back to
18
1996. And the ability to even get quercetin of any
19
form into a suspension that could be parenterally
20
administered was very, very, very difficult at that
21
time. And I would argue it's difficult at this
22
time, too, but we know more than we did.
A Matter of Record (301) 890-4188
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1
So this is a quote from the briefing
2
document from FDA, and it's exactly the same as
3
what was given already. This is the Ferry paper
4
from '96, and they were looking at dose ranges that
5
were fairly robust in intravenous administration.
6
If you look at that paper and you look at the
7
pharmacology of what's going on with it, there's
8
probably some issues in taking a 1996 approach and
9
extrapolating that to what pharmacies are doing
10
right now. And I will circle back around to
11
current compounding pharmacy activity with respect
12
to parenteral use of quercetin coming up.
13
The first thing is -- and this is something
14
probably we would have done in 1996 not knowing,
15
and even the authors, if you read the Ferry paper,
16
talk about, well, this is a phase 1 trial and we're
17
supposed to be learning what works and what doesn't
18
work, essentially. They took the quercetin, and
19
the only way that they could get it to stay in
20
suspension was with a very, very concentrated dose
21
of DMSO. So 50 mLs of RIMSO, or DMSO, and they
22
diluted it, the RIMSO, 50 percent water, and then
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1
they put the quercetin in that solution to keep it
2
in suspension.
3
The thing that they did that created most of
4
the trouble -- and they discussed at length in the
5
paper -- is that they then took that -- and hard to
6
imagine now doing this, but they gave it by
7
intravenous push. So you're taking essentially a
8
solution that's 50 percent DMSO on its own, which
9
would not be recommended to be given by IV push,
10
and you put quercetin in it, and then you give it
11
by IV push.
12
Well, there are a couple of things that
13
happen. One is, of course, you have no dilution
14
effect, which actually the authors of the paper in
15
their conclusion come around and say we should have
16
done that. But the other thing is this is an
17
extremely fibrogenic, so the pain at the injection
18
site you would expect actually, as opposed to that
19
being a surprise side effect.
20
This is not at all what would be being done
21
now, which I will describe in a little bit, and
22
it's also certainly nowhere in standard practice
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1
for parental administration of, really, anything
2
that I can think of at this point.
3
With regard to the renal issues, one of the
4
things that's potentially possible is that this
5
bolus of 50 percent DMSO that was holding the
6
quercetin on its own could cause some renal issues.
7
And then if you take that potential and then you
8
add this molecule that you saw earlier of
9
quercetin, you're getting a very large, fast bolus
10
of two potentially nephrotoxic agents hitting the
11
kidneys very, very rapidly.
12
Now, one of the things that they said -- and
13
it's the second bullet point here -- being clear
14
that simple IV prehydration could at least
15
partially aggregate the nephrotoxicity, et cetera.
16
And if you look through the paper as they're
17
discussing what happened well and did not go well,
18
essentially what they came to was we need to do
19
this if we do another trial in some sort of
20
dilution. That is something I'll be getting to
21
that we have found more in modern times.
22
Recent use, there is intravenous use of
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1
quercetin, but there is quite a different way of
2
both producing it and administering it. In the
3
last six years, there have been 5 different
4
compounding pharmacies that made parenteral
5
quercetin available. Much of it is for this
6
particular trial that I had mentioned, and in the
7
preparation, it's either prepared as an emulsion or
8
it is prepared in cyclodextrin, which was mentioned
9
for another drug earlier today. There is no
10
preparation using DMSO currently in modern times.
11
The dose escalation that has been used most
12
commonly -- and this again would be germane to the
13
oncology prospective study that's going
14
on -- 1 milligram per kilogram is the test dose,
15
and they have escalated up to 50 milligrams per
16
kilogram.
17
The other thing that's very different from
18
the 1996 paper, which is what they foreshadowed in
19
forecasted in their advice to future drug studiers,
20
was that it is very highly dilute. What has been
21
found over the time, over these six years -- so it
22
goes between a half and 1 and a half liters given
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1
over a fairly slow amount of time. It's given on a
2
dose-per-time basis. So unlike 1996, it's never
3
pushed. It is highly diluted. And what has been
4
found and reported back to me is that most of those
5
side effects, there's not been a single event where
6
either the creatinine or the eGFR has risen.
7
There's not been a single high-grade side effect
8
since changing, based essentially on the
9
recommendations of Ferry in '96.
