amp - fda warning sent out april 2015
TRANSCRIPT
A Matter of Record
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FOOD AND DRUG ADMINISTRATION 1
CENTER FOR DRUG EVALUATION AND RESEARCH 2
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PHARMACY COMPOUNDING ADVISORY COMMITTEE 6
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Morning Session 9
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Monday, February 23, 2015 12
8:28 a.m. to 11:34 a.m. 13
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FDA White Oak Campus 18
Building 31, The Great Room 19
White Oak Conference Center 20
Silver Spring, Maryland 21
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Meeting Roster 1
DESIGNATED FEDERAL OFFICER (Non-Voting) 2
Jayne Peterson, BSPharm, JD 3
Division of Advisory Committee and Consultant 4
Management 5
Office of Executive Programs 6
Center for Drug Evaluation and Research 7
8
PHARMACY COMPOUNDING ADVISORY COMMITTEE MEMBERS 9
(Voting) 10
Michael A. Carome, MD, FASHP 11
Consumer Representative 12
Director of Health Research Group 13
Public Citizen 14
Washington, District of Columbia 15
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Gigi S. Davison, BSPh, DICVP 1
U.S. Pharmacopeial Convention 2
(USP) Representative- February 23rd only 3
Director of Clinical Pharmacy Services 4
North Carolina State University 5
College of Veterinary Medicine 6
Raleigh, North Carolina 7
8
Robert DeChristoforo, MS, FASHP 9
Chief of Clinical Center Pharmacy Department 10
National Institutes of Health 11
Bethesda, Maryland 12
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John J. DiGiovanna, MD 14
Staff Clinician, DNA Repair Section 15
Dermatology Branch, Center for Cancer Research 16
National Cancer Institute 17
National Institutes of Health 18
Bethesda, Maryland 19
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Padma Gulur, MD 1
Professor, Department of Anesthesiology and 2
Perioperative Care 3
University of California, Irvine 4
Orange, California 5
6
William A. Humphrey, BSPharm, MBA, MS 7
Director of Pharmacy Operations 8
St. Jude’s Children’s Research Hospital 9
Memphis, Tennessee 10
11
Elizabeth Jungman, JD 12
Director, Public Health Programs 13
The Pew Charitable Trusts 14
Washington, District of Columbia 15
16
Katherine Pham, PharmD 17
Neonatal Intensive Care Unit Pharmacy Specialist 18
Children’s National Medical Center 19
Washington, District of Columbia 20
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Allen J. Vaida, BSc, PharmD, FASHP 1
Executive Vice President 2
Institute for Safe Medication Practices 3
Horsham, Pennsylvania 4
5
Jürgen Venitz, MD, PhD 6
Chairperson 7
Associate Professor 8
Department of Pharmaceutics 9
School of Pharmacy 10
Virginia Commonwealth University 11
Richmond, Virginia 12
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Stephen W. Hoag, PhD 14
Professor 15
Department of Pharmaceutical Science 16
University of Maryland, Baltimore 17
Baltimore, Maryland 18
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PHARMACY COMPOUNDING ADVISORY COMMITTEE MEMBERS 1
(Voting) cont. 2
Donna Wall, PharmD 3
National Association of Boards of Pharmacy 4
(NABP) Representative 5
Clinical Pharmacist 6
Indiana University Hospital 7
Indianapolis, Indiana 8
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PHARMACY COMPOUNDING ADVISORY COMMITTEE INDUSTRY 10
REPRESENTATIVE MEMBERS (Non-Voting) 11
Ned S. Braunstein, MD 12
Senior Vice President and Head of Regulatory 13
Affairs 14
Regeneron Pharmaceuticals, Inc. 15
Tarrytown, New York 16
17
William Mixon, RPh, MS, FIACP 18
Owner-Manager 19
The Compounding Pharmacy 20
Hickory, North Carolina 21
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TEMPORARY MEMBERS (Voting) 1
Jeanne Sun, PharmD 2
USP Representative 3
February 24th only 4
Associate Scientific Liaison, Compounding 5
U.S. Pharmacopeial Convention 6
Rockville, Maryland 7
8
FDA PARTICIPANTS (Non-Voting) 9
Jane Axelrad, JD 10
Associate Director for Policy, CDER and 11
Agency Lead on Compounding, FDA 12
13
Frances Gail Bormel, Rph, JD 14
Director (acting), Division of Prescription Drugs 15
Office of Unapproved Drugs and Labeling 16
Compliance, Office of Compliance, CDER, FDA 17
18
Olivia Ziolkowski, JD, MPH 19
Regulatory Counsel 20
ORP, CDER, FDA 21
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Mwango A. Kashoki, MD, MPH 1
Associate Director for Safety 2
Office of New Drugs (OND) 3
Immediate Office, CDER, FDA 4
5
Nancy Xu, MD 6
Medical Officer, Division of Cardiosvascular and 7
Renal Products, Office of Drug Evaluation 8
(ODE) I, OND, CDER, FDA 9
10
Dmitri Iarikov, MD, PhD 11
Clinical Team Leader (acting) 12
Division of Anti-Infective Products 13
Office of Antimicrobial Products (OAP) 14
OND, CDER, FDA 15
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C O N T E N T S 1
AGENDA ITEM PAGE 2
Call to Order and Introduction of Committee 3
Jurgen Venitz, MD, PhD 11 4
Conflict of Interest Statement 5
Jayne Peterson, BS Pharm, JD 17 6
FDA Introductory Remarks and Overview of 7
Withdrawn and Removed List 8
Jane Axelrad, JD 24 9
Clarifying Questions from the Committee 42 10
FDA Presentations 11
Identification of Drugs Withdrawn or Removed 12
from the Market for Safety Reasons 13
Mwango Kashoki, MD, MPH 46 14
Clarifying Questions from the Committee 56 15
Adenosine Phosphate 16
Nancy Xu, MD 62 17
Clarifying Questions from the Committee 68 18
Chloramphenicol 19
Dmitri Iarikov, MD, PhD 71 20
Clarifying Questions from the Committee 76 21
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C O N T E N T S (continued) 1
AGENDA ITEM PAGE 2
Open Public Hearing 90 3
Committee Discussion and Vote on 4
Withdrawn or Removed List 93 5
Adjournment 157 6
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P R O C E E D I N G S 1
(8:28 a.m.) 2
Call to Order 3
Introduction of Committee 4
DR. VENITZ: Good morning again. My name is 5
Jurgen Venitz. I am the Chair of the Pharmacy 6
Compounding Advisory Committee, otherwise referred 7
to as PCAC. I will now call the committee to 8
order. 9
We will now ask those at the table, 10
including FDA staff and committee members, to 11
introduce themselves, starting with the FDA to my 12
left and moving along to the industry 13
representative, Mr. Ned Braunstein. So let's start 14
to the left, please. 15
DR. IARIKOV: Dmitri Iarikov, medical 16
officer, Division of Anti-Infective Products, FDA. 17
DR. XU: Good morning. My name is Nancy Xu. 18
I'm a medical officer, Division of Cardiovascular 19
and Renal Products, Office of New Drugs. 20
MS. ZIOLKOWSKI: My name is Olivia 21
Ziolkowski. I'm a regulatory counsel with the 22
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Office of Regulatory Policy. 1
MS. AXELRAD: Jane Axelrad. I'm the 2
associate director for policy in the Center for 3
Drug Evaluation and Research and the agency lead on 4
compounding. 5
MS. BORMEL: My name is Gail Bormel. I'm 6
with the CDER Office of Compliance, Office of 7
Unapproved Drugs and Labeling Compliance. 8
MR. HUMPHREY: I'm William Humphrey. I'm 9
the Director of Pharmacy Operations at St. Jude 10
Children's Research Hospital in Memphis. 11
DR. PHAM: My name is Kathy Pham. I am the 12
NICU Clinical Pharmacy Specialist at Children's 13
National Medical Center. 14
DR. WALL: My name is Donna Wall. I'm a 15
clinical pharmacist at IU Hospital in Indianapolis, 16
and I'm representing NABP. 17
DR. VAIDA: Allen Vaida. I'm executive vice 18
president at the Institute for Safe Medication 19
Practices, and I'm a pharmacist. 20
MS. PETERSON: Good morning. I'm Jayne 21
Peterson. I'm the designated federal officer for 22
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the Pharmacy Compounding Advisory Committee. 1
DR. VENITZ: I'm Jurgen Venitz. I'm a 2
clinical pharmacologist and professor at the VCU 3
School of Pharmacy. 4
DR. DiGIOVANNA: I'm John DiGiovanna. I'm a 5
dermatologist at the National Cancer Institute at 6
NIH. 7
DR. GULUR: I'm Padma Gulur. I'm a 8
professor in the Department of Anesthesiology and 9
Perioperative Care at the University of California, 10
Irvine. 11
DR. HOAG: I'm Steve Hoag, a professor at 12
the University of Maryland School of Pharmacy, in 13
the Department of Pharmaceutical Sciences. 14
MS. JUNGMAN: I'm Elizabeth Jungman. I 15
direct public health programs at the Pew Charitable 16
Trusts. 17
MR. DeCHRISTOFORO: Good morning. My name 18
is Bob DeChristoforo, and I have a disclaimer to 19
read. 20
I am chief of the Clinical Center Pharmacy 21
Department at the NIH. I would like to disclose 22
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that as part of my federal duties in 2014, I 1
reviewed and provided input into NIH's comments 2
that were submitted to FDA regarding FDA's proposed 3
list of drug products that may not be compounded 4
because the drug products have been withdrawn or 5
removed from the market. These comments were 6
specific to chloramphenicol. 7
I will be participating fully in the 8
deliberations of this meeting, but will not be 9
voting, but I will vote on other voting questions. 10
MS. DAVIDSON: I'm Gigi Davidson. I'm the 11
director of the pharmacy at North Carolina State 12
University College of Veterinary Medicine. I'm 13
currently the chair of the USP Compounding Expert 14
Committee, and I'm representing USP. 15
DR. CAROME: Good morning. My name is Mike 16
Carome. I'm director of Public Citizens' Health 17
Research Group, and I'm the consumer representative 18
on the committee. 19
MR. MIXON: Good morning. Bill Mixon. I 20
own the compounding pharmacy in Hickory, North 21
Carolina. I'm also on the North Carolina Board of 22
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Pharmacy and am a member of the USP Expert 1
Committee for Compounding. 2
DR. BRAUNSTEIN: Good morning. I'm Ned 3
Braunstein. I'm senior vice president for 4
regulatory affairs of Regeneron Pharmaceuticals. 5
I'm the industry representative. I'm also a 6
physician. 7
DR. VENITZ: Thank you very much, and 8
welcome to the inaugural meeting of the 9
Pharmaceutical Compounding Advisory Committee. Let 10
me read a few remarks for the record. 11
For topics such as those being discussed at 12
today's meeting, there is often a variety of 13
opinions, some of which are quite strongly held. 14
Our goal is that today's meeting will be a fair and 15
open forum for discussion of these issues and that 16
individuals can express their views without 17
interruption. Thus, as a gentle reminder, 18
individuals will be allowed to speak into the 19
record only if recognized by the chair. We look 20
forward to a productive meeting. 21
In the spirit of the Federal Advisory 22
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Committee Act and the Government in the Sunshine 1
Act, we ask that the advisory committee members 2
take care that their conversations about the topic 3
at hand take place in the open forum of the 4
meeting. 5
We are aware that members of the media may 6
be anxious to speak with the FDA about these 7
proceedings. However, FDA will refrain from 8
discussing the details of this meeting with the 9
media until its conclusion. 10
Also, the committee is reminded to please 11
refrain from discussing the meeting topic during 12
the breaks or over lunch. 13
Over the next two days, we will cover two 14
topics. On the morning of the first day, we will 15
consider drug products proposed for inclusion on 16
the list of drugs that have been withdrawn or 17
removed from the market because they have been 18
found to be unsafe or ineffective. 19
During session 1, we will hear presentations 20
from FDA, ask clarifying questions, hold an open 21
public hearing, and then have committee discussion 22
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and voting. 1
This afternoon and continuing through 2
tomorrow, we will hear presentations about the 3
criteria for placing drug substances on the list of 4
bulk drug substances that can be used in 5
compounding under Section 503A and on six bulk 6
substances nominated for inclusion on the list. 7
We will hear FDA presentations, two at a 8
time, ask clarifying questions, hear presentations 9
from nominators, hold an open public hearing, and 10
have a committee discussion and voting on each 11
pair. Thus, we will have four open public hearings 12
and hold four separate voting sessions. 13
Let us begin. We will now have Ms. Jayne 14
Peterson, to my left, read the Conflict of Interest 15
Statement. Thank you. 16
Ms. Peterson? 17
Conflict of Interest Statement 18
MS. PETERSON: Thank you. 19
The Food and Drug Administration is 20
convening today's meeting of the Pharmacy 21
Compounding Advisory Committee under the authority 22
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of the Federal Advisory Committee Act of 1972. 1
With the exception of the National Association of 2
Boards of Pharmacy, the United States Pharmacopeia, 3
and the industry representatives, all members and 4
temporary voting members of the committee are 5
special government employees or regular federal 6
employees from other agencies and are subject to 7
the federal conflict of interest laws and 8
regulations. 9
The following information on the status of 10
this committee's compliance with federal ethics and 11
conflict of interests laws covered by, but not 12
limited to, those found at 18 USC Section 208 is 13
being provided to participants in today's meeting 14
and to the public. 15
FDA has determined that members and 16
temporary voting members of this committee are in 17
compliance with federal ethics and conflict of 18
interest laws. Under 18 USC Section 208, Congress 19
has authorized FDA to grant waivers to special 20
government employees and regular government 21
employees who have potential financial conflicts 22
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when it is determined that the agency's need for a 1
special government employee's services outweighs 2
his or her potential financial conflict of 3
interest, or when the interest of a regular federal 4
employee is not so substantial as to be deemed 5
likely to affect the integrity of the services, 6
which the government may expect from the employee. 7
Related to discussions of today's meeting, 8
members and temporary voting members of this 9
committee have been screened for potential 10
financial conflicts of interest of their own, as 11
well as those imputed to them, including those of 12
their spouses or minor children and, for purposes 13
of 18 USC Section 208, their employers. These 14
interests may include investments, consulting, 15
expert witness testimony, contracts, grants, 16
CRADAs, teaching, speaking, writing, patents and 17
royalties, and primary employment. 18
During this morning's session, the committee 19
will discuss proposed revisions to the list of drug 20
products that may not be compounded under the 21
exemptions provided by the Food, Drug and Cosmetic 22
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Act because the drug products have been withdrawn 1
or removed from the market, because such drug 2
products or components of such drug products have 3
been found to be unsafe or not effective. 4
The list of products is currently codified 5
at 21 CFR 216.24, and FDA is proposing to revise 6
and update the list at Section 216.24 for purposes 7
of both 503A and 503B of the Food, Drug and 8
Cosmetic Act. 9
On July 2, 2014, FDA published a proposed 10
rule that would add 25 drug products to this list 11
and modify the description of one drug product on 12
this list to add an exception. 13
FDA received two specific comments on the 14
proposed rule. One comment requested that FDA 15
clarify whether the entry for adenosine phosphate 16
that is currently included on the list, which 17
currently reads "all drug products containing 18
adenosine phosphate," is intended to include all 19
three forms of adenosine phosphate, the mono-, di- 20
and triphosphate. 21
The second comment requested that 22
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chloramphenicol tablets 250 mgs be excluded from 1
the list. FDA will discuss both of these comments 2
with the committee. 3
This is a particular matters meeting during 4
which the specific matters related to the 27 5
products will be discussed. Based on the agenda 6
for today's meeting and all financial interests 7
reported by the committee members and temporary 8
voting members, no conflict of interest waivers 9
have been issued in connection with this meeting. 10
Dr. Venitz has been recused from 11
participating in the discussions and voting for 12
oxycodone hydrochloride. Dr. Hoag has been recused 13
from participating in discussions and voting for 14
cerivastatin sodium, methoxyflurane, and pergolide 15
mesylate. 16
To ensure transparency, we encourage all 17
standing committee members and temporary voting 18
members to discuss any public comments that they 19
have made concerning the products at issue. 20
We would like to note that Dr. Donna Wall is 21
a representative member from the National 22
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Association of Boards of Pharmacy, and Ms. Gigi 1
Davidson is a representative member from the United 2
States Pharmacopeia. 3
Section 102 of the Drug Quality and Security 4
Act amended the Federal Food, Drug and Cosmetic Act 5
with respect to the Advisory Committee on 6
Compounding to include as standing members 7
representatives from the NABP and the USP. Their 8
role is to provide the committee with the points of 9
view of NABP and USP. 10
Unlike the other members of the committee, 11
representative members are not appointed to the 12
committee to provide their own individual judgment 13
on the particular matters at issue. Instead, they 14
serve as the voice of NABP and USP, entities with a 15
financial or other stake in the particular matters 16
before the advisory committee. 17
With respect to FDA's invited industry 18
representatives, we would like to disclose that 19
Dr. Ned Braunstein and Mr. William Mixon are 20
participating in this meeting as nonvoting industry 21
reps acting on behalf of regulated industry. Their 22
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role at this meeting is to represent industry in 1
general and not any particular company. 2
Dr. Braunstein is employed by Regeneron 3
Pharmaceuticals and Dr. Mixon is the owner of The 4
Compounding Pharmacy. 5
We would like to remind members and 6
temporary voting members that if the discussions 7
involve any other products or firms not already on 8
the agenda for which an FDA participant has a 9
personal or imputed financial interest, the 10
participants need to exclude themselves from such 11
involvement and their exclusion will be noted for 12
the record. 13
FDA encourages all other participants to 14
advise the committee of any financial relationships 15
that they may have with the products at issue. 16
Thank you. 17
DR. VENITZ: Thank you. 18
We will now proceed with opening remarks and 19
an overview of the withdrawn and removed list from 20
Dr. Jane Axelrad, the associate director for Policy 21
in the Center for Drug Evaluation Research and the 22
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agency lead on compounding. 1
I would like to remind public observers at 2
this meeting that while this meeting is open for 3
public observation, public attendees may not 4
participate except at the specific request of the 5
panel. Thank you. 6
FDA Introductory Remarks – Jane Axelrad 7
MS. AXELRAD: Good morning. I'd like to 8
welcome all of you to the first meeting of the 9
newly configured Pharmacy Compounding Advisory 10
Committee, and I'd like to thank all of the members 11
for being willing to serve on the committee. 12
As you know, the committee was originally 13
established in 1998 after the passage of the Food 14
and Drug Administration Modernization Act in 1997. 15
That law added Section 503A to the Federal Food, 16
