AMP - FDA Warning Sent Out April 2015

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FOOD AND DRUG ADMINISTRATION1
CENTER FOR DRUG EVALUATION AND RESEARCH2
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PHARMACY COMPOUNDING ADVISORY COMMITTEE6
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8
Morning Session9
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Monday, February 23, 201512
8:28 a.m. to 11:34 a.m.13
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FDA White Oak Campus18
Building 31, The Great Room19
White Oak Conference Center20
Silver Spring, Maryland21
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Meeting Roster1
DESIGNATED FEDERAL OFFICER (Non-Voting)2
Jayne Peterson, BSPharm, JD3
Division of Advisory Committee and Consultant4
Management5
Office of Executive Programs6
Center for Drug Evaluation and Research7
8
PHARMACY COMPOUNDING ADVISORY COMMITTEE MEMBERS9
(Voting)10
Michael A. Carome, MD, FASHP11
Consumer Representative12
Director of Health Research Group13
Public Citizen14
Washington, District of Columbia15
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Gigi S. Davison, BSPh, DICVP1
U.S. Pharmacopeial Convention2
(USP) Representative- February 23rd only3
Director of Clinical Pharmacy Services4
North Carolina State University5
College of Veterinary Medicine6
Raleigh, North Carolina7
8
Robert DeChristoforo, MS, FASHP9
Chief of Clinical Center Pharmacy Department10
National Institutes of Health11
Bethesda, Maryland12
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John J. DiGiovanna, MD14
Staff Clinician, DNA Repair Section15
Dermatology Branch, Center for Cancer Research16
National Cancer Institute17
National Institutes of Health18
Bethesda, Maryland19
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Padma Gulur, MD1
Professor, Department of Anesthesiology and2
Perioperative Care3
University of California, Irvine4
Orange, California5
6
William A. Humphrey, BSPharm, MBA, MS7
Director of Pharmacy Operations8
St. Jude’s Children’s Research Hospital9
Memphis, Tennessee10
11
Elizabeth Jungman, JD12
Director, Public Health Programs13
The Pew Charitable Trusts14
16
Katherine Pham, PharmD17
Neonatal Intensive Care Unit Pharmacy Specialist18
Children’s National Medical Center19
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Allen J. Vaida, BSc, PharmD, FASHP1
Executive Vice President2
Institute for Safe Medication Practices3
Horsham, Pennsylvania4
5
Jürgen Venitz, MD, PhD6
Chairperson7
Associate Professor8
Department of Pharmaceutics9
School of Pharmacy10
Virginia Commonwealth University11
Richmond, Virginia12
13
Stephen W. Hoag, PhD14
Professor15
Department of Pharmaceutical Science16
University of Maryland, Baltimore17
Baltimore, Maryland18
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PHARMACY COMPOUNDING ADVISORY COMMITTEE MEMBERS1
(Voting) cont.2
Donna Wall, PharmD3
National Association of Boards of Pharmacy4
(NABP) Representative5
Clinical Pharmacist6
Indiana University Hospital7
Indianapolis, Indiana8
9
PHARMACY COMPOUNDING ADVISORY COMMITTEE INDUSTRY10
REPRESENTATIVE MEMBERS (Non-Voting)11
Ned S. Braunstein, MD12
Senior Vice President and Head of Regulatory13
Affairs14
Regeneron Pharmaceuticals, Inc.15
Tarrytown, New York16
17
William Mixon, RPh, MS, FIACP18
Owner-Manager19
The Compounding Pharmacy20
Hickory, North Carolina21
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TEMPORARY MEMBERS (Voting)1
Jeanne Sun, PharmD2
USP Representative3
February 24th only4
Associate Scientific Liaison, Compounding5
U.S. Pharmacopeial Convention6
Rockville, Maryland7
8
FDA PARTICIPANTS (Non-Voting)9
Jane Axelrad, JD10
Associate Director for Policy, CDER and11
Agency Lead on Compounding, FDA12
13
Frances Gail Bormel, Rph, JD14
Director (acting), Division of Prescription Drugs15
Office of Unapproved Drugs and Labeling16
Compliance, Office of Compliance, CDER, FDA17
18
Olivia Ziolkowski, JD, MPH19
Regulatory Counsel20
ORP, CDER, FDA21
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Mwango A. Kashoki, MD, MPH1
Associate Director for Safety2
Office of New Drugs (OND)3
Immediate Office, CDER, FDA4
5
Nancy Xu, MD6
Medical Officer, Division of Cardiosvascular and7
Renal Products, Office of Drug Evaluation8
(ODE) I, OND, CDER, FDA9
10
Dmitri Iarikov, MD, PhD11
Clinical Team Leader (acting)12
Division of Anti-Infective Products13
Office of Antimicrobial Products (OAP)14
OND, CDER, FDA15
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C O N T E N T S1
AGENDA ITEM PAGE2
Call to Order and Introduction of Committee3
Jurgen Venitz, MD, PhD 114
Conflict of Interest Statement5
Jayne Peterson, BS Pharm, JD 176
FDA Introductory Remarks and Overview of7
Withdrawn and Removed List8
Jane Axelrad, JD 249
Clarifying Questions from the Committee 4210
FDA Presentations11
Identification of Drugs Withdrawn or Removed12
from the Market for Safety Reasons13
Mwango Kashoki, MD, MPH 4614
Adenosine Phosphate16
Nancy Xu, MD 6217
Chloramphenicol19
Dmitri Iarikov, MD, PhD 7120
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C O N T E N T S (continued)1
AGENDA ITEM PAGE2
Open Public Hearing 903
Committee Discussion and Vote on4
Withdrawn or Removed List 935
Adjournment 1576
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P R O C E E D I N G S1
(8:28 a.m.)2
Call to Order3
Introduction of Committee4
DR. VENITZ: Good morning again. My name is5
Jurgen Venitz. I am the Chair of the Pharmacy6
Compounding Advisory Committee, otherwise referred7
to as PCAC. I will now call the committee to8
order.9
We will now ask those at the table,10
including FDA staff and committee members, to11
introduce themselves, starting with the FDA to my12
left and moving along to the industry13
representative, Mr. Ned Braunstein. So let's start14
to the left, please.15
DR. IARIKOV: Dmitri Iarikov, medical16
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 Cardiovascular19
and Renal Products, Office of New Drugs.20
MS. ZIOLKOWSKI: My name is Olivia21
Ziolkowski. I'm a regulatory counsel with the22

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Office of Regulatory Policy.1
MS. AXELRAD: Jane Axelrad. I'm the2
associate director for policy in the Center for3
Drug Evaluation and Research and the agency lead on4
compounding.5
MS. BORMEL: My name is Gail Bormel. I'm6
with the CDER Office of Compliance, Office of7
Unapproved Drugs and Labeling Compliance.8
MR. HUMPHREY: I'm William Humphrey. I'm9
the Director of Pharmacy Operations at St. Jude10
Children's Research Hospital in Memphis.11
DR. PHAM: My name is Kathy Pham. I am the12
NICU Clinical Pharmacy Specialist at Children's13
National Medical Center.14
DR. WALL: My name is Donna Wall. I'm a15
clinical pharmacist at IU Hospital in Indianapolis,16
and I'm representing NABP.17
DR. VAIDA: Allen Vaida. I'm executive vice18
president at the Institute for Safe Medication19
Practices, and I'm a pharmacist.20
MS. PETERSON: Good morning. I'm Jayne21
Peterson. I'm the designated federal officer for22

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the Pharmacy Compounding Advisory Committee.1
DR. VENITZ: I'm Jurgen Venitz. I'm a2
clinical pharmacologist and professor at the VCU3
School of Pharmacy.4
DR. DiGIOVANNA: I'm John DiGiovanna. I'm a5
dermatologist at the National Cancer Institute at6
NIH.7
DR. GULUR: I'm Padma Gulur. I'm a8
professor in the Department of Anesthesiology and9
Perioperative Care at the University of California,10
Irvine.11
DR. HOAG: I'm Steve Hoag, a professor at12
the University of Maryland School of Pharmacy, in13
the Department of Pharmaceutical Sciences.14
MS. JUNGMAN: I'm Elizabeth Jungman. I15
direct public health programs at the Pew Charitable16
Trusts.17
MR. DeCHRISTOFORO: Good morning. My name18
is Bob DeChristoforo, and I have a disclaimer to19
read.20
I am chief of the Clinical Center Pharmacy21
Department at the NIH. I would like to disclose22

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that as part of my federal duties in 2014, I1
reviewed and provided input into NIH's comments2
that were submitted to FDA regarding FDA's proposed3
list of drug products that may not be compounded4
because the drug products have been withdrawn or5
removed from the market. These comments were6
specific to chloramphenicol.7
I will be participating fully in the8
deliberations of this meeting, but will not be9
voting, but I will vote on other voting questions.10
MS. DAVIDSON: I'm Gigi Davidson. I'm the11
director of the pharmacy at North Carolina State12
University College of Veterinary Medicine. I'm13
currently the chair of the USP Compounding Expert14
Committee, and I'm representing USP.15
DR. CAROME: Good morning. My name is Mike16
Carome. I'm director of Public Citizens' Health17
Research Group, and I'm the consumer representative18
on the committee.19
MR. MIXON: Good morning. Bill Mixon. I20
own the compounding pharmacy in Hickory, North21
Carolina. I'm also on the North Carolina Board of22

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Pharmacy and am a member of the USP Expert1
Committee for Compounding.2
DR. BRAUNSTEIN: Good morning. I'm Ned3
Braunstein. I'm senior vice president for4
regulatory affairs of Regeneron Pharmaceuticals.5
I'm the industry representative. I'm also a6
physician.7
DR. VENITZ: Thank you very much, and8
welcome to the inaugural meeting of the9
Pharmaceutical Compounding Advisory Committee. Let10
me read a few remarks for the record.11
For topics such as those being discussed at12
today's meeting, there is often a variety of13
opinions, some of which are quite strongly held.14
Our goal is that today's meeting will be a fair and15
open forum for discussion of these issues and that16
individuals can express their views without17
interruption. Thus, as a gentle reminder,18
individuals will be allowed to speak into the19
record only if recognized by the chair. We look20
forward to a productive meeting.21
In the spirit of the Federal Advisory22

