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A Matter of Record
(301) 890-4188
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FOOD AND DRUG ADMINISTRATION1
CENTER FOR DRUG EVALUATION AND RESEARCH2
3
4
5
PHARMACY ...
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Meeting Roster1
DESIGNATED FEDERAL OFFICER (Non-Voting)2
Jayne Peterson, BSPharm, JD3
...
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Gigi S. Davison, BSPh, DICVP1
U.S. Pharmacopeial Convention2
(USP) Representative- Feb...
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Padma Gulur, MD1
Professor, Department of Anesthesiology and2
Perioperative Care3
Univ...
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Allen J. Vaida, BSc, PharmD, FASHP1
Executive Vice President2
Institute for Safe Medic...
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PHARMACY COMPOUNDING ADVISORY COMMITTEE MEMBERS1
(Voting) cont.2
Donna Wall, PharmD3
N...
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TEMPORARY MEMBERS (Voting)1
Jeanne Sun, PharmD2
USP Representative3
February 24th only...
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Mwango A. Kashoki, MD, MPH1
Associate Director for Safety2
Office of New Drugs (OND)3
...
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C O N T E N T S1
AGENDA ITEM PAGE2
Call to Order and Introduction of Committee3
Jurgen...
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C O N T E N T S (continued)1
AGENDA ITEM PAGE2
Open Public Hearing 903
Committee Disc...
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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. VEN...
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Office of Regulatory Policy.1
MS. AXELRAD: Jane Axelrad. I'm the2
associate director ...
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the Pharmacy Compounding Advisory Committee.1
DR. VENITZ: I'm Jurgen Venitz. I'm a2
c...
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that as part of my federal duties in 2014, I1
reviewed and provided input into NIH's ...
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Pharmacy and am a member of the USP Expert1
Committee for Compounding.2
DR. BRAUNSTEI...
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Committee Act and the Government in the Sunshine1
Act, we ask that the advisory commi...
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and voting.1
This afternoon and continuing through2
tomorrow, we will hear presentati...
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of the Federal Advisory Committee Act of 1972.1
With the exception of the National As...
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when it is determined that the agency's need for a1
special government employee's ser...
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Act because the drug products have been withdrawn1
or removed from the market, becaus...
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chloramphenicol tablets 250 mgs be excluded from1
the list. FDA will discuss both of ...
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Association of Boards of Pharmacy, and Ms. Gigi1
Davidson is a representative member ...
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role at this meeting is to represent industry in1
general and not any particular comp...
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agency lead on compounding.1
I would like to remind public observers at2
this meeting...
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result of litigation over the validity of1
Section 503A, the agency suspended its eff...
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Today, we'll be talking about two lists.1
The first is a list of drugs that may not b...
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the conditions in Section 503A necessary to qualify1
for the exemptions are primarily...
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whom the prescription order will be provided, or1
the licensed practitioner who will ...
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In addition to these conditions, another1
condition of Section 503A is that bulk drug...
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what we're going to be talking about.1
Section 503A also states that to qualify for2
...
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or cause to be distributed compounded drug products1
out of the state in which they a...
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found in Title I of the Drug Quality and Security1
Act, removes from Section 503A cer...
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they meet the conditions, be exempt from the new1
drug approval requirements and the ...
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are the same or similar to the conditions necessary1
to qualify for the exemptions un...
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REMS, with elements to assure safe use, or from a1
bulk drug substance that is a comp...
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Section 503A, bulk drug substances and other1
ingredients used to compound under Sect...
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it has paid the annual establishment fee.1
Under the law, if a compounded drug does n...
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or 503B.1
FDA began compiling this list as soon as2
Section 503A was enacted in 1997....
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So the final rule was published in March1
1999, and it is codified in FDA's regulatio...
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rule to add 25 products to the list that was1
already codified in 216.24, and we also...
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and to take any questions that you might have1
before we ask you to vote on whether t...
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productive and interesting two days here. Thanks.1
Clarifying Questions from the Comm...
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products that may not be compounded because they1
have been removed from the market d...
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removed for safety reasons, but we're not going to1
put it on a list."2
So I don't kn...
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arguing against that. But sometimes there's a drug1
shortage that's on the ASHP list ...
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ask a question, please introduce yourself by name1
before you do that so we can captu...
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2008 and which outlines CDER's updated policies and1
procedures to ensure that equal ...