Drug and Cosmetic Act. Section 503A contained 17
provisions addressing compounding, pharmacy 18
compounding, and called for the creation of an 19
advisory committee on compounding. 20
The committee was convened several times 21
between October 1998 and July of 2000, but as a 22
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result of litigation over the validity of 1
Section 503A, the agency suspended its efforts to 2
implement that section of the statute and published 3
a notice terminating the committee in 2002. 4
In April of 2012, FDA filed the charter 5
reestablishing the committee. In November of 2013, 6
the Drug Quality and Security Act removed from 7
Section 503A the provisions that were found to be 8
unconstitutional by the U.S. Supreme Court in 2002, 9
removing uncertainty concerning the validity of 10
Section 503A and creating a new Section 503B 11
concerning outsourcing facilities. 12
Section 503B also requires FDA to consult 13
with an advisory committee on compounding before 14
issuing one of the regulations implementing that 15
section. 16
We then amended the charter of the committee 17
to reflect the relevant statutory changes and 18
solicited nominations for members. It has been a 19
long process, but at last we have arrived at this 20
point, and we're ready to begin our work to address 21
several important issues concerning compounding. 22
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Today, we'll be talking about two lists. 1
The first is a list of drugs that may not be 2
compounded under the exemptions provided by 3
Section 503A because they or their components have 4
been found to be unsafe or not effective. The 5
second list we'll be discussing today and tomorrow 6
is a list of bulk drug substances that can be used 7
to compound in accordance with Section 503A. 8
But to set the stage, I'd like to briefly 9
describe the overall framework in Section 503A and 10
503B so that we can all understand where the lists 11
that we're going to be discussing today and 12
tomorrow fit into the overall regulation of 13
compounding. 14
Section 503A describes the conditions under 15
which certain compounded human drug products are 16
entitled to exemptions from three sections of the 17
Act that require FDA approval prior to marketing, 18
compliance with current good manufacturing practice 19
requirements, and labeling with adequate directions 20
for use. 21
Pharmacies engaged in compounding that meet 22
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the conditions in Section 503A necessary to qualify 1
for the exemptions are primarily regulated by the 2
states, although some federal requirements still 3
apply. For example, these pharmacies can't 4
compound drugs under insanitary conditions or 5
they'll be found in violation of the adulteration 6
provisions of Section 501A(2)(a) of the Act, from 7
which 503A does not offer any exemptions. 8
To qualify for the exemptions under 9
Section 503A, a drug product must be compounded by 10
a licensed pharmacist in a state-licensed pharmacy 11
or federal facility or by a licensed physician. 12
The drug product must be compounded for an 13
identified individual patient based upon receipt of 14
a valid prescription order for an identified 15
individual patient. 16
Drug products may be compounded in limited 17
quantities before receipt of a prescription order 18
if it is based on a history of prescription orders 19
for the compounding of the drug product generated 20
within an established relationship between the 21
pharmacist or physician, and either the patient for 22
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whom the prescription order will be provided, or 1
the licensed practitioner who will write the 2
prescription order. 3
One of the conditions in Section 503A that 4
must be met to qualify for the exemptions concerns 5
bulk drug substances. Generally, we refer to those 6
as the active ingredients in drug products that are 7
used in compounding. 8
Under Section 503A, bulk drug substances 9
used in compounding must comply with the standards 10
of an applicable USP or national formulary 11
monograph, if there is one, and the USP chapters on 12
pharmacy compounding; or be a component of an FDA 13
approved drug product if an applicable monograph 14
doesn't exist; or if a USP or national formulary 15
monograph doesn't exist and the bulk drug substance 16
is not a component of an FDA drug product, appear 17
on a list of drug products that may be used for 18
compounding developed by FDA through regulation. 19
Later today and tomorrow, we'll be 20
discussing some of the substances that have been 21
nominated for inclusion on this list. 22
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In addition to these conditions, another 1
condition of Section 503A is that bulk drug 2
substances must be manufactured by a facility that 3
is registered with FDA under Section 510 of the 4
Food, Drug and Cosmetic Act, and they have to be 5
accompanied by valid certificates of analysis. 6
Other ingredients in compounded drugs 7
besides bulk drug substances, such as inactive 8
ingredients, must also comply with USP or national 9
formulary monographs if they exist for the 10
ingredient and the USP chapters on pharmacy 11
compounding. 12
To qualify for the exemptions under 13
Section 503A, a compounder cannot compound drug 14
products that appear on an FDA list of drugs 15
published in the Federal Register that have been 16
withdrawn or removed from the market because they 17
or their components have been found to be unsafe or 18
not effective. We call this the withdrawn or 19
removed list, and this is one of the lists we'll be 20
discussing this morning. So this is another really 21
important condition that's directly relevant to 22
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what we're going to be talking about. 1
Section 503A also states that to qualify for 2
the exemptions, a compounder cannot compound a drug 3
product that is identified by FDA by regulation as 4
a drug product that presents demonstrable 5
difficulties for compounding that reasonably 6
demonstrate an adverse effect on the safety or 7
effectiveness of that drug product. 8
We haven't yet published regulations 9
containing a list of drugs that are difficult to 10
compound, and we will be seeking the advice of this 11
advisory committee at a future meeting on what 12
drugs should be placed on that list. 13
Section 503A contains provisions that 14
address copying of commercially available drug 15
products. Under Section 503A, a compounder cannot 16
compound regularly or in inordinate amounts what 17
are essentially copies of commercially available 18
drug products. 19
Section 503A contains provisions that 20
address certain distributions of compounded drugs. 21
Under Section 503A, a compounder cannot distribute 22
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or cause to be distributed compounded drug products 1
out of the state in which they are compounded in 2
excess of 5 percent of the total prescription 3
orders dispensed or distributed by that pharmacy or 4
physician, unless they are located in a state that 5
has signed a memorandum of understanding that 6
provides for appropriate investigation of 7
complaints related to drugs distributed outside of 8
the state and that addresses the distribution of 9
inordinate amounts of compounded drug products 10
interstate. 11
So some of these things are not on the 12
agenda today and some of them are, but I wanted to 13
give you the overall framework so you can see how 14
it all fits together. 15
So that covers the conditions under which 16
compounded drug products can qualify for the 17
exemptions under 503A. As you know, after the 18
fungal meningitis outbreak in 2012, Congress passed 19
new legislation addressing the oversight of 20
compounding. 21
The Compounding Quality Act, which can be 22
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found in Title I of the Drug Quality and Security 1
Act, removes from Section 503A certain provisions 2
that were found to be unconstitutional by the 3
Supreme Court in 2002, as I already said. 4
By removing the unconstitutional provisions, 5
the new law removes uncertainty regarding the 6
validity of Section 503A, which is applicable to 7
compounders nationwide, which is why we're able to 8
move forward today with implementing that section. 9
The new legislation also contains a new 10
Section 503B, which created a category of 11
facilities called outsourcing facilities. Under 12
Section 503B, compounders can register with FDA as 13
outsourcing facilities, pay a fee, and compound 14
drugs without prescriptions, but they are required 15
to make them in compliance with current good 16
manufacturing practice requirements and are subject 17
to inspection by FDA according to a risk-based 18
schedule. 19
In addition, they have to meet certain 20
conditions to be exempt from certain provisions of 21
the Food, Drug and Cosmetic Act. And they can, if 22
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they meet the conditions, be exempt from the new 1
drug approval requirements and the requirement to 2
label their products for adequate directions for 3
use. But as I said, they have to follow current 4
good manufacturing practices, which is different 5
than a facility that is complying with the 6
conditions under 503A. 7
An entity that registers with FDA as an 8
outsourcing facility must report upon initial 9
registration and twice each year specific 10
information about the products that it compounds. 11
This includes filing a list of all drug products it 12
compounded during the previous six months and 13
information about those products, such as the 14
source of the active ingredients used to compound 15
them. 16
In addition, the outsourcing facility has to 17
report adverse events and label its products with 18
certain information, including the fact that it's a 19
compounded drug. 20
Outsourcing facilities must comply with 21
certain other conditions, as well, some of which 22
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are the same or similar to the conditions necessary 1
to qualify for the exemptions under 503A and some 2
of which are different. 3
Compounded drug products cannot qualify for 4
the exemptions in 503B if they appear on an FDA 5
list of drug products that have been withdrawn or 6
removed from the market because the drug products 7
or their components have been found to be unsafe or 8
not effective or on an FDA list of drug products 9
that present demonstrable difficulties for 10
compounding. 11
So I've already mentioned those lists with 12
regard to 503A, and the withdrawn and removed lists 13
that we'll be talking about this morning will be 14
applicable to both compounding under 503A and under 15
503B. 16
Under Section 503B, outsourcing facilities 17
cannot compound drugs that are essentially copies 18
of FDA approved drugs. So they just can't compound 19
them at all. Outsourcing facilities also cannot 20
compound from a drug that is the subject of a risk 21
evaluation and mitigation strategy, which we call a 22
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REMS, with elements to assure safe use, or from a 1
bulk drug substance that is a component of such 2
drug unless the outsourcing facility demonstrates 3
to FDA before beginning compounding that it will 4
use controls comparable to controls under a REMS. 5
Section 503B also contains conditions for 6
bulk drug substances that can be used in 7
compounding, some of which are different than those 8
for bulk drug substances used by facilities seeking 9
to qualify for the exemptions under 503A and some 10
of which are the same. 11
Under Section 503B, an outsourcing facility 12
cannot compound from bulk drug substances unless 13
the drug it is compounding either appears on the 14
FDA drug shortage list or the bulk drug substance 15
appears on a list that's going to be compiled by 16
FDA identifying bulk drug substances for which 17
there is a clinical need. FDA may be seeking the 18
advice of this committee at future meetings on the 19
drugs that should be placed on this 503B bulks 20
list. 21
Like the conditions for compounding under 22
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Section 503A, bulk drug substances and other 1
ingredients used to compound under Section 503B 2
must apply with applicable USP or national 3
formulary monographs, if they exist. The bulk drug 4
substances used by outsourcing facilities have to 5
be manufactured in facilities that have registered 6
with FDA under Section 510, and they must be 7
accompanied by a valid certificate of analysis. 8
Under the statutory definition of an 9
outsourcing facility, an outsourcing facility is 10
defined as a facility engaged in the compounding of 11
sterile drugs that has elected to register under 12
503B as an outsourcing facility and that complies 13
with all of the conditions in 503B. 14
An outsourcing facility is not required to 15
be a licensed pharmacy, but compounding must be by 16
or under the direct supervision of a licensed 17
pharmacist, and an outsourcing facility may or may 18
not obtain prescriptions for identified individual 19
patients. 20
Under Section 503B, an outsourcing facility 21
will not be considered registered unless and until 22
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it has paid the annual establishment fee. 1
Under the law, if a compounded drug does not 2
meet the conditions for exemptions in 503B or 503A, 3
it will be subject to all of the requirements 4
applicable to drugs made by conventional drug 5
manufacturers. For example, it would have to be 6
subject to an approved new drug application and be 7
made under current good manufacturing practice 8
requirements. That's why the conditions that are 9
laid out in 503A and 503B and the lists that we're 10
going to be talking to you about today are so 11
important. 12
This completes my summary of Sections 503A 13
and 503B and where the lists that we're going to be 14
discussing today and tomorrow fit in. Next, I'm 15
going to introduce with a little more detail the 16
withdrawn and removed list. 17
As I mentioned, FDA must develop a list of 18
drugs that have been withdrawn or removed from the 19
market because they or their components have been 20
found to be unsafe or not effective. Drugs on this 21
list can't be compounded under either Section 503A 22
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or 503B. 1
FDA began compiling this list as soon as 2
Section 503A was enacted in 1997. To compile the 3
list, FDA consulted with FDA review divisions and 4
examined public documents, such as Federal Register 5
notices, press releases, and safety announcements, 6
to identify products that had been withdrawn or 7
removed from the market for safety or efficacy 8
reasons. 9
Then we published as a proposed rule a list 10
of these drugs on October 8, 1998. We proposed 60 11
drugs for inclusion on the list at that time, and 12
you have this document in your background package. 13
The preamble to the proposed rule described 14
the basis for including each of the products on the 15
list. Right after the proposed rule was published, 16
we then consulted with the newly created Pharmacy 17
Compounding Advisory Committee about the drug 18
products that we had proposed for inclusion on the 19
list, and the committee did not suggest any 20
changes. There was a bunch of discussion, but they 21
did not suggest changes to what we were proposing. 22
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So the final rule was published in March 1
1999, and it is codified in FDA's regulations at 2
216.24, and it remained on the books for the entire 3
16 years since we did it. 4
However, obviously, developing this list has 5
to be a continuous process because we learn about 6
new safety or efficacy problems with drugs over 7
time as new drugs are approved, and then they come 8
into use in the market. 9
So sort of reading the tea leaves on moving 10
forward with 503A, a few years ago, we began to 11
compile a list of additional drugs that had been 12
withdrawn or removed from the market since the 13
original list was published, including five drugs 14
that were considered by the Pharmacy Compounding 15
Advisory Committee in 2000 and that were the 16
subject of another rulemaking that was never 17
actually completed because we suspended work under 18
503A. Then, as I said, after the Drug Quality and 19
Security Act was enacted, we determined that one 20
list should be used for both sections. 21
On July 2nd of 2014, we issued a proposed 22
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rule to add 25 products to the list that was 1
already codified in 216.24, and we also proposed to 2
modify the description of one product on the list, 3
to add an exception that would allow the product to 4
be compounded in accordance with Sections 503A and 5
503B under certain circumstances. 6
Today we're going to be seeking your advice 7
on the products proposed to be added to the list, 8
as well as on an issue concerning one of the 9
original listings, adenosine phosphate, which was 10
raised by a comment in the July 2014 proposed rule. 11
We'll be focusing our presentations today on 12
adenosine phosphate and on chloramphenicol, a drug 13
that we proposed for inclusion in the July 2014 14
proposed rule. We don't intend to make formal 15
presentations about the other 24 drugs proposed for 16
inclusion because we didn't get any comments on 17
those in the comment period on the proposed rule. 18
But you have all the supporting information that we 19
used and relied on to make the determination about 20
those drugs in your background package, and we are 21
certainly prepared to have a discussion about that 22
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and to take any questions that you might have 1
before we ask you to vote on whether to include 2
them on the list. 3
So our next presenter is going to be 4
Dr. Mwango Kashoki, the associate director for 5
safety in the Office of New Drugs. And I thought 6
it would be helpful to have Mwango explain what we 7
go through in terms of making a decision on whether 8
a drug has been removed from the market for safety 9
or efficacy reasons. 10
Our focus, all the drugs that we're talking 11
about here really are for safety, and that was our 12
focus in the original rule. Our focus on the drugs 13
today are drugs that have been removed for safety 14
reasons. So she is going to explain how we go 15
about that, how we determine that there is a safety 16
problem, and how we remove the drug from the market 17
if we think that it's appropriate. We will then 18
present our views, the FDA views, on adenosine 19
phosphate and chloramphenicol and take clarifying 20
questions. 21
Thank you. I'm looking forward to a 22
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productive and interesting two days here. Thanks. 1
Clarifying Questions from the Committee 2
DR. VENITZ: Thank you, Dr. Axelrad. We 3
have a little time for clarifying questions in case 4
anyone on the committee would like to ask 5
Dr. Axelrad any. Please? 6
DR. CAROME: Mike Carome, director of Public 7
Citizen's Health Research Group. I have one 8
question, and I wanted to make a disclosure 9
statement. 10
I would like to disclose Public Citizen 11
submitted petitions, issued statements, and wrote 12
letters to the FDA and testified at advisory 13
committee meetings between 1998 and 2009 regarding 14
11 of the drug products' active ingredients being 15
discussed at this session. For eight of them, we 16
petitioned to have the products removed from the 17
market, and the other three we wrote letters and 18
testified against having the products come to 19
market or remain on the market. 20
FDA is proposing to include these 11 drug 21