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Committee Act and the Government in the Sunshine1
Act, we ask that the advisory committee members2
take care that their conversations about the topic3
at hand take place in the open forum of the4
meeting.5
We are aware that members of the media may6
be anxious to speak with the FDA about these7
proceedings. However, FDA will refrain from8
discussing the details of this meeting with the9
media until its conclusion.10
Also, the committee is reminded to please11
refrain from discussing the meeting topic during12
the breaks or over lunch.13
Over the next two days, we will cover two14
topics. On the morning of the first day, we will15
consider drug products proposed for inclusion on16
the list of drugs that have been withdrawn or17
removed from the market because they have been18
found to be unsafe or ineffective.19
During session 1, we will hear presentations20
from FDA, ask clarifying questions, hold an open21
public hearing, and then have committee discussion22

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and voting.1
This afternoon and continuing through2
tomorrow, we will hear presentations about the3
criteria for placing drug substances on the list of4
bulk drug substances that can be used in5
compounding under Section 503A and on six bulk6
substances nominated for inclusion on the list.7
We will hear FDA presentations, two at a8
time, ask clarifying questions, hear presentations9
from nominators, hold an open public hearing, and10
have a committee discussion and voting on each11
pair. Thus, we will have four open public hearings12
and hold four separate voting sessions.13
Let us begin. We will now have Ms. Jayne14
Peterson, to my left, read the Conflict of Interest15
Statement. Thank you.16
Ms. Peterson?17
Conflict of Interest Statement18
MS. PETERSON: Thank you.19
The Food and Drug Administration is20
convening today's meeting of the Pharmacy21
Compounding Advisory Committee under the authority22

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of the Federal Advisory Committee Act of 1972.1
With the exception of the National Association of2
Boards of Pharmacy, the United States Pharmacopeia,3
and the industry representatives, all members and4
temporary voting members of the committee are5
special government employees or regular federal6
employees from other agencies and are subject to7
the federal conflict of interest laws and8
regulations.9
The following information on the status of10
this committee's compliance with federal ethics and11
conflict of interests laws covered by, but not12
limited to, those found at 18 USC Section 208 is13
being provided to participants in today's meeting14
and to the public.15
FDA has determined that members and16
temporary voting members of this committee are in17
compliance with federal ethics and conflict of18
interest laws. Under 18 USC Section 208, Congress19
has authorized FDA to grant waivers to special20
government employees and regular government21
employees who have potential financial conflicts22

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when it is determined that the agency's need for a1
special government employee's services outweighs2
his or her potential financial conflict of3
interest, or when the interest of a regular federal4
employee is not so substantial as to be deemed5
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 this9
committee have been screened for potential10
financial conflicts of interest of their own, as11
well as those imputed to them, including those of12
their spouses or minor children and, for purposes13
of 18 USC Section 208, their employers. These14
interests may include investments, consulting,15
expert witness testimony, contracts, grants,16
CRADAs, teaching, speaking, writing, patents and17
royalties, and primary employment.18
During this morning's session, the committee19
will discuss proposed revisions to the list of drug20
products that may not be compounded under the21
exemptions provided by the Food, Drug and Cosmetic22

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Act because the drug products have been withdrawn1
or removed from the market, because such drug2
products or components of such drug products have3
been found to be unsafe or not effective.4
The list of products is currently codified5
at 21 CFR 216.24, and FDA is proposing to revise6
and update the list at Section 216.24 for purposes7
of both 503A and 503B of the Food, Drug and8
Cosmetic Act.9
On July 2, 2014, FDA published a proposed10
rule that would add 25 drug products to this list11
and modify the description of one drug product on12
this list to add an exception.13
FDA received two specific comments on the14
proposed rule. One comment requested that FDA15
clarify whether the entry for adenosine phosphate16
that is currently included on the list, which17
currently reads "all drug products containing18
adenosine phosphate," is intended to include all19
three forms of adenosine phosphate, the mono-, di-20
and triphosphate.21
The second comment requested that22

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chloramphenicol tablets 250 mgs be excluded from1
the list. FDA will discuss both of these comments2
with the committee.3
This is a particular matters meeting during4
which the specific matters related to the 275
products will be discussed. Based on the agenda6
for today's meeting and all financial interests7
reported by the committee members and temporary8
voting members, no conflict of interest waivers9
have been issued in connection with this meeting.10
Dr. Venitz has been recused from11
participating in the discussions and voting for12
oxycodone hydrochloride. Dr. Hoag has been recused13
from participating in discussions and voting for14
cerivastatin sodium, methoxyflurane, and pergolide15
mesylate.16
To ensure transparency, we encourage all17
standing committee members and temporary voting18
members to discuss any public comments that they19
have made concerning the products at issue.20
We would like to note that Dr. Donna Wall is21
a representative member from the National22

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Association of Boards of Pharmacy, and Ms. Gigi1
Davidson is a representative member from the United2
States Pharmacopeia.3
Section 102 of the Drug Quality and Security4
Act amended the Federal Food, Drug and Cosmetic Act5
with respect to the Advisory Committee on6
Compounding to include as standing members7
representatives from the NABP and the USP. Their8
role is to provide the committee with the points of9
view of NABP and USP.10
Unlike the other members of the committee,11
representative members are not appointed to the12
committee to provide their own individual judgment13
on the particular matters at issue. Instead, they14
serve as the voice of NABP and USP, entities with a15
financial or other stake in the particular matters16
before the advisory committee.17
With respect to FDA's invited industry18
representatives, we would like to disclose that19
Dr. Ned Braunstein and Mr. William Mixon are20
participating in this meeting as nonvoting industry21
reps acting on behalf of regulated industry. Their22

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role at this meeting is to represent industry in1
general and not any particular company.2
Dr. Braunstein is employed by Regeneron3
Pharmaceuticals and Dr. Mixon is the owner of The4
Compounding Pharmacy.5
We would like to remind members and6
temporary voting members that if the discussions7
involve any other products or firms not already on8
the agenda for which an FDA participant has a9
personal or imputed financial interest, the10
participants need to exclude themselves from such11
involvement and their exclusion will be noted for12
the record.13
FDA encourages all other participants to14
advise the committee of any financial relationships15
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 and19
an overview of the withdrawn and removed list from20
Dr. Jane Axelrad, the associate director for Policy21
in the Center for Drug Evaluation Research and the22

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agency lead on compounding.1
I would like to remind public observers at2
this meeting that while this meeting is open for3
public observation, public attendees may not4
participate except at the specific request of the5
panel. Thank you.6
FDA Introductory Remarks – Jane Axelrad7
MS. AXELRAD: Good morning. I'd like to8
welcome all of you to the first meeting of the9
newly configured Pharmacy Compounding Advisory10
Committee, and I'd like to thank all of the members11
for being willing to serve on the committee.12
As you know, the committee was originally13
established in 1998 after the passage of the Food14
and Drug Administration Modernization Act in 1997.15
That law added Section 503A to the Federal Food,16
Drug and Cosmetic Act. Section 503A contained17
provisions addressing compounding, pharmacy18
compounding, and called for the creation of an19
advisory committee on compounding.20
The committee was convened several times21
between October 1998 and July of 2000, but as a22

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result of litigation over the validity of1
Section 503A, the agency suspended its efforts to2
implement that section of the statute and published3
a notice terminating the committee in 2002.4
In April of 2012, FDA filed the charter5
reestablishing the committee. In November of 2013,6
the Drug Quality and Security Act removed from7
Section 503A the provisions that were found to be8
unconstitutional by the U.S. Supreme Court in 2002,9
removing uncertainty concerning the validity of10
Section 503A and creating a new Section 503B11
concerning outsourcing facilities.12
Section 503B also requires FDA to consult13
with an advisory committee on compounding before14
issuing one of the regulations implementing that15
section.16
We then amended the charter of the committee17
to reflect the relevant statutory changes and18
solicited nominations for members. It has been a19
long process, but at last we have arrived at this20
point, and we're ready to begin our work to address21
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 be2
compounded under the exemptions provided by3
Section 503A because they or their components have4
been found to be unsafe or not effective. The5
second list we'll be discussing today and tomorrow6
is a list of bulk drug substances that can be used7
to compound in accordance with Section 503A.8
But to set the stage, I'd like to briefly9
describe the overall framework in Section 503A and10
503B so that we can all understand where the lists11
that we're going to be discussing today and12
tomorrow fit into the overall regulation of13
compounding.14
Section 503A describes the conditions under15
which certain compounded human drug products are16
entitled to exemptions from three sections of the17
Act that require FDA approval prior to marketing,18
compliance with current good manufacturing practice19
requirements, and labeling with adequate directions20
for use.21
Pharmacies engaged in compounding that meet22

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the conditions in Section 503A necessary to qualify1
for the exemptions are primarily regulated by the2
states, although some federal requirements still3
apply. For example, these pharmacies can't4
compound drugs under insanitary conditions or5
they'll be found in violation of the adulteration6
provisions of Section 501A(2)(a) of the Act, from7
which 503A does not offer any exemptions.8
To qualify for the exemptions under9
Section 503A, a drug product must be compounded by10
a licensed pharmacist in a state-licensed pharmacy11
or federal facility or by a licensed physician.12
The drug product must be compounded for an13
identified individual patient based upon receipt of14
a valid prescription order for an identified15
individual patient.16
Drug products may be compounded in limited17
quantities before receipt of a prescription order18
if it is based on a history of prescription orders19
for the compounding of the drug product generated20
within an established relationship between the21
pharmacist or physician, and either the patient for22

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whom the prescription order will be provided, or1
the licensed practitioner who will write the2
prescription order.3
One of the conditions in Section 503A that4
must be met to qualify for the exemptions concerns5
bulk drug substances. Generally, we refer to those6
as the active ingredients in drug products that are7
used in compounding.8
Under Section 503A, bulk drug substances9
used in compounding must comply with the standards10
of an applicable USP or national formulary11
monograph, if there is one, and the USP chapters on12
pharmacy compounding; or be a component of an FDA13
approved drug product if an applicable monograph14
doesn't exist; or if a USP or national formulary15
monograph doesn't exist and the bulk drug substance16
is not a component of an FDA drug product, appear17
on a list of drug products that may be used for18
compounding developed by FDA through regulation.19
Later today and tomorrow, we'll be20
discussing some of the substances that have been21
nominated for inclusion on this list.22

