Thank you for the link . Very interesting .
Here is the looooong text:

Quote:

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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 modified-release products are potentially dangerous even in legitimate medical practice when their unique pharmacokinetic and pharmacodynamic characteristics are not fully understood.

Overdose and death and patients being converted from one high potency, high-dose opiate to another and inappropriate use by inexperienced physicians must concern us.

Chronic pain is still undertreated in millions of patients. Misconceptions about the normal physiological dependence that occurs with opiate analgesic treatment and its role in addiction abound. Irrational fears based on myth and lore often interfere with the proper treatment of the patients most in need. Chronic pain claims a huge toll on individuals and on the American economy, and this must concern us.

How can we intervene to reduce prescription opiate abuse, assure safe use in the medical setting, and yet assure appropriate access to patients with chronic pain who need opiates for proper treatment? Risk management interventions have been touted as one of the potential solutions to this perplexing dilemma.

The Agency has implemented risk management plans for other drug products and we will attempt to familiarize you with the scope and the range of those plans today.

We have reviewed a number of risk management plans for extended release opiate analgesics that we will also describe to you, which elements of risk management work and which don't, which elements might even have a counterproductive effect.

For the most part, that sort of data may not even exist. Do we even know the proper methodology for collecting the data? In fact, these are the very questions that we will pose to you over the next two days.

We have assembled some of the leading experts both from the government and from academic to review the extent of the problem for you. You will hear from SAMHSA representatives about the data they have collected on prescription opiate abuse and from the FDA Office of Drug Safety on the current medical usage data for these products.

Representatives from the DEA will describe their role in diversion control and risk management and their perspective on the problem of opiate analgesic diversion. The FDA Controlled Substance staff will outline the Agency's authority and responsibility under the Controlled Substances Act, and the Deputy Director of the Center for Drug Evaluation and Research will define the challenge of risk management for long-acting opiate analgesics under the authority of the Food, Drugs, and Cosmetics Act.

In addition, experts in the medical use of opiate analgesics and their misuse in the medical setting will present the most recent information from the clinical academic community on the benefits and challenges that are inherent in the use of these products.

As this meeting is centered on the development of risk management plans for opiate analgesics, you will also hear from the Agency's drug safety staff and the New Product Review staff regarding the existing risk management plans for both opiate analgesics and other drug products.

We will define the elements of these plans for you and ask you to help assess their value, reliability, and inherent risks. We will ask you to address what role education, restricted access, surveillance, and other elements may play in the risk management of prescription opiate use, how might these elements be implemented, how can their success or failure be measured, where might those elements aimed at lessening diversion and misuse be in conflict with appropriate patient care, and what research projects should be considered to inform these programs.

Finally, during the open public hearing, there will be an opportunity for experts, advocates, concerned citizens, and most importantly, patients from both the pain and addiction populations to speak to you about their experiences and about their concerns.

Tomorrow, we will discuss a specific risk management plan. Representatives from Purdue Pharma will review the basis for their New Drug Application for Palladone and extended release hydromorphone product.

They will focus their presentation on their proposed risk management plan for Palladone and provide data in support of that plan from a similar plan that has been designed for their other extended release opiate analgesic drug product OxyContin.

The Agency's Controlled Substances staff will provide their perspective on the abuse liability of Palladone and Dr. Mary Jeanne Kreek will provide a broader perspective in her discussion on the challenges of pharmacotherapy with long acting opiates.

You will then be asked to provide the FDA staff with recommendations regarding the Palladone risk management plan. It is important to recognize that formal risk management for pharmaceuticals is still a young endeavor. There are no well traveled paths to follow.

As experts in the treatment of pain, in the treatment and epidemiology of abuse and addiction, and in risk management strategy and communication, we are hopeful that you will provide us with guidance and direction as we attempt to find new paths towards reasoned and sustainable solutions to a difficult and complex problem.

