ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

 

FOOD AND DRUG ADMINISTRATION

 

CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

ANESTHETIC AND LIFE SUPPORT DRUGS

 

ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tuesday, September 9, 2003

 

8:10 a.m.

 

 

 

 

 

 

 

 

 

 

 

 

Holiday Inn Bethesda

Bethesda, Maryland

 

 

PARTICIPANTS

 

Nathaniel Katz, M.D., Chair

Johanna Clifford, M.S., RN, BSN, Executive Secretary

 

MEMBERS

 

          Solomon Aronson, M.D.

          Mary Beth Bobek, Pharm D.

          Vera Bril, M.D.

          Madelyn Kahana, M.D.

          Bhupinder Saini, M.D.

          Steven L. Shafer, M.D.

          Carol Rose, M.D.

 

VOTING CONSULTANTS

 

          Louis E. Baxter, Sr., M.D.

          Domenic Ciraulo, M.D.

          Stephanie Crawford, Ph.D., M.S.

          John Cush, M.D.

          Robert Dworkin, Ph.D.

          Jacqueline Gardner, Ph.D., M.P.H.

          Jane Maxwell, Ph.D.

          Steven Passik, Ph.D.

          Russell Portenoy, M.D.

          Gregory Skipper, M.D., F.A.S.M.

          Brian Strom, M.D., M.P.H.

          David J. Wlody, M.D.

 

VOTING PATIENT REPRESENTATIVE

 

          James Gillett, Ph.D.

 

NON-VOTING INDUSTRY REPRESENTATIVE

 

          Charles McLeskey, M.D.

 

NON-VOTING PARTICIPANTS

 

          Laura Nagel, DEA

 

FDA

 

          Sharon Hertz, M.D.

          John Jenkins, M.D.

          Deborah B. Leiderman, M.D., M.A.

          Robert Meyer, M.D.

          Bob Rappaport, M.D.

          Victor Raczkowski, M.D.

 

 

C O N T E N T S

 

PAGE

 

Call to Order and Opening Remarks:

          Nathaniel Katz, M.D.                                                   5

 

Introduction of Committee                                                      6

 

Conflict of interest Statement:

          Johanna Clifford, M.S., RN, BSN                             11

 

Opening Remarks:

          Bob Rappaport, M.D.                                      20

 

Risk Management of Opiate Analgesics

 

FDA's Role in the Risk Management of Opiate

Analgesics:

          Steven Galson, M.D., M.P.H.                                    27

 

Risk Management and the Controlled Substances Act:

the FDA Perspective:

          Deborah B. Leiderman, M.D., M.A.                            37

 

DEA's Role in Risk Management of Opiate Analgesics:

          Terrance Woodworth, M.S.                                 46

 

Open Public Hearing

          Congressman Harold Rogers                             69

          Congressman Frank Wolf                             79

 

Opioid Risk: Benefit Contradiction:

          Arthur G. Lipman, Pharm. D.                                      84

 

Opiate Use Data:

          Gianna Rigoni, Pharm. D., M.S.                               119

 

Misuse and Abuse of Opiate Analgesics

in the Medical Setting:

          Steven Passik, Ph.D.                                      136

 

Nonmedical Use of Pain Relievers: Data from

the National Survey on Drug Use and Health:

          Joe Gfroerer                                                 174

 

Data on Treatment Admissions for Opiate Use:

          Deborah Trunzo                                 185

 

Opiate Abuse Data:

          Judy Ball, Ph.D., M.P.A.                                          196

 

Diversion of Prescription Opiates:

          Elizabeth Willis, Ed.D.                                        221

C O N T E N T S (Continued)

 

Open Public Hearing

          Barry Eliot Cole, M.D.                                               252

          Jeffery Ebel, M.D.                                                258

          Art Van Zee, M.D.                                              261

          Siobhan Reynolds                                            265

          Gregory Walter, M.D.                                     271

          Mary Baluss                                           272

          Bruce Canaday, M.D.                                276

          Arthur H. Horn, M.D.                        281

          Jan Towers, Ph.D.                                                     285

          David E. Joranson, M.D.                                            290

          Daniel B. Carr, M.D.                                            300

 

Existing Risk Management Plans

 

Introduction: Goals of Risk Management Plans

Non-Opiate Risk Management Plans:

          Anne Trontell, M.D., M.P.H.                306

 

Current Opioid Risk Management Plans:

          Celia Winchell, M.D.                       330

 

Committee Discussion                                                354

P R O C E E D I N G S

Call to Order and Opening Remarks

          DR. KATZ:  Good morning.  Welcome to the meeting of the Anesthetic and Life Support Drugs Advisory Committee the purpose of which will be to advise the FDA on risk management programs for opioid analgesics, in particular modified-release products.