10
From those 5 pharmacies that we're producing
11
it over the 6 years that we have been monitoring
12
currently, I believe there's 2 or 3 that are still
13
making either an emulsion or a cyclodextrin based
14
parenteral product. And this essentially goes to
15
both current use and historical use, so I want to
16
make sure that you knew that it was out in the
17
compounding world.
18
No high grade; transient nausea and
19
flushing, which were self-limited in 10 percent of
20
the cases, and essentially that was relieved by
21
slowing the infusion rate or diluting the infusion
22
to a higher degree. he level of adverse events at
A Matter of Record (301) 890-4188
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1
this point, none high grade and most are very, very
2
transient and self-limited. But because this type
3
of parenteral use is not anything that is currently
4
published but is ongoing, I want to make sure, at
5
least for historical use, you know that that has
6
happened or is happening.
7
The other thing that I found of interest in
8
looking because of our experience -- so when I say
9
"our," I gave you the trial number, I was a
10
founding member of the first center. There are 8
11
centers where it's going. And since, I have moved
12
on to other work, but I'm still in contact with the
13
centers, and I keep track of the experimental
14
things that they're doing. So that's where I got
15
that information.
16
But in looking, what I found also curious
17
was quercetin, again, in either animal models or
18
very early research, there is a lot of research
19
going on that is looking at parenteral forms,
20
whether for interarticular or subcutaneous mostly
21
for intravenous use. And most of these are from
22
either this year or 2012 essentially. So it's not
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1
something that is not being looked into and not
2
being researched because of at least the
3
mechanistic papers that have gone on proof of
4
concept, but it's not something that is in large,
5
wide-scale human trials either. So it is still at
6
that stage.
7
The one comment from the study group that I
8
was asked to share was, if quercetin is unable to
9
be compounded in the future, then they would have
10
to go back and do an IND, et cetera, and by the
11
time that was done, this particular trial would be
12
over.
13
In summary, a few things. Modern use from
14
my own personal but also monitoring other groups,
15
whether parenteral in the modern sense, in the
16
modern way that it's done or oral in very stable
17
systems has been very safe. We have
18
looked -- really, the CAERS and the FAERS data was
19
looked through. And we've already gone over that a
20
few times, so I don't need to go over it. It's
21
exactly the same story. You can't really trace
22
much back to quercetin as a problem in the CAERS or
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1
FAERS data.
2
This is a summary paper or a review paper
3
looking just at the safety. Most of them, really,
4
when you look at them -- and I will admit that this
5
is limited by the fact that they may be reviewing
6
numbers of different types of oral quercetin, for
7
example, that were used. So it may not exactly be
8
the type that we're talking about completely. But
9
generally, there's very little concern, at least,
10
around safety.
11
This comes directly from the nomination
12
statement, "intend to preserve for nomination all
13
routes until adequate time to prepare a response,
14
but intravenous, intramuscular, oral, sublingual
15
uses."
16
Clarifying Questions from the Committee
17
DR. VAIDA: Thank you.
18
Any clarifying questions? We'll start with
19
that. Dr. Carome?
20
DR. CAROME: Mike Carome. In your
21
presentation -- I just want to make sure I'm fairly
22
interpreting what you said -- I didn't hear you say
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1
anything that refuted FDA's assessment that there
2
is no good data on the effectiveness for any of the
3
diseases for which this drug was nominated. Am I
4
understanding correctly?
5
DR. ANDERSON: I would say, based on the
6
fact that all of the data that FDA presented and
7
the summary data that I presented come from the
8
same place, if the standard is large-scale human
9
trials of this particular molecule, then we are in
10
agreement.
11
DR. VAIDA: Dr. Wall?
12
DR. WALL: I may be in a little bit of an
13
afternoon fog, but just to clarify, are there any
14
patients or type of situations currently in which
15
you would go to this agent and say, yes, I believe
16
it can help somebody in this situation? Or is it
17
mostly we still need to do studies and keep going
18
with figuring out where it's going to fit into the
19
various processes?
20
DR. ANDERSON: That's a good question. And
21
if I missed the first couple of words and I answer
22
this wrong, let me know, and I'll re-answer it, but
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1
I believe I got what you said. Based on
2
traditional use, as far as it being generally safe
3
in its oral form, especially, the types of patients
4
most commonly, where quercetin is an additive
5
therapy, are in asthma-allergy, allergic phenomena,
6
especially digestive tract, either eosinophilic
7
digestive problems or that sort of allergy.