We know that the FDA cannot hope to implement or sustain any solution to this problem by itself. It will be of paramount importance for you to keep in mind that there are many stakeholders in this effort - other government agencies, the academic community, the pharmaceutical industry, the clinical community, and the patients and their caregivers and families.

Each of these has important, but often differing perspectives and differing roles, however, as individuals and as members of organizations and communities, we must all share in the work ahead, so that we may all share in the rewards.

Once again, I would like to thank you for being generous with your time and expertise by participating in this important meeting.

DR. KATZ: Thank you, Dr. Rappaport.

I would like to now introduce Dr. Steven Galson, who is the Deputy Center Director of the Center for Drug Evaluation and Research, and who will be speaking with us about the FDA role in the risk management of opiate analgesics.

FDA's Role in the Risk Management

of Opiate Analgesics

DR. GALSON: Thank you very much. I am extremely happy to be here this morning and I want to start by thanking the members of the committee and the Chair for your sense of public purpose and commitment in being here. I know we can't really compensate you for your time, you are all very, very busy.

We will rely very heavily on your clear-eyed and objective answers to the questions that we pose to you in making our decisions about steps to take regarding this group of products and the product that you are hearing about tomorrow. So, again thank you very much.

[Slide.]

I am here today to talk about the FDA's role in the risk management of opiate analgesics and I want to start by taking you back to the very beginning. This is review for a lot of you, I will go fairly quickly, but just so that you understand clearly what the role of the Agency is.

The Food, Drug, and Cosmetic Act tells us that we can require from drug applicants, from sponsors, tests that are reasonably applicable to show whether or not these drugs are safe for use under the conditions for which the application is designed.

[Slide.]

But what does drug safety mean? No drug is 100 percent safe, all drugs have risks. We all know that.

We define based on the requirements of the Food, Drug, and Cosmetic Act that the benefits of the drugs that we approve outweigh the foreseeable risks for the specific indication, the medical indication, and for the specific population for which they are designed.

[Slide.]

We use a large variety of tests to assure this. We require nonclinical studies of laboratory animals, a lot of human data, which I will focus on very quickly in a second. We also don't keep the requirements static. We incorporate new science when it has been demonstrated to help us in assisting our reviewers to look at safety and efficacy about the products in front of us.

We are continually using new information and we are not standing still.

[Slide.]

With regard to human data, we applications for drugs that have been exposed to approximately 10,000 people for varying duration and dosing. The people who take these drugs in clinical trials frequently have other concurrent illnesses.

We have the statistical power to detect an association for an event occurring 1 in 100 to 1 in 1,000 people depending on the background rate of that condition. We don't have capacity in the methods that we currently use to review and approve drugs of detecting and quantitating very infrequent events more rare than noted there.

[Slide.]

For predicting the benefit, we use randomized, controlled trials, as you all know. These, however, lack generalizability to populations that were not participants in the controls, the larger society, and, as well, these clinical trials don't study all domains of benefit.

There may be nonquantifiable, but very important benefits to patients that aren't quantified in these studies, and we also can't predict in these studies the uncertainties of certain kinds of use and certainly not the uncertainties of abuse.

[Slide.]

So, before we approve a drug, we are assured that the benefit outweighs the risks, as you see in this simple chart.

[Slide.]

But there are lots of things that can happen after a drug is approved. Certainly, abuse, as you all know about, we may not have done a good job of predicting the risk for a variety of reasons, that some of these risks may have been unpredictable.

There may be errors involved in the way the drug is used, committed both by patients or by participants in the healthcare system, or there may be inherent risks with the drugs. We know, as I said before, that all drugs have risks, and these inherent risks may be more important than we had anticipated.

[Slide.]

Therefore, we know a drug is less safe and if it is used in a way that decreases the foreseeable benefit and if it is used in a way or in a way that increases risk of if the actual risks are greater than the predicted risks. There are a lot of different things that can, quote "go wrong."

[Slide.]