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In addition to these conditions, another1
condition of Section 503A is that bulk drug2
substances must be manufactured by a facility that3
is registered with FDA under Section 510 of the4
Food, Drug and Cosmetic Act, and they have to be5
accompanied by valid certificates of analysis.6
Other ingredients in compounded drugs7
besides bulk drug substances, such as inactive8
ingredients, must also comply with USP or national9
formulary monographs if they exist for the10
ingredient and the USP chapters on pharmacy11
compounding.12
To qualify for the exemptions under13
Section 503A, a compounder cannot compound drug14
products that appear on an FDA list of drugs15
published in the Federal Register that have been16
withdrawn or removed from the market because they17
or their components have been found to be unsafe or18
not effective. We call this the withdrawn or19
removed list, and this is one of the lists we'll be20
discussing this morning. So this is another really21
important condition that's directly relevant to22

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what we're going to be talking about.1
Section 503A also states that to qualify for2
the exemptions, a compounder cannot compound a drug3
product that is identified by FDA by regulation as4
a drug product that presents demonstrable5
difficulties for compounding that reasonably6
demonstrate an adverse effect on the safety or7
effectiveness of that drug product.8
We haven't yet published regulations9
containing a list of drugs that are difficult to10
compound, and we will be seeking the advice of this11
advisory committee at a future meeting on what12
drugs should be placed on that list.13
Section 503A contains provisions that14
address copying of commercially available drug15
products. Under Section 503A, a compounder cannot16
compound regularly or in inordinate amounts what17
are essentially copies of commercially available18
drug products.19
Section 503A contains provisions that20
address certain distributions of compounded drugs.21
Under Section 503A, a compounder cannot distribute22

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or cause to be distributed compounded drug products1
out of the state in which they are compounded in2
excess of 5 percent of the total prescription3
orders dispensed or distributed by that pharmacy or4
physician, unless they are located in a state that5
has signed a memorandum of understanding that6
provides for appropriate investigation of7
complaints related to drugs distributed outside of8
the state and that addresses the distribution of9
inordinate amounts of compounded drug products10
interstate.11
So some of these things are not on the12
agenda today and some of them are, but I wanted to13
give you the overall framework so you can see how14
it all fits together.15
So that covers the conditions under which16
compounded drug products can qualify for the17
exemptions under 503A. As you know, after the18
fungal meningitis outbreak in 2012, Congress passed19
new legislation addressing the oversight of20
compounding.21
The Compounding Quality Act, which can be22

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found in Title I of the Drug Quality and Security1
Act, removes from Section 503A certain provisions2
that were found to be unconstitutional by the3
Supreme Court in 2002, as I already said.4
By removing the unconstitutional provisions,5
the new law removes uncertainty regarding the6
validity of Section 503A, which is applicable to7
compounders nationwide, which is why we're able to8
move forward today with implementing that section.9
The new legislation also contains a new10
Section 503B, which created a category of11
facilities called outsourcing facilities. Under12
Section 503B, compounders can register with FDA as13
outsourcing facilities, pay a fee, and compound14
drugs without prescriptions, but they are required15
to make them in compliance with current good16
manufacturing practice requirements and are subject17
to inspection by FDA according to a risk-based18
schedule.19
In addition, they have to meet certain20
conditions to be exempt from certain provisions of21
the Food, Drug and Cosmetic Act. And they can, if22

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they meet the conditions, be exempt from the new1
drug approval requirements and the requirement to2
label their products for adequate directions for3
use. But as I said, they have to follow current4
good manufacturing practices, which is different5
than a facility that is complying with the6
conditions under 503A.7
An entity that registers with FDA as an8
outsourcing facility must report upon initial9
registration and twice each year specific10
information about the products that it compounds.11
This includes filing a list of all drug products it12
compounded during the previous six months and13
information about those products, such as the14
source of the active ingredients used to compound15
them.16
In addition, the outsourcing facility has to17
report adverse events and label its products with18
certain information, including the fact that it's a19
compounded drug.20
Outsourcing facilities must comply with21
certain other conditions, as well, some of which22

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are the same or similar to the conditions necessary1
to qualify for the exemptions under 503A and some2
of which are different.3
Compounded drug products cannot qualify for4
the exemptions in 503B if they appear on an FDA5
list of drug products that have been withdrawn or6
removed from the market because the drug products7
or their components have been found to be unsafe or8
not effective or on an FDA list of drug products9
that present demonstrable difficulties for10
compounding.11
So I've already mentioned those lists with12
regard to 503A, and the withdrawn and removed lists13
that we'll be talking about this morning will be14
applicable to both compounding under 503A and under15
503B.16
Under Section 503B, outsourcing facilities17
cannot compound drugs that are essentially copies18
of FDA approved drugs. So they just can't compound19
them at all. Outsourcing facilities also cannot20
compound from a drug that is the subject of a risk21
evaluation and mitigation strategy, which we call a22

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REMS, with elements to assure safe use, or from a1
bulk drug substance that is a component of such2
drug unless the outsourcing facility demonstrates3
to FDA before beginning compounding that it will4
use controls comparable to controls under a REMS.5
Section 503B also contains conditions for6
bulk drug substances that can be used in7
compounding, some of which are different than those8
for bulk drug substances used by facilities seeking9
to qualify for the exemptions under 503A and some10
of which are the same.11
Under Section 503B, an outsourcing facility12
cannot compound from bulk drug substances unless13
the drug it is compounding either appears on the14
FDA drug shortage list or the bulk drug substance15
appears on a list that's going to be compiled by16
FDA identifying bulk drug substances for which17
there is a clinical need. FDA may be seeking the18
advice of this committee at future meetings on the19
drugs that should be placed on this 503B bulks20
list.21
Like the conditions for compounding under22

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Section 503A, bulk drug substances and other1
ingredients used to compound under Section 503B2
must apply with applicable USP or national3
formulary monographs, if they exist. The bulk drug4
substances used by outsourcing facilities have to5
be manufactured in facilities that have registered6
with FDA under Section 510, and they must be7
accompanied by a valid certificate of analysis.8
Under the statutory definition of an9
outsourcing facility, an outsourcing facility is10
defined as a facility engaged in the compounding of11
sterile drugs that has elected to register under12
503B as an outsourcing facility and that complies13
with all of the conditions in 503B.14
An outsourcing facility is not required to15
be a licensed pharmacy, but compounding must be by16
or under the direct supervision of a licensed17
pharmacist, and an outsourcing facility may or may18
not obtain prescriptions for identified individual19
patients.20
Under Section 503B, an outsourcing facility21
will not be considered registered unless and until22

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it has paid the annual establishment fee.1
Under the law, if a compounded drug does not2
meet the conditions for exemptions in 503B or 503A,3
it will be subject to all of the requirements4
applicable to drugs made by conventional drug5
manufacturers. For example, it would have to be6
subject to an approved new drug application and be7
made under current good manufacturing practice8
requirements. That's why the conditions that are9
laid out in 503A and 503B and the lists that we're10
going to be talking to you about today are so11
important.12
This completes my summary of Sections 503A13
and 503B and where the lists that we're going to be14
discussing today and tomorrow fit in. Next, I'm15
going to introduce with a little more detail the16
withdrawn and removed list.17
As I mentioned, FDA must develop a list of18
drugs that have been withdrawn or removed from the19
market because they or their components have been20
found to be unsafe or not effective. Drugs on this21
list can't be compounded under either Section 503A22

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or 503B.1
FDA began compiling this list as soon as2
Section 503A was enacted in 1997. To compile the3
list, FDA consulted with FDA review divisions and4
examined public documents, such as Federal Register5
notices, press releases, and safety announcements,6
to identify products that had been withdrawn or7
removed from the market for safety or efficacy8
reasons.9
Then we published as a proposed rule a list10
of these drugs on October 8, 1998. We proposed 6011
drugs for inclusion on the list at that time, and12
you have this document in your background package.13
The preamble to the proposed rule described14
the basis for including each of the products on the15
list. Right after the proposed rule was published,16
we then consulted with the newly created Pharmacy17
Compounding Advisory Committee about the drug18
products that we had proposed for inclusion on the19
list, and the committee did not suggest any20
changes. There was a bunch of discussion, but they21
did not suggest changes to what we were proposing.22

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So the final rule was published in March1
1999, and it is codified in FDA's regulations at2
216.24, and it remained on the books for the entire3
16 years since we did it.4
However, obviously, developing this list has5
to be a continuous process because we learn about6
new safety or efficacy problems with drugs over7
time as new drugs are approved, and then they come8
into use in the market.9
So sort of reading the tea leaves on moving10
forward with 503A, a few years ago, we began to11
compile a list of additional drugs that had been12
withdrawn or removed from the market since the13
original list was published, including five drugs14
that were considered by the Pharmacy Compounding15
Advisory Committee in 2000 and that were the16
subject of another rulemaking that was never17
actually completed because we suspended work under18
503A. Then, as I said, after the Drug Quality and19
Security Act was enacted, we determined that one20
list should be used for both sections.21
On July 2nd of 2014, we issued a proposed22

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rule to add 25 products to the list that was1
already codified in 216.24, and we also proposed to2
modify the description of one product on the list,3
to add an exception that would allow the product to4
be compounded in accordance with Sections 503A and5
503B under certain circumstances.6
Today we're going to be seeking your advice7
on the products proposed to be added to the list,8
as well as on an issue concerning one of the9
original listings, adenosine phosphate, which was10
raised by a comment in the July 2014 proposed rule.11
We'll be focusing our presentations today on12
adenosine phosphate and on chloramphenicol, a drug13
that we proposed for inclusion in the July 201414
proposed rule. We don't intend to make formal15
presentations about the other 24 drugs proposed for16
inclusion because we didn't get any comments on17
those in the comment period on the proposed rule.18
But you have all the supporting information that we19
used and relied on to make the determination about20
those drugs in your background package, and we are21
certainly prepared to have a discussion about that22