8
So those are areas where it is very
9
commonly, in its oral form, used very early in
10
therapy. Because there are no papers looking at it
11
head to head with other things because it's
12
normally used as an additive therapy, clinically
13
what we see -- and this is an anecdotal statement.
14
But clinically what I have seen and observed in
15
others is that the escalation in an atopic allergic
16
patient to other medications can often be truncated
17
at the addition of quercetin. So the atopic
18
conditions are a very common use for it.
19
This also is based on the second part of the
20
question in respect to the cancer research that's
21
going on. There are not enough cases where it has
22
been used parenterally to string together a
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1
particular benefit scenario, et cetera, but based
2
on the first two years where it's been used
3
parenterally, there are about -- I believe among
4
the 8 centers, there's probably about 8 to 10 cases
5
where as a single agent additive, it made a
6
difference in either disease progression or
7
particular side effect profiles from other
8
therapies that were being given.
9
Those would be, I would say, the two areas.
10
One is very research oriented; one is traditional
11
use, and the atopic oral use is the most common
12
reason.
13
DR. VAIDA: Any other questions?
14
DR. BOGNER: I guess this is to the FDA
15
since it was your presentation. I thought I might
16
hear it, but I did not. You note that it's stable
17
in its solid form when protected from oxygen. How
18
are we imagining this will be protected from oxygen
19
when it's distributed?
20
DR. ZHANG: This is Ben Zhang from FDA.
21
When you start oral dosage forms, you can formulate
22
it with antioxidants to prevent it from oxidation.
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1
DR. BOGNER: The other thing that I was
2
looking at in the literature trying to find
3
quercetin and what purity you could get it. And
4
even in the research realm, they're able to get
5
maybe 96, 97 percent quercetin. Some of the solid
6
state characterization was extraordinarily
7
difficult because of different forms.
8
How well characterized is this stuff? There
9
are so many different oxidation states to it and
10
different hydration, and solvates are in there. So
11
I'm not feeling comfortable that it's well
12
characterized.
13
DR. ZHANG: For traditional analytical
14
methods, it's easy to characterize whether this is
15
in the proposed structure or it is in the proposed
16
hydrous form. It's not that difficult.
17
DR. BOGNER: Okay.
18
DR. ZHANG: As for the impurities, you
19
probably want to know the impurity profiles, what
20
is left, 3 percent. That thing, we don't have that
21
information to make judgment.
22
DR. VAIDA: One question. You had mentioned
A Matter of Record (301) 890-4188
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1
that there were 500 compounding pharmacies,
2
compounding the parenteral.
3
DR. ANDERSON: Five.
4
DR. VAIDA: Five?
5
DR. ANDERSON: Not 500. Sorry.
6
DR. DAY: And there was about 2500 doses.
7
DR. ANDERSON: Yes.
8
DR. VAIDA: This information is from --
9
DR. ANDERSON: That information is from my
10
monitoring of the 8 sites that are doing that
11
current trial, who are the primary users of
12
parenteral quercetin.
13
DR. VAIDA: One more question, Dr. Humphrey?
14
DR. HUMPHREY William Humphrey. The sites
15
where they're doing the clinical trials, I don't
16
understand why there's not an IND.
17
DR. ANDERSON: I'm just thinking back to the
18
beginning. So the trial was begun in Seattle and
19
the IRB was through the University of Washington.
20
And then it was set up as a multisite trial because
21
at the time that it was set up, under this
22
particular process, there had been no hearing about
A Matter of Record (301) 890-4188
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1
the substance. And it's not the only substance
2
that they use. And because it was a generally
3
available from compounding pharmacies, the IRB
4
passed on the use of it as a generally available
5
substance.
6
What I don't know because I'm not on the
7
UDUB [ph] board, whether they looked at it and
8
characterized it as a dietary supplement in that
9
respect or how they did that. But that's how that
10
happened.
11
DR. VAIDA: Dr. Ganley?
12
DR. GANLEY: A study that you mentioned, is
13
that an oral or parenteral?
14
DR. ANDERSON: It's both actually. It's not
15
a single-agent study. It's a multi-agent study.
16
Open Public Hearing
17
DR. VAIDA: Okay. Thank you.
18
We'll now proceed to hear the open public
19
hearing speakers, and we have two of them. Our
20
first speaker?