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necessary, actions. Once the actions are1
implemented, the team will monitor any indi...
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The comprehensive review of a postmarket1
drug safety signal will encompass all avail...
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policy considerations.1
CDER's benefit-risk assessment is a2
qualitative one, and it'...
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withdrawal of FDA approval, and "removal" to refer1
to withdrawal of a product from s...
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We consider a drug safety issue to be an1
emergency if it involves fatalities or has2...
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the safety issue and the considerations for1
withdrawal. When the decision is made fo...
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its approval of the application.1
Now, a different manufacturer who then wants2
to ma...
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We also reviewed the documentation1
describing the withdrawals or removals. For2
exam...
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Thank you.1
Clarifying Questions from the Committee2
DR. VENITZ: Thank you. Any clari...
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of events and associations between drug and event.1
If there are any more definitive ...
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DR. KASHOKI: It is an important1
consideration, particularly when you think of the2
n...
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on a population basis.1
MS. JUNGMAN: Population level.2
DR. KASHOKI: Yes. So if there...
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do-not-compound list, in order for it to be used1
for an individual patient, that it ...
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which case it would not need to be compounded.1
DR. DiGIOVANNA: I'm sorry. I don't qu...
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drug of interest, and that's adenosine phosphate,1
Dr. Nancy Xu. She is a medical off...
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Drugs, Office of Pharmaceutical Quality, OPQ-I, and1
the Division of Clinical Pharmac...
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unapproved products do not provide common names to1
the FDA, only brand names were av...
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phosphorylated.1
Adenosine phosphate is not a MSH, medical2
subject heading, term in ...
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current nomenclature for adenosine di- and1
triphosphates. As you can see, for adenos...
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of course, bind to the adenosine receptors that1
cause its effect.2
So this slide sho...
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adenosine 5-prime monophosphate, in parens, AMP,1
adenosine 5-prime diphosphate, pare...
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clarifying questions?1
Can I ask you to go back to your second to2
last slide? So on ...
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product. We find only, like I said, in vitro or1
ex vivo studies that raise some conc...
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introduce the drug product.1
FDA Presentation – Dmitri Iarikov2
DR. IARIKOV: Good mor...
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injection is approved and still marketed in the1
United States.2
Chloramphenicol is a...
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boxed warning of the product label. And bone1
marrow toxicities may present as either...
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after chloramphenicol administration.1
Importantly, aplastic anemia appeared to be2
m...
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I'm going to present you a brief regulatory1
history of the product. Chloramphenicol ...
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the drug.1
Once again, the risk of aplastic anemia may2
be greater after oral as comp...
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DR. IARIKOV: There have been several1
publications investigating the issues -- I can2...
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to understand what's happening.1
DR. WALL: Thank you.2
DR. VENITZ: Dr. Pham?3
DR. PHA...
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or have we thought about the boxed warning being1
expanded because -- I don't advocat...
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with patients infected with multidrug resistant1
bacteria and having life-threatening...
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for revision of that boxed warning come into play1
if this was removed for oral admin...
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oral before it was removed from the market. So1
since the product isn't being markete...
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you have an approved drug.1
DR. VENITZ: Any other questions? Go ahead.2
DR. DiGIOVANN...
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drug was removed from the market.1
So is there a way to -- when a drug is on2
the wit...
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mechanism, which ensures that patients are advised1
of the risks of the drug, what's ...
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If you want me to get details, I'd probably1
want to get somebody from the divisions ...
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made every day with every drug. Thank you.1
DR. IARIKOV: Certainly I'd like to2
inter...
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think of any, for the most part.1
DR. VENITZ: Dr. Gulur, and then Dr. Carome.2
DR. GU...
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to turn to chloramphenicol, and the patient is so1
sick that that patient should be a...
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no kind of wave of requests for almost two decades.1
It's not on the market anymore, ...
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information-gathering and decision-making. To1
ensure such transparency at the open p...
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The FDA and this committee place great1
importance in the open public hearing process...
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adenosine, as well as the triphosphate, is specific1
to IV bolus and infusion therapy...
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My name is Sumathi Nambiar. I'm the director in1
the Division of Anti-Infective Produ...
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DR. NAMBIAR: No. It doesn't even take1
24 hours. As soon as we get a request from the...
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you go to the FDA website, the information is1
available. After hours, all the inform...