          My name is Nathaniel Katz.  I will be chairing the meeting this morning, and my job will be to make sure that we succeed in providing all of the relevant input that has been asked to this division of the FDA.

          To my right is Johanna Clifford.  She is actually the real person who is running the meeting, and her job is to make sure that I do my job and that the meeting stays on track.

          Now, the Division has worked very hard to create a truly interdisciplinary group of individuals representing many of the relevant stakeholders on this issue.  While I have a number of ground rules for the committee that I would like to go over, what I would like to do first is begin with introductions.  There are a new people on the committee and many invited guests.  We don't all know each other, so I would like to start with taking a minute for us all to introduce ourselves.

          Let me just remind people from the government that many of us don't know what the specific committee or agency that you are involved with does, so it would also be appropriate for you to take a sentence or two to describe, not only who you are, but the place that you are from.

          Why don't we begin at that corner, Dr. Jenkins.

Introduction of Committee

          DR. JENKINS:  Good morning.  I am John Jenkins.  I am the Director of the Office of New Drugs at the Food and Drug Administration.  My office is responsible for all the divisions that review and approve new drugs.

          DR. MEYER:  Dr. Bob Meyer.  I am the Director of the Office of Drug Evaluation II in the Center for Drugs, and my office has the Division of Anesthetics, Critical Care, and Addiction Drug Products within it.

          DR. RAPPAPORT:  Good morning.  I am Bob Rappaport. I am the Director of the Division of Anesthetics, Critical Care, and Addiction Drug Products.

          DR. HERTZ:  Good morning.  I am Sharon Hertz.  I am the Medical Team Leader for the Analgesic Group in the Division of Anesthetics.

          DR. LEIDERMAN:  I am Dr. Deborah Leiderman.  I direct the Controlled Substances staff within the Office of the Center Director.  In CDER, we are responsible for all aspects of abuse liability assessment and interface with other federal agencies around issues of abuse and drug scheduling.

          DR. RACZKOWSKI:  Good morning.  My name is Victor Raczkowski.  I am the Director of the Office of Drug Safety in the Center for Drugs.  Our office is heavily involved in risk assessment, risk communication, risk management, and medication errors.  We work closely with the Office of New Drugs both before and after approval to ensure drugs appropriate use.

          MS. NAGEL:  My name is Laura Nagel.  I am from the Drug Enforcement Administration, Office of Diversion Control.  We are responsible for the enforcement of the Controlled Substance Act particularly as it pertains to legitimately manufactured drugs.

          DR. CRAWFORD:  Good morning.  My name is Stephanie Crawford. I am from the University of Illinois at Chicago, College of Pharmacy.  I am a guest participant from the Drug Safety and Risk Management Advisory Committee.

          DR. SHAFER:  Steve Shafer, Professor of Anesthesia, Stanford University.

          DR. BAXTER:  Lou Baxter.  I am Executive Medical Director of Medical Society of New Jersey, Physicians Health Program, and I am brand new.  I am here and that is about all that I can tell you.

          DR. GARDNER:  I am Jacqueline Gardner, the University of Washington School of Pharmacy, and I also am from the Drug Safety and Risk Management Committee.

          DR. ARONSON:  Solomon Aronson.  I am the Chief of the Anesthesiology Services for Vanguard Health Systems in Chicago.

          DR. SAINI:  Bhupinder Saini.  I am an anesthesiologist by background.  I practice full-time pain management.  I am president of a 12-man group who are totally dedicated to pain management.

          DR. KAHANA:  I am Madelyn Kahana.  I am a Professor of Anesthesiology, Pediatrics, and Critical Care Medicine at the University of Chicago.

          MS. CLIFFORD:  Good morning.  I am Johanna Clifford.  Nat already provided you with my job description.  I will be the Exec Sec to this meeting.

          DR. BRIL:  Good morning.  I am Vera Bril.  I am a Professor of Medicine at the University of Toronto with an interest in neuromuscular disorders.  I am a member of the Advisory Committee.

          DR. ROSE:  Good morning.  I am Carol Rose.  I am an Assistant Professor of Anesthesiology at the University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center.  I am a clinical anesthesiologist.

          DR. WLODY:  Good morning.  My name is David Wlody. I am academic anesthesiologist at the State University of New York Downstate Medical Center.  I am a consultant to the committee.

          DR. PASSIK:  Steve Passik.  I am a clinical psychologist and I direct the Palliative Care program at the Markey Cancer Center at the University of Kentucky.

          DR. DWORKIN:  Hi.  I am Bob Dworkin.  I am a Professor in the Department of Anesthesiology at the University of Rochester in upstate New York.

          DR. CUSH:  Good morning.  I am Jack Cush.  I am Chief of Rheumatology and Clinical Immunology at the Presbyterian Hospital of Dallas and the University of Texas Southwestern Medical School in Dallas.  I am here representing the Arthritis Advisory Committee.