products' active ingredients on the list of drug 22
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products that may not be compounded because they 1
have been removed from the market due to safety or 2
efficacy concerns. The documents and testimony 3
that Public Citizen provided requested a ban on the 4
use or withdrawal from the market of these 11 drug 5
products. And as of 2011, FDA has closed out all 6
of our petitions regarding the eight drugs we 7
petitioned on. 8
For this session, I will be participating 9
fully in the deliberations and voting on the 10
questions posed to the committee. 11
I just have a very brief question. If FDA 12
has made a formal decision that a drug product was 13
removed from the market because of concerns that 14
the product was unsafe or ineffective, under the 15
law, does the agency have discretion about whether 16
to include that product on the withdrawn list? 17
MS. AXELRAD: Well, we generally are trying 18
to find all the drugs that have been withdrawn for 19
safety reasons, and we are generally putting them 20
on the list. I'm not sure we're looking at drugs 21
and saying, "Oh, okay, we think this drug was 22
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removed for safety reasons, but we're not going to 1
put it on a list." 2
So I don't know whether I would say whether 3
we -- obviously, we have to make a judgment on 4
whether it was or wasn't removed for safety 5
reasons. But once we conclude that it was, I 6
think, generally, we would be putting them on the 7
list. 8
If I saw one that we didn't think so, I'd 9
have to sort of look at the question as to whether 10
we have that discretion, but we haven't come across 11
that yet. 12
DR. VENITZ: Thank you. 13
MR. DeCHRISTOFORO: As just an informational 14
item, pharmacists that have been dealing with drug 15
shortages every day, there is another drug shortage 16
list by the American Society of Health System 17
Pharmacists. And I've been told that sometimes the 18
FDA does not necessarily put everything on the list 19
because industry has asked them not to so there 20
won't be a run on the drug. 21
So I just want to bring that up. I'm not 22
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45
arguing against that. But sometimes there's a drug 1
shortage that's on the ASHP list that may not be on 2
the FDA list. 3
DR. DiGIOVANNA: You mentioned that the 4
outsourcing facility is one engaged in the 5
compounding of sterile drugs. Does that exclude 6
topicals or are topicals considered sterile drugs? 7
And if so, what are non-sterile drugs? 8
MS. AXELRAD: Well, we recently, just very 9
recently, Friday last week, issued a guidance that 10
talks about this. And, as I said, the definition 11
says that an outsourcing facility is engaged in the 12
compounding of sterile drugs. That doesn't mean 13
that that's the only thing they do, but it means 14
that they have to be engaged in the compounding of 15
at least one or more or two sterile drugs, since it 16
has an S on the end, in order to qualify under the 17
definition of outsourcing facility. But they might 18
also be making non-sterile drugs, and many of them 19
do. 20
DR. VENITZ: Thank you, Dr. Axelrad. 21
Just a reminder, committee members, when you 22
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ask a question, please introduce yourself by name 1
before you do that so we can capture that for the 2
record. 3
Let's now proceed with the next 4
presentation. Dr. Kashoki, the Deputy Associate 5
Director for Safety, Office of New Drugs, will 6
discuss the process of identifying drugs to be 7
removed. 8
FDA Presentation – Mwango Kashoki 9
DR. KASHOKI: Good morning. In my talk, I 10
will provide an overview of how postmarket drug 11
safety signals are identified and evaluated; how 12
CDER reaches decisions about whether or not a drug 13
should be withdrawn or removed because of the 14
safety signal; and I will broadly describe how the 15
current list of withdrawn or removed drugs was 16
identified. 17
The agency continually assesses or evaluates 18
the safety of drug products, and CDER's ongoing 19
commitment to rigorous and continued drug safety 20
evaluation in the postmarket period is reflected in 21
its Safety First initiative, which was launched in 22
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2008 and which outlines CDER's updated policies and 1
procedures to ensure that equal focus or equal 2
attention is given to postmarket drug safety as is 3
given during pre-market drug review. 4
During drug development, FDA assesses the 5
safety of a drug as it is being tested and reviews 6
the data in marketing applications to ensure that 7
the benefits of the drug outweigh its risks. And 8
after approval, as a result of broader use of the 9
drug, additional information can emerge about 10
adverse drug experiences while patients are being 11
treated. And so FDA will evaluate the information 12
to assess the relationship of those adverse events 13
or those adverse experiences to the drug. 14
This is a general schematic of the 15
postmarket drug safety review process. It starts 16
when a safety issue is identified and proceeds with 17
a preliminary assessment of the issue and planning 18
for the review process. 19
A comprehensive review from a 20
multidisciplinary team from all relevant 21
disciplines informs the regulatory decision and, if 22
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necessary, actions. Once the actions are 1
implemented, the team will monitor any indicated 2
responses from the drug manufacturer and will 3
periodically reassess the issue as necessary. 4
There are numerous sources of drug safety 5
signals, some of which are listed on this slide. 6
Signals can come from, for example, FDA 7
surveillance, spontaneous adverse event reporting, 8
adverse event reporting from patients, caregivers. 9
Signals can come from, for example, FDA 10
surveillance, adverse event reporting, postmarket 11
drug safety trials or studies that are done to 12
further evaluate the safety or efficacy of a 13
product. And signals can even come from 14
manufacturing or quality information sources. For 15
example, a newly identified impurity that's 16
identified during a manufacturing process may raise 17
concerns about patient toxicity. 18
So when CDER becomes aware of a drug safety 19
signal, it will evaluate whether it represents a 20
potential risk to patients and warrants further 21
evaluation. 22
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The comprehensive review of a postmarket 1
drug safety signal will encompass all available 2
information, some of which may be additional 3
information from the drug manufacturer or other 4
regulatory agencies, the medical literature, and so 5
on. 6
The comprehensive review is conducted to 7
determine if there's a causal association between 8
the adverse event or events and the drug. And it 9
is done to determine the risk that is posed to 10
patients, to better understand the effect of this 11
new information on the benefit-risk profile of the 12
drug, and to inform the regulatory decisions and 13
actions. 14
Now, with regard to the benefit-risk 15
assessment that's conducted as part of this 16
comprehensive review, the agency will determine, 17
again, the safety and effectiveness of the drug. 18
The benefit-risk assessment is conducted within the 19
applicable legal, regulatory and policy framework. 20
For example, a safety issue involving an orphan 21
drug for a rare disease would necessitate certain 22
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policy considerations. 1
CDER's benefit-risk assessment is a 2
qualitative one, and it's based on the benefits and 3
the risks specific to that drug product. And key 4
factors in the assessment are the severity of the 5
condition that's being treated, the availability of 6
other therapies for the condition, evidence of 7
benefit of the drug and evidence of risk posed by 8
the drug, and what risk management options are 9
available or indicated. 10
At the conclusion of the comprehensive 11
review of a drug safety signal, FDA may determine 12
that one or more actions is indicated. This talk 13
focuses on decisions regarding the last two items 14
on this slide; namely, removal of the drug from the 15
market and removal from FDA approval of the 16
marketing application or the approved indication. 17
Before we go on, I do want to mention that 18
for the purposes of updating the sections of the 19
regulations that pertain to the list of withdrawn 20
and removed drugs, namely, Section 216.24, we're 21
using the term "withdrawal" to refer only to 22
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withdrawal of FDA approval, and "removal" to refer 1
to withdrawal of a product from sale or marketing. 2
Marketing withdrawal is sometimes used 3
interchangeably with removal of a drug from the 4
market. 5
After a comprehensive review of the drug 6
safety issue, multiple factors go into our 7
reassessment of the benefit-risk profile of a drug 8
and decisions about what to do next. The major 9
factor, of course, is the nature of the safety 10
issue itself. Some characteristics of a postmarket 11
drug safety issue that may lead to consideration of 12
removal of a drug from the market or withdrawal of 13
FDA approval include, but are not necessarily 14
limited to, if it's a new serious adverse event, 15
meaning that it's not already described in the 16
product labeling; if there's an increase in the 17
severity of the labeled adverse event; if there's a 18
high likelihood of occurrence of the risk or the 19
adverse event in the treated population; if there 20
isn't a viable or feasible strategy to mitigate the 21
risk; and if the issue is an emergency. 22
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We consider a drug safety issue to be an 1
emergency if it involves fatalities or has 2
potential for serious harm, including fatalities, 3
and if it has the potential to affect a large 4
number of patients, and if we can do something to 5
prevent harm or to save lives if we act quickly. 6
So once a decision is made that a postmarket 7
drug safety issue necessitates removal of a drug 8
from the market or FDA approval, how does this 9
occur? The process begins by expanding the 10
multidisciplinary team to include senior FDA 11
management and legal staff. And then discussions 12
are held with the holder of the drug application to 13
discuss the safety issue and the agency's concerns. 14
These discussions may lead to the 15
application holder agreeing to market withdrawal or 16
removal of the drug or to voluntarily requesting 17
that FDA withdraw its approval of the drug or 18
indication. 19
Alternatively, FDA may issue a notice of 20
opportunity for hearing, which is a public meeting 21
in which the FDA and the application holder discuss 22
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the safety issue and the considerations for 1
withdrawal. When the decision is made for 2
withdrawal, we identify the legal basis for that 3
withdrawal. 4
We ensure that there's appropriate 5
documentation so that the agency's reasoning and 6
basis for the removal or withdrawal are clear, and, 7
of course, it's important for the removal or 8
withdrawal action to be communicated to the public, 9
and so we do that via various means. For those 10
products that are withdrawn, the official 11
withdrawal occurs via publication of a notice in 12
the Federal Register. 13
I need to mention another way by which FDA 14
makes determinations about whether a drug has been 15
withdrawn for reasons of safety or effectiveness. 16
A holder of an approved new drug application, or 17
NDA, may at some point voluntarily discontinue sale 18
of its product, for example, for financial reasons. 19
And in some cases, because a drug is no longer 20
being manufactured or sold, that application 21
holder, that NDA holder may request FDA to withdraw 22
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its approval of the application. 1
Now, a different manufacturer who then wants 2
to make a generic version of the discontinued drug 3
may petition FDA via a relisting petition to make 4
the determination about whether the drug was 5
discontinued and, if it's applicable, whether the 6
drug was withdrawn for reasons of safety or 7
effectiveness. 8
So FDA will review the information about the 9
NDA drug and the NDA holder's reasons for 10
discontinuation or removal and request for 11
withdrawal. And after that, we will publish in the 12
Federal Register the determination as to whether or 13
not the drug was withdrawn for reasons of safety or 14
effectiveness. 15
This brings us to the current proposal for 16
the additions to that list of withdrawn or removed 17
drugs. We identified those proposed drugs by first 18
searching our records for drugs whose withdrawal 19
had been published in the Federal Register and 20
those that had been removed from the market for 21
safety or efficacy reasons. 22
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We also reviewed the documentation 1
describing the withdrawals or removals. For 2
example, we looked at Federal Register notices and 3
other FDA or official documentation, such as public 4
health advisories and so on that announced the 5
withdrawal or removal, and any other supporting 6
documentation. The background materials for this 7
meeting contain the specifics about those 8
withdrawals and removals. 9
So in summary, we continually assess the 10
safety of a drug over its life cycle. Drug safety 11
signals are frequently identified in the postmarket 12
safety period. FDA has multidisciplinary teams to 13
evaluate postmarket safety signals to determine the 14
impacts on the benefit-risk profile of the drug and 15
to inform our regulatory decisions. 16
In some cases, our decision may be to 17
withdraw the drug or to remove it from the market 18
or to withdraw approval of the product. And our 19
removal or withdrawal decisions are based on the 20
safety issue, and it's undertaken within the 21
appropriate legal and regulatory framework. 22
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Thank you. 1
Clarifying Questions from the Committee 2
DR. VENITZ: Thank you. Any clarifying 3
questions by committee members? 4
(No response.) 5
DR. VENITZ: Then let me ask you. You 6
listed a whole series of resources that you use to 7
assess postmarketing safety signals. Probably the 8
most difficult, I would guess, is to assess 9
causality. So how high is your burden of proof to 10
identify that a drug product has caused what you 11
consider to be the safety signal rather than being 12
associated with it? 13
DR. KASHOKI: Right. There are multiple 14
factors that go into a determination or a decision 15
about causality. Timing, for example, we're really 16
trying to assess the relationship of the event to a 17
period or point that the patient was taking the 18
drug. 19
This is where there is some clinical 20
judgment. There is judgment based on knowledge and 21
experience of pharmacovigilance and the evaluation 22
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of events and associations between drug and event. 1
If there are any more definitive studies or 2
trials that may better inform your decision about 3
causality, those are always looked at. It's always 4
more challenging if what you're relying upon is 5
solely spontaneous adverse event reports. 6
In the end, it becomes part clinical 7
judgment, part regulatory judgment, and then the 8
scientific component, as well. If there are things 9
like plausibility, whether it's based on a 10
mechanism of action, whether it's based on prior to 11
X manufacturing period, there was no impurity, 12
voila, there's an impurity and now we're seeing 13
adverse events, you make a decision in a much 14
clearer and easier way. 15
There is no specific threshold. There is no 16
number, per se. So it really is, as I said, a 17
qualitative assessment of the benefit and the risk 18
of the drug. 19
DR. VENITZ: Just a follow-up. How 20
important is the availability of alternative 21
therapies to your ultimate decision? 22
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DR. KASHOKI: It is an important 1
consideration, particularly when you think of the 2
nature of the condition being treated. If 3
it's -- I'm just making this up -- a 100th 4
antihypertensive, your threshold maybe a little bit 5
more different than if this is the sole therapy for 6
a rare condition. 7
DR. VENITZ: Thank you. Go ahead. 8
MS. JUNGMAN: I'm not sure whether you're 9
the right person for this or whether this is a 10
question for -- 11
DR. VENITZ: Can you please state your name? 12
MS. JUNGMAN: I'm sorry. I'm Elizabeth 13
Jungman. But I'm trying to get a sense of the 14
standard that you're applying in making these 15
decisions. And if I understand your presentation, 16
FDA really is weighing the risk -- kind of 17
re-weighing the risk and the benefit of the drug in 18
the way that they would in making an approval 19
decision, not making a decision that this drug is 20
never appropriate for any patient; is that correct? 21
DR. KASHOKI: So the decision is made based 22
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on a population basis. 1
MS. JUNGMAN: Population level. 2
DR. KASHOKI: Yes. So if there comes a 3
point, for example, we make a determination that a 4
product should be withdrawn for reasons of safety 5
or effectiveness from the population basis, that we 6
tend to look at products, and then there is an 7
individual provider who thinks that this particular 8
product may be helpful to their individual patient, 9
there is a way through which a patient may receive 10
a product that's been withdrawn for reasons of 11
safety or effectiveness by our expanded access 12
process, which is via an IND, or investigational 13
new drug application. And in that case, on a 14
case-by-case basis, we will make the determination 15
as to whether not treatment with that particular 16
product for that individual in that circumstance is 17
warranted. 18
MS. JUNGMAN: That was my follow-up. Thank 19
you. 20
DR. DiGIOVANNA: John DiGiovanna. So if I 21
understand you correctly, a drug that's on the 22
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do-not-compound list, in order for it to be used 1
for an individual patient, that it can be done, but 2
it requires an IND. 3
DR. KASHOKI: So I will speak from the 4
perspective of if it's on the withdrawn or removed 5
list. I'm looking at Jane Axelrad, who looks like 6
she wants to say something. 7
MS. AXELRAD: Well, the answer is yes. If 8
it's on the withdrawn or removed list, it cannot be 9
compounded. And if somebody wants to use it to 10
treat an individual patient, they would do it under 11
an IND. 12
DR. DiGIOVANNA: And then under those 13
circumstances, it's compounded for that individual 14
patient under the IND. 15
MS. AXELRAD: Well, it could be compounded, 16
or in many of these cases -- in some cases, not 17
many. But in some cases, the companies still make 18
it available under a limited access protocol or 19
some kind of an IND. So some of the drugs that 20
have been withdrawn or removed from the market, 21
like cisapride, you can get from the company, in 22
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which case it would not need to be compounded. 1
DR. DiGIOVANNA: I'm sorry. I don't quite 2
understand how a drug can be on the withdrawn list 3
because it has been removed from the market, but is 4
still being manufactured and sold. 5
MS. AXELRAD: Yes. It's not manufactured 6
and sold. It's provided under a limited access 7
protocol by the sponsor, because as Mwango said, 8
we're making these judgments on a population basis, 9
but there may have been patients who were on it. 10
And in some cases, they're for serious or life-11
threatening diseases. And for that individual 12