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DR. VENITZ: Dr. Pham?1
DR. PHAM: Kathy Pham from Children's2
National Medical Center....
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these, but I would think we should be able to work1
with the physician and the suppli...
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not take doxycycline or a patient who is allergic1
to doxycycline. They could be star...
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frequency, would it be possible for that physician1
to get more of a general dispens...
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interrupt us.1
So any comments, any discussion, any2
questions regarding oral chlora...
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
AMP - FDA Warning Sent Out April 2015
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AMP - FDA Warning Sent Out April 2015

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AMP - FDA Warning Sent Out April 2015

  1. 1. A Matter of Record (301) 890-4188 1 FOOD AND DRUG ADMINISTRATION1 CENTER FOR DRUG EVALUATION AND RESEARCH2 3 4 5 PHARMACY COMPOUNDING ADVISORY COMMITTEE6 7 8 Morning Session9 10 11 Monday, February 23, 201512 8:28 a.m. to 11:34 a.m.13 14 15 16 17 FDA White Oak Campus18 Building 31, The Great Room19 White Oak Conference Center20 Silver Spring, Maryland21 22
  2. 2. A Matter of Record (301) 890-4188 2 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 16 17 18 19 20 21 22
  3. 3. A Matter of Record (301) 890-4188 3 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 13 John J. DiGiovanna, MD14 Staff Clinician, DNA Repair Section15 Dermatology Branch, Center for Cancer Research16 National Cancer Institute17 National Institutes of Health18 Bethesda, Maryland19 20 21 22
  4. 4. A Matter of Record (301) 890-4188 4 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 Washington, District of Columbia15 16 Katherine Pham, PharmD17 Neonatal Intensive Care Unit Pharmacy Specialist18 Children’s National Medical Center19 Washington, District of Columbia20 21 22
  5. 5. A Matter of Record (301) 890-4188 5 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 19 20 21 22
  6. 6. A Matter of Record (301) 890-4188 6 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 22
  7. 7. A Matter of Record (301) 890-4188 7 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 22
  8. 8. A Matter of Record (301) 890-4188 8 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 16 17 18 19 20 21 22
  9. 9. A Matter of Record (301) 890-4188 9 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 Clarifying Questions from the Committee 5615 Adenosine Phosphate16 Nancy Xu, MD 6217 Clarifying Questions from the Committee 6818 Chloramphenicol19 Dmitri Iarikov, MD, PhD 7120 Clarifying Questions from the Committee 7621 22
  10. 10. A Matter of Record (301) 890-4188 10 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 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
  11. 11. A Matter of Record (301) 890-4188 11 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
  12. 12. A Matter of Record (301) 890-4188 12 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
  13. 13. A Matter of Record (301) 890-4188 13 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
  14. 14. A Matter of Record (301) 890-4188 14 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
  15. 15. A Matter of Record (301) 890-4188 15 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
  16. 16. A Matter of Record (301) 890-4188 16 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
  17. 17. A Matter of Record (301) 890-4188 17 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
  18. 18. A Matter of Record (301) 890-4188 18 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
  19. 19. A Matter of Record (301) 890-4188 19 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
  20. 20. A Matter of Record (301) 890-4188 20 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
  21. 21. A Matter of Record (301) 890-4188 21 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
  22. 22. A Matter of Record (301) 890-4188 22 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
  23. 23. A Matter of Record (301) 890-4188 23 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
  24. 24. A Matter of Record (301) 890-4188 24 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
  25. 25. A Matter of Record (301) 890-4188 25 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
  26. 26. A Matter of Record (301) 890-4188 26 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
  27. 27. A Matter of Record (301) 890-4188 27 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
  28. 28. A Matter of Record (301) 890-4188 28 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
  29. 29. A Matter of Record (301) 890-4188 29 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
  30. 30. A Matter of Record (301) 890-4188 30 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
  31. 31. A Matter of Record (301) 890-4188 31 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
  32. 32. A Matter of Record (301) 890-4188 32 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
  33. 33. A Matter of Record (301) 890-4188 33 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
  34. 34. A Matter of Record (301) 890-4188 34 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
  35. 35. A Matter of Record (301) 890-4188 35 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
  36. 36. A Matter of Record (301) 890-4188 36 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
  37. 37. A Matter of Record (301) 890-4188 37 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
  38. 38. A Matter of Record (301) 890-4188 38 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
  39. 39. A Matter of Record (301) 890-4188 39 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
  40. 40. A Matter of Record (301) 890-4188 40 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
  41. 41. A Matter of Record (301) 890-4188 41 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
  42. 42. A Matter of Record (301) 890-4188 42 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
  43. 43. A Matter of Record (301) 890-4188 43 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