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and to take any questions that you might have1
before we ask you to vote on whether to include2
them on the list.3
So our next presenter is going to be4
Dr. Mwango Kashoki, the associate director for5
safety in the Office of New Drugs. And I thought6
it would be helpful to have Mwango explain what we7
go through in terms of making a decision on whether8
a drug has been removed from the market for safety9
or efficacy reasons.10
Our focus, all the drugs that we're talking11
about here really are for safety, and that was our12
focus in the original rule. Our focus on the drugs13
today are drugs that have been removed for safety14
reasons. So she is going to explain how we go15
about that, how we determine that there is a safety16
problem, and how we remove the drug from the market17
if we think that it's appropriate. We will then18
present our views, the FDA views, on adenosine19
phosphate and chloramphenicol and take clarifying20
questions.21
Thank you. I'm looking forward to a22

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productive and interesting two days here. Thanks.1
Clarifying Questions from the Committee2
DR. VENITZ: Thank you, Dr. Axelrad. We3
have a little time for clarifying questions in case4
anyone on the committee would like to ask5
Dr. Axelrad any. Please?6
DR. CAROME: Mike Carome, director of Public7
Citizen's Health Research Group. I have one8
question, and I wanted to make a disclosure9
statement.10
I would like to disclose Public Citizen11
submitted petitions, issued statements, and wrote12
letters to the FDA and testified at advisory13
committee meetings between 1998 and 2009 regarding14
11 of the drug products' active ingredients being15
discussed at this session. For eight of them, we16
petitioned to have the products removed from the17
market, and the other three we wrote letters and18
testified against having the products come to19
market or remain on the market.20
FDA is proposing to include these 11 drug21
products' active ingredients on the list of drug22

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products that may not be compounded because they1
have been removed from the market due to safety or2
efficacy concerns. The documents and testimony3
that Public Citizen provided requested a ban on the4
use or withdrawal from the market of these 11 drug5
products. And as of 2011, FDA has closed out all6
of our petitions regarding the eight drugs we7
petitioned on.8
For this session, I will be participating9
fully in the deliberations and voting on the10
questions posed to the committee.11
I just have a very brief question. If FDA12
has made a formal decision that a drug product was13
removed from the market because of concerns that14
the product was unsafe or ineffective, under the15
law, does the agency have discretion about whether16
to include that product on the withdrawn list?17
MS. AXELRAD: Well, we generally are trying18
to find all the drugs that have been withdrawn for19
safety reasons, and we are generally putting them20
on the list. I'm not sure we're looking at drugs21
and saying, "Oh, okay, we think this drug was22

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removed for safety reasons, but we're not going to1
put it on a list."2
So I don't know whether I would say whether3
we -- obviously, we have to make a judgment on4
whether it was or wasn't removed for safety5
reasons. But once we conclude that it was, I6
think, generally, we would be putting them on the7
list.8
If I saw one that we didn't think so, I'd9
have to sort of look at the question as to whether10
we have that discretion, but we haven't come across11
that yet.12
MR. DeCHRISTOFORO: As just an informational14
item, pharmacists that have been dealing with drug15
shortages every day, there is another drug shortage16
list by the American Society of Health System17
Pharmacists. And I've been told that sometimes the18
FDA does not necessarily put everything on the list19
because industry has asked them not to so there20
won't be a run on the drug.21
So I just want to bring that up. I'm not22

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arguing against that. But sometimes there's a drug1
shortage that's on the ASHP list that may not be on2
the FDA list.3
DR. DiGIOVANNA: You mentioned that the4
outsourcing facility is one engaged in the5
compounding of sterile drugs. Does that exclude6
topicals or are topicals considered sterile drugs?7
And if so, what are non-sterile drugs?8
MS. AXELRAD: Well, we recently, just very9
recently, Friday last week, issued a guidance that10
talks about this. And, as I said, the definition11
says that an outsourcing facility is engaged in the12
compounding of sterile drugs. That doesn't mean13
that that's the only thing they do, but it means14
that they have to be engaged in the compounding of15
at least one or more or two sterile drugs, since it16
has an S on the end, in order to qualify under the17
definition of outsourcing facility. But they might18
also be making non-sterile drugs, and many of them19
do.20
DR. VENITZ: Thank you, Dr. Axelrad.21
Just a reminder, committee members, when you22

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ask a question, please introduce yourself by name1
before you do that so we can capture that for the2
record.3
Let's now proceed with the next4
presentation. Dr. Kashoki, the Deputy Associate5
Director for Safety, Office of New Drugs, will6
discuss the process of identifying drugs to be7
removed.8
FDA Presentation – Mwango Kashoki9
DR. KASHOKI: Good morning. In my talk, I10
will provide an overview of how postmarket drug11
safety signals are identified and evaluated; how12
CDER reaches decisions about whether or not a drug13
should be withdrawn or removed because of the14
safety signal; and I will broadly describe how the15
current list of withdrawn or removed drugs was16
identified.17
The agency continually assesses or evaluates18
the safety of drug products, and CDER's ongoing19
commitment to rigorous and continued drug safety20
evaluation in the postmarket period is reflected in21
its Safety First initiative, which was launched in22

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2008 and which outlines CDER's updated policies and1
procedures to ensure that equal focus or equal2
attention is given to postmarket drug safety as is3
given during pre-market drug review.4
During drug development, FDA assesses the5
safety of a drug as it is being tested and reviews6
the data in marketing applications to ensure that7
the benefits of the drug outweigh its risks. And8
after approval, as a result of broader use of the9
drug, additional information can emerge about10
adverse drug experiences while patients are being11
treated. And so FDA will evaluate the information12
to assess the relationship of those adverse events13
or those adverse experiences to the drug.14
This is a general schematic of the15
postmarket drug safety review process. It starts16
when a safety issue is identified and proceeds with17
a preliminary assessment of the issue and planning18
for the review process.19
A comprehensive review from a20
multidisciplinary team from all relevant21
disciplines informs the regulatory decision and, if22

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necessary, actions. Once the actions are1
implemented, the team will monitor any indicated2
responses from the drug manufacturer and will3
periodically reassess the issue as necessary.4
There are numerous sources of drug safety5
signals, some of which are listed on this slide.6
Signals can come from, for example, FDA7
surveillance, spontaneous adverse event reporting,8
adverse event reporting from patients, caregivers.9
Signals can come from, for example, FDA10
surveillance, adverse event reporting, postmarket11
drug safety trials or studies that are done to12
further evaluate the safety or efficacy of a13
product. And signals can even come from14
manufacturing or quality information sources. For15
example, a newly identified impurity that's16
identified during a manufacturing process may raise17
concerns about patient toxicity.18
So when CDER becomes aware of a drug safety19
signal, it will evaluate whether it represents a20
potential risk to patients and warrants further21
evaluation.22

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The comprehensive review of a postmarket1
drug safety signal will encompass all available2
information, some of which may be additional3
information from the drug manufacturer or other4
regulatory agencies, the medical literature, and so5
on.6
The comprehensive review is conducted to7
determine if there's a causal association between8
the adverse event or events and the drug. And it9
is done to determine the risk that is posed to10
patients, to better understand the effect of this11
new information on the benefit-risk profile of the12
drug, and to inform the regulatory decisions and13
actions.14
Now, with regard to the benefit-risk15
assessment that's conducted as part of this16
comprehensive review, the agency will determine,17
again, the safety and effectiveness of the drug.18
The benefit-risk assessment is conducted within the19
applicable legal, regulatory and policy framework.20
For example, a safety issue involving an orphan21
drug for a rare disease would necessitate certain22

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policy considerations.1
CDER's benefit-risk assessment is a2
qualitative one, and it's based on the benefits and3
the risks specific to that drug product. And key4
factors in the assessment are the severity of the5
condition that's being treated, the availability of6
other therapies for the condition, evidence of7
benefit of the drug and evidence of risk posed by8
the drug, and what risk management options are9
available or indicated.10
At the conclusion of the comprehensive11
review of a drug safety signal, FDA may determine12
that one or more actions is indicated. This talk13
focuses on decisions regarding the last two items14
on this slide; namely, removal of the drug from the15
market and removal from FDA approval of the16
marketing application or the approved indication.17
Before we go on, I do want to mention that18
for the purposes of updating the sections of the19
regulations that pertain to the list of withdrawn20
and removed drugs, namely, Section 216.24, we're21
using the term "withdrawal" to refer only to22

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withdrawal of FDA approval, and "removal" to refer1
to withdrawal of a product from sale or marketing.2
Marketing withdrawal is sometimes used3
interchangeably with removal of a drug from the4
market.5
After a comprehensive review of the drug6
safety issue, multiple factors go into our7
reassessment of the benefit-risk profile of a drug8
and decisions about what to do next. The major9
factor, of course, is the nature of the safety10
issue itself. Some characteristics of a postmarket11
drug safety issue that may lead to consideration of12
removal of a drug from the market or withdrawal of13
FDA approval include, but are not necessarily14
limited to, if it's a new serious adverse event,15
meaning that it's not already described in the16
product labeling; if there's an increase in the17
severity of the labeled adverse event; if there's a18
high likelihood of occurrence of the risk or the19
adverse event in the treated population; if there20
isn't a viable or feasible strategy to mitigate the21
risk; and if the issue is an emergency.22

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We consider a drug safety issue to be an1
emergency if it involves fatalities or has2
potential for serious harm, including fatalities,3
and if it has the potential to affect a large4
number of patients, and if we can do something to5
prevent harm or to save lives if we act quickly.6
So once a decision is made that a postmarket7
drug safety issue necessitates removal of a drug8
from the market or FDA approval, how does this9
occur? The process begins by expanding the10
multidisciplinary team to include senior FDA11
management and legal staff. And then discussions12
are held with the holder of the drug application to13
discuss the safety issue and the agency's concerns.14
These discussions may lead to the15
application holder agreeing to market withdrawal or16
removal of the drug or to voluntarily requesting17
that FDA withdraw its approval of the drug or18
indication.19
Alternatively, FDA may issue a notice of20
opportunity for hearing, which is a public meeting21
in which the FDA and the application holder discuss22