21
MR. DUMOFF: Good afternoon. My name is
22
Alan Dumoff. I'm an attorney. I represent the
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1
American Association of Naturopathic Physicians and
2
the Integrative Medicine Consortium, which is a
3
group that's composed of a professional association
4
and practice, functional and integrative medicine.
5
The topics I want to discuss today I think
6
go directly to the important exchange that occurred
7
between Dr. Carome and Dr. Anderson about the
8
standards of evidence and review of these kinds of
9
uses. I want to approach the idea of functional
10
medicine and functional uses very quickly through
11
three different topics. The first is the
12
definition of a drug and whether a functional use
13
is a sufficient use rather than requiring a disease
14
indication.
15
Secondly, I want to talk about the
16
[inaudible - audio break] in the way that drugs are
17
considered.
18
We got a different mic? Thank you.
19
So I want to discuss some of the particular,
20
what I would say are some tunnel-vision decisions
21
that have come out of the committee, and discussing
22
quercetin as an example. I want to discuss the way
A Matter of Record (301) 890-4188
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1
FDA has characterized one of those studies with
2
regard to hypertension.
3
We are discussing professional differences
4
of viewpoints. These are the organizations that I
5
represent, and I want to note that, for example,
6
integrative medicine, which is not really
7
represented before the committee, is board
8
certified, recognized by the American Board of
9
Physician Specialties, and naturopathic
10
naturopathic medicine is licensed in 20 states.
11
Before I proceed, I want to just say that
12
the AANP and IMC very much appreciate the decisions
13
being made today and the discussion that are
14
getting into the functional issues, but we've been
15
raising with FDA that a drug that's claim is a
16
functional use is by law a drug. If I market
17
something just for functional use, unless it's
18
under DSHEA, I am violating drug law.
19
Nothing in DQSA or in the Modernization Act,
20
which governs 503A, excludes functional uses as an
21
adequate and sufficient basis for use. And the
22
requirement that we demonstrate disease indications
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1
is taking valuable components out of physicians'
2
hands who are well trained and using these
3
functional approaches by requiring these disease
4
standards.
5
We've been hearing at our course center
6
[indiscernible], for example, that antioxidant was
7
insufficient. A physician may want to use
8
anti-inflammatory or antioxidants for a number of
9
reasons, maybe targeting a physiologic or
10
functional cause.
11
I'm hearing today discussion of adjunctive
12
uses and some of the interactions. That's
13
positive, but in the past, we've not really heard
14
that a physician may want to use an approved drug
15
and have a functional adjunctive part of their
16
armamentarium to use as well, as well as
17
compounding for nutritional purposes, which has not
18
been discussed.
19
So we're reducing as a head to head, and the
20
evidence of risk on the approved drug is not really
21
being considered. So I want to give two quick
22
examples. MSM we were told could not be approved
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1
because there were 4 cases of bleeding or elevated
2
INR. But instead, physicians should prescribe
3
Celebrex, which has a black box warning for stroke.
4
So physicians are being told that the choice is so
5
clear, because of those few bleeding episodes, that
6
they should instead use a Cox-2 inhibitor. That is
7
to us not a sensible outcome.
8
With 5-HTP, we were told that because it's
9
used for the indication of depression that we have
10
to be able to prove that 5-HTP doesn't have the
11
same side effects. So the outcome of that was, we
12
were told, we have to use a synthetic
13
pharmaceutical, known have these side effects,
14
because the physiologic ingredient might have those
15
effects. That's not a sensible outcome.
16
Now finally, I want to talk about the
17
quercetin presentation. We heard from Dr. Ganley,
18
and in the report, it said that the data in the
19
meta-studies did not align with the result. But if
20
you look at what they said, they said that only one
21
genotype was efficiently demonstrated, but that
22
genotype was 70 percent of the population. There
A Matter of Record (301) 890-4188
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1
were only 3 genotypes -- one was underpowered with
2
three. So it's not a fair assessment to say that
3
the significant swing of up to 12 points in
4
systolic blood pressure was not a significant
5
outcome.
6
In fact, as Dr. Ganley mentioned, there was
7
skewed because in the case of many of the
8
physiologic and functional items, they only work
9
where there's a problem. So the normotensive
10
patients, there was no effect, and this cohort had
11
a number of normotensive patients.