  44. 44. A Matter of Record (301) 890-4188 44 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 DR. VENITZ: Thank you.13 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
  45. 45. A Matter of Record (301) 890-4188 45 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
  46. 46. A Matter of Record (301) 890-4188 46 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
  47. 47. A Matter of Record (301) 890-4188 47 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
  48. 48. A Matter of Record (301) 890-4188 48 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
  49. 49. A Matter of Record (301) 890-4188 49 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
  50. 50. A Matter of Record (301) 890-4188 50 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
  51. 51. A Matter of Record (301) 890-4188 51 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
  52. 52. A Matter of Record (301) 890-4188 52 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
  53. 53. A Matter of Record (301) 890-4188 53 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
  54. 54. A Matter of Record (301) 890-4188 54 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
  55. 55. A Matter of Record (301) 890-4188 55 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
  56. 56. A Matter of Record (301) 890-4188 56 Thank you.1 Clarifying Questions from the Committee2 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
  57. 57. A Matter of Record (301) 890-4188 57 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
  58. 58. A Matter of Record (301) 890-4188 58 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
  59. 59. A Matter of Record (301) 890-4188 59 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
  60. 60. A Matter of Record (301) 890-4188 60 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
  61. 61. A Matter of Record (301) 890-4188 61 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
  62. 62. A Matter of Record (301) 890-4188 62 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
  63. 63. A Matter of Record (301) 890-4188 63 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
  64. 64. A Matter of Record (301) 890-4188 64 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
  65. 65. A Matter of Record (301) 890-4188 65 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
  66. 66. A Matter of Record (301) 890-4188 66 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
  67. 67. A Matter of Record (301) 890-4188 67 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
  68. 68. A Matter of Record (301) 890-4188 68 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 Clarifying Questions from the Committee21 DR. VENITZ: Thank you, Dr. Xu. Any22
  69. 69. A Matter of Record (301) 890-4188 69 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
  70. 70. A Matter of Record (301) 890-4188 70 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 DR. VENITZ: Thank you.11 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
  71. 71. A Matter of Record (301) 890-4188 71 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
  72. 72. A Matter of Record (301) 890-4188 72 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
  73. 73. A Matter of Record (301) 890-4188 73 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
  74. 74. A Matter of Record (301) 890-4188 74 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
  75. 75. A Matter of Record (301) 890-4188 75 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
  76. 76. A Matter of Record (301) 890-4188 76 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 Clarifying Questions from the Committee14 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
  77. 77. A Matter of Record (301) 890-4188 77 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
  78. 78. A Matter of Record (301) 890-4188 78 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
  79. 79. A Matter of Record (301) 890-4188 79 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
  80. 80. A Matter of Record (301) 890-4188 80 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
  81. 81. A Matter of Record (301) 890-4188 81 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
  82. 82. A Matter of Record (301) 890-4188 82 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
  83. 83. A Matter of Record (301) 890-4188 83 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
  84. 84. A Matter of Record (301) 890-4188 84 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
  85. 85. A Matter of Record (301) 890-4188 85 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
  86. 86. A Matter of Record (301) 890-4188 86 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
  87. 87. A Matter of Record (301) 890-4188 87 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
  88. 88. A Matter of Record (301) 890-4188 88 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
  89. 89. A Matter of Record (301) 890-4188 89 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
  90. 90. A Matter of Record (301) 890-4188 90 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
  91. 91. A Matter of Record (301) 890-4188 91 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
  92. 92. A Matter of Record (301) 890-4188 92 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
  93. 93. A Matter of Record (301) 890-4188 93 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
  94. 94. A Matter of Record (301) 890-4188 94 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
  95. 95. A Matter of Record (301) 890-4188 95 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
  96. 96. A Matter of Record (301) 890-4188 96 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
  97. 97. A Matter of Record (301) 890-4188 97 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
  98. 98. A Matter of Record (301) 890-4188 98 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
  99. 99. A Matter of Record (301) 890-4188 99 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
  100. 100. A Matter of Record (301) 890-4188 100 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
  101. 101. A Matter of Record (301) 890-4188 101 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

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