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the safety issue and the considerations for1
withdrawal. When the decision is made for2
withdrawal, we identify the legal basis for that3
withdrawal.4
We ensure that there's appropriate5
documentation so that the agency's reasoning and6
basis for the removal or withdrawal are clear, and,7
of course, it's important for the removal or8
withdrawal action to be communicated to the public,9
and so we do that via various means. For those10
products that are withdrawn, the official11
withdrawal occurs via publication of a notice in12
the Federal Register.13
I need to mention another way by which FDA14
makes determinations about whether a drug has been15
withdrawn for reasons of safety or effectiveness.16
A holder of an approved new drug application, or17
NDA, may at some point voluntarily discontinue sale18
of its product, for example, for financial reasons.19
And in some cases, because a drug is no longer20
being manufactured or sold, that application21
holder, that NDA holder may request FDA to withdraw22

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its approval of the application.1
Now, a different manufacturer who then wants2
to make a generic version of the discontinued drug3
may petition FDA via a relisting petition to make4
the determination about whether the drug was5
discontinued and, if it's applicable, whether the6
drug was withdrawn for reasons of safety or7
effectiveness.8
So FDA will review the information about the9
NDA drug and the NDA holder's reasons for10
discontinuation or removal and request for11
withdrawal. And after that, we will publish in the12
Federal Register the determination as to whether or13
not the drug was withdrawn for reasons of safety or14
effectiveness.15
This brings us to the current proposal for16
the additions to that list of withdrawn or removed17
drugs. We identified those proposed drugs by first18
searching our records for drugs whose withdrawal19
had been published in the Federal Register and20
those that had been removed from the market for21
safety or efficacy reasons.22

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We also reviewed the documentation1
describing the withdrawals or removals. For2
example, we looked at Federal Register notices and3
other FDA or official documentation, such as public4
health advisories and so on that announced the5
withdrawal or removal, and any other supporting6
documentation. The background materials for this7
meeting contain the specifics about those8
withdrawals and removals.9
So in summary, we continually assess the10
safety of a drug over its life cycle. Drug safety11
signals are frequently identified in the postmarket12
safety period. FDA has multidisciplinary teams to13
evaluate postmarket safety signals to determine the14
impacts on the benefit-risk profile of the drug and15
to inform our regulatory decisions.16
In some cases, our decision may be to17
withdraw the drug or to remove it from the market18
or to withdraw approval of the product. And our19
removal or withdrawal decisions are based on the20
safety issue, and it's undertaken within the21
appropriate legal and regulatory framework.22

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Thank you.1
DR. VENITZ: Thank you. Any clarifying3
questions by committee members?4
(No response.)5
DR. VENITZ: Then let me ask you. You6
listed a whole series of resources that you use to7
assess postmarketing safety signals. Probably the8
most difficult, I would guess, is to assess9
causality. So how high is your burden of proof to10
identify that a drug product has caused what you11
consider to be the safety signal rather than being12
associated with it?13
DR. KASHOKI: Right. There are multiple14
factors that go into a determination or a decision15
about causality. Timing, for example, we're really16
trying to assess the relationship of the event to a17
period or point that the patient was taking the18
drug.19
This is where there is some clinical20
judgment. There is judgment based on knowledge and21
experience of pharmacovigilance and the evaluation22

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of events and associations between drug and event.1
If there are any more definitive studies or2
trials that may better inform your decision about3
causality, those are always looked at. It's always4
more challenging if what you're relying upon is5
solely spontaneous adverse event reports.6
In the end, it becomes part clinical7
judgment, part regulatory judgment, and then the8
scientific component, as well. If there are things9
like plausibility, whether it's based on a10
mechanism of action, whether it's based on prior to11
X manufacturing period, there was no impurity,12
voila, there's an impurity and now we're seeing13
adverse events, you make a decision in a much14
clearer and easier way.15
There is no specific threshold. There is no16
number, per se. So it really is, as I said, a17
qualitative assessment of the benefit and the risk18
of the drug.19
DR. VENITZ: Just a follow-up. How20
important is the availability of alternative21
therapies to your ultimate decision?22

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DR. KASHOKI: It is an important1
consideration, particularly when you think of the2
nature of the condition being treated. If3
it's -- I'm just making this up -- a 100th4
antihypertensive, your threshold maybe a little bit5
more different than if this is the sole therapy for6
a rare condition.7
DR. VENITZ: Thank you. Go ahead.8
MS. JUNGMAN: I'm not sure whether you're9
the right person for this or whether this is a10
question for --11
DR. VENITZ: Can you please state your name?12
MS. JUNGMAN: I'm sorry. I'm Elizabeth13
Jungman. But I'm trying to get a sense of the14
standard that you're applying in making these15
decisions. And if I understand your presentation,16
FDA really is weighing the risk -- kind of17
re-weighing the risk and the benefit of the drug in18
the way that they would in making an approval19
decision, not making a decision that this drug is20
never appropriate for any patient; is that correct?21
DR. KASHOKI: So the decision is made based22

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on a population basis.1
MS. JUNGMAN: Population level.2
DR. KASHOKI: Yes. So if there comes a3
point, for example, we make a determination that a4
product should be withdrawn for reasons of safety5
or effectiveness from the population basis, that we6
tend to look at products, and then there is an7
individual provider who thinks that this particular8
product may be helpful to their individual patient,9
there is a way through which a patient may receive10
a product that's been withdrawn for reasons of11
safety or effectiveness by our expanded access12
process, which is via an IND, or investigational13
new drug application. And in that case, on a14
case-by-case basis, we will make the determination15
as to whether not treatment with that particular16
product for that individual in that circumstance is17
warranted.18
MS. JUNGMAN: That was my follow-up. Thank19
you.20
DR. DiGIOVANNA: John DiGiovanna. So if I21
understand you correctly, a drug that's on the22

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do-not-compound list, in order for it to be used1
for an individual patient, that it can be done, but2
it requires an IND.3
DR. KASHOKI: So I will speak from the4
perspective of if it's on the withdrawn or removed5
list. I'm looking at Jane Axelrad, who looks like6
she wants to say something.7
MS. AXELRAD: Well, the answer is yes. If8
it's on the withdrawn or removed list, it cannot be9
compounded. And if somebody wants to use it to10
treat an individual patient, they would do it under11
an IND.12
DR. DiGIOVANNA: And then under those13
circumstances, it's compounded for that individual14
patient under the IND.15
MS. AXELRAD: Well, it could be compounded,16
or in many of these cases -- in some cases, not17
many. But in some cases, the companies still make18
it available under a limited access protocol or19
some kind of an IND. So some of the drugs that20
have been withdrawn or removed from the market,21
like cisapride, you can get from the company, in22

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which case it would not need to be compounded.1
DR. DiGIOVANNA: I'm sorry. I don't quite2
understand how a drug can be on the withdrawn list3
because it has been removed from the market, but is4
still being manufactured and sold.5
MS. AXELRAD: Yes. It's not manufactured6
and sold. It's provided under a limited access7
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 individual12
patient, the benefits of the drug, in the view of13
the prescriber, continue to outweigh the risks, and14
the company has been willing to continue to make15
the drug available to those patients.16
DR. VENITZ: Thank you. Any other17
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 first22

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drug of interest, and that's adenosine phosphate,1
Dr. Nancy Xu. She is a medical officer at the2
Division of Cardiovascular and Renal Products,3
Office of Drug Evaluation I. She will introduce4
the drug product.5
FDA Presentation – Nancy Xu6
DR. XU: Good morning, everyone. Welcome,7
the audience and the committee members, for being8
here today. You bring a range of expertise and9
perspective to the FDA, and we believe this is very10
important to our mission in promoting the safe and11
effective use of drugs and being responsive to the12
evolving needs and concerns from the community at13
large. Today, my presentation will focus on14
clarifying the term adenosine phosphate on the15
withdrawn or removed list.16
First, I would like to acknowledge all my17
colleagues who had worked so diligently and under18
sometimes tight time pressure on this review for19
this presentation. They include people from the20
Office of New Drugs in my division and other21
offices and divisions within the Office of New22

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Drugs, Office of Pharmaceutical Quality, OPQ-I, and1
the Division of Clinical Pharmacology I, as well,2
of course, Office of Regulatory Policy.3
Let me begin with giving you some background4
on the entry for adenosine phosphate on the5
withdrawn or removed list.6
The 1999 withdrawn or removed list indicated7
adenosine phosphate or drug products containing8
adenosine phosphate may not be compounded. The9
rationale, as indicated in the Federal Register10
notice for the proposed rule, was that adenosine11
phosphate, singular, was determined to be neither12
safe nor effective for its intended use as a13
vasodilator or an anti-inflammatory.14
In 1973, an injectable combination15
containing adenosine 5-monophosphate and16
vitamin B12 was removed from the market. That was17
an unapproved product removed from the market for18
the aforementioned reason.19
Subsequently, FDA has also removed several20
unapproved products, unapproved adenosine phosphate21
products, from the market. Because these22

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unapproved products do not provide common names to1
the FDA, only brand names were available. We2
believe they might -- it's possible they might have3
contained other, one or more of the three commonly4
known adenosine phosphates, which you will hear5
about in the next slide.6
In 2014, FDA received an anonymous comment7
asking if the entry term adenosine phosphate on the8
list was intended to include all three forms of9
adenosine phosphate, mono-, di-, and triphosphate.10
Let me review how scientific communities11
currently use or interpret the term adenosine12
phosphate. First, I would like to make a general13
statement, and that is nomenclature can change over14
time, thus creating a need for clarification.15
As you can see, the term adenosine phosphate16
is currently an ambiguous and nonsystematic term.17
It can be used to describe a specific structure,18
adenosine 5-monophosphate, by some chemical19
nomenclature organizations. However, it is20
currently also being interpreted broadly to mean21
any adenosine, I mean any adenosine that is22