12
So if you look at the actual result, it was
13
actually more significant than the study authors
14
showed. So we'd ask you to consider those things
15
as you review quercetin and their other
16
nominations. Thank you for your time.
17
DR. VAIDA: Second speaker?
18
DR. OSBORNE: Good afternoon. I'm
19
Dr. Virginia Osborne, and I'm also with the
20
Integrative Medicine Consortium and the AANP. I
21
have 23 years of experience as a practitioner, a
22
[inaudible - mic fades] -- Portland, Oregon, and
A Matter of Record (301) 890-4188
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1
also now an international lecturer on many of the
2
topics that you cover in these [inaudible - mic
3
fades].
4
This is a critical applications aspect.
5
[Inaudible - mic fades] -- a number of doctors, I'd
6
say tens of thousands of patients, in what we
7
experience in our offices. And we are looking at a
8
number of these agents and integrating many of
9
them. What we're seeing here is that we have all
10
taken the oath of first do no harm, so the proven
11
scientific applications for safe and effective
12
treatments are what we have our guidelines on. Our
13
treatment plans are for the patient, resulting in
14
quality-of-life outcomes.
15
Quercetin was one of these, and we've gone
16
over a number of these discussions here already,
17
which provides a safe option. We have the benefit
18
of improving the vasodilation, and [indiscernible]
19
flavonoids, and the muscle contraction, and
20
improvement of cardiac and pulmonary diseases or
21
prevention.
22
Really, what we're trying to do here is
A Matter of Record (301) 890-4188
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1
prevention, to get this before it gets to the point
2
of a disease process. We have these things
3
available to us that we can have options when our
4
patients walk through the door.
5
Talking about the alpha lipoic earlier with
6
Dr. Berkson and demonstrating the clinical
7
applications, thank you so much. The benefits that
8
my patients receive from this is the same as he has
9
explained today. So we are thankful for that, that
10
I don't have to go back and tell those patients,
11
"Sorry. It's not available anymore."
12
We're looking at an anti-inflammatory and
13
antioxidants through the reduction of inflammation,
14
through the nutrients that we are able to provide,
15
both infusibly through peripheral and parenteral,
16
oral, and the biochemical and physiological
17
responses that they receive.
18
When they have been ill and they finally are
19
starting to feel better, the improvement of
20
oxygenation through alpha lipoic, the quercetin,
21
CoQ10, improving mitochondrial function, this is
22
the thing that can turn around their lives and
A Matter of Record (301) 890-4188
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1
improve immensely; and the P5P we find with those
2
who have impaired liver function and now able to
3
bypass that antiemetic action that is required with
4
pyridoxine and certainly has been shown in the
5
research for autism.
6
I'm just reiterating that, what was just
7
proved here, I have used this for the last couple
8
of decades. And certainly thanks to Dr. Stanley
9
Jacobs, where I first met him in Oregon, where I
10
practiced and lectured. He had multiple research
11
papers on that. There are hundreds of them online
12
and books that he has written.
13
I've seen now, since that, many researchers
14
who have come after him to reiterate what he has
15
found. Yes, there is platelet aggregation. It's
16
knowing your patient, knowing them well, knowing
17
what you're choosing to give them. And maybe that
18
was what they needed. So we're looking at the
19
benefits of this through several metabolic
20
disorders that can be the anti-inflammatory action
21
of MSM.
22
This is just a case, and this is leading up
A Matter of Record (301) 890-4188
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1
to all of this. This is a 57-year-old woman who
2
was in bed for 10 years due to the tick-borne
3
infections, ehrlichia, babesia, and bartonella.
4
She went through the many pharmaceuticals and the
5
visits to the well-known clinics and hospitals in
6
our area. She was referred to me in 2016. At this
7
point, we reviewed her labs and her nutrients and
8
gave her MSM.
9
I look back on this because I just saw her
10
2 weeks ago for a post follow-up of -- we've been
11
working together for 2 years. And in that time,
12
and the improvements and with changes that we've
13
been able to make as we've gone through this, she
14
now has the ability to get out of bed and have
15
dinner with her husband, g get out in her garden
16
[inaudible - mic fades] -- and her grandsons now
17
know her as their well grandmother instead of the
18
ill one in the bedroom.