Getting more specific to the products you are interested in here, moving towards that, our goal in managing risk is to look at it throughout the product life cycle. We begin this in drug review and approval process through the methods that I have just talked about, and we use multiple risk management tools, such as the language in the drug label that is distributed with the drugs, restrictions on use of the drug or on the distribution or other special requirements to try to assure that the risks of the drug are maintained in a manageable way throughout the life cycle.

This process continues after drugs are approved. I don't have time to go into a lot of detail about this, but we conduct passive surveillance with our adverse event reporting system where practitioners, patients, and others can send reports in when they notice them to the Agency. We keep track of those, collate them, and look at them very carefully.

There are lot of other systems to look at the safety of drugs that are on the market including four opiates, just as an example, here the Drug Abuse Warning Network, which is not run by the FDA, but detects increases in reports through emergency rooms of drug abuse problems.

We can also conduct special studies when we are concerned about a particular problem with the drug, and others in the medical community and in the research community conduct these studies for us, or may conduct them for other reasons, and we look at them to weigh all of these pieces of information after a drug is approved.

[Slide.]

So, we conduct periodic evaluation of risks and benefits of drugs that are on the market if the use changes beyond what we had anticipated, if new risk-benefit data come up through the scientific process or through another means, or if for some reason we are aware that our risk management steps have not been effective enough.

In those cases, we may make changes in the way that the drug is labeled or in other aspects of the way the drug is used and distributed in consultation with the drug sponsors, but these changes have to be consistent with our statutes and with our regulations.

We are watched very closely in those regards, and we have a limited number of degrees of freedom that we can go in making changes to drugs once they are approved.

We also, as I think you all know, enforce advertising regulations which can be very important for this group of compounds. We also coordinate with other federal agencies, particularly with DEA, around the opiates, or other organizations to try to control risk, to try to work to mitigate information which may be incorrect about these compounds.

[Slide.]

In the special case of opiate analgesics, which you are here to talk about today, we know that these drugs are a very important part of our medical arms chest. They are safe and effective when used properly, but we do have indications that there have been increases in opiate-related abuse and deaths, and that is one of the reasons that you are here.

The Federal Government regulatory authority and responsibility for risk management for this group of drugs is shared with the Drug Enforcement Administration, with the FDA being responsible for the items that I have talked about previously, and the DEA responsible for enforcing the regulations and the laws to reduce abuse, and you are going to hear about that from DEA speakers later in this meeting.

[Slide.]

What are our challenges in risk management of this group of drugs in 2003? We need to maintain a positive risk-benefit balance, as I have been talking about. We need to maintain access for the patients who need these drugs, and we want to be able to use the label that we approve for these drugs appropriately to foster risk management.

We need to base our decisions about changes and approval of these drugs on science, not on emotion, and we need to base them on what we can assess to be the current medical practice consensus. That is why you are here, that is why you represent different parts of the medical community, and as you know, a lot of medical groups have been working on trying to assess what the right way to use opiate analgesics for many, many years, there has been a lot of consensus work done in medical organizations, and we need to pay very close attention to that because the medical community and the healthcare community is really one of our most important stakeholders in the Agency.

We can also consider other risk management steps, unusual risk management steps, things that haven't been tried before.

[Slide.]

What is the context under which we are asking you to be here today? The problem of opioid abuse is a complex societal problem with a lot of different causes. As you know, as scientists, any complex problem demands a complex solution. There is not a simple solution to this problem.

It is a combination of regulation, public policy, education, and research, which is being applied and which continues to need to be applied to this problem. We all recognize that it is not going to be solved overnight and will only be solved by an incremental improvement in how we manage these risks.

As I have mentioned, addressing the problem is the shared responsibility of not just the Federal Government, but of other agencies, not just the regulatory agencies, but other federal agencies, some of which are represented here, the Substance Abuse and Mental Health Administration, and the part of the NIH, NIDA, that handles drug abuse research, State and local governments, teachers, parents, nongovernmental organizations, religious groups, the Boy Scouts, et cetera. This is a societal problem, and that is the context in which we want you to look at the questions that we are asking you today.