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phosphorylated.1
Adenosine phosphate is not a MSH, medical2
subject heading, term in the PubMed. So I would3
say one can interpret the term adenosine phosphate4
to mean the three commonly known adenosine5
phosphates in the question posed to the FDA, and I6
will show you those structures and nomenclature in7
the next two slides.8
In this slide, you see adenosine9
monophosphate, and it is also referred to as10
adenosine 5-prime monophosphate, commonly used with11
the abbreviation AMP.12
Adenine is right here. When it binds to13
ribose, this structure is called adenosine. When a14
single phosphate is attached to the 5-prime15
position, the 5-prime hydroxyl position of the16
ribose, you have what's called adenosine17
monophosphate, which is often referred to with the18
abbreviation AMP. For the rest of the talk, I will19
use the abbreviation AMP to refer to this20
structure.21
In this slide, you see the structure in the22

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current nomenclature for adenosine di- and1
triphosphates. As you can see, for adenosine2
5-prime diphosphate, you have two phosphate units3
attached to the 5-prime hydroxy position.4
Similarly, for the adenosine 5-prime triphosphate,5
you have three phosphate units attached to the6
5-prime position. Also shown here is the FDA7
unique structure identifier.8
So may AMP, ADP, and ATP share a similar9
pharmacological profile? We believe the answer is10
yes. This is because ATP, ADP, and AMP are rapidly11
converted to adenosine by a series of12
dephosphorylation that takes place outside the13
cell.14
So may AMP, ADP, and ATP share a similar15
safety profile? We believe the answer is yes.16
Based on our review of the medical literature, ADP17
has not been directly administered to humans as a18
drug product. However, it has been tested in vitro19
or ex vivo. It might have additional safety events20
which we cannot rule out, but we believe ADP will21
have the same -- can be compared to adenosine and,22

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of course, bind to the adenosine receptors that1
cause its effect.2
So this slide shows you just the adverse3
events, the safety profile as described in the4
approved adenosine products and what we learned5
from medical literature.6
I wanted to point out although two IV7
adenosine products have been approved in the U.S.,8
their use has been restricted to a highly monitored9
setting where resuscitative measures are available,10
and the reason, you can see, is listed here. It11
can cause fatal cardiac arrest, high degree heart12
block, ventricular arrhythmia requiring13
resuscitation, myocardial infarct, bronchospasm,14
and many others. You can see here when ATP is also15
given as an IV bolus or infusion, serious adverse16
events as shown, as described in the adenosine17
labeling.18
So in conclusion, the entry term on the list19
should be modified. FDA recommends the entry term20
on the list be updated to state adenosine21
phosphates, plural, or drug products containing22

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adenosine 5-prime monophosphate, in parens, AMP,1
adenosine 5-prime diphosphate, parens, ADP, and2
adenosine 5-prime triphosphate, parens (ATP).3
This is because these three drug products4
might have been in the unapproved products that5
were removed from the market. And furthermore,6
these three products likely share the same7
pharmacologic and safety profile.8
We believe using this terminology, adenosine9
5-prime mono, adenosine 5-prime diphosphate,10
adenosine 5-prime triphosphate, is unambiguous even11
without accompanying chemical structure. We12
include it as abbreviations because we believe most13
health care providers, pharmacists, compounders,14
would know what these terms mean.15
So in closing, we believe building clarity16
in terminology is an important step going forward.17
Clarity lays a solid foundation for further18
discussion. And I thank you for your attention.19
I'd be happy to take any clarifying questions.20
DR. VENITZ: Thank you, Dr. Xu. Any22

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clarifying questions?1
Can I ask you to go back to your second to2
last slide? So on the left-hand side, you have3
adverse reactions that are associated with the4
approved adenosine. Right? On the right-hand side5
you have observed or expected adverse events.6
DR. XU: Reported adverse events in medical7
literature.8
DR. VENITZ: Because I was just looking at9
your references. So there are clinical studies out10
there where they looked at ATP.11
DR. XU: ATP, yes. The ATP is approved in12
some countries, also the U.S., for indications13
similar to adenosine. It has been studied in14
humans in clinical trials, studies, and there have15
been case reports of adverse events. We looked at16
the medical literature with respect to ATP not17
limiting to just the U.S.18
DR. VENITZ: But you didn't find anything on19
AMP or ADP.20
DR. XU: ADP, we didn't find evidence that21
this is directly administered to humans as a drug22

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product. We find only, like I said, in vitro or1
ex vivo studies that raise some concern about2
additional platelet aggregation side effects. AMP,3
the adverse events, we didn't see anything to4
alleviate the concern of AMP use.5
DR. VENITZ: And that's based on your6
assumption that ATP ultimately gets metabolized to7
adenosine. Right? So AMP would be in the --8
DR. XU: Yes. They are in the pathway of9
dephosphorylation.10
Any other questions for Dr. Xu? Last12
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 is18
chloramphenicol, and we have Dr. Iarikov. He's a19
clinical team leader in the Division of20
Anti-Infective Products in the Office of21
Antimicrobial Products, and he is going to22

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introduce the drug product.1
FDA Presentation – Dmitri Iarikov2
DR. IARIKOV: Good morning. My name is3
Dmitri Iarikov. I'm acting clinical team leader of4
the Division of Anti-Infective Products at the FDA.5
And today I'm going to discuss oral formulations of6
chloramphenicol, with an emphasis on its safety7
profile and reasons for oral formulations of8
chloramphenicol withdrawal from the markets.9
I'd like to emphasize at the beginning of my10
presentation the intravenous formulation of11
chloramphenicol is still available and marketed in12
the United States.13
I will start by describing chloramphenicol14
properties, then I will discuss the chloramphenicol15
safety profile, emphasizing aplastic anemia16
associated with its use. I will then provide you17
with a brief regulatory history for this product18
and conclude by providing you a rationale for the19
FDA determination that oral chloramphenicol was20
withdrawn from the market for reasons of safety and21
effectiveness. And once again, chloramphenicol for22

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injection is approved and still marketed in the1
United States.2
Chloramphenicol is an antibacterial drug3
that acts by inhibiting protein synthesis by4
irreversibly binding to bacterial ribosome. Its5
oral formulations are rapidly absorbed with6
bioavailability of approximately 80 percent. It is7
metabolized and inactivated in the liver with a8
half-life of approximately 4 hours. And it's9
active against aerobic and anaerobic gram-positive10
and gram-negative organisms and rickettsiae.11
Prior to its removal from the market, oral12
chloramphenicol was approved for the treatment of13
various gram-negative infections, including14
salmonella, as well as rickettsiae and Chlamydia.15
Importantly, the label of chloramphenicol16
included a boxed warning stating that17
chloramphenicol must not be used when less18
potentially dangerous agents will be effective.19
Major adverse reactions associated with20
chloramphenicol use included bone marrow21
toxicities, and these toxicities were listed in the22

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boxed warning of the product label. And bone1
marrow toxicities may present as either reversible2
bone marrow depression, which was dose-related and3
responsive to drug withdrawal, or as aplastic4
anemia, which was not dose-related, irreversible,5
and associated with a high mortality.6
Major adverse reactions also included7
neurotoxic reactions such as delirium, optic and8
peripheral neuritis, hypersensitivity reactions,9
including anaphylaxis, and Gray syndrome in the10
newborn. This syndrome results from impaired11
inactivation of the product in the newborn and12
presented as abdominal distension, cyanosis,13
hypertension, and frequently resulted in death.14
Chloramphenicol-associated aplastic anemia15
was the major safety concern associated with the16
product. Once again, it was irreversible, usually17
fatal, and it could terminate in leukemia.18
Aplastic anemia occurred at the rate of 1 case for19
every 22,000-41,000 courses of the drug. It could20
occur up to any dose of chloramphenicol, and21
aplastic anemia could develop months or even years22

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after chloramphenicol administration.1
Importantly, aplastic anemia appeared to be2
more common after oral administration of3
chloramphenicol. It has been hypothesized that4
chloramphenicol undergoes metabolization by5
intestinal bacteria and its metabolite, in6
particular, dehydro-chloramphenicol, might undergo7
further nitro reduction in the bone marrow. And8
these products can cause DNA breaks and result in9
carcinogenicity and aplastic anemia.10
Dosing for chloramphenicol required11
additional safety precautions, such as blood12
studies every two days to monitor for bone marrow13
toxicities and measurement of blood concentration14
of chloramphenicol in patients with impaired15
metabolic processes. And hospitalization during16
the therapy was recommended to facilitate safety17
monitoring.18
Importantly, the boxed warning in the oral19
chloramphenicol label stated that blood studies20
cannot be relied on to detect bone marrow21
depression prior to development aplastic anemia.22

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I'm going to present you a brief regulatory1
history of the product. Chloramphenicol was2
introduced in 1948. In October of 2007, the3
sponsor of the product requested withdrawal of the4
application because oral chloramphenicol was no5
longer marketed.6
In February of 2009, FDA announced that7
approval would be withdrawn, and the drug would be8
moved to the discontinued drug products list, or9
the Orange Book. In July of 2012, after10
considering a petition to reintroduce the11
250 milligram oral chloramphenicol capsules to the12
market, FDA determined that the product was13
withdrawn for reasons of safety and effectiveness.14
The FDA based its determination on the fact15
that less toxic and more efficacious antibacterial16
drugs are available for all chloramphenicol17
indications, and poor clinical outcomes and the18
high mortality were reported in patients treated19
with chloramphenicol as compared to those treated20
with other antibacterial drugs. These studies21
included both intravenous and oral formulations of22

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the drug.1
Once again, the risk of aplastic anemia may2
be greater after oral as compared to intravenous3
administration of the drug. In addition, in a4
report on carcinogens, that is a congressionally-5
mandated public health document, at least oral6
chloramphenicol is a human carcinogen that may7
result in leukemia.8
I'd like to conclude my presentation by9
stating that all oral formulations of10
chloramphenicol, regardless of the specific forms11
or strength, are expected to have a similar safety12
profile. And I'll be happy to field any questions.13
DR. VENITZ: Thank you very much. Any15
questions?16
DR. WALL: Your comment said that it17
appears -- it's under the chloramphenicol18
associated aplastic anemia that it appears to be19
more common after oral administration.20
Do you have any more specific data other21
than it just appears?22