patient, the benefits of the drug, in the view of 13
the prescriber, continue to outweigh the risks, and 14
the company has been willing to continue to make 15
the drug available to those patients. 16
DR. VENITZ: Thank you. Any other 17
clarifying questions? 18
(No response.) 19
DR. VENITZ: Thank you very much. 20
DR. KASHOKI: Thank you. 21
DR. VENITZ: Then we proceed with our first 22
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drug of interest, and that's adenosine phosphate, 1
Dr. Nancy Xu. She is a medical officer at the 2
Division of Cardiovascular and Renal Products, 3
Office of Drug Evaluation I. She will introduce 4
the drug product. 5
FDA Presentation – Nancy Xu 6
DR. XU: Good morning, everyone. Welcome, 7
the audience and the committee members, for being 8
here today. You bring a range of expertise and 9
perspective to the FDA, and we believe this is very 10
important to our mission in promoting the safe and 11
effective use of drugs and being responsive to the 12
evolving needs and concerns from the community at 13
large. Today, my presentation will focus on 14
clarifying the term adenosine phosphate on the 15
withdrawn or removed list. 16
First, I would like to acknowledge all my 17
colleagues who had worked so diligently and under 18
sometimes tight time pressure on this review for 19
this presentation. They include people from the 20
Office of New Drugs in my division and other 21
offices and divisions within the Office of New 22
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Drugs, Office of Pharmaceutical Quality, OPQ-I, and 1
the Division of Clinical Pharmacology I, as well, 2
of course, Office of Regulatory Policy. 3
Let me begin with giving you some background 4
on the entry for adenosine phosphate on the 5
withdrawn or removed list. 6
The 1999 withdrawn or removed list indicated 7
adenosine phosphate or drug products containing 8
adenosine phosphate may not be compounded. The 9
rationale, as indicated in the Federal Register 10
notice for the proposed rule, was that adenosine 11
phosphate, singular, was determined to be neither 12
safe nor effective for its intended use as a 13
vasodilator or an anti-inflammatory. 14
In 1973, an injectable combination 15
containing adenosine 5-monophosphate and 16
vitamin B12 was removed from the market. That was 17
an unapproved product removed from the market for 18
the aforementioned reason. 19
Subsequently, FDA has also removed several 20
unapproved products, unapproved adenosine phosphate 21
products, from the market. Because these 22
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unapproved products do not provide common names to 1
the FDA, only brand names were available. We 2
believe they might -- it's possible they might have 3
contained other, one or more of the three commonly 4
known adenosine phosphates, which you will hear 5
about in the next slide. 6
In 2014, FDA received an anonymous comment 7
asking if the entry term adenosine phosphate on the 8
list was intended to include all three forms of 9
adenosine phosphate, mono-, di-, and triphosphate. 10
Let me review how scientific communities 11
currently use or interpret the term adenosine 12
phosphate. First, I would like to make a general 13
statement, and that is nomenclature can change over 14
time, thus creating a need for clarification. 15
As you can see, the term adenosine phosphate 16
is currently an ambiguous and nonsystematic term. 17
It can be used to describe a specific structure, 18
adenosine 5-monophosphate, by some chemical 19
nomenclature organizations. However, it is 20
currently also being interpreted broadly to mean 21
any adenosine, I mean any adenosine that is 22
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phosphorylated. 1
Adenosine phosphate is not a MSH, medical 2
subject heading, term in the PubMed. So I would 3
say one can interpret the term adenosine phosphate 4
to mean the three commonly known adenosine 5
phosphates in the question posed to the FDA, and I 6
will show you those structures and nomenclature in 7
the next two slides. 8
In this slide, you see adenosine 9
monophosphate, and it is also referred to as 10
adenosine 5-prime monophosphate, commonly used with 11
the abbreviation AMP. 12
Adenine is right here. When it binds to 13
ribose, this structure is called adenosine. When a 14
single phosphate is attached to the 5-prime 15
position, the 5-prime hydroxyl position of the 16
ribose, you have what's called adenosine 17
monophosphate, which is often referred to with the 18
abbreviation AMP. For the rest of the talk, I will 19
use the abbreviation AMP to refer to this 20
structure. 21
In this slide, you see the structure in the 22
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current nomenclature for adenosine di- and 1
triphosphates. As you can see, for adenosine 2
5-prime diphosphate, you have two phosphate units 3
attached to the 5-prime hydroxy position. 4
Similarly, for the adenosine 5-prime triphosphate, 5
you have three phosphate units attached to the 6
5-prime position. Also shown here is the FDA 7
unique structure identifier. 8
So may AMP, ADP, and ATP share a similar 9
pharmacological profile? We believe the answer is 10
yes. This is because ATP, ADP, and AMP are rapidly 11
converted to adenosine by a series of 12
dephosphorylation that takes place outside the 13
cell. 14
So may AMP, ADP, and ATP share a similar 15
safety profile? We believe the answer is yes. 16
Based on our review of the medical literature, ADP 17
has not been directly administered to humans as a 18
drug product. However, it has been tested in vitro 19
or ex vivo. It might have additional safety events 20
which we cannot rule out, but we believe ADP will 21
have the same -- can be compared to adenosine and, 22
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of course, bind to the adenosine receptors that 1
cause its effect. 2
So this slide shows you just the adverse 3
events, the safety profile as described in the 4
approved adenosine products and what we learned 5
from medical literature. 6
I wanted to point out although two IV 7
adenosine products have been approved in the U.S., 8
their use has been restricted to a highly monitored 9
setting where resuscitative measures are available, 10
and the reason, you can see, is listed here. It 11
can cause fatal cardiac arrest, high degree heart 12
block, ventricular arrhythmia requiring 13
resuscitation, myocardial infarct, bronchospasm, 14
and many others. You can see here when ATP is also 15
given as an IV bolus or infusion, serious adverse 16
events as shown, as described in the adenosine 17
labeling. 18
So in conclusion, the entry term on the list 19
should be modified. FDA recommends the entry term 20
on the list be updated to state adenosine 21
phosphates, plural, or drug products containing 22
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adenosine 5-prime monophosphate, in parens, AMP, 1
adenosine 5-prime diphosphate, parens, ADP, and 2
adenosine 5-prime triphosphate, parens (ATP). 3
This is because these three drug products 4
might have been in the unapproved products that 5
were removed from the market. And furthermore, 6
these three products likely share the same 7
pharmacologic and safety profile. 8
We believe using this terminology, adenosine 9
5-prime mono, adenosine 5-prime diphosphate, 10
adenosine 5-prime triphosphate, is unambiguous even 11
without accompanying chemical structure. We 12
include it as abbreviations because we believe most 13
health care providers, pharmacists, compounders, 14
would know what these terms mean. 15
So in closing, we believe building clarity 16
in terminology is an important step going forward. 17
Clarity lays a solid foundation for further 18
discussion. And I thank you for your attention. 19
I'd be happy to take any clarifying questions. 20
Clarifying Questions from the Committee 21
DR. VENITZ: Thank you, Dr. Xu. Any 22
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clarifying questions? 1
Can I ask you to go back to your second to 2
last slide? So on the left-hand side, you have 3
adverse reactions that are associated with the 4
approved adenosine. Right? On the right-hand side 5
you have observed or expected adverse events. 6
DR. XU: Reported adverse events in medical 7
literature. 8
DR. VENITZ: Because I was just looking at 9
your references. So there are clinical studies out 10
there where they looked at ATP. 11
DR. XU: ATP, yes. The ATP is approved in 12
some countries, also the U.S., for indications 13
similar to adenosine. It has been studied in 14
humans in clinical trials, studies, and there have 15
been case reports of adverse events. We looked at 16
the medical literature with respect to ATP not 17
limiting to just the U.S. 18
DR. VENITZ: But you didn't find anything on 19
AMP or ADP. 20
DR. XU: ADP, we didn't find evidence that 21
this is directly administered to humans as a drug 22
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product. We find only, like I said, in vitro or 1
ex vivo studies that raise some concern about 2
additional platelet aggregation side effects. AMP, 3
the adverse events, we didn't see anything to 4
alleviate the concern of AMP use. 5
DR. VENITZ: And that's based on your 6
assumption that ATP ultimately gets metabolized to 7
adenosine. Right? So AMP would be in the -- 8
DR. XU: Yes. They are in the pathway of 9
dephosphorylation. 10
DR. VENITZ: Thank you. 11
Any other questions for Dr. Xu? Last 12
chance. 13
(No response.) 14
DR. VENITZ: Thank you again, Dr. Xu. 15
Appreciate it. 16
DR. XU: You're very welcome. 17
DR. VENITZ: Our next drug of interest is 18
chloramphenicol, and we have Dr. Iarikov. He's a 19
clinical team leader in the Division of 20
Anti-Infective Products in the Office of 21
Antimicrobial Products, and he is going to 22
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introduce the drug product. 1
FDA Presentation – Dmitri Iarikov 2
DR. IARIKOV: Good morning. My name is 3
Dmitri Iarikov. I'm acting clinical team leader of 4
the Division of Anti-Infective Products at the FDA. 5
And today I'm going to discuss oral formulations of 6
chloramphenicol, with an emphasis on its safety 7
profile and reasons for oral formulations of 8
chloramphenicol withdrawal from the markets. 9
I'd like to emphasize at the beginning of my 10
presentation the intravenous formulation of 11
chloramphenicol is still available and marketed in 12
the United States. 13
I will start by describing chloramphenicol 14
properties, then I will discuss the chloramphenicol 15
safety profile, emphasizing aplastic anemia 16
associated with its use. I will then provide you 17
with a brief regulatory history for this product 18
and conclude by providing you a rationale for the 19
FDA determination that oral chloramphenicol was 20
withdrawn from the market for reasons of safety and 21
effectiveness. And once again, chloramphenicol for 22
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injection is approved and still marketed in the 1
United States. 2
Chloramphenicol is an antibacterial drug 3
that acts by inhibiting protein synthesis by 4
irreversibly binding to bacterial ribosome. Its 5
oral formulations are rapidly absorbed with 6
bioavailability of approximately 80 percent. It is 7
metabolized and inactivated in the liver with a 8
half-life of approximately 4 hours. And it's 9
active against aerobic and anaerobic gram-positive 10
and gram-negative organisms and rickettsiae. 11
Prior to its removal from the market, oral 12
chloramphenicol was approved for the treatment of 13
various gram-negative infections, including 14
salmonella, as well as rickettsiae and Chlamydia. 15
Importantly, the label of chloramphenicol 16
included a boxed warning stating that 17
chloramphenicol must not be used when less 18
potentially dangerous agents will be effective. 19
Major adverse reactions associated with 20
chloramphenicol use included bone marrow 21
toxicities, and these toxicities were listed in the 22
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boxed warning of the product label. And bone 1
marrow toxicities may present as either reversible 2
bone marrow depression, which was dose-related and 3
responsive to drug withdrawal, or as aplastic 4
anemia, which was not dose-related, irreversible, 5
and associated with a high mortality. 6
Major adverse reactions also included 7
neurotoxic reactions such as delirium, optic and 8
peripheral neuritis, hypersensitivity reactions, 9
including anaphylaxis, and Gray syndrome in the 10
newborn. This syndrome results from impaired 11
inactivation of the product in the newborn and 12
presented as abdominal distension, cyanosis, 13
hypertension, and frequently resulted in death. 14
Chloramphenicol-associated aplastic anemia 15
was the major safety concern associated with the 16
product. Once again, it was irreversible, usually 17
fatal, and it could terminate in leukemia. 18
Aplastic anemia occurred at the rate of 1 case for 19
every 22,000-41,000 courses of the drug. It could 20
occur up to any dose of chloramphenicol, and 21
aplastic anemia could develop months or even years 22
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after chloramphenicol administration. 1
Importantly, aplastic anemia appeared to be 2
more common after oral administration of 3
chloramphenicol. It has been hypothesized that 4
chloramphenicol undergoes metabolization by 5
intestinal bacteria and its metabolite, in 6
particular, dehydro-chloramphenicol, might undergo 7
further nitro reduction in the bone marrow. And 8
these products can cause DNA breaks and result in 9
carcinogenicity and aplastic anemia. 10
Dosing for chloramphenicol required 11
additional safety precautions, such as blood 12
studies every two days to monitor for bone marrow 13
toxicities and measurement of blood concentration 14
of chloramphenicol in patients with impaired 15
metabolic processes. And hospitalization during 16
the therapy was recommended to facilitate safety 17
monitoring. 18
Importantly, the boxed warning in the oral 19
chloramphenicol label stated that blood studies 20
cannot be relied on to detect bone marrow 21
depression prior to development aplastic anemia. 22
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I'm going to present you a brief regulatory 1
history of the product. Chloramphenicol was 2
introduced in 1948. In October of 2007, the 3
sponsor of the product requested withdrawal of the 4
application because oral chloramphenicol was no 5
longer marketed. 6
In February of 2009, FDA announced that 7
approval would be withdrawn, and the drug would be 8
moved to the discontinued drug products list, or 9
the Orange Book. In July of 2012, after 10
considering a petition to reintroduce the 11
250 milligram oral chloramphenicol capsules to the 12
market, FDA determined that the product was 13
withdrawn for reasons of safety and effectiveness. 14
The FDA based its determination on the fact 15
that less toxic and more efficacious antibacterial 16
drugs are available for all chloramphenicol 17
indications, and poor clinical outcomes and the 18
high mortality were reported in patients treated 19
with chloramphenicol as compared to those treated 20
with other antibacterial drugs. These studies 21
included both intravenous and oral formulations of 22
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the drug. 1
Once again, the risk of aplastic anemia may 2
be greater after oral as compared to intravenous 3
administration of the drug. In addition, in a 4
report on carcinogens, that is a congressionally-5
mandated public health document, at least oral 6
chloramphenicol is a human carcinogen that may 7
result in leukemia. 8
I'd like to conclude my presentation by 9
stating that all oral formulations of 10
chloramphenicol, regardless of the specific forms 11
or strength, are expected to have a similar safety 12
profile. And I'll be happy to field any questions. 13
Clarifying Questions from the Committee 14
DR. VENITZ: Thank you very much. Any 15
questions? 16
DR. WALL: Your comment said that it 17
appears -- it's under the chloramphenicol 18
associated aplastic anemia that it appears to be 19
more common after oral administration. 20
Do you have any more specific data other 21
than it just appears? 22
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DR. IARIKOV: There have been several 1
publications investigating the issues -- I can 2
provide you with specific references -- and has 3
been studied in animal models that chloramphenicol 4
is metabolized by intestinal flora, and this flora 5
produced dehydro-chloramphenicol. And this 6
metabolite, when it goes to bone marrow cells, it 7
undergoes nitro reduction. And this nitro-reduced 8
dehydro-chloramphenicol causes DNA breaks. It has 9
been shown in animal studies. 10
DR. WALL: But we haven't seen it in 11
the -- no human studies went back and looked at 12
that or examined it when you pulled out the side 13
effect profiles. 14
DR. IARIKOV: I'm not aware of any more data 15
supporting this hypothesis. My understanding is it 16
would be hard to conduct these studies in humans 17
because aplastic anemia developed at the time when 18
the product is no longer staying in the body, years 19
and months after treatment is stopped. So you're 20
dealing with the facts and statistics basically. 21
And these studies were done retrospectively trying 22
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to understand what's happening. 1
DR. WALL: Thank you. 2
DR. VENITZ: Dr. Pham? 3
DR. PHAM: Kathy Pham, NICU specialist at 4
Children's National Medical Center. I feel kind of 5
subjectively that in practice a lot of these 6
considerations of the toxicity is already accounted 7
for, and that is it is not first-line therapy, as 8
far as I can tell. But due to the widespread news 9
of broad spectrum antibiotics now, it remains a 10
very good anti-infective as it retains 11
susceptibility in a lot of the organisms due to its 12
underuse. 13
Although the IV formulation exists, I worry 14
about it being specifically for severe infections 15
or infections guided by susceptibility profiles as 16
an agent of choice for prolonged duration of 17
therapy, perhaps 14-21 days, easily, in some of 18
these infections that I would suspect its use in. 19
So as patients stabilize, are we burdening 20
the health care system with ongoing IV therapy if 21
it remains the only available dosage formulation, 22
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or have we thought about the boxed warning being 1
expanded because -- I don't advocate for this, 2
obviously, but what if someone extrapolates using 3
the IV formulation as PO since it already comes in 4
solution -- sorry, as oral -- as it already comes 5
in solution. 6
So I think it would just be prudent to 7
anticipate some of the further consequences of 8
withdrawing an oral formulation. 9
I completely agree with the concerns. I was 10
surprised to hear -- actually, this is the first 11
time I've heard about the intestinal bacteria and 12
the metabolites causing some concern for the 13
toxicity of the oral formulation. But without any 14
further clarification on the boxed warning, it is 15
very feasible that in practice, someone may think, 16
well, I don't have oral anymore; maybe I'll just 17
use the intravenous as oral. 18
DR. IARIKOV: Your point about multidrug 19
resistant bacteria is very well taken, and this is 20
why the intravenous formulation of chloramphenicol 21
is on the market. It still potentially can be used 22
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with patients infected with multidrug resistant 1
bacteria and having life-threatening disease. 2
Under this circumstance, I would imagine that 3
probably these patients will receive intravenous 4
formulation of chloramphenicol, and it would be 5
patients with health care-associated pneumonia, 6