Thank you very much again for being here. We look forward to your advice, and good luck for a good meeting.

My yellow light isn't on, so I can take any questions if folks have them based on my comments, otherwise, we will move on.

DR. KATZ: Does anybody around the table have any questions for Dr. Galson?

[No response.]

DR. GALSON: Thank you very much.

DR. KATZ: Thank you very much.

Before we go on to our next speaker, there is a new person at the table who missed the introductions earlier, so, Dr. Portenoy, would you like to take half a minute and tell us who you are?

DR. PORTENOY: Thank you. I am sorry about being late, you know, D.C. traffic.

I am Russ Portenoy. I chair the Department of Pain, Medicine, and Palliative Care at the Beth Israel Medical Center in New York City.

DR. KATZ: Our next speaker will be Dr. Deborah Leiderman. She is the Director of the Controlled Substance staff at FDA, as you all heard. She will be speaking with us about Risk Management and the Controlled Substances Act: the FDA Perspective.

Risk Management and the Controlled Substances Act:

The FDA Perspective

DR. LEIDERMAN: Good morning.

I will be talking about risk management and the Controlled Substances Act through the lens of the FDA. Now, Dr. Galson has outlined the general framework of risk management that CDER utilizes, the Center for Drugs and FDA utilize.

In advance, I want to acknowledge that my comments about drug control and drug scheduling are from the perspective of the FDA, and that the DEA will be speaking in greater detail about some of the law and roles that I am addressing later in the meeting.

[Slide.]

The Controlled Substances Act of 1970, which I will refer to from hereon in as the CSA, was enacted to comply with international treaties, as well as to address issues of international drug trafficking and to assure the availability of legitimate drugs for medical use.

The CSA established five schedules and level of control, C1 through 5. The major drug classes that are regulated by the CSA are the opioids, depressants, stimulants, and hallucinogens.

[Slide.]

Under the CSA, Schedule I is the most restrictive. It is reserved for drugs with the highest abuse potential and no recognized medical use. Examples of drugs within this class include heroin and LSD.

Schedules II through V are used for drugs that have medical use in the United States and have, in descending order, levels of abuse potential and restrictiveness, II being the highest of medically approved drugs and V the lowest.

[Slide.]

The subject of today's meeting, of the two-day meeting, are, of course, the Schedule II opioid analgesics. Now, these drugs have the highest potential for abuse. Abuse potential is defined under the CSA, placement in Schedule II, means the risk is comparable to that of CI drugs. The distinction again is the medical use.

Thus, these drugs are subject to the highest level of control and, by definition, pose the greatest risk to the public health.

[Slide.]

I think, as Dr. Galson suggested, that we have to look at the use of any drug, but certainly the Schedule II opioid analgesics in the context of the larger healthcare system and the society.

Certainly, healthcare, the society have changed dramatically since enactment of the CSA. Advances in science, medicine, pharmacotherapeutics information have changed, and it can be argued that what was previously relatively limited, acute disease, often terminal, has been transformed into chronic illness. Thus, the CII drugs, the opiate analgesics, which 30 or 40 years ago, the use was primarily confined to the hospital setting, the operating room, and the inpatient ward, have been moved, as has much medical care, into the outpatient setting.

[Slide.]

The Schedule II opioid analgesics that we are primarily concerned with, oxycodone, morphine, fentanyl, hydromorphone, again are all Schedule II under the CSA.

Now, the Schedule II designation applies to all strengths and dosage forms of each drug. The Controlled Substances Act and the scheduling designation does not differentiate between a 5 mg oxycodone and a 160 mg OxyContin, between an injectable hospital use fentanyl formulation and the 2 mg patch. A morphine 5 mg tablet is the same Schedule II as the methylphenidate 5 mg tablet.