19
The last case -- and this is a case of a
20
40-year-old male who has now been out of the
21
military. But he had viral illnesses and certainly
22
heavy chemical exposures while in Iraq and
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1
Afghanistan. I just threw in there, there are
2
multiple pharmaceuticals, hospitalizations, pre-
3
and post-discharge from military service. This is
4
ongoing for him. He was exposed to deep-well
5
contamination fluids, which he had to be in up to
6
his chest, which lead to cardiac issues.
7
So he was referred to me, so we went again
8
to [inaudible - mic fades] some of his biochemical
9
pathways through these nutrients we have been
10
talking about today -- were all a part of this, and
11
of course the MSM, the quercetin, the CoQ10, were
12
all a part of that, and the P5P; alpha lipoic acid
13
for reoxygenation of the cells and, of course,
14
reducing of his neuropathies.
15
We were going to continue on, but these
16
things became less and less available, and he could
17
see what was going to happen, and he left the
18
country for his health care. And that's what I'm
19
starting to see now. I'm starting to hear from
20
patients, like, "You know what? This is getting
21
too expensive for me. Things are no longer
22
available. I need to leave the country to get my
A Matter of Record (301) 890-4188
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1
health care."
2
I just want you to be aware of what we are
3
dealing with out there. And with that, I just want
4
you to know that we have done our best to educate
5
and to make available information for many
6
physicians to know. Because that was a question
7
that came up earlier. "How do they know about
8
this? Are they relying just on the pharmacies when
9
they call them?"
10
No, we are trying to be out there to educate
11
practitioners on the [inaudible - mic
12
fades] -- what's efficacy on all of these
13
nutrients. Thank you.
14
DR. VAIDA: Thank you.
15
DR. FAJICULAY: Jay Fajiculay, designated
16
federal officer for the PCAC. Just a quick
17
announcement. I received notice that our voting
18
system detected an additional vote for the first
19
4 voting sessions. So for the record, I would like
20
to correct this to say there were 16 voting
21
members, not 17.
22
The first 3 sessions for alpha lipoic acid,
A Matter of Record (301) 890-4188
147
1
coenzyme Q10, and creatine monohydrate, the vote
2
results for each of these 3 voting sessions should
3
be corrected to 16, yes; zero, no; and zero,
4
abstain. Additionally, for the pyridoxal 5
5
phosphate session, there were 13 voting members,
6
not 14, and the vote results should be corrected to
7
13, yes; zero, no; and zero, abstain.
8
Now we will proceed with the final voting
9
question.
10
Committee Discussion and Vote
11
DR. VAIDA: Thank you. That concludes our
12
open session, our public session, and now we'll go
13
onto the vote. Any discussion? The vote is that
14
FDA is proposing that quercetin dihydrate not be
15
included on the 503A bulk list. Should quercetin
16
dihydrate be placed on the list?
17
Any discussion? Dr. Bogner?
18
DR. BOGNER: Can we split the question?
19
Many of the other candidates that we're talking
20
about have gone on the list with a route of
21
administration, and I was wondering if we can split
22
the route of administration here.
A Matter of Record (301) 890-4188
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1
DR. VAIDA: I'm taking for granted, FDA,
2
that it doesn't matter what route, right?
3
DR. GANLEY: Yes. Our recommendation was
4
not for any route. That's what you're voting on.
5
So if you think there is a route of administration,
6
then you would say that you don't agree with our
7
recommendation, and then just clarify that in your
8
comments.
9
DR. VAIDA: So you're saying you would put
10
that in the comment, for the route?
11
DR. GANLEY: No. When she does --
12
DR. VAIDA: Oral or IV, right?
13
DR. BORMEL: The vote is on the question,
14
should quercetin dihydrate be placed on the list?
15
You either will vote, yes, it should be placed on
16
the list, or no, it shouldn't be placed on the
17
list. And then whatever your vote is, when it
18
comes time to explain it, you can put a comment to
19
that.
20
DR. VAIDA: Dr. Wall?
21
DR. WALL: I wanted to thank the last couple
22
of speakers from the audience because they're
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1
providing a different view of medicine that I
2
really don't have a lot of exposure to. And I
3
would like to know a little bit more on some of
4
those things. That's all.
5
DR. VAIDA: Dr. Johnson [sic]?
6
DR. JUNGMAN: So this is for FDA, I think,
7
and I may not be a fair question. But as we think
8
about the oral formulation, one issue that comes to
9
mind is this is available as a dietary supplement.
10
It's been proposed here as a drug for the treatment
11
of several conditions, including cancer. So as I
12
understand it, if FDA it on the list, it could be
13
marketed and advertised for those conditions.