bacteremia. Under this circumstance, switching to 7
oral may be potentially a problem, but it would be 8
a relatively right situation, an inconvenience. 9
The risk of having these products, from my 10
perspective, as an oral drug on the market for 11
almost every possible indication, including Rocky 12
Mountain Spotted Fever, there is a high mortality 13
associated with its use because it is less 14
efficacious. 15
I think that considering the risk and 16
benefits ratio associated with the presence of the 17
oral drugs on the market when it can be used 18
inappropriately outweighs potential, but I'm 19
emphasizing this for inconvenience of oral switch 20
in an individual patient. 21
DR. PHAM: Again, would maybe the potential 22
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for revision of that boxed warning come into play 1
if this was removed for oral administration? 2
DR. IARIKOV: You mean revising the boxed 3
warning in terms of -- 4
DR. PHAM: I don't remember what the 5
original boxed warning -- it says chloramphenicol 6
must not be used when less potentially dangerous 7
agents will be effective, which I think is probably 8
widespread current practice due to everyone's 9
hesitation to use chloramphenicol. 10
As the NICU specialist, you think it's odd 11
that I'm advocating for chloramphenicol due to the 12
Gray baby syndrome, but we now have weight-based 13
dosing that appropriately accounts for that issue 14
of metabolization in neonates. But it's just the 15
fact that it really doesn't speak to the concerns 16
with oral administration. It only speaks to just 17
not using it first line. 18
MS. AXELRAD: If I could just make a 19
clarification. The drug has been removed from the 20
market. So the slide up here says that its safety 21
precautions were recommended for the dosing of the 22
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oral before it was removed from the market. So 1
since the product isn't being marketed, it's not 2
appropriate to talk about changing the label of the 3
drug to add a warning. It's been removed from the 4
market. 5
DR. VENTIZ: Thank you. Any further 6
questions? Dr. Jungman? 7
MS. JUNGMAN: This is Elizabeth Jungman. So 8
just to kind of put a point on that. As I 9
understand it, if this drug were not placed on the 10
withdrawn and removed list, then it would be 11
available for compounding by 503As and there would 12
be no labeling requirements associated with that. 13
There are some labeling requirements 14
associated with 503Bs. But I want to make sure 15
that I'm correctly understanding that we would 16
really be talking about making this available in 17
oral formulation barely probably without those 18
labeling restrictions that apply to the approved 19
product. 20
MS. AXELRAD: Yes. Compounded drugs do not 21
have the same kind of labeling that you have when 22
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you have an approved drug. 1
DR. VENITZ: Any other questions? Go ahead. 2
DR. DiGIOVANNA: John DiGiovanna. I think 3
this is perhaps a point of clarification for me. 4
It seems that the interest in compounded drugs is 5
often for the individual patient that has a 6
particular type of disease that is different from 7
the general population for which a drug might have 8
been approved. And often those are situations 9
where the physician feels that they're boxed in a 10
corner and is looking for another therapy, possibly 11
one they have found to be useful from the 12
literature. 13
I don't understand if there is a mechanism 14
to allow for availability for compounding only on a 15
prescription basis for an individual patient, 16
rather than allowing it available for bulk usage, 17
which would appear to me to address many of the 18
situations that have been raised -- where one has 19
an unusual situation of a disorder and maybe the 20
risk profile isn't necessarily appropriate for that 21
particular patient and may not relate to why the 22
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drug was removed from the market. 1
So is there a way to -- when a drug is on 2
the withdrawn list, it appears that it's still not 3
available either for bulk compounding nor for 4
prescription for an individual patient. But is 5
there an availability for the unusual situation for 6
an individual patient that doesn't open the drug up 7
to being widely bulk prepared and sold that might 8
put a different risk-benefit profile to a 9
population rather than that individual patient? 10
I hope I'm not too unclear. 11
MS. AXELRAD: I don't know. I was wondering 12
if other members of the committee might have a view 13
on that. I could talk about my thoughts about 14
that. 15
It's a factual question. I sort of already 16
answered it, which is when a drug has been 17
withdrawn or removed from the market for safety 18
reasons and it's put on this list, it isn't 19
available for compounding. And if someone believes 20
that it ought to be used for an individual patient, 21
then they need to make that case through the IND 22
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mechanism, which ensures that patients are advised 1
of the risks of the drug, what's been found in 2
terms of the benefit-risk of the drug, and the 3
safety profile, and that they are getting informed 4
of those. And then if the physician decides that 5
that's the appropriate treatment, then that's fine. 6
But there is no real way once you put 7
it -- if you don't put it on the list -- to limit 8
it in any way. I mean, anybody could compound it 9
and offer it for sale, period. 10
DR. VENITZ: Dr. Davidson? 11
MS. DAVIDSON: Gigi Davidson. Jane, could 12
you perhaps explain what is involved in filing an 13
IND? I think that would help many of us decide 14
whether this is a significant impairment to patient 15
access or not. Thank you. 16
MS. AXELRAD: Yes. We just issued a 17
guidance that has a short abbreviated form for 18
filing an expanded access IND for an individual 19
patient, if you're doing it for an individual 20
patient. It is done fairly frequently and it has 21
as limited burden as one can make. 22
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If you want me to get details, I'd probably 1
want to get somebody from the divisions that handle 2
them. But we have recently put out two guidance 3
documents, one that talks generally about all the 4
different options for how you can get a drug under 5
an IND, and then this more recent guidance that was 6
just issued, I think, a couple of weeks ago that 7
explains -- has a new form that's proposed for use 8
in an expanded access IND that makes it, I think, 9
as easy as one can to get permission to use it. 10
DR. VENITZ: Go ahead. 11
MR. MIXON: Bill Mixon, industry 12
representative. In all due respect, I don't 13
believe that the FDA could respond in a very rapid 14
manner when the decision is made that 15
chloramphenicol is the drug of choice for an 16
individual patient by a physician. And I just 17
would encourage the committee to not take this drug 18
out of the armamentarium. 19
When a physician makes the decision to use 20
this drug, despite its drawback and concerns and 21
warnings and side effects, I mean, that decision is 22
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made every day with every drug. Thank you. 1
DR. IARIKOV: Certainly I'd like to 2
interject. 3
DR. VENITZ: Hold on. Dr. Gulur? 4
DR. IARIKOV: Please take into consideration 5
for an individual patient, if there's a strong case 6
for it, the drug is available and is still 7
marketed. So if you have someone with a multidrug 8
resistant infection, the drug is available in 9
intravenous formulation. 10
This is probably the circumstance where this 11
formulation would be more appropriate. And as 12
indicated, it's still produced and marketed in the 13
rest of the world. So the company potentially 14
can -- if there is, once again, a very strong case 15
for oral formulation, it can be provided under your 16
emergency use IND access. 17
But if somebody needs chloramphenicol for 18
any particular reason, the drug is approved, not 19
capsules. And as an infectious disease physician, 20
I'm trying to imagine the circumstance where oral 21
chloramphenicol capsules can be used, and I cannot 22
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think of any, for the most part. 1
DR. VENITZ: Dr. Gulur, and then Dr. Carome. 2
DR. GULUR: Could somebody help clarify? 3
The intravenous formulation is available. Does it 4
require special compounding for oral use? The 5
intravenous solution that's available, can that be 6
used as an oral formulation? What are the 7
limitations, I guess. 8
DR. IARIKOV: It does not require 9
compounding. It's a commercially manufactured 10
product, so there is no compounding involved. 11
There is an actual NDA that covers this product. 12
Can you use -- I believe if it's 1 percent. 13
I'm not sure if you can use this intravenous 14
formulation to dose appropriately. I have not 15
considered this scenario. 16
DR. VENITZ: Dr. Carome, and then Mr. Mixon 17
is last. 18
DR. CAROME: Mike Carome. I think of there 19
is a patient out there who is so sick that none of 20
the other available antibiotics that are much safer 21
are not the choice for therapy, and someone needs 22
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to turn to chloramphenicol, and the patient is so 1
sick that that patient should be appropriately 2
treated probably in a hospital with the IV 3
formulation, as marketed, with appropriate 4
monitoring. And the IV therapy, based upon some 5
studies you mentioned, is probably a safer way to 6
go. So I don't think there is any need for the 7
oral formulation in capsule form. 8
DR. VENITZ: Mr. Mixon, last question. 9
MR. MIXON: I just wanted to respond that to 10
use the intravenous form orally, if this drug is 11
added to the negative list for oral use, it would 12
not be appropriate for a compounder to take the 13
intravenous form and put it into an oral form. We 14
wouldn't do that. 15
DR. VENITZ: We have more room for 16
discussion. 17
DR. IARIKOV: Just one last remark. 18
DR. VENITZ: Go ahead. 19
DR. IARIKOV: Please consider that the oral 20
formulation of chloramphenicol has not been 21
effectively on the market since 1995, and there is 22
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no kind of wave of requests for almost two decades. 1
It's not on the market anymore, and the company 2
just withdrew it in 2007. But since 1995, it has 3
not been marketed because there had been no use for 4
it. 5
DR. VENITZ: Thank you, Dr. Iarikov. 6
It's time for our first break. We can 7
continue our discussion, but right after we 8
reconvene at 10:15, we have our first open public 9
hearing. So we'll take a break and reconvene at 10
10:15. 11
(Whereupon, a recess was taken.) 12
Open Public Hearing 13
DR. VENITZ: Can you take your seats, 14
please? And while you're taking your seat, let me 15
just do the preliminaries for our first open 16
hearing session. 17
So we will now convene our first OPH 18
session, in which we have one speaker. I will now 19
read the OPH statement into the record. 20
Both the Food and Drug Administration and 21
the public believe in a transparent process for 22
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information-gathering and decision-making. To 1
ensure such transparency at the open public hearing 2
session of the advisory committee meeting, FDA 3
believes that it is important to understand the 4
context of an individual's presentation. 5
For this reason, FDA encourages you, the 6
open public hearing speaker, at the beginning of 7
your written or oral statement, to advise the 8
committee of any financial relationship that you 9
may have with the product and, if known, its direct 10
competitors. For example, this financial 11
information may include the payment by a drug 12
supplier or a compounding pharmacy of your travel, 13
lodging, or other expenses in connection with your 14
attendance at the meeting. 15
Likewise, FDA encourages you, at the 16
beginning of your statement, to advise the 17
committee if you do not have any such financial 18
relationships. If you choose not to address this 19
issue of financial relationships at the beginning 20
of the statement, it will not preclude you from 21
speaking, however. 22
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The FDA and this committee place great 1
importance in the open public hearing process. The 2
insights and comments provided can help the agency 3
and this committee in their consideration of the 4
issues before them. 5
That said, in many instances and for many 6
topics, there will be a variety of opinions, and 7
one of our goals today is for this open public 8
hearing to be conducted in a fair and open way, 9
where every participant is listened to carefully 10
and treated with dignity, courtesy, and respect. 11
Therefore, please speak only when recognized by the 12
chair. Thank you for your cooperation. 13
So may we now have the registered speaker 14
step up to the microphone and provide his comment, 15
please? 16
DR. DAY: Good morning. My name is A.J. 17
Day. I'm a pharmacist employed by PCCA, 18
Professional Compounding Centers of Houston. And I 19
would like to propose that regarding adenosine, the 20
entry into the list be specific to drugs -- for use 21
for parenteral use. All of the data presented for 22
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adenosine, as well as the triphosphate, is specific 1
to IV bolus and infusion therapy. Because that is 2
where the concern lies with safety, it seems 3
logical that the entry into the list of drugs to 4
not compound with for safety and efficacy reasons 5
be specific to the injectable form. 6
Committee Discussion and 7
Vote on Withdrawn or Removed List 8
DR. VENITZ: Thank you for your comment. We 9
have no further speakers. So the open public 10
hearing portion of this meeting has now been 11
concluded, and we will no longer take comments from 12
the audience. The committee will now turn its 13
attention to address the task at hand, the careful 14
consideration of the data before the committee, as 15
well as the public comments. 16
During the break, Dr. Axelrad has indicated 17
that we will have one or two speakers to tell the 18
committee more about the IND process, as that is an 19
issue that we discussed earlier today. 20
Dr. Axelrad? 21
DR. NAMBIAR: Thank you and good morning. 22
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My name is Sumathi Nambiar. I'm the director in 1
the Division of Anti-Infective Products. I just 2
wanted to respond to an earlier comment about 3
emergency access to products. I know a lot of our 4
processes are rather onerous, but this is not that 5
onerous. We do respond to physician's requests in 6
very short time. Twenty-four hours a day, seven 7
days a week somebody is available, and the 8
physician that's interested in procuring the 9
product reaches out to the division. And somebody 10
from the division does call the physician, and we 11
make arrangements for the product to be available. 12
Now, we don't ship the product. Obviously, 13
that has to come from the supplier. And really, 14
it's done all through the weekend. I just did four 15
of them this past weekend. So I think it's 16
certainly not as time-consuming as it may appear. 17
Are there any questions that I can answer 18
about the exact process? 19
DR. VENITZ: Mr. Mixon? 20
MR. MIXON: So if I understood you 21
correctly, you said within 24 hours? 22
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DR. NAMBIAR: No. It doesn't even take 1
24 hours. As soon as we get a request from the 2
physician, somebody from the division -- if it's 3
during working hours, it's one of the medical 4
officers reaches out to the physician. If it's 5
after hours, it's usually me. 6
We talk to them, get the details on the 7
patient. And usually there's a basic set of forms 8
that they need to fill out. But if it's after 9
hours, we sometimes do it over the phone. 10
The delay often is in getting the product 11
from the manufacturer. That's not what we control. 12
But in terms of the FDA's end of things, it doesn't 13
even take 24 hours. It's a matter of a few hours. 14
MR. MIXON: So that could be initiated 15
verbally. 16
DR. NAMBIAR: Yes, depending on the 17
situation, depending on the time of the day, the 18
day of the week. 19
MR. MIXON: How easy is it to find the 20
contact information for your office? 21
DR. NAMBIAR: It's all on the website. If 22
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you go to the FDA website, the information is 1
available. After hours, all the information for 2
the emergency coordinator is available. They take 3
the basic information, and they reach out to the 4
division contact, which is usually me, and it 5
happens pretty quickly. 6
MR. MIXON: Thank you. That is very 7
helpful. 8
MS. DAVIDSON: Gigi Davidson. This is a 9
very odd question, but in the event that a human 10
manufacturer of chloramphenicol oral dosage forms 11
could not be located, veterinary dosage forms are 12
widely available. Would the agency consider 13
allowing use of that under an IND for a patient in 14
need? 15
DR. NAMBIAR: I don't think I'm in a 16
position to answer the specific question regarding 17
chloramphenicol because I don't know on the 18
specifics, but there is certainly one other product 19
that we do get requests to use under emergency IND, 20
and the only product available currently is a 21
veterinary product. 22
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DR. VENITZ: Dr. Pham? 1
DR. PHAM: Kathy Pham from Children's 2
National Medical Center. After that process is 3
approved, is the storage and handling or any other 4
documentation specific to having to go through an 5
investigational drug service pharmacy at these 6
practice sites, or once it has come from the 7
manufacturer, the pharmacy department is able to 8
handle it however it chooses? 9
DR. NAMBIAR: I think that really depends on 10
your institutions. We don't get into those 11
details. And we typically work with the hospital 12
pharmacists, and they're able to coordinate with 13
the institution. But as the investigator and the 14
sponsor of the IND, you are still responsible for 15
submitting adverse events and maintaining whatever 16
the requirements of the IND are. 17
MS. JUNGMAN: If we were talking about a 18
product that isn't available from a manufacturer, 19
but that would have to be compounded, would that 20
alter your process at all? 21
DR. NAMBIAR: I've really never done one of 22
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these, but I would think we should be able to work 1
with the physician and the supplier and make things 2
possible. Now, typically, when these kinds of 3
drugs are used, patients are in dire situations. 4
But now with chloramphenicol, with intravenous 5
chloramphenicol available, it shouldn't be an 6
issue. 7
With oral chloramphenicol, if it's a patient 8
who is going to get it as step-down therapy, we 9
have some time to work these things out. So it's 10
not that you would need oral chloramphenicol in a 11
couple of hours. I think we should be able to work 12
something out. 13
I'll have to talk to my colleagues from CMC 14
to understand exactly what kind of information they 15
need, but I think that's something -- we probably 16
will have a little more time with oral 17
chloramphenicol, and IV is available for a sick 18
patient. 19
MS. DAVIDSON: Gigi Davidson. One more 20
question. The obvious case would be a pregnant 21
woman with Rocky Mountain Spotted Fever who could 22
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not take doxycycline or a patient who is allergic 1
to doxycycline. They could be started on IV 2
chloramphenicol for a few days, but the course of 3
therapy for that disease is about 21 days of 4
hospitalization. 5