Schedule II, thus, encompasses a broad range of drug dosages and potency, and as we will see, a broad range of drug classes.

[Slide.]

Now, this figure is intended to illustrate the range of drug classes, as well as dosages and formulations. As you can see, the opiates on the left are all in yellow, the barbiturates are in lavender, and the stimulant drugs, on the right, are in red. Again, we can see that there are intravenous, transdermal, oral formulations in the opiate class, and that the range of strengths is quite large.

[Slide.]

Just for comparison, looking at the range of drugs controlled under Schedules III through V, we see that some of the less potent opioids, also in yellow here, are placed in Schedules III, IV, and V, and that depressants, stimulants, and other drugs, again a range of pharmacologic classes, are controlled under Schedules III through V.

[Slide.]

What does it mean for a drug to be controlled under Schedule II? Again, the DEA will go into this in much greater detail, but from our perspective, manufacturing quotas are established by the DEA with input on medical need from the FDA.

Distribution is tracked. There are import and export controls, prescribers and dispensers of Schedule II drugs must be registered, and Schedule II designation does not permit refills. That is a federal law, will not vary across states.

[Slide.]

What Schedule II does not require: physician or practitioner education, limits on the drug quantity prescribed or dispensed, nor does the CSA make any provision for or Schedule II designation mean that there will be any prescription monitoring.

[Slide.]

This is a schematic of all the parties that play a role in the regulation of controlled substances. The two federal agencies that FDA, in the left lower corner, and the DEA, with the Scales of Justice in the middle, both regulate the manufacture in the upper left corner.

The FDA, of course, is responsible for drug review, approval, and labeling. The DEA established quotas and registers manufacturers. Both federal agencies have responsibilities with respect to different aspects of inspection and compliance.

The state regulatory authorities, which are represented by the multicolored figure of the country--there is no significance to my knowledge of the particular color scheme, it is provided by Microsoft--state regulatory authorities regulate prescribers and dispensers through licensure.

The DEA also licenses prescribers and dispensers. We can see that patients and the community, represented in the right lower corner, and I have shown this with a dotted line because they are, in fact, not regulated. Prescribers and dispensers interact with the patients and the community, but essentially, they are out of the regulatory loop, that is, the federal and state regulatory loop.

[Slide.]

Again, just to briefly compare and differentiate DEA's role from FDA's role and the state role. DEA registers drug manufacturers, establishes quotas, and registers dispensers and prescribers. It does not have a role in prescriber education, any knowledge assessment of the registered prescribers or dispensers, and it does not ensure active surveillance.

[Slide.]

The FDA role, of course, again is to approve drug products and assure safety and effectiveness, as Dr. Galson described. The primary method for the Agency to communicate information to prescribers and dispensers is the drug label.

The FDA is also responsible for postmarketing safety and phamacovigilance. It is very important to note that the Food, Drug, and Cosmetics Act does not distinguish between controlled and other drug products.

[Slide.]

The State's role is primarily achieved through boards of pharmacy and medicine, that is, they are the primary regulators of physicians and pharmacy practice.

States may impose additional drug controls beyond that of the CSA. Authority, regulations, practices, and resources, however, vary enormously across states.

[Slide.]

Prescription drug monitoring programs have been introduced over the past 15 years or so as a regulatory tool for the states. They are under the purview of the states, there is no national program, and their goal is to reduce illicit use of prescription drugs through deterring and identifying so-called doctor shopping, that is, when patients obtain medications from multiple physicians simultaneously, illicit sales of prescriptions and drugs, and forged prescriptions.

Prescription drug monitoring programs--and I should note the members of the Advisory Committee did have the General Accounting Office report on PDMPs included in your background materials--these programs collect, review, and analyze prescription data from pharmacies.

These programs have varied structures, very varied resources. In 2001, there were 15 states that had active PDMPs. I believe one additional state has come on line in 2003. They vary whether they are electronic or paper, whether it's a database that can be queried or whether there is more active ongoing surveillance.