14
That raises for me questions about how it is
15
currently marketed and advertised in the dietary
16
supplement context. I'm just trying to wrap my
17
head around, as an oral formulation that's
18
available as a dietary supplement as opposed to as
19
available as a drug for this particular substance,
20
what are the kinds of differences you would expect
21
to see in the claims that folks who are trying to
22
sell the substance could make about the product?
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1
DR. VAIDA: Mr. Mixon?
2
MR. MIXON: I just want to mention that it's
3
widely available; it's an over-the-counter
4
supplement. There's no need to compound it. I
5
mean, it's regulated as a dietary supplement, it'[s
6
widely available, and, no, that's not
7
available -- I mean, that's not appropriate use for
8
intravenous use, but for oral use, it's not a
9
problem.
10
DR. JUNGMAN: That's helpful.
11
DR. VAIDA: Yes, Dr. Bogner?
12
DR. BOGNER: What's the difference between
13
compounding with a bulk substance of quercetin
14
versus compounding with a commercially available
15
dietary supplement in a bottle, opening it up and
16
compounding with it? Does one fall into 503A and
17
the other doesn't? How does this all work?
18
DR. BORMEL: I think we spoke about this.
19
Sara Rothman, during our presentation, spoke about
20
this, this morning. If you take a dietary
21
supplement that's marketed, and you manipulate it,
22
and you're making another dietary supplement,
A Matter of Record (301) 890-4188
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1
you're not doing anything other than repackaging or
2
mixing it with other dietary ingredients and
3
complying with all of the FDA laws and regulations
4
pertaining to dietary supplements, it does not
5
belong in what we're considering here, 503A,
6
compounding by a 503A facility in compliance with
7
the conditions of 503A.
8
What we're talking about here is taking bulk
9
quercetin and making it into a drug pursuant to a
10
patient's specific prescription.
11
DR. BOGNER: Thank you.
12
DR. VAIDA: Dr. Ganley?
13
DR. GANLEY: I think it's important also to
14
understand -- and I think this ingredient in
15
particular -- there are real issues about how much
16
you actually can absorb from the dihydrate, whether
17
it's a dietary supplement or a drug. Under the
18
dietary supplement regulations, there's no
19
requirement for them to provide data to the agency
20
that show these to get absorbed.
21
When we look at things from a drug
22
perspective, though, we have an expectation that if
A Matter of Record (301) 890-4188
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1
you're going to get a compounded drug, there are
2
going to be absorptions of it. There's no point in
3
taking it if you can't get it to the site of
4
action, if it is an effective therapy. And you
5
have to, I think look at it in the context of that.
6
The other thing on the drug side are these
7
issues with drug interactions. You have a
8
situation here where there's clearly suggestions
9
that this ingredient causes or is associated with
10
some interaction with cytochrome P450. And now
11
you're going to say, I'm going to throw this on top
12
as a drug, where that's what we're thinking of
13
here.
14
A dietary supplement is completely
15
different, but as a drug, I have a lot of
16
confidence that I can take an antihypertensive
17
agent and then just throw this as a drug in there
18
and not be concerned about drug interactions.
19
Well, that's not how we think about drugs. We're
20
on a different playing field here, and that's how
21
you have to think about it for these things when
22
you're putting them on the 503 list.
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1
DR. VAIDA: Dr. Hoag?
2
DR. HOAG: Steve Hoag. Two points of
3
clarification. Am I correct in saying that dietary
4
supplements have to be taken orally? Right? You
5
could have an IV dietary supplement. And then
6
also, that's got a negative or a not. So if I vote
7
yes, I'm voting not?
8
DR. BORMEL: At first with number 5, we're
9
telling what the FDA proposal is. Our proposal is
10
that quercetin dihydrate not be included on the
11
503A bulk list. The question that you're voting
12
on, though, is should quercetin dihydrate be placed
13
on the list. If you vote yes, you're voting to
14
place it on the list. If you vote no, you're
15
voting not to place it on the 503A bulks list.
16
DR. HOAG: Well, I shouldn't read that
17
[inaudible - off mic].
18
DR. BORMEL: You should read the question
19
and respond to the question, which is the second
20
statement on number 5.
21
DR. VAIDA: Correct. If you vote no, you're
22
recommending FDA not place the bulk drug on the
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1
list, on the 503 list.