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DR. IARIKOV: There have been several1
publications investigating the issues -- I can2
provide you with specific references -- and has3
been studied in animal models that chloramphenicol4
is metabolized by intestinal flora, and this flora5
produced dehydro-chloramphenicol. And this6
metabolite, when it goes to bone marrow cells, it7
undergoes nitro reduction. And this nitro-reduced8
dehydro-chloramphenicol causes DNA breaks. It has9
been shown in animal studies.10
DR. WALL: But we haven't seen it in11
the -- no human studies went back and looked at12
that or examined it when you pulled out the side13
effect profiles.14
DR. IARIKOV: I'm not aware of any more data15
supporting this hypothesis. My understanding is it16
would be hard to conduct these studies in humans17
because aplastic anemia developed at the time when18
the product is no longer staying in the body, years19
and months after treatment is stopped. So you're20
dealing with the facts and statistics basically.21
And these studies were done retrospectively trying22

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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 at4
Children's National Medical Center. I feel kind of5
subjectively that in practice a lot of these6
considerations of the toxicity is already accounted7
for, and that is it is not first-line therapy, as8
far as I can tell. But due to the widespread news9
of broad spectrum antibiotics now, it remains a10
very good anti-infective as it retains11
susceptibility in a lot of the organisms due to its12
underuse.13
Although the IV formulation exists, I worry14
about it being specifically for severe infections15
or infections guided by susceptibility profiles as16
an agent of choice for prolonged duration of17
therapy, perhaps 14-21 days, easily, in some of18
these infections that I would suspect its use in.19
So as patients stabilize, are we burdening20
the health care system with ongoing IV therapy if21
it remains the only available dosage formulation,22

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or have we thought about the boxed warning being1
expanded because -- I don't advocate for this,2
obviously, but what if someone extrapolates using3
the IV formulation as PO since it already comes in4
solution -- sorry, as oral -- as it already comes5
in solution.6
So I think it would just be prudent to7
anticipate some of the further consequences of8
withdrawing an oral formulation.9
I completely agree with the concerns. I was10
surprised to hear -- actually, this is the first11
time I've heard about the intestinal bacteria and12
the metabolites causing some concern for the13
toxicity of the oral formulation. But without any14
further clarification on the boxed warning, it is15
very feasible that in practice, someone may think,16
well, I don't have oral anymore; maybe I'll just17
use the intravenous as oral.18
DR. IARIKOV: Your point about multidrug19
resistant bacteria is very well taken, and this is20
why the intravenous formulation of chloramphenicol21
is on the market. It still potentially can be used22

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with patients infected with multidrug resistant1
bacteria and having life-threatening disease.2
Under this circumstance, I would imagine that3
probably these patients will receive intravenous4
formulation of chloramphenicol, and it would be5
patients with health care-associated pneumonia,6
bacteremia. Under this circumstance, switching to7
oral may be potentially a problem, but it would be8
a relatively right situation, an inconvenience.9
The risk of having these products, from my10
perspective, as an oral drug on the market for11
almost every possible indication, including Rocky12
Mountain Spotted Fever, there is a high mortality13
associated with its use because it is less14
efficacious.15
I think that considering the risk and16
benefits ratio associated with the presence of the17
oral drugs on the market when it can be used18
inappropriately outweighs potential, but I'm19
emphasizing this for inconvenience of oral switch20
in an individual patient.21
DR. PHAM: Again, would maybe the potential22

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for revision of that boxed warning come into play1
if this was removed for oral administration?2
DR. IARIKOV: You mean revising the boxed3
warning in terms of --4
DR. PHAM: I don't remember what the5
original boxed warning -- it says chloramphenicol6
must not be used when less potentially dangerous7
agents will be effective, which I think is probably8
widespread current practice due to everyone's9
hesitation to use chloramphenicol.10
As the NICU specialist, you think it's odd11
that I'm advocating for chloramphenicol due to the12
Gray baby syndrome, but we now have weight-based13
dosing that appropriately accounts for that issue14
of metabolization in neonates. But it's just the15
fact that it really doesn't speak to the concerns16
with oral administration. It only speaks to just17
not using it first line.18
MS. AXELRAD: If I could just make a19
clarification. The drug has been removed from the20
market. So the slide up here says that its safety21
precautions were recommended for the dosing of the22

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oral before it was removed from the market. So1
since the product isn't being marketed, it's not2
appropriate to talk about changing the label of the3
drug to add a warning. It's been removed from the4
market.5
DR. VENTIZ: Thank you. Any further6
questions? Dr. Jungman?7
MS. JUNGMAN: This is Elizabeth Jungman. So8
just to kind of put a point on that. As I9
understand it, if this drug were not placed on the10
withdrawn and removed list, then it would be11
available for compounding by 503As and there would12
be no labeling requirements associated with that.13
There are some labeling requirements14
associated with 503Bs. But I want to make sure15
that I'm correctly understanding that we would16
really be talking about making this available in17
oral formulation barely probably without those18
labeling restrictions that apply to the approved19
product.20
MS. AXELRAD: Yes. Compounded drugs do not21
have the same kind of labeling that you have when22

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you have an approved drug.1
DR. VENITZ: Any other questions? Go ahead.2
DR. DiGIOVANNA: John DiGiovanna. I think3
this is perhaps a point of clarification for me.4
It seems that the interest in compounded drugs is5
often for the individual patient that has a6
particular type of disease that is different from7
the general population for which a drug might have8
been approved. And often those are situations9
where the physician feels that they're boxed in a10
corner and is looking for another therapy, possibly11
one they have found to be useful from the12
literature.13
I don't understand if there is a mechanism14
to allow for availability for compounding only on a15
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 the18
situations that have been raised -- where one has19
an unusual situation of a disorder and maybe the20
risk profile isn't necessarily appropriate for that21
particular patient and may not relate to why the22

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drug was removed from the market.1
So is there a way to -- when a drug is on2
the withdrawn list, it appears that it's still not3
available either for bulk compounding nor for4
prescription for an individual patient. But is5
there an availability for the unusual situation for6
an individual patient that doesn't open the drug up7
to being widely bulk prepared and sold that might8
put a different risk-benefit profile to a9
population rather than that individual patient?10
I hope I'm not too unclear.11
MS. AXELRAD: I don't know. I was wondering12
if other members of the committee might have a view13
on that. I could talk about my thoughts about14
that.15
It's a factual question. I sort of already16
answered it, which is when a drug has been17
withdrawn or removed from the market for safety18
reasons and it's put on this list, it isn't19
available for compounding. And if someone believes20
that it ought to be used for an individual patient,21
then they need to make that case through the IND22

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mechanism, which ensures that patients are advised1
of the risks of the drug, what's been found in2
terms of the benefit-risk of the drug, and the3
safety profile, and that they are getting informed4
of those. And then if the physician decides that5
that's the appropriate treatment, then that's fine.6
But there is no real way once you put7
it -- if you don't put it on the list -- to limit8
it in any way. I mean, anybody could compound it9
and offer it for sale, period.10
DR. VENITZ: Dr. Davidson?11
MS. DAVIDSON: Gigi Davidson. Jane, could12
you perhaps explain what is involved in filing an13
IND? I think that would help many of us decide14
whether this is a significant impairment to patient15
access or not. Thank you.16
MS. AXELRAD: Yes. We just issued a17
guidance that has a short abbreviated form for18
filing an expanded access IND for an individual19
patient, if you're doing it for an individual20
patient. It is done fairly frequently and it has21
as limited burden as one can make.22

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If you want me to get details, I'd probably1
want to get somebody from the divisions that handle2
them. But we have recently put out two guidance3
documents, one that talks generally about all the4
different options for how you can get a drug under5
an IND, and then this more recent guidance that was6
just issued, I think, a couple of weeks ago that7
explains -- has a new form that's proposed for use8
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, industry12
representative. In all due respect, I don't13
believe that the FDA could respond in a very rapid14
manner when the decision is made that15
chloramphenicol is the drug of choice for an16
individual patient by a physician. And I just17
would encourage the committee to not take this drug18
out of the armamentarium.19
When a physician makes the decision to use20
this drug, despite its drawback and concerns and21
warnings and side effects, I mean, that decision is22

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made every day with every drug. Thank you.1
DR. IARIKOV: Certainly I'd like to2
interject.3
DR. VENITZ: Hold on. Dr. Gulur?4
DR. IARIKOV: Please take into consideration5
for an individual patient, if there's a strong case6
for it, the drug is available and is still7
marketed. So if you have someone with a multidrug8
resistant infection, the drug is available in9
intravenous formulation.10
This is probably the circumstance where this11
formulation would be more appropriate. And as12
indicated, it's still produced and marketed in the13
rest of the world. So the company potentially14
can -- if there is, once again, a very strong case15
for oral formulation, it can be provided under your16
emergency use IND access.17
But if somebody needs chloramphenicol for18
any particular reason, the drug is approved, not19
capsules. And as an infectious disease physician,20
I'm trying to imagine the circumstance where oral21
chloramphenicol capsules can be used, and I cannot22

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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 it4
require special compounding for oral use? The5
intravenous solution that's available, can that be6
used as an oral formulation? What are the7
limitations, I guess.8
DR. IARIKOV: It does not require9
compounding. It's a commercially manufactured10
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 intravenous14
formulation to dose appropriately. I have not15
considered this scenario.16
DR. VENITZ: Dr. Carome, and then Mr. Mixon17
is last.18
DR. CAROME: Mike Carome. I think of there19
is a patient out there who is so sick that none of20
the other available antibiotics that are much safer21
are not the choice for therapy, and someone needs22