[Slide.]

Again, this schematic just to remind us of the parties that have a role in the regulation of controlled substances, and again that the patients and the community are mostly out of the regulatory loop.

[Slide.]

So, where do we stand on the issues of risk management, drug scheduling, and the CSA? I think we can see that scheduling under the Controlled Substances Act does not manage all the risks of misuse, abuse, and overdose of prescription drugs.

Drug scheduling alone cannot address all the challenges posed by the high-dose, extended-release opioid analgesics in the context of the modern healthcare system, and it is important to remember again that Schedule II designation does not distinguish between high-dose, high- potency opioids and low-dose, immediate-release Schedule II drugs.

Thank you, and I guess I also have an opportunity for some questions.

DR. KATZ: Any questions?

[No response.]

DR. KATZ: Thank you very much.

I would now like to introduce Terrance Woodworth from the Drug Enforcement Administration, who will be speaking with us about the DEA's Role in the Risk Management of Opioid Analgesics.

FDA's Role in the Risk Management of

Opiate Analgesics

MR. WOODWORTH: Well, it is much too early for this slide. Good morning.

Thank you very much for the opportunity to express some of the views of the Drug Enforcement Administration concerning the legal framework that DEA and FDA operate under together in order to fulfill our mandate to protect the public health and safety.

Although very beneficial in the treatment of pain, recently approved potent high-dose, extended-release opioids, coupled with aggressive and persuasive marketing practices, have brought new and unique challenges to our agencies.

Dating back to the passages of the Federal Food, Drug and Cosmetic Act in 1906, the United States Congress recognized the critical importance of indicating the proven uses of prescription drugs for legitimate medical needs. It signaled its full recognition of the abuse potential of certain prescription drugs in 1914, when it passed the Harrison Narcotic Act regulating the sale of opiates for the first time.

Additional drug legislation over the years including the Controlled Substances Act has become part of Title 21, Food and Drugs. With this, Congress has indicated its full expectation of a cooperative, coordinated interagency process of reviewing a substance and its drug products, assessing that drug's safety and efficacy, and identifying whether it has an abuse potential before permitting its marketing to the public.

FDA and DEA have collaborated extremely well in this regard for more than 30 years.

It is important to note that there are significant differences between the Controlled Substances Act and the Food and Drug Cosmetic Act with regard to drugs. One of the most fundamental is that the CSA and its controls focus on substances, morphine, oxycodone, where the FDCA focuses on products, MS-Contin, Percodan, Adderall.

The Controlled Substances Act places all substances with abuse potential into one of five schedules based on accepted medical use, potential for abuse, safety, or dependence liability.

Schedule I is for those with no accepted medical use, such as heroin. Substances with accepted medical use are in Schedules II through V, II being the most restrictive, V being the least restrictive.

When a substance is already in Schedule II of the Controlled Substances Act, and Schedule II controls are not sufficient, we must look outside the Controlled Substances Act for additional mechanisms to prevent diversion and abuse.

The substances that we are addressing today and tomorrow are all Schedule II substances under the Controlled Substances Act, thus, there are no opportunities for increased levels of control under the CSA.

The FDCA, on the other hand, can address product (or class of product) safety needs on a product-by-product basis.

In all candor, DEA has not been able to address all of the criminal activity associated with high-dose, extended-release opioids in recent years. Compounding this difficulty are the indications that FDA's risk management plan for at least one extended-release opioid has not proven effective.

Segments of the pharmaceutical industry in certain cases have exceeded traditional drug promotion boundaries and been a significant factor in the increased abuse and diversion. State medical boards are unable to regulate the increasing numbers of dated, duped, disabled, and dishonest practitioners, and physicians themselves acknowledge a need for further information and education concerning pain management and the use of opioids.

The CSA includes seven major control mechanisms: scheduling, registration, quotas, records and reports, import and export authorizations, security, and investigational authority.