My question is, if you received enough INDs 6
for oral chloramphenicol, would there be 7
consideration maybe even by this body to take it 8
off the list? 9
DR. NAMBIAR: Honestly, we haven't received 10
any emergency IND requests for oral chloramphenicol 11
in a long, long time. We do get requests for many 12
other investigational products and, like I said, a 13
product that's also available for veterinary use. 14
But in the last several years, I don't recollect 15
getting a single request for oral chloramphenicol. 16
DR. VENITZ: Dr. Jungman? 17
MS. JUNGMAN: Sorry, just one more. The IND 18
process, does it have to be specific to an 19
individual patient or, for example, maybe not 20
specific to chloramphenicol, but with a product 21
that a particular physician used with some 22
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frequency, would it be possible for that physician 1
to get more of a general dispensation to use the 2
product? 3
DR. NAMBAIR: What I'm talking about are 4
single-patient INDs. And under the expanded access 5
INDs, there's something known as expanded access 6
INDs, intermediate size population, there the 7
procedure is a little different. But there are 8
certain drugs where you're getting repeated uses in 9
a certain clinical condition, and there is a 10
protocol involved, and somebody can hold an IND, 11
expanded access IND, for an intermediate sized 12
patient population. 13
DR. VENITZ: Any further questions? 14
(No response.) 15
DR. VENITZ: Thank you very much for your 16
clarification. 17
We are now moving to the discussion and the 18
voting session. And I'm told that Dr. Iarikov has 19
to leave by 11:00, so I'd like to start our 20
discussion by continuing the chloramphenicol story 21
that we got involved in before I had to rudely 22
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interrupt us. 1
So any comments, any discussion, any 2
questions regarding oral chloramphenicol? 3
MS. JUNGMAN: What are the 4
circumstances -- and I'm kind of looking to the 5
clinicians around the table -- where you would want 6
to have an oral version of chloramphenicol? 7
So Dr. Pham mentioned the burden on the 8
health care system. But are there clinical 9
circumstances in which a patient would not be 10
appropriate for an IV form, they would really need 11
an oral dosage form? 12
DR. PHAM: I think that still goes back to 13
maintaining the duration of therapy and the 14
continuity of care. I think that we all agree it 15
would be reserved for serious infections or 16
contraindications. I think we all probably feel as 17
clinicians that IV therapy is always appropriate to 18
start. But you just don't know how stable that 19
patient is going to get in a prolonged duration of 20
therapy. 21
So I think that it's noted that the switch 22
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from IV to oral would probably not be a clinically 1
urgent need where you would have time to process 2
this. The problem is that in practicality side, 3
the path of least resistance is the way to go. And 4
I don't know that people are going to start the IND 5
process if they are more tempted to do IV as oral 6
and not know the risks or harm that that may be 7
provide, whether it's different pH balance 8
affecting the absorption of that solution versus an 9
orally-compounded solution. 10
Those are all hypotheticals. I just know 11
that in practice, being a representative of 12
pediatric health care, there is always going to be 13
limitations on appropriate dosage formulations for 14
certain populations. So we're used to things not 15
coming as liquid, and that's always the path of 16
least resistance. 17
It's just regardless of what we intend to 18
happen, that is going to be the way probably some 19
people will extrapolate this, whether they actually 20
dig down to whether it's appropriate or not. 21
That's the only reason I initially also 22
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brought up the boxed warning, and I get that it's 1
not appropriate to change the labeling if it's 2
going to be on the withdrawn list. But there are 3
going to be providers that don't know that you 4
can't just give something IV as oral and assume the 5
same bioavailability. And how do you educate the 6
providers on that? Because providers really just 7
assume that the pharmacist knows what to do with 8
that interchange. 9
So, again, I think it's like what if that 10
patient stabilizes in seven days. We keep talking 11
about the cost to health care. And if you are 12
delaying discharge from the institution because you 13
want to maintain IV antibiotics, even if you do the 14
home infusion, there is still going to be some cost 15
that's higher than oral. 16
So I appreciate the fact that the lack of 17
availability of oral capsules is already an issue. 18
I guess to also bring another question up in 19
this discussion, is there a base -- I mean, 20
compounding pharmacies I feel like are very 21
resourceful. So even if we know that the capsules 22
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aren't being marketed, is there a way to get 1
chloramphenicol base where it could feasibly still 2
be compounded and made available if it was not on 3
this list? 4
DR. IARIKOV: I just want to make this point 5
one more time. Even oral formulation of 6
chloramphenicol required hospitalization. So there 7
is no data to indicate this reason. So even if you 8
switch a person to an oral drug, it is still 9
recommended to keep this person in the hospital. 10
So it's not an outpatient product. You 11
still have to monitor blood levels and monitor 12
blood counts. So it's a little bit different with 13
this particular drug. So you're not going to save 14
much. It's a question about the cost-effectiveness 15
for oral chloramphenicol. I mean, somebody can 16
venture and discharge the person, but it's just 17
against the safety recommendation on the boxed 18
warning. 19
MR. MIXON: So you are saying that it's 20
never appropriate to use this drug on an outpatient 21
basis? 22
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DR. IARIKOV: I'm saying that it is indeed 1
recommended to keep the person in the hospital 2
while administering chloramphenicol. The word 3
"never" has kind of a very heavy connotation, but 4
this is what they're responsible to do, because 5
they're not certain what's going to happen with 6
this product -- I mean, with the patient. 7
So maybe under some circumstance when very 8
close follow-up is possible, you might possibly 9
construct this hypothetical scenario. But once 10
again, a general recommendation, keep the person in 11
the hospital. 12
MR. MIXON: Well, that's precisely the role 13
of the compounding pharmacists. We're the last 14
resort many times. And if the drug is available 15
intravenously, then I think it should be available 16
orally via a compounding pharmacist. We don't have 17
crystal balls, folks. And when it comes to patient 18
care, I don't see why you want to tie the hands of 19
the practitioners. 20
DR. IARIKOV: Once again, the safety profile 21
for this product is different for oral and IV. 22
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There is a relatively strong basis to suggest that 1
oral formulations are more toxic for the bone 2
marrow in terms of aplastic anemia than intravenous 3
formulation. 4
For the last many, many years, there have 5
been no requests for oral chloramphenicol 6
formulations because for the most indications, even 7
this scenario for pregnant women, high mortality is 8
observed -- was reported for particularly Rocky 9
Mountain Spotted Fever. So not very many providers 10
would decide to treat a pregnant person with a drug 11
that was associated with high mortality because 12
it's less efficacious. They want to save the 13
person's life. 14
Of course, it would be taken into 15
consideration potential risks for the fetus, but 16
for Rocky Mountain Spotted Fever, the doxycycline 17
limitations, sometimes they do not play a major 18
role because you're talking about life-threatening 19
disease frequently. 20
DR. VENITZ: Dr. Wall? 21
DR. WALL: Thank you. A couple of different 22
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things that are going through my mind. One, if we 1
were to approve it going forward, keep it on the 2
list where it could be compounded, being a clinical 3
pharmacist, I need to know things like what is the 4
actual bioavailability; with the IV formulation, 5
can you even get what you need with the oral 6
formulation going forward. 7
So the labeling, I know with compounding, is 8
just almost not there, and that's a safety concern 9
that I have. But at the same time, I understand 10
the concerns, because being in the hospital, you 11
may think you're going to keep them in there, but 12
in reality, they're going to rehabs. They're going 13
to step-downs. And these folks have a lot of 14
different monitoring parameters associated with 15
them. 16
So to think that someone is going to stay in 17
the hospital for the total time is not realistic in 18
this environment. 19
The other thing is I'm seeing 20
patients -- when we look at resistant gram-negative 21
infections Cystic fibrosis patients, I've got 22
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patients in their 20s and 30s right now with cystic 1
fibrosis who are resistant now. We've maxed 2
everything out. 3
So do we want to keep this patient in-house 4
for three weeks for a treatment course if we have a 5
different option that has shown that it is 6
available? 7
So these are just some of the ideas that I'm 8
just sort of messing around with of what is the 9
safety of being able to say I can do this 10
adequately, I can attain the concentrations that I 11
need to do it safely with the patient, with the 12
other health concerns that they've mentioned that's 13
going on on the outside. 14
DR. GULUR: I just want to put a practicing 15
clinician perspective on this. The oral 16
formulation has not been available for quite some 17
time in the market. As a practicing clinician, if 18
I am aware of the fact, which I should be if I'm 19
prescribing the drug, that the intravenous 20
formulation has been -- the reason the oral 21
formulations were removed was the risk of aplastic 22
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anemia is higher in them. And I'm sorry, the cost 1
of a few days cost savings will not be as primary 2
as the fact that the aplastic anemia is a 3
significant concern in the treatment of these 4
patients. So that would be of much import to me 5
and to most practicing clinicians. 6
The other fact where we say that the patient 7
can't get discharged or when we're arguing that 8
fact, we send patients home with IV therapy drugs 9
all the time. And, yes, it is slightly more 10
expensive than an oral pill, but, again, weighing 11
the benefit-risk, and the risk is the increased 12
risk of aplastic anemia, I think for most 13
clinicians that's not going to be a -- that's 14
pretty much a no-brainer. 15
The fact that we would push for an oral 16
formulation because we are concerned that it costs 17
lesser than the IV formulation, with all due 18
respect, compounding adds its own costs to these 19
medications. If they're mass manufactured, it's a 20
different issue. 21
The other fact, I know that Katherine Pham 22
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has brought it up a few times, which was also a 1
little bit of my concern in asking the question, 2
was what if unknowingly the intravenous 3
formulation, which is available -- especially in 4
pediatrics, there's a tendency to do a little 5
off-label use -- a lack of awareness of the 6
increased risk of aplastic anemia with oral 7
formulations, will that result in a safety issue in 8
trying to convert it just to oral? 9
Honestly, I recognize that you can't be 10
adding labels to everything and we have to be 11
responsible prescribers with respect to -- I 12
understand why we're not pushing for that too much. 13
Again, I just want to summarize and say that 14
given the very established risk, given the fact 15
that it's been off the market for as long as it 16
has, given the fact that we have heard from them 17
that they haven't been receiving INDs asking for 18
this oral formulation, there doesn't seem to be as 19
much of a demand. 20
There is a safety to having this on the 21
do-not-compound list to ensure there is no 22
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accidental use of this without an awareness of the 1
increased risk of aplastic anemia. 2
DR. BRAUNSTEIN: Ned Braunstein, the 3
industry rep, but also a physician. 4
So one of the things I think is very 5
important here is that the IND process brings in 6
informed consent. And as a physician and given my 7
role here on the industry, this is a product whose 8
oral use I don't think should be done outside of 9
informed consent, adequate informed consent. 10
So that doesn't preclude that there might be 11
rare individual circumstances where the drug might 12
have to be used. But the IND process brings in the 13
informed consent, and I think I would be much more 14
comfortable knowing that that's how the drug would 15
be used than possibly without that. 16
DR. VENITZ: Dr. Vaida? 17
DR. VAIDA: Allen Vaida. I just want to 18
make sure I'm correct in this. The drug hasn't 19
been available for over a decade, correct, in its 20
oral form? 21
DR. IARIKOV: ANDA, the last market 22
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application was withdrawn in 2009. But at the time 1
of withdrawal in 2007, it was submitted, the 2
company reported that since 1995, the drug was not 3
marketed anymore in the United States. There was 4
no demand for it. 5
So theoretically, it could be available 6
until 2007, but it has not been used at least since 7
1995 on a large basis. 8
DR. VAIDA: And we're not sure it's ever 9
been compounded out there in the last decade, since 10
it even hasn't been available on the market. And 11
the reason it's coming up here is because it's 12
already on the list, it's not available, but it's 13
coming up to say that if it was due to safety and 14
effectiveness versus just off the market. Correct? 15
MS. AXELRAD: When we did our look to see 16
what drugs had been withdrawn or removed from the 17
market for safety reasons since we did the last 18
rule in 1999, we came up with this drug for all the 19
reasons that we've described, and we proposed to 20
put it on the list. 21
The reason we're actually spending more time 22
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discussing this here is because we got a comment on 1
the proposed rule that asked that it not be 2
included on the list. Correct? 3
MS. ZIOLKOWSKI: Olivia Ziolkowski from 4
Office of Regulatory Policy. So it was not on the 5
original list that was codified in 1999. 6
Now, since we're looking at this again and 7
we're reinvigorating our efforts to update the list 8
to make sure that everything that has been 9
withdrawn since 1999 for safety reasons is on the 10
list, that's why we're proposing it. 11
DR. CAROME: So I'd just like to echo 12
support for the comments made by Dr. Gulur. I 13
think when you look at the risk-benefit assessment 14
of this product, it really should not be available 15
in oral form through compounding. 16
The FDA was very clear. They made a clear 17
determination that it was removed from the market 18
for safety concerns, that it was unsafe. It's not 19
even clear to me, sort of following on my question, 20
I think FDA has a little discretion in keeping this 21
off the list. 22
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MR. DeCHRISTOFORO: Bob DeChristoforo. I 1
have to admit we compounded it twice, but it wasn't 2
on the list. And it wasn't an emergency, and we 3
also were able to find material made under GMP 4
conditions with certificate of analysis and stuff 5
like that. 6
So in the future, though -- it was for two 7
patients with chronic granulomatous disease, and 8
they get weird infections. But in the future, we 9
will follow the rules. If we have to get an 10
emergency IND or a treatment IND, we'll do that. 11
DR. PHAM: I just think it still goes back 12
to the information that's available. Even last 13
night, actually just did a Google search, and Mayo 14
Clinic's website even still talks about oral dosing 15
of chloramphenicol, and claims that it is available 16
through capsule and suspension and has this 17
information as if they were available, which, 18
again, begs the point is there a way to get the 19
product for compounding. 20
That was going back to the whole can you get 21
a base powder under USP or whatever type of grading 22
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or are people -- is there not a request for 1
compounding because people are taking the IV 2
solution and giving it orally? 3
Just because the information is not out 4
there doesn't mean that there are workarounds out 5
there. If there is any dosing available, if there 6
is not some sort of labeling or resources where the 7
dosing references out there are citing the issues 8
with the oral toxicities, you're going to still be 9
able to find oral dosing information, and people 10
will probably extrapolate from practice doing the 11
IV as oral. 12
I think it goes back to the fact that it is 13
not widespread knowledge enough about the safety 14
concerns. And I wholeheartedly support that that's 15
the right thing to do, but how do we make that 16
information available to the public and the 17
providers? 18
DR. VENITZ: Any more? Dr. Jungman? 19
MS. JUNGMAN: Just responding to that -- and 20
I can't speak to the availability of the base 21
compound. But on the labeling issue, it seems to 22
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me that if we vote to put this or to recommend that 1
this be put on the do-not-compound list, then we're 2
in a situation where only the IV formulation is 3
available. That does have a label. 4
So that's something that if FDA decided was 5
appropriate -- or it may already suggest that you 6
shouldn't be converting the IV into an oral 7
solution because of the safety concerns. 8
But if we were to vote to not include this 9
on the list, then it would be a situation where 10
this product would be available in oral dosage form 11
through both traditional compounders and through 12
outsourcing facilities, which don't even have to 13
have individual patient prescriptions, without that 14
labeling information. 15
So I think there are kind of labeling 16
implications either way we go here. If I'm 17
misunderstanding the labeling circumstance there, 18
I'd love for somebody to point that out. 19
DR. VENITZ: Dr. DiGiovanna? 20
DR. DiGIOVANNA: DiGiovanna. If this was 21
placed on the list, could it be compounded 22
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topically; and if not, why not? 1
MS. AXELRAD: If we put it on the list, it's 2
chloramphenicol oral formulation, so it could be 3
done other ways. 4
DR. VENITZ: Are we done with 5
chloramphenicol? It looks like we are. 6
Now, as you know, our committee has to vote 7
on 27 different drug products. What I'd like to 8
do, since we finished chloramphenicol, let's just 9
finish up our discussion of adenosine, the second 10
drug product that we heard not only a comment 11
during the public hearing, but we had an FDA 12
presentation on before. 13
So any further discussion of adenosine? 14
DR. DiGIOVANNA: Yes. I wanted to make a 15
comment about the public presentation with respect 16
to separating out for particular drugs, whether 17
they should be withdrawn from all use or from 18
specific use. I think with chloramphenicol, I 19
missed the issue that it was specifically labeled 20
oral. But many of the drugs that are listed are 21
listed for general use. 22
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As a dermatologist, very often we want to 1