2
Everybody understand? Are we ready to vote?
3
Please vote yes, no, or abstain.
4
(Voting.)
5
DR. FAJICULAY: For the record, the results
6
are zero, yes; 11, no; zero, abstain; and 1, no
7
voting.
8
DR. VAIDA: Okay. If we want to go around
9
the room and state your name, your vote, and any
10
comment. Dr. Sun?
11
DR. SUN: Jeanne Sun. I voted no. I want
12
to note that USP does have dietary supplement
13
monograph, but as per the comments around the
14
table, it seems like it is widely available over
15
the counter. And if it needs to be available in
16
other dosage forms, there are other routes like an
17
investigational new drug application that might be
18
available.
19
DR. DESAI: Seemal Desai. This one,
20
personally, was difficult for me because I felt
21
that the research that I had done prior to coming,
22
based on the materials provided in the docket, from
A Matter of Record (301) 890-4188
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1
what I heard from the FDA, and what I heard from
2
the nominator, there were some similarities but a
3
good amount of conflicting information.
4
Ultimately, I did vote no, however, I will
5
make a comment that we do have a USP monograph, as
6
Jeanne mentioned, so potentially, the oral
7
formulation is something that I think could be
8
still looked at it, particularly if you're talking
9
about a few of the indications that were discussed
10
from the nominator's presentation.
11
DR. JUNGMAN: Elizabeth Jungman from Pew. I
12
voted no. Glad to see that there is an ongoing
13
study in the substance, but at this point, the
14
effectiveness data just doesn't seem to be there.
15
DR. WALL: Donna Wall. I voted no. I
16
appreciated the comments from some of our
17
naturopaths and different uses of it, but I would
18
like to see more substantial information before I
19
could actually go forward with it.
20
DR. CAROME: Mike Carome. I voted no
21
because there's a lack of reasonable data on
22
effectiveness for any of the proposed uses. And
A Matter of Record (301) 890-4188
156
1
for the proposed uses, there are numerous
2
FDA-approved products that have been proven to be
3
safe and effective, and there are plausible
4
concerns about drug-drug interactions with this and
5
other drugs.
6
DR. BOGNER: Robin Bogner. I voted no
7
because all of the work that I know that's being
8
done in formulation involves complex dosage forms,
9
which give highly variable bioavailability. I look
10
forward to the 2500 patients or subjects in that
11
study, the parenteral study. And if that pans out,
12
I think you should come back.
13
DR. VAIDA: Allen Vaida. I voted no, mostly
14
for the reason that was just mentioned by
15
Dr. Carome. I think, for today, this was one of
16
the products that there are a lot of different
17
products that are available for these conditions.
18
DR. PATEL: Kuldip Patel. I voted no for
19
some of the reasons that have already been stated.
20
MR. HUMPHREY: William Humphrey. I voted no
21
for similar reasons. I do think that the use of
22
the intravenous product needs to be within the
A Matter of Record (301) 890-4188
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1
context of a clinical trial.
2
DR. HOAG: Steve Hoag. I voted no for all
3
the reasons mentioned. And just to emphasize, this
4
is available orally, and it can be manipulated
5
orally, but this does affect the IV use of this.
6
And I wasn't quite sure of the IV use. And
7
certainly as more data and things become available,
8
then that's something we should perhaps reconsider.
9
DR. VAIDA: Committee members who are on the
10
phone? Dr. Gulur?
11
DR. GULUR: Padma Gulur. I voted no for the
12
reasons that have been stated by Dr. Vaida and
13
Dr. Carome. And if the IV formulation data should
14
be stronger in the future, it's definitely worth a
15
second look at that point. Thank you.
16
DR. VAIDA: Dr. Venitz? Oh, I'm sorry He's
17
off.
18
All right. This convenes the meeting. I
19
want to thank everyone for bearing with us, and we
20
almost got back on time.
21
Adjournment
22
DR. VAIDA: I just have to read one more
A Matter of Record (301) 890-4188
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1
line. We will now adjourn the meeting. Panel
2
members, please leave your name badges here on the
3
table so they may be recycled, and please take all
4
your personal belongings with you, as the room is
5
cleaned at the end of the meeting day. Meeting
6
materials left on the table will be disposed of.
7
Thank you.
8
(Whereupon, at 4:36 p.m., the afternoon
9
session was adjourned.)
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A Matter of Record (301) 890-4188
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