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to turn to chloramphenicol, and the patient is so1
sick that that patient should be appropriately2
treated probably in a hospital with the IV3
formulation, as marketed, with appropriate4
monitoring. And the IV therapy, based upon some5
studies you mentioned, is probably a safer way to6
go. So I don't think there is any need for the7
oral formulation in capsule form.8
DR. VENITZ: Mr. Mixon, last question.9
MR. MIXON: I just wanted to respond that to10
use the intravenous form orally, if this drug is11
added to the negative list for oral use, it would12
not be appropriate for a compounder to take the13
intravenous form and put it into an oral form. We14
wouldn't do that.15
DR. VENITZ: We have more room for16
discussion.17
DR. IARIKOV: Just one last remark.18
DR. VENITZ: Go ahead.19
DR. IARIKOV: Please consider that the oral20
formulation of chloramphenicol has not been21
effectively on the market since 1995, and there is22

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no kind of wave of requests for almost two decades.1
It's not on the market anymore, and the company2
just withdrew it in 2007. But since 1995, it has3
not been marketed because there had been no use for4
it.5
DR. VENITZ: Thank you, Dr. Iarikov.6
It's time for our first break. We can7
continue our discussion, but right after we8
reconvene at 10:15, we have our first open public9
hearing. So we'll take a break and reconvene at10
10:15.11
(Whereupon, a recess was taken.)12
Open Public Hearing13
DR. VENITZ: Can you take your seats,14
please? And while you're taking your seat, let me15
just do the preliminaries for our first open16
hearing session.17
So we will now convene our first OPH18
session, in which we have one speaker. I will now19
read the OPH statement into the record.20
Both the Food and Drug Administration and21
the public believe in a transparent process for22

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information-gathering and decision-making. To1
ensure such transparency at the open public hearing2
session of the advisory committee meeting, FDA3
believes that it is important to understand the4
context of an individual's presentation.5
For this reason, FDA encourages you, the6
open public hearing speaker, at the beginning of7
your written or oral statement, to advise the8
committee of any financial relationship that you9
may have with the product and, if known, its direct10
competitors. For example, this financial11
information may include the payment by a drug12
supplier or a compounding pharmacy of your travel,13
lodging, or other expenses in connection with your14
attendance at the meeting.15
Likewise, FDA encourages you, at the16
beginning of your statement, to advise the17
committee if you do not have any such financial18
relationships. If you choose not to address this19
issue of financial relationships at the beginning20
of the statement, it will not preclude you from21
speaking, however.22

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The FDA and this committee place great1
importance in the open public hearing process. The2
insights and comments provided can help the agency3
and this committee in their consideration of the4
issues before them.5
That said, in many instances and for many6
topics, there will be a variety of opinions, and7
one of our goals today is for this open public8
hearing to be conducted in a fair and open way,9
where every participant is listened to carefully10
and treated with dignity, courtesy, and respect.11
Therefore, please speak only when recognized by the12
chair. Thank you for your cooperation.13
So may we now have the registered speaker14
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 I19
would like to propose that regarding adenosine, the20
entry into the list be specific to drugs -- for use21
for parenteral use. All of the data presented for22

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adenosine, as well as the triphosphate, is specific1
to IV bolus and infusion therapy. Because that is2
where the concern lies with safety, it seems3
logical that the entry into the list of drugs to4
not compound with for safety and efficacy reasons5
be specific to the injectable form.6
Committee Discussion and7
Vote on Withdrawn or Removed List8
DR. VENITZ: Thank you for your comment. We9
have no further speakers. So the open public10
hearing portion of this meeting has now been11
concluded, and we will no longer take comments from12
the audience. The committee will now turn its13
attention to address the task at hand, the careful14
consideration of the data before the committee, as15
well as the public comments.16
During the break, Dr. Axelrad has indicated17
that we will have one or two speakers to tell the18
committee more about the IND process, as that is an19
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 in1
the Division of Anti-Infective Products. I just2
wanted to respond to an earlier comment about3
emergency access to products. I know a lot of our4
processes are rather onerous, but this is not that5
onerous. We do respond to physician's requests in6
very short time. Twenty-four hours a day, seven7
days a week somebody is available, and the8
physician that's interested in procuring the9
product reaches out to the division. And somebody10
from the division does call the physician, and we11
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 four15
of them this past weekend. So I think it's16
certainly not as time-consuming as it may appear.17
Are there any questions that I can answer18
about the exact process?19
DR. VENITZ: Mr. Mixon?20
MR. MIXON: So if I understood you21
correctly, you said within 24 hours?22

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DR. NAMBIAR: No. It doesn't even take1
24 hours. As soon as we get a request from the2
physician, somebody from the division -- if it's3
during working hours, it's one of the medical4
officers reaches out to the physician. If it's5
after hours, it's usually me.6
We talk to them, get the details on the7
patient. And usually there's a basic set of forms8
that they need to fill out. But if it's after9
hours, we sometimes do it over the phone.10
The delay often is in getting the product11
from the manufacturer. That's not what we control.12
But in terms of the FDA's end of things, it doesn't13
even take 24 hours. It's a matter of a few hours.14
MR. MIXON: So that could be initiated15
verbally.16
DR. NAMBIAR: Yes, depending on the17
situation, depending on the time of the day, the18
day of the week.19
MR. MIXON: How easy is it to find the20
contact information for your office?21
DR. NAMBIAR: It's all on the website. If22

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you go to the FDA website, the information is1
available. After hours, all the information for2
the emergency coordinator is available. They take3
the basic information, and they reach out to the4
division contact, which is usually me, and it5
happens pretty quickly.6
MR. MIXON: Thank you. That is very7
helpful.8
MS. DAVIDSON: Gigi Davidson. This is a9
very odd question, but in the event that a human10
manufacturer of chloramphenicol oral dosage forms11
could not be located, veterinary dosage forms are12
widely available. Would the agency consider13
allowing use of that under an IND for a patient in14
need?15
DR. NAMBIAR: I don't think I'm in a16
position to answer the specific question regarding17
chloramphenicol because I don't know on the18
specifics, but there is certainly one other product19
that we do get requests to use under emergency IND,20
and the only product available currently is a21
veterinary product.22

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DR. VENITZ: Dr. Pham?1
DR. PHAM: Kathy Pham from Children's2
National Medical Center. After that process is3
approved, is the storage and handling or any other4
documentation specific to having to go through an5
investigational drug service pharmacy at these6
practice sites, or once it has come from the7
manufacturer, the pharmacy department is able to8
handle it however it chooses?9
DR. NAMBIAR: I think that really depends on10
your institutions. We don't get into those11
details. And we typically work with the hospital12
pharmacists, and they're able to coordinate with13
the institution. But as the investigator and the14
sponsor of the IND, you are still responsible for15
submitting adverse events and maintaining whatever16
the requirements of the IND are.17
MS. JUNGMAN: If we were talking about a18
product that isn't available from a manufacturer,19
but that would have to be compounded, would that20
alter your process at all?21
DR. NAMBIAR: I've really never done one of22

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these, but I would think we should be able to work1
with the physician and the supplier and make things2
possible. Now, typically, when these kinds of3
drugs are used, patients are in dire situations.4
But now with chloramphenicol, with intravenous5
chloramphenicol available, it shouldn't be an6
issue.7
With oral chloramphenicol, if it's a patient8
who is going to get it as step-down therapy, we9
have some time to work these things out. So it's10
not that you would need oral chloramphenicol in a11
couple of hours. I think we should be able to work12
something out.13
I'll have to talk to my colleagues from CMC14
to understand exactly what kind of information they15
need, but I think that's something -- we probably16
will have a little more time with oral17
chloramphenicol, and IV is available for a sick18
patient.19
MS. DAVIDSON: Gigi Davidson. One more20
question. The obvious case would be a pregnant21
woman with Rocky Mountain Spotted Fever who could22

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not take doxycycline or a patient who is allergic1
to doxycycline. They could be started on IV2
chloramphenicol for a few days, but the course of3
therapy for that disease is about 21 days of4
hospitalization.5
My question is, if you received enough INDs6
for oral chloramphenicol, would there be7
consideration maybe even by this body to take it8
off the list?9
DR. NAMBIAR: Honestly, we haven't received10
any emergency IND requests for oral chloramphenicol11
in a long, long time. We do get requests for many12
other investigational products and, like I said, a13
product that's also available for veterinary use.14
But in the last several years, I don't recollect15
getting a single request for oral chloramphenicol.16
DR. VENITZ: Dr. Jungman?17
MS. JUNGMAN: Sorry, just one more. The IND18
process, does it have to be specific to an19
individual patient or, for example, maybe not20
specific to chloramphenicol, but with a product21
that a particular physician used with some22

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frequency, would it be possible for that physician1
to get more of a general dispensation to use the2
product?3
DR. NAMBAIR: What I'm talking about are4
single-patient INDs. And under the expanded access5
INDs, there's something known as expanded access6
INDs, intermediate size population, there the7
procedure is a little different. But there are8
certain drugs where you're getting repeated uses in9
a certain clinical condition, and there is a10
protocol involved, and somebody can hold an IND,11
expanded access IND, for an intermediate sized12
patient population.13
DR. VENITZ: Any further questions?14
(No response.)15
DR. VENITZ: Thank you very much for your16
clarification.17
We are now moving to the discussion and the18
voting session. And I'm told that Dr. Iarikov has19
to leave by 11:00, so I'd like to start our20
discussion by continuing the chloramphenicol story21
that we got involved in before I had to rudely22

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interrupt us.1
So any comments, any discussion, any2
questions regarding oral chloramphenicol?3
MS. JUNGMAN: What are the4
circumstances -- and I'm kind of looking to the5
clinicians around the table -- where you would want6
to have an oral version of chloramphenicol?7
So Dr. Pham mentioned the burden on the8
health care system. But are there clinical9
circumstances in which a patient would not be10
appropriate for an IV form, they would really need11
an oral dosage form?12
DR. PHAM: I think that still goes back to13
maintaining the duration of therapy and the14
continuity of care. I think that we all agree it15
would be reserved for serious infections or16
contraindications. I think we all probably feel as17
clinicians that IV therapy is always appropriate to18
start. But you just don't know how stable that19
patient is going to get in a prolonged duration of20
therapy.21
So I think that it's noted that the switch22

AMP - FDA Warning Sent Out April 2015

AMP - FDA Warning Sent Out April 2015

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