          DR. BOBEK:  Good morning.  I am Mary Beth Bobek.  I am the consumer representative.  I am also Clinical Faculty at University of North Carolina College of Pharmacy.

          DR. SKIPPER:  I am Dr. Greg Skipper.  I am an internist and addiction medicine specialist on the faculty at the University of Alabama at Birmingham.  I am also the Medical Director of the Physician Health Program in Alabama. I am here for the Drug Abuse Advisory Subcommittee.

          DR. CIRAULO:  I am Dom Ciraulo.  I am Chairman of Psychiatry at Boston University School of Medicine.  I am also on the Drug Abuse Advisory Subcommittee.  I have had a long-standing interest in developing clinical pharmacology laboratory paradigms for abuse liability.

          DR. MAXWELL:  I am Jane Maxwell.  I am a research professor at the University of Texas at Austin and on the Drug Abuse Subcommittee.

          DR. STROM:  I am Brian Strom.  I am Professor and Chair of Biostatistics and Epidemiology, although I am not a biostatistician, I am an epidemiologist, and I am from the Drug Safety and Risk Management Committee.

          DR. GILLETT:  Good morning.  I am Jim Gillett.  I am Professor of Ecotoxicology and Director of Graduate Studies in Risk Analysis and Cornell University.  I am here as patient representative, as President of Esophageal Cancer Awareness Association.

          DR. McLESKEY:  Charlie McLeskey.  I am the industry representative on this committee, and I am an anesthesiologist employed at Abbott Laboratories, Global Medical Director for Anesthesia and Sedation Products.

          DR. KATZ:  Thank you, everybody.

          Ms. Clifford will read the Conflict of Interest Statement.

Conflict of Interest Statement

          MS. CLIFFORD:  The following announcement addresses conflict of interest issues with respect to this meeting and is made a part of the record to preclude even the appearance of impropriety at this meeting.

          The topics to be discussed today will not focus on any particular product or company, but rather may affect those companies that make or are developing modified-release opiate analgesic drug products.

          The conflict of interest statutes prohibit special Government employees from participating in matters that could affect their own or their employer's financial interests.

          All participants have been screened for interests in the products and companies that could be affected by today's discussions.

          In accordance with 18 United States Code section 208(b)(3), the Food and Drug Administration has granted waivers to the following individuals because the Agency has determined that the need for their services outweighs the potential for a conflict of interest.  They are:  Dr. Nathaniel Katz, Dr. Robert Dworkin, Dr. Steven Shafer, Dr. Steven Passik, Dr. Russell Portenoy.

          A copy of the waiver statements may be obtained by submitting a written request to the Agency's Freedom of Information Office, Room 12A-30 of the Parklawn Building.

          We would also like to note that Dr. Charles McLeskey is participating as a non-voting industry representative, acting on behalf of regulated industry.  Dr. McLeskey is an employee of Abbott Laboratories and is a shareholder.

          With respect to FDA's invited guests, there are reported interests that we believe should be made public to allow the participants to objectively evaluate their comments.

          Dr. Arthur Lipman has consulted for Purdue Pharma and Endo Pharmaceuticals.  In recent years, he has received support from literally all the analgesic manufacturers through unrestricted educational grants and through speakers' bureaus.

          In the event the discussions involve products or firms not on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record.

          With respect to all participants, ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.

          In addition, we have received a number of letters from the public.  These have been provided to the committee and are available for viewing today at the registration desk, and they will be made part of the public record, as well.

          DR. KATZ:  Thank you, Johanna.

          Since many around the table are new to the Advisory Committee process, I wanted to take a minute or two to provide an orientation and to give a charge to the committee for our work task for the next two days.  Right after that we will go to Dr. Rappaport's opening comments.

          First of all, just to briefly summarize--and many of our other speakers will go into this in great detail--why we are here.

          The purpose of this meeting is because it has been recognized that opioids are essential in the management of patients with chronic pain, but yet that they are associated with risks, so that individuals and sponsors have proposed risk management programs in order to diminish those risks while not interfering with appropriate medical management.

          So, our task here today will be to advise this Division of the FDA and give them feedback on the pros and cons of various risk management approaches that have been proposed, both in general today, and tomorrow with respect to a particular product called Palladone.

          One of the first points I would like to make is that approval of any drug is a complicated process that depends upon a lot more than just the risk management plan, so I would like to make it clear from the outset that whether Palladone should or should not be approved will be beyond the scope of our discussion both today and tomorrow. What we will be focusing on is just one component of information relevant to that, which is the risk management program itself.

          The two days will be divided into two different sorts of activities.  The first will be lectures with a little bit of question and answer, and that will really occupy most of today.  Then, there will be some time for discussion today and then tomorrow, there will be a large chunk of time for discussion of issues that come up both today tomorrow.  That discussion will be structured in the form of questions which everybody around the table should have received and may have had a chance to look at by now.