DEA essentially controls the drug and its movement. We register all persons who handle opioids, we inspect the documentation of opioid distribution, we control and import and export. We control the amount produced, bought, sold, or otherwise transferred.

One would think with all these controls in the so-called closed system of distribution that there would be minimal risk of abuse and diversion. These controls have been extremely effective in preventing diversion at the import or manufacturer and distributor levels, however, the vast majority of diversion occurs at the retail level once the product is in the hands of practitioners and patients.

Significant weaknesses in two of the controls, quotas and investigational authority have contributed to the increases in abuse and diversion.

With regard to investigational authority, it is estimated that more than 90 percent of the diversion occurs at the doctor/pharmacy level, however, at this retail level, it is primarily the states and the professional boards responsibility, not DEA, to regulate and oversee controlled substances activities. DEA is not directly involved in the establishment of medical or pharmacy standards, nor are we directly involved in the regulation or investigation of medical or pharmacy practice.

DEA investigates physicians who are acting outside the norms of accepted medical practice, thus, the responsibility at the retail level for controlled substances rests, in general, with a wide array of different state and medical and pharmacy boards.

[Break due to power failure.]

DR. KATZ: Our break seems to be finished, so we will continue.

Mr. Woodworth.

MR. WOODWORTH: Well, a lot of people have said DEA is in the dark on these issues, but that is a little bit much.

[Laughter.]

MR. WOODWORTH: In evaluating a physician's or a pharmacist's activities relating to the management of pain and the use of opioids, the state boards rely heavily on the FDA approved labeling for opioids, as do physicians themselves.

FDA-approved labeling provides guidance to the medical community regarding conditions for safe use, as well as providing safety and other warnings. Labeling and risk management plans have a direct impact on the extent of abuse and diversion of opioids, but DEA has no statutory authority to participate in the development of the labeling or risk management plans except for our role in scheduling, as Dr. Leiderman mentioned.

At present, under Section 201(f), when HHS receives a New Drug Application for a stimulant, depressant, or hallucinogenic drug, and the drug appears to have an abuse potential, HHS is required to forward that information to DEA for scheduling purposes. For substances already in Schedule II, DEA has no authority to require additional controls.

The key to having the ability to further deter and prevent abuse and diversion becomes the labeling of new formulations of already controlled substances. When FDA-approved labeling indicates that extended-release forms of opioids may have less abuse liability, as was the case with OxyContin, this significantly affects decisions of physicians to prescribe a drug, as well as the medical board's action in reviewing a physician's activities.

With regard to quotas, DEA and FDA are responsible for ensuring an adequate and uninterrupted supply of opioids for medical, scientific, and research needs of the United States. We accomplished this by establishing quotas for the total quantity of each basic class of controlled substances, oxycodone, for example, which may be manufactured in the United States on an annual basis.

The purpose of the quota system is to limit the availability of legitimately manufactured controlled substances which may be diverted into the illicit market. Increased availability and access to controlled substances are direct causes of abuse and diversion.

Quotas are established considering sales from the previous year, estimates of year-end inventory, and estimates of legitimate medical needs in the future provided to DEA by FDA.

On the surface, the quota system appears to be an effective means of limiting the supply of opioids to what is legitimately needed for medicine and science in this country. After all, the drugs have been approved for safety and efficacy, and the pharmaceutical manufacturers have been through a rigorous FDA and DEA approval process.

However, both DEA and FDA are receiving the using incomplete information regarding what actually are the legitimate medical needs for opioids in this country. Again, legitimate medical need is largely determined by sales.

Sales are prescriptions, all prescriptions for extended-release, high-dose opioids are counted in the total sales figures to establish quotas regardless of whether those prescriptions were illegal, indiscriminate, or inappropriate.

How can the estimates of legitimate medical needs for extended-release, high-dose opioids be based on totals that include illegitimate sales, and what is the volume of those i

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"Whosoever is spared personal pain must feel himself called to help in diminishing the pain of others." Dr Albert Schweitzer

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