compound drugs that may be used topically. And if 2
they have been removed for safety reasons, very 3
often the safety reason is one that is related to 4
its systemic use. 5
So it's a great concern to us to have a 6
large number of drugs removed from ability to be 7
able to use for compounding topically when they do 8
not have a -- when the risk that's been defined is 9
a systemic risk. 10
DR. VENITZ: Does anybody want to comment on 11
the FDA side, systemic risk if topically used? 12
MS. AXELRAD: I would simply say that the 13
decisions to take a drug off the market for safety 14
reasons are based on the data that we have 15
available to us. I don't think that we know, for 16
one thing, what its absorption would be. It may 17
have been based on whatever form was being marketed 18
at the time. But we don't know whether, if you 19
used it topically, it would be systemically 20
absorbed. 21
So I think that -- and we may or may not 22
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have any data about any other formulations. Where 1
something was withdrawn or removed from the market 2
for a particular use, but then it got approved for 3
something else -- like there was one that was taken 4
off the market for one reason, but then an 5
ophthalmic formulation was approved -- we are 6
proposing to modify a list to qualify that. But 7
generally for these drugs, I don't think we know 8
whether the safety concerns that we have are 9
limited to a particular form and I think it would 10
be a concern, particularly since we don't know what 11
their absorption would be, to freely allow them to 12
be compounded in any other form just because the 13
data that we have for serious cardiovascular 14
effects, aplastic anemia and other things, we just 15
don't know what the effect of that would be for a 16
compounded product. 17
DR. DiGIOVANNA: DiGiovanna. Again, as a 18
dermatologist, we widely prefer to use topical 19
drugs because they are generally poorly absorbed 20
and it often gives us a wide range of safety as 21
opposed to systemic use. 22
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I would be concerned about using a systemic 1
toxicity to withdraw a drug from availability 2
because of the theoretical possibility that it 3
could be absorbed and give the same type of 4
toxicity, when generally the purpose of the skin is 5
to be a barrier and prevent absorption. 6
So there are many, many drugs that are 7
approved and widely used very safely topically that 8
would be quite toxic systemically. 9
So I would think that it would be wise to 10
consider the particular specific data that was used 11
in determining that the drug should be not 12
available and if there is evidence that it's for a 13
topical use, well, then that would make great 14
sense. But if it's a drug that's toxicity has been 15
systemic, then I think you're limiting a great deal 16
widespread dermatologic use of drugs and the 17
possibility that some of the drugs might be 18
available. So I think that should be considered. 19
DR. VENITZ: Dr. Carome? 20
DR. CAROME: Mike Carome. Dr. DiGiovanna, 21
are you aware of adenosine phosphate being used 22
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topically? 1
DR. DiGIOVANNA: No, I'm not. 2
DR. VENITZ: Any further discussion? 3
Dr. Gulur? 4
DR. GULUR: I'd just like to round that off 5
also by saying in the same way, it would be nice, 6
before we specify that it can be used topically by 7
being specific that it was just systemic, that we 8
knew the absorption of these drugs. 9
Without that data, I would agree that if we 10
don't actually have studies and data that show that 11
this is poorly absorbed or an indication, that it 12
shouldn't be included in this when we know that 13
there are side effects of the drug. 14
So just from that perspective, perhaps it 15
should be presented specifically for topical use. 16
DR. DiGIOVANNA: I'm sorry. I didn't quite 17
get your point. Are you agreeing with me or 18
disagreeing with me? 19
DR. GULUR: In a way, I feel like a qualify 20
should be added. We should actually have data on 21
absorption before we specifically say only the oral 22
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and IV formulations this is unsafe for, because we 1
don't want to by default say but topically it's 2
fine at the same time. 3
DR. DiGIOVANNA: So it actually dates back 4
probably long before I was born, but dermatology 5
has a very rich history of compounding drugs. And 6
I don't have the expertise that some of my mentors 7
had, but they had a large compendia of drugs that 8
were thought to be quite effective, may have been 9
toxic. 10
Those have dwindled over the years, but 11
occasionally there are those products that have 12
been very effective for a long period of time and 13
are thought to be very useful. Generally, they are 14
not well studied with respect to toxicity, but to 15
create a list that basically makes it extremely 16
difficult to use those drugs when the likelihood is 17
that their absorption is going to be minimal, 18
without the data to support that I think is very 19
limiting and would not be favored by most 20
dermatologists. 21
DR. HOAG: Two quick questions. Are there 22
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any forms of this adenosine on the market in any 1
dosage form? And is there any possibility that 2
that could be done by the DSHEA Act in terms of how 3
that is used? 4
MS. BORMEL: This is Gail Bormel. There is 5
adenosine that has been approved, from the talk, 6
just plain adenosine, not the phosphate. So under 7
Section 503A, a drug can be compounded if they're a 8
component of an FDA approved drug, if they are 9
subject to a monograph, and applicable monograph in 10
the USP or appear on the bulk drug substances list. 11
Remember there are numerous drugs that can 12
be compounded pursuant to that section of the Act. 13
MR. MIXON: This is Bill Mixon. Will the 14
vote for adenosine and chloramphenicol be the same 15
vote? 16
DR. VENITZ: We have a total of 27 votes 17
ahead of us, each individually. 18
MR. MIXON: Can we modify our request for 19
adenosine to be intravenous use only? 20
DR. VENITZ: You can make that comment, but 21
I'm not sure that we can change the voting 22
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question. I'm looking at the FDA. 1
So we have to vote on the questions as they 2
are, but you can make that as a comment. Whatever 3
your vote is, you would only vote in favor of -- 4
MR. MIXON: Well, I'm a nonvoting member. 5
DR. VENITZ: But what I am saying, any 6
committee member that can vote can make a comment. 7
MR. MIXON: Thank you. 8
DR. VENITZ: Yes? 9
MS. JUNGMAN: A couple of things. One is 10
that my understanding is there were some additional 11
public comments that were circulated over the 12
weekend that some committee members got and some 13
didn't. 14
If any of those relate to this -- just 15
because they got caught up in e-mail. If those 16
relate to the topics that we're about to vote on, 17
then I think it would be helpful to see those 18
before we have to vote. 19
The second, though, is that my understanding 20
of Dr. DiGiovanna's comment is not 21
specific -- correct me if I'm wrong -- it's not 22
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specific to adenosine phosphate, but basically any 1
product on this list. 2
So my question to you would be, are there 3
products on this list that have current 4
dermatological applications that we should be 5
thinking about or not? 6
DR. DiGIOVANNA: I would think that my 7
comment relates to all the products on the list. I 8
think if the product has been removed for systemic 9
reasons, then I think unless there is some evidence 10
that there is some toxicity, some unusual 11
absorption or toxicity, then it shouldn't be 12
withdrawn from the ability to be compounded 13
topically. 14
I think there is a tremendous discordance 15
between topical absorption and systemic absorption, 16
and there are an enormous number of products that 17
we use quite safely and effectively topically that 18
would never be used systemically. 19
So my comment is that I think for all of the 20
drugs that are on the list, where they have been 21
put on the list because there is a safety or an 22
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efficacy concern, that it be specific for systemic 1
use versus topical use. 2
DR. VENITZ: As far as the comments are 3
concerned, I didn't get anything -- I'm not sure 4
what you were referring to in terms of information 5
that was shared. You got a list of public 6
speakers. 7
MS. JUNGMAN: Yes. There were comments that 8
came around. 9
MS. AXELRAD: There were some comments that 10
were submitted to the website, and there are 11
written submissions of the public. And there are 12
some articles from 1979, 1988, 1980, on adenosine. 13
So there are some articles on various uses of 14
adenosine dating back from quite some number of 15
years ago. 16
DR. VENITZ: You didn't get that? 17
MS. JUNGMAN: No. I didn't receive it. I 18
think there are other members who may not have. 19
But my neighbor here has given it to me. 20
DR. VENITZ: It looks like several members 21
didn't get that. So it's being sent out as we 22
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speak. I'm not sure how that's going to help us 1
with the vote that's looming over us in about 2
30 minutes or so. So you might have to do a quick 3
read. 4
But any other comments right now related to 5
adenosine phosphate? 6
(No response.) 7
DR. VENITZ: Then we have 25 other drugs to 8
vote on. So I'm now opening the floor for any 9
comments, any discussion items relating to any of 10
the compounds we are going to vote on in a few 11
minutes. 12
Does anybody have any questions, any 13
comments, any clarification for FDA? 14
Dr. DiGiovanna? 15
DR. DiGIOVANNA: So I was unfamiliar with 16
the first list that was constructed, and the first 17
time I saw the list was for this meeting. 18
There is a drug that I had been involved 19
with years ago, which was taken off the market. It 20
was called etretinate, Tegison, and was withdrawn 21
from the market by the pharmaceutical company for 22
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reasons that, at the time, they had developed 1
another drug, which was the hydrolysis product of 2
etretinate; so that if you took etretinate, the 3
blood levels you would get would be both drugs. 4
And the second drug was water soluble, so it was 5
more quickly eliminated. 6
Both of the drugs had the unfortunate 7
problem of being teratogen. So no one was happy 8
with their persistence. And etretinate persists 9
for a longer time. So it made sense that they 10
didn't want to manufacture both drugs. 11
But I was surprised that it was on the list 12
of being withdrawn for safety and lack of efficacy 13
because there is a large volume of literature to 14
show that it's quite effective and has been. 15
Apparently, it is still available in Japan 16
and marketed in Japan. Because of my experience 17
with the drug, I was aware that there had been 18
reports that there are some patients who respond to 19
that, but do not respond to the drug that the 20
pharmaceutical company used to replace it that have 21
a rare disease called Darier's disease, which is 22
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quite severe and debilitating. 1
So I was surprised to see that and actually 2
noticed in the Federal Register, which is this 3
Volume 79, number 127, page 37691, which says that 4
the company had submitted a letter to the FDA, but 5
also says -- the letter also stated that the drug 6
was not withdrawn for safety reasons. 7
So it really led me to wonder what went into 8
constructing the list that now says the drugs were 9
withdrawn for safety reasons and for lack of 10
efficacy, when my experience was that the drug was 11
efficacious. It's still available in another 12
country. 13
There are some literature published that 14
says that the other drug isn't as effective for 15
some patients, and now it would be withdrawn from 16
the -- I wasn't even aware it could have been 17
compounded, but would be withdrawn from the market. 18
So it really raised the question to me as to 19
what goes into the assessment of putting a drug on 20
this list for safety and efficacy purposes and a 21
concern as to why this particular drug was on the 22
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list. 1
MS. AXELRAD: I can address that. And I'd 2
like you to turn your attention to tab 24, where 3
there is a Federal Register notice that talks about 4
it. 5
It says in a letter dated September 23, 6
1999, Hoffman-La Roche requested that FDA withdraw 7
approval of Tegison -- I'm paraphrasing -- 8
etretinate capsules, stating it had discontinued 9
marketing and that it wasn't withdrawn for safety. 10
In FDA's acknowledgment letter of 11
December 30, 2002, the agency informed 12
Hoffman-La Roche that Tegison capsules, a treatment 13
for psoriasis, was removed from the market under 14
314.150(d) because it poses a greater risk of birth 15
defects than Soriatane, the product that replaced 16
Tegison. 17
Acitetrin, the active metabolite of 18
etretinate, has a much shorter half-life than 19
etretinate. Thus, acitetrin poses a risk of 20
serious birth defects for a shorter period of time 21
than etretinate after a woman stops taking the drug 22
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product. 1
Hoffman-La Roche waived its opportunity for 2
a hearing. So we had evidence that the agency had 3
specifically looked at this and determined that 4
this particular product was withdrawn for safety 5
reasons. 6
DR. DiGIOVANNA: So it poses no safety risk 7
to a male, and it poses a safety risk to a small 8
percentage of the population certainly. But 9
putting it on a list for withdrawing its ability to 10
be compounded seems to be taking any safety risk 11
and applying it to the whole group of people 12
who -- or to the few people that may find it of 13
benefit. 14
MS. AXELRAD: I guess I have to address this 15
philosophically, that for these drugs where we've 16
made a decision that the drug should be withdrawn 17
or removed from the market for safety reasons, we 18
have said that the manufacturer -- either the 19
manufacturer has agreed to or the manufacturer 20
shouldn't be marketing the product. 21
So I guess the question is whether it's 22
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appropriate for a compounder to be able to market 1
the product instead. I mean, basically what we're 2
talking about is we would allow a compounder to 3
make something that a determination has been made 4
should not be marketed by the manufacturer, and I 5
guess we would have some concerns about that. 6
DR. BRAUNSTEIN: And industry would have 7
very grave concerns about a backdoor process where 8
the manufacturer is not able to manufacturer and 9
sell a product, but somehow a compounding pharmacy 10
could, in fact, do the same thing. 11
DR. VENITZ: Any other comments? Dr. Hoag? 12
DR. HOAG: Just in general, on this list, it 13
seemed like number 1 and number 24 were the same 14
thing chemically speaking, or am I missing things? 15
I could be mistaken. The Trovan. 16
DR. VENITZ: I think number 1 is a prodrug 17
of number 23. 18
DR. HOAG: Pardon me? 19
DR. VENITZ: I think number 1 is a prodrug 20
for number 23. So chemically they are different, 21
but the active moiety is the same. 22
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MS. AXELRAD: Dr. Venitz, we have somebody 1
who can speak to that. 2
DR. VENITZ: Good. Go ahead. 3
DR. TOERNER: Hi. My name is Joe Toerner. 4
I'm the deputy director for safety in the Division 5
of Anti-Infective Products. And that comment was 6
exactly correct. One is a prodrug. So the 7
intravenous formulation is different than the oral 8
formulation, but they're both metabolized through 9
the same active moiety. 10
So you could consider them to be the same 11
drug, but just technically they are very different. 12
The intravenous formulation is different than the 13
oral formulation. And both were marketed as having 14
the same trade name, which is Trovan. 15
DR. VENITZ: Thank you. Dr. Davidson, you 16
had a question. 17
MS. DAVIDSON: Just a general question. 18
When reviewing the list of drugs to go on the 19
withdrawn or removed list, there were two that 20
seemed to be missing, to me. I'm from the 21
veterinary world. That would be bromides and 22
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phenylbutazone, which are known to be quite toxic 1
to humans and were withdrawn over the years for 2
safety reasons. 3
The reason I ask is -- and I know those two 4
drugs are not within the context of this 5
conversation and this vote. But the reason I ask 6
is that this list has been used over the last 7
several years by CVM to consider which drugs should 8
not be compounded for food producing animals. 9
So I'm wondering. Is this an ongoing 10
process where candidates will be added to this list 11
over time? 12
MS. AXELRAD: Yes. As I said, this is 13
definitely a continuing process. And if there are 14
drugs that you know of that you think were 15
withdrawn from the market for human use that should 16
be considered for this, we'd like to hear about 17
those. 18
Our system for doing this is not -- it's 19
sort of trolling, trying to figure out what has 20
been done, and particularly in this case where we 21
had to go back over many years in order to figure 22
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it out. 1
When we did the list the first time, it was 2
a big effort to try and pull from documentation and 3
people's memories and things like that. And then 4
over the last 10, 15 years, we did the same thing. 5
But we're working on a process for identifying them 6
sort of as they come up and keeping it current. 7
But if you have drugs that you think we 8
might have missed, we'd be happy to hear about 9
that. We have a few that we're considering now 10
that we'll present at a future meeting, and, again, 11
we're working on a process to identify these in a 12
more real-time way and then talk about them. 13
It might be easier, also, to discuss them at 14
the advisory committee when it's fresh in 15
everybody's minds about what the problem was and 16
what the data say rather than doing it from a paper 17
review. 18
DR. VENITZ: Thank you, Dr. Axelrad. 19
Dr. Vaida? 20
DR. VAIDA: Allen Vaida. Just overall, I 21
had a question on -- some of these are all drug 22
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products, but then some are -- like except 1
ophthalmic or with the esmolol 250 mg. So am I 2
assuming when we vote on this, and that means 3
compounders can make ophthalmic and they could 4
compound esmolol at 200 milligrams per ml? 5
MS. AXELRAD: Yes. What we've tried to do 6
is to be accurate in terms of basically what we 7
know about it. And if there is another use, like 8
the IV chloramphenicol we know is on the market, we 9
are limiting the entry to the oral formulation. 10
There are a few other cases where the safety 11
finding was at a certain dosage form or a strength, 12
and we're trying to characterize that as best we 13
can and capture that. And if it doesn't fit that 14
specific entry that was withdrawn, then it could be 15
compounded. 16
DR. VAIDA: And there is no limit on -- like 17
if you're going to do an ophthalmic, that has to be 18
less than .2 percent. I didn't see anything on 19
here and I know that -- I'm just trying to get an 20
understanding. 21
MS. AXELRAD: Are you talking about a 22
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particular drug? 1
DR. VAIDA: Yes. Like if it was the 2
gatifloxacin or -- I mean, one of them, you're 3
excluding an ophthalmic, and that just means you 4