          Now, my own experience, this is the second Advisory Committee meeting that I have chaired that relates to opioids, and my own experience both here and elsewhere is that opioids may be more be, more than many other areas of medicine, seem to create a lot of excitement and passion among the people involved in the discussion.

          So, what I would like to do is to create a sense of collaboration of the people around the table.  Since this is an informational meeting, it is not a requirement that we all come to consensus or agree with each other or persuade each other about our different perspectives, and furthermore, our different perspectives may be very true, but may be only true for the sorts of patients that we see or the particular area that we practice in or the sort of training that we come from or all sorts of other biases that we bring to the table.

          So, our job today will be to not necessarily come to any consensus with definitive answers and everything, but at least to illuminate where there are different schools of thought, to outline the evidence based behind different perspectives on this issue, and to share the information and perspectives, so that the division can go back with all this information and make decisions that day I need to make.

          So, what will work well for us around the table will be to focus primarily on the content issues.  What tends not to work as well is when folks like us start saying that this government agency ought to do this or that one ought to do that since training and the exact scope and authority of different government agencies is certainly beyond my expertise and probably beyond the expertise of many folks around the table.  So, we are here to provide content information and hopefully, our collaboration will illuminate this issue more to an extent that will be helpful to the division.

          Now, as far as practical details, though, there are a few practical things I just want to let you know about.  In order to speak, the procedure is if you just raise your hand, Johanna will write your name down and we will try to go in more or less a first come-first serve way, but there are times where it will be important for me to violate that rule and try to foster particularly discussion that might seem productive, so don't feel like you are being discriminated against if you raise your hand next, but I am not calling on your next.

          However, sometimes things come up where I can't see you, particularly the people in these corners are sometimes hard to see, so if you do feel that for some reason, we have not been recognizing you appropriately, just grab myself or Johanna during the break.

          When you go to speak, turn on your microphone and when you are done speaking, turn off your microphone unless you want all of your little comments to the side to be heard by everybody.

          There will be a very helpful system for speakers, as well as for people in the open public forum, and that system is called a red light.  I will tell you more about that when the time comes.  For speakers who are getting up, there will be both a yellow light and a red light, so the yellow light, if you are up speaking at the podium, the yellow light will come on two minutes before you are ready to stop.

          Now, there has been no time for question and answer built into the lecture, so if you want to have people to have the opportunity to ask questions and to have a dialogue, when your yellow light comes on, stop then and that will give about two minutes for a couple of quick questions and answers.  Obviously, there will be ample time for discussion later.

          When your red light comes on, then, you are done. So, what I really want to do is apologize to all the speakers in advance, because I will cut you off when that red light comes on, so don't take it personally, it's just for the purpose of making sure that we get our job done over the next two days, and I will cut people off equally and fairly when that red light comes on.

          Another issue is that people around the table may have questions for people also around the table or for speakers or for other people sitting around the table.  If you do have any questions, then, the protocol is just go through me, so raise your hand, I will address you, and if you have a question, just let me know and depending on how the meeting is flowing, we will see if we can pose those questions to other folks around the table.

          If there is anything we can do to make you more comfortable, let us know.

          I think those were all my procedural comments.

          With that, let me introduce Dr. Bob Rappaport, who, as he said, is Division Director of the Anesthetic, Critical Care, and Addiction Products Division, who will give us opening comments.

Opening Remarks

          DR. RAPPAPORT:  Thank you, Dr. Katz.

          Good morning.  Dr. Katz, members of the committee, invited guests, I would like to thank you at the outset of this meeting for your participation.  You will be addressing an important public health issue during this session - how do we approach the issue of prescription opiate abuse while assuring the proper treatment of pain.

          Prescription drug abuse is a growing problem in this country and opiate analgesics are some of the most widely abused and misused prescription products available today, however, one of the very reasons that these products have become widespread in use and availability is that for the first time in modern history, the appropriate treatment of chronic pain is receiving the acceptance and the recognition in the medical community that it so urgently deserves.

          Tens of millions of Americans are estimated to suffer from chronic pain.  Many of those people are appropriately treated with opiate analgesics and for many that treatment will provide them with relief from suffering and the possibility of returning to a normal life in a manner that is not currently available with non-opiate treatments.

          Therein lies a conundrum, opiates are abused and because they are abused, some prescription opiates are diverted and the more potent modified-release products that are available today are of particular interest to abusers, not only to the seasoned addict and those that hope to profit from human frailty, but also to the teenager who wants to experiment with these intriguing potions and yet may die after a single large exposure.

          In our role as public health advocates, the increasing incidence of abuse, addiction and overdose in this country must concern us.  These potent modifie