could compound any strength of ophthalmic, is 5
basically what this is -- just trying to get a feel 6
for what we're voting on. 7
MS. AXELRAD: There are other provisions 8
that I mentioned. The reason I mention them is you 9
can't make what is essentially a copy of a 10
commercially available product regularly or in 11
inordinate amounts. So there are other conditions 12
that apply in terms of copying a commercially 13
available product. 14
But if there is a need to do an ophthalmic 15
formulation that's more diluted or something else 16
and it would make a clinical difference for the 17
patient, then this would not preclude that. 18
DR. VAIDA: Okay. Thank you. And I just 19
have one comment that I feel I should make. It's 20
that in my line of work, the majority of serious 21
events we get in, especially dealing with poison 22
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centers, are with systemic absorption of topical 1
drugs. 2
I know we had a lot of discussion about 3
that. That's a big concern of mine. I mean, these 4
topical drugs, depending on the concentration, are 5
absorbed. Thanks. 6
DR. VENITZ: Dr. Wall? 7
DR. WALL: A quick question about the 8
half-lifely, because all of us have used these 9
various components of the Halflytely quite safely. 10
Is this removal just for this one combination of 11
those two things together in that formulation? 12
DR. KORVICK: Hi. I'm Dr. Korvick. I'm the 13
deputy director for safety in the Division of 14
Gastroenterology and Inborn Errors Products. And 15
you are right. This was a product-specific 16
association because of the combination use and this 17
one-package product. So it was really specific 18
toward the combination co-packaging of a bowel 19
preparation and the PEG and electrolyte solution 20
with the oral bisacodyl capsules. 21
So this is relating to that particular 22
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co-packaged product, and the adverse event was 1
ischemic colitis. 2
DR. VENITZ: Thank you. Any other comments, 3
questions? Yes, Dr. Hoag? 4
DR. HOAG: I have one question about the 5
oxycodone. How come it's specific to oxycodone? 6
Why not hydromorphone? I assume that it excludes 7
immediate release products. 8
DR. VENITZ: Go ahead. 9
DR. RACOOSIN: Judy Racoosin. I'm the 10
deputy director for safety in the Division of 11
Anesthesia, Analgesia, and Addiction Products. 12
We're talking here specifically about the 13
original formulation of OxyContin, which is an 14
extended-release oxycodone that does not have abuse 15
deterrent properties. So when the OxyContin was 16
reformulated into an abuse-deterrent formulation, 17
the agency determined that the original formulation 18
of OxyContin was withdrawn for reasons of safety 19
because it was shown to be more abusable via the IV 20
and nasal routes than the reformulated OxyContin. 21
So here we're talking specifically about the 22
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original formulation of OxyContin, not about other 1
oxycodone formulations. 2
DR. HOAG: So what you're saying is that a 3
practicing pharmacist -- or a compounding 4
pharmacist, excuse me, could compound sustained 5
release oxycodone products as long as they don't 6
have an abuse deterrent claim in them? I was a 7
little confused by the wording here. 8
DR. RACOOSIN: Right. Do you want to answer 9
that? 10
MS. AXELRAD: I think the answer is that 11
they -- unless they have an extended-release drug 12
product containing oxycodone hydrochloride that has 13
somehow been determined by the FDA to have abuse 14
deterrent properties, then they could not compound 15
an extended-release version of that. 16
DR. RACOOSIN: Right. So the product, the 17
reformulated product was reformulated with specific 18
properties, physiochemical properties and 19
excipients to create an abuse-deterrent formulation 20
that has been shown in a series of trials to be 21
less abusable than the original formulation. And 22
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the agency has made the determination that this new 1
formulation can be labeled as an abuse deterrent 2
formulation. 3
So presumably, a compounded version would 4
have to have the same degree of or the same types 5
of excipients and formulation to deter abuse in the 6
same way that the branded reformulated OxyContin 7
does. 8
DR. HOAG: Because that could be a little 9
bit tricky. For example, they could mix naloxone 10
versus -- there are different ways of doing 11
abuse-deterrent formulations. But maybe a general 12
comment is actually I don't think pharmacists 13
should be compounding extended-release opioid 14
products as a general rule. 15
DR. RACOOSIN: Do you want to answer that, 16
Jane? I think we would agree with that. 17
MS. AXELRAD: Yes. I don't think we need to 18
agree or disagree, but anyway, we're happy to hear 19
that view. And we did say in the proposed rule 20
that we would look very carefully at anybody who is 21
compounding something that they were claiming to be 22
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abuse resistant, because basically we feel that 1
determination is best made through the approval 2
process. Even manufacturers have a hard time 3
getting through with that kind of a claim. 4
MR. DeCHRISTOFORO: Bob DeChristoforo. Why 5
wouldn't that fall under the rule that there's 6
something commercially available anyway? In other 7
words, not do it because there is a commercial 8
product. 9
MS. AXELRAD: They would have to determine 10
that it's essentially a copy of a commercially 11
available product, and then they would not be 12
allowed to do it regularly or in inordinate amounts 13
under 503A. 14
MS. JUNGMAN: As I understand the way that 15
this question 27 is formulated, it would have to be 16
FDA that makes the determination that the 17
compounded product has abuse-deterrent properties 18
for it to be compounded, correct? It wouldn't be a 19
matter of the pharmacist on its own could decide. 20
MS. AXELRAD: Right. Only FDA could decide 21
that it did. 22
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DR. VENITZ: Okay. Any last questions 1
before we proceed with the official votes? 2
Dr. Jungman? 3
MS. JUNGMAN: One more. I'm thinking about 4
how to handle the comments that have been made 5
about the dermatological products, because I think 6
what we're faced with here is an up or down vote 7
that doesn't have those sorts of distinctions. 8
So as a procedural matter, it weighs on me 9
that this list has been out there for a little 10
while. There's been a public comment period, and 11
we haven't seen people writing in with evidence 12
that these particular products are not systemically 13
absorbed and kind of making the case for topical 14
use. 15
If that were to happen subsequent to the 16
vote, is there then an opportunity to modify the 17
list to, for example, exclude topical products? 18
MS. AXELRAD: Yes. After the list -- once 19
we put out the final rule and put the products on 20
the list, that we have determined belong on the 21
list, people can submit a citizen's petition and 22
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ask us to modify the list, to adjust the entry, 1
that there is some topical use or something like 2
that. And we would want to look and see what data 3
there was to suggest that it was different than the 4
systemically absorbed oral or IV formulation. 5
DR. VENITZ: Thank you. Any final 6
questions? 7
(No response.) 8
DR. VENITZ: Okay. Then let me read to you 9
what we're going to do. 10
The panel will be using an electronic voting 11
system for this meeting. Each voting member has 12
three voting buttons on your microphone: yes, no 13
and abstain. Please vote by pressing your 14
selection firmly three times. After everyone has 15
voted, the vote will be complete. 16
Voting will encompass 27 drug products. It 17
is our intention to move swiftly through the vote 18
on questions posed about these products, all but 19
two of which relate to whether these products 20
should be included on the withdrawn or removed 21
list. 22
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To accomplish this, we will refrain from 1
going around the table to have members speak their 2
names and how they voted into the record. Instead, 3
we will move from question to question until voting 4
is complete. 5
We hope to hear any views you have regarding 6
inclusion of particular substances on the list 7
during the discussion period before the vote, which 8
we just completed. 9
At any time, should an FDA official need to 10
hear from members about why they voted a certain 11
way, we will take the time necessary. 12
Again, for this session, we will not read 13
the vote from the screen into the record, as is 14
typical for FDA advisory committee meetings. 15
Instead, we will immediately display a screen 16
detailing the vote from each member. 17
I will summarize the results into the 18
record, and we will immediately move to the next 19
question. We will not go around the table to hear 20
individual comments unless requested by FDA 21
officials. 22
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So any final comments before we proceed? 1
(No response.) 2
DR. VENITZ: Thank you. Then let's vote on 3
question number 1. 4
FDA is proposing that alatrofloxacin 5
mesylate, all products containing alatrofloxacin 6
mesylate be added to the withdrawn or removed list. 7
Do you agree? Please press yes, no, or 8
abstain. 9
(Voting.) 10
DR. VENITZ: All right. So for the record, 11
we have unanimous yes votes. 12
Question number 2. FDA is proposing that 13
aminopyrine, all drug products containing 14
aminopyrine be added to the withdrawn or removed 15
list. 16
Do you agree? Please press yes, no, or 17
abstain. 18
(Voting.) 19
DR. VENITZ: So for the record, we have a 20
12-0, unanimous vote for yes, as well. 21
Question number 3. FDA is proposing that 22
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astemizole, all drug products containing astemizole 1
be added to the withdrawn or removed list. Do you 2
agree? Yes, no, or abstain? 3
(Voting.) 4
DR. VENITZ: For the record, we have a 5
unanimous 12-0 vote in favor. 6
Question number 4. FDA is proposing that 7
the current listing of bromfenac sodium, all drug 8
products containing bromfenac sodium on the 9
withdrawn or removed list be modified to bromfenac 10
sodium, all drug products containing bromfenac 11
sodium, except ophthalmic solutions. 12
Do you agree? Please press yes, no, or 13
abstain. 14
(Voting.) 15
DR. VENITZ: Another unanimous 12-0 vote in 16
favor. 17
Now, at question number 5, we have one 18
recusal. Dr. Hoag is recused from voting here. 19
So question number 5. FDA is proposing that 20
cerivastatin sodium, all products containing 21
cerivastatin sodium be added to the withdrawn or 22
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removed list. 1
Do you agree? Yes, no, or abstain? 2
(Voting.) 3
DR. VENITZ: We have a unanimous vote, 11-0, 4
in favor. 5
Question number 6. FDA is proposing that 6
cisapride, all drug products containing cisapride 7
be added to the withdrawn or removed list. 8
Do you agree? Yes, no, or abstain? 9
(Voting.) 10
DR. VENITZ: Another 12-0 unanimous vote in 11
favor of question number 6. 12
Question number 7. FDA is proposing that 13
esmolol hydrochloride, all parenteral drug products 14
containing esmolol hydrochloride that supply 15
250 milligrams per milliliter of concentrated 16
esmolol per 10 milliliter ampule be added to the 17
withdrawn or removed list. 18
Do you agree? Yes, no, or abstain? 19
(Voting.) 20
DR. VENITZ: Another unanimous 12-0 vote. 21
Question number 8. FDA is proposing that 22
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etretinate, all drug products containing etretinate 1
be added to the withdrawn or removed list. 2
Do you agree? Yes, no, or abstain? 3
(Voting.) 4
DR. VENITZ: We have not a unanimous vote. 5
We have 11 in favor, 1 against. 6
Question number 9. FDA is proposing that 7
gatifloxacin, all drug products containing 8
gatifloxacin except ophthalmic solutions be added 9
to the withdrawn or removed list. 10
Do you agree? Yes, no, or abstain? 11
(Voting.) 12
DR. VENITZ: Question number 9, we have a 13
unanimous 12-0 vote in favor. 14
Question number 10. FDA is proposing that 15
grepafloxacin, all drug products containing 16
grepafloxacin be added to the withdrawn or removed 17
list. 18
Do you agree? Yes, no, or abstain? 19
(Voting.) 20
DR. VENITZ: We have a unanimous vote, 12-0 21
in favor. 22
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Question number 11. We have a recusal. 1
Dr. Hoag is recused. For the rest of us, FDA is 2
proposing that methoxyflurane, all drug products 3
containing methoxyflurane be added to the withdrawn 4
or removed list. 5
Do you agree? Yes, no, or abstain? 6
(Voting.) 7
DR. VENITZ: We have an 11-0 unanimous vote. 8
Question number 12. FDA is proposing that 9
novobiocin sodium, all drug products containing 10
novobiocin sodium be added to the withdrawn or 11
removed list. 12
Do you agree? 13
(Voting.) 14
DR. VENITZ: We have another unanimous 12-0 15
vote in favor. 16
Question number 13. FDA is proposing that 17
pemoline, all drug products containing pemoline be 18
added to the withdrawn or removed list. 19
Do you agree? Yes, no, or abstain? 20
(Voting.) 21
DR. VENITZ: Almost halfway through, another 22
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unanimous 12-0 vote. 1
Question number 14. We have a recusal. 2
Dr. Hoag is recused. The rest of us, FDA is 3
proposing that pergolide mesylate, all drug 4
products containing pergolide mesylate be added to 5
the withdrawn or removed list. 6
Do you agree? Yes, no, or abstain? 7
(Voting.) 8
DR. VENITZ: We have a unanimous 11-0 vote 9
in favor. 10
Question 16. FDA is proposing that -- I'm 11
sorry. I am skipping question 15. We are back to 12
question 15. 13
Phenylpropanolamine, all drug products 14
containing PPA be added to the withdrawn or removed 15
list. 16
Do you agree? Question 15. 17
(Voting.) 18
DR. VENITZ: We have a unanimous 12-0 in 19
favor. 20
Question 16. FDA is proposing that 21
polyethylene glycol sodium chloride, sodium 22
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bicarbonate, potassium chloride, and bisacodyl, all 1
drug products containing PEG-3350, sodium chloride, 2
sodium bicarbonate and potassium chloride for oral 3
solution and 10 milligrams or more of bisacodyl 4
delayed release tablet be added to the withdrawn or 5
removed list. 6
Do you agree? Yes, no, or abstain? 7
(Voting.) 8
DR. VENITZ: Unanimous 12-0 in favor. 9
Question 17. FDA is proposing that 10
propoxyphene, all drug products containing 11
propoxyphene be added to the withdrawn or removed 12
list. 13
Do you agree? Yes, no, or abstain? 14
(Voting.) 15
DR. VENITZ: We have another unanimous 12-0 16
vote in favor. 17
Question 18. FDA is proposing that 18
rapacuronium bromide, all drug products containing 19
rapacuronium bromide be added to the withdrawn or 20
removed list. 21
Do you agree? Yes, no, or abstain? 22
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(Voting.) 1
DR. VENITZ: Unanimous 12-0 in favor. 2
Question 19. FDA is proposing that 3
rofecoxib, all drug products containing rofecoxib 4
be added to the withdrawn or removed list. 5
Do you agree? Yes, no, or abstain? 6
(Voting.) 7
DR. VENITZ: Unanimous vote, 12-0 in favor. 8
Question 20. FDA is proposing that 9
sibutramine hydrochloride, all drug products 10
containing sibutramine hydrochloride be added to 11
the withdrawn or removed list. 12
Yes, no, or abstain? 13
(Voting.) 14
DR. VENITZ: Unanimous 12-0 in favor. 15
Question 21. FDA is proposing that 16
tegaserod maleate, all drug products containing 17
tegaserod maleate be added to the withdrawn or 18
removed list. 19
Do you agree? Yes, no, or abstain? 20
(Voting.) 21
DR. VENITZ: We have a unanimous 12-0 vote 22
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in favor. 1
Question 22. FDA is proposing that 2
troglitazone, all drug products containing 3
troglitazone be added to the withdrawn or removed 4
list. 5
Do you agree? Yes, no, or abstain? 6
(Voting.) 7
DR. VENITZ: We have a unanimous 12-0 vote 8
in favor. 9
Question 23. FDA is proposing that 10
trovafloxacin mesylate, all drug products 11
containing trovafloxacin mesylate be added to the 12
withdrawn or removed list. 13
Do you agree? Yes, no, or abstain? 14
(Voting.) 15
DR. VENITZ: Question 24 [sic], we've got a 16
unanimous 12-0 vote in favor. 17
Question 24. FDA is proposing that 18
valdecoxib, all drug products containing valdecoxib 19
be added to the withdrawn or removed list. 20
Do you agree? Yes, no, or abstain? 21
(Voting.) 22
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DR. VENITZ: Unanimous 12-0 in favor. 1
Now we've got the two problem children 2
coming up. 3
FDA is now proposing that the current entry 4
of adenosine phosphate, all drug products 5
containing adenosine phosphate on the list of drug 6
products that have been withdrawn or removed from 7
the market because such drug products or components 8
of such drug products have been found to be unsafe 9
or not effective, codified at 21 CFR 2016.24, be 10
updated to state all drug products containing 11
adenosine 5-prime monophosphate, adenosine 5-prime 12
diphosphate, and adenosine 5-prime triphosphate. 13
Do you agree? Yes, no, or abstain? 14
(Voting.) 15
DR. VENITZ: We have a 12-0 unanimous vote. 16
Question 26. We have a recusal. 17
Dr. DeChristoforo is recused. For the rest of us, 18
FDA is proposing that chloramphenicol, all oral 19
drug products containing chloramphenicol be added 20
to the withdrawn or removed list. 21
Do you agree? Yes, no or abstain? 22
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(Voting.) 1
DR. VENITZ: We have a split vote, 9 in 2
favor, 2 opposed. 3
Then question number 27. We have a recusal, 4
yours truly. I'm recused. So you all have to vote 5
on my behalf. 6
FDA is proposing that -- I will refrain from 7
stating the question. Dr. Vaida, please? 8
DR. VAIDA: Question number 27. We have one 9
recusal. 10
FDA is proposing that oxycodone 11
hydrochloride, all extended-release drug products 12
containing oxycodone hydrochloride that have not 13
been determined by FDA to have abuse-deterrent 14
properties be added to the withdrawn or removal 15
list. 16
Do you agree? 17
(Voting.) 18
DR. VAIDA: We have a unanimous decision. 19
Thank you. 20
DR. VENITZ: Thank you very much. Thank 21
you, Dr. Vaida, for taking over. And thank you all 22
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for doing your voting duties. You voted 27 times. 1
That's a lot. 2
I appreciate it. I think we are a little 3
bit ahead of time, and I think I'm able to use the 4
chair's discretion and start our break early. I'm 5
looking at Jane. 6
MS. AXELRAD: It's fine with me. I guess we 7
have to stick to the way we have it set up, right? 8
We can't move. 9
DR. VENITZ: We would get a longer break. 10
MS. AXELRAD: Yes. We'd just get a longer 11
break. We can't move something up. 12
Adjournment 13
DR. VENITZ: Unless there are pressing 14
issues that somebody wants to bring up. Remember, 15
you are between your committee members and lunch. 16
So I have to do the formal reading. 17
We will now break for lunch. We will 18
reconvene again in this room in an hour and a half 19
from now, or an hour and 45 minutes almost, at 20
1:15 p.m. Please take any personal belongings you 21
may want with you at this time. The ballroom will 22
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be secured by FDA staff during the lunch break. 1
Panel members, please remember that there 2
should be no discussion of the meeting during lunch 3
amongst yourselves or with any member of the 4
audience. 5
Thank you and enjoy lunch. 6
(Whereupon, at 11:34 a.m., the morning 7
session was adjourned.